dermatologia e venereologia

Transcription

GIORNALE ITALIANO DI
DERMATOLOGIA E VENEREOLOGIA
Vol. 149
October 2014
No. 5
CONTENTS
SKIN INVOLVEMENT
IN CONNECTIVE TISSUE DISEASES
Guest Editor: P. AMERIO
525
Cancer risk in dermatomyositis: a systematic review
of the literature
Di Rollo D., Abeni D., Tracanna M., Capo A., Amerio P.
481
539
Preface
Amerio P.
The Italian version of the systemic sclerosis questionnaire: a comparison of quality of life in patients
with systemic sclerosis and with other connective
tissue disorders
483
Uras C., Tabolli S., Giannantoni P., Rocco G., Abeni D.
Cutaneous manifestations of rheumatic diseases.
Clinical presentation and underlying pathophysiology
549
Gkogkolou P., Luger T. A., Böhm M.
Cutaneous manifestations of lupus erythematosus
505
555
Parodi A., Cozzani E.
Auriemma M., Capo A., Meogrossi G., Amerio P.
Hair disorders associated with autoimmune connective tissue diseases
519
567
Boccaletti V., Di Nuzzo S., Feliciani C., Fabrizi G., Pagliarello
C.
Kostaki D., Antonini A., Peris K., Fargnoli M. C.
Cutaneous signs of classical dermatomyositis
An update on juvenile dermatomyositis
Vol. 149 - No. 5
Cassano N., Amerio P., D’Ovidio R., Vena G. A.
Skin cancer risk in autoimmune connective tissue diseases
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
XI
CONTENTS
573
607
Verdelli A., Antiga E., Bonciolini V., Bonciani D., Volpi W.,
Caproni M.
Consensus on the use of cyclosporine in dermatological practice
Drug induction in connective tissue diseases
CONSENSUS PAPER
Altomare G., Ayala F., Bardazzi F., Bellia G., Chimenti S.,
Colombo D., Flori M. L., Girolomoni G., Micali G., Parodi A.,
Peris K., Vena G. A.
581
ORIGINAL ARTICLES
The use of skin needling for the delivery of a eutectic mixture of local anesthetics
Fabbrocini G., De Vita V., Izzo R., Monfrecola G.
627
CORRESPONDENCE
Scabies acquired in Chinese massage centers
Veraldi S., Çuka E., Francia C., Persico M. C.
587
REVIEWS
Pyoderma gangrenosum: a systematic review
Cozzani E., Gasparini G., Parodi A.
628
Lymphedema and immunocompromised districts
Ruocco E., Piccolo V., Russo T., Schwartz R. A.
601
629
Spitz/Reed nevi: proposal of management recommendations by the Dermoscopy Study Group of the
Italian Society of Dermatology (SIDeMaST)
Murdaca F., Feci L., Acciai S., Biagioli M., Fimiani M.
Occupational argyria
GUIDELINES
Broganelli P., Titli S., Lallas A., Alaibac M., Annetta A.,
Battarra V., Brunetti B., Castagno I., Cavicchini S., Ferrari A.,
Ghigliotti G., Landi C., Manganoni A., Moscarella E., Pellacani
G., Pizzichetta M. A., Rosina P., Rubegni P., Satta R., Scalvenzi
M., Stanganelli I., Stinco G., Zalaudek I., Zampieri P.,
Argenziano G.
XII
631
A controversial pigmented lesion located in the left
subscapular region: a case of “collision” tumor
Feci L., Trovato E., Pellegrino M., Miracco C., Taddeucci P.,
Fimiani M.
October 2014

SKIN INVOLVEMENT IN CONNECTIVE TISSUE DISEASES
Guest Editor: P. Amerio
G ITAL DERMATOL VENEREOL 2014;147:481
Preface
N. COGNOME
T
his issue of the Giornale Italiano di Dermatologia e Venereologia contains a special section on the dermatological aspects of Connective Tissue Diseases (CTDs).The aim of this section is to focus the readers’ interest on the clinical and pathogenetical aspects of different CTDs such as dermatomyositis, systemic
scleroderma, and lupus.
In the context of a multidisciplinary approach, in fact, dermatologists play an important role in the management of these diseases, together with rheumatologists and other specialists.
The papers by Prof. Luger and Prof. Bohm will introduce the cutaneous manifestations of rheumatic diseases from a clinical and pathogenetical point of view.
Healthcare providers who deal with CTDs may also be interested in the clinical description of the common and uncommon cutaneous signs of adult dermatomyositis (discussed by Auriemma et al.) and childhood dermatomyositis (presented by Feliciani et al.).
In a review of the literature, Di Rollo et al. will correlate the principal cutaneous features associated with
paraneoplastic dermatomiositis. Abeni et al. present the validation of a QoL assessment tool in its Italian
version for systemic sclerosis patients. Parodi et al. will focus on the cutaneous aspects of lupus erythematosus.
Finally, highly experienced dermatologists such as Prof. Vena, Dr. Cassano, Prof. Fargnoli and Prof.
Caproni will discuss different aspects of CTDs such as hair involvement, the risk of skin cancer and induction by drugs.
Vol. 147 - No. 5
P. Amerio
Department of Dermatology and Venereology
University of Chieti-Pescara
Chieti, Italy
481

G ITAL DERMATOL VENEREOL 2014;149:483-503
Cutaneous manifestations of rheumatic diseases.
Clinical presentation and underlying pathophysiology
P. GKOGKOLOU, T. A. LUGER, M. BÖHM
Being the largest organ of the human body, skin is frequently
affected in many rheumatic diseases. Thus, it can serve as an
important indicator for the correct diagnosis of a rheumatic
disease and also as a marker of disease activity in distinct
rheumatic disorders. In this review we will highlight the clinical features of these cutaneous manifestations of the major
rheumatic diseases. We will also provide an update on the
complex pathobiology of these diseases based on the most recent developments in clinical and translational research.
Key words: Skin - Rheumatic diseases - Lupus erythematosus,
systemic - Scleroderma, systemic.
S
kin changes occur in a large proportion of patients
with rheumatic diseases. They are thus clinically
highly important for both dermatologists and rheumatologists. Not only can they guide clinicians to the
correct diagnosis of a particular rheumatic disease
but may also serve as an indicator for disease activity. Due to the function of skin as a barrier organ
to the patient’s outer world it is also essential to be
aware of the psychosocial burden chronic and often
mutilating skin changes may elicit in patients with
rheumatic diseases.
In this review we will highlight cutaneous manifestations of the major systemic rheumatic diseases.
The focus of the clinical part of this review will be
on so-called specific skin changes, i.e., those lesions that display characteristic and sometimes even
pathognomonic features along with a typical histopathology encountered, e.g. Gottron’s papules in
dermatomyositis. These specific skin changes have
Corresponding author: M. Böhm, MD, Associate Professor, Department of Dermatology, University of Münster, Von Esmarch-Str. 58,
D-48149 Münster, Germany. E-mail: [email protected]
Vol. 149 - No. 5
Department of Dermatology
University of Münster, Münster, Germany
to be differentiated from non-specific skin signs
which occur in a diversity of rheumatic as well as
in non-rheumatic systemic diseases. In addition to
specific and non-specific skin signs a variety of other
skin diseases have been noted to be associated in
more or less frequency with rheumatic diseases. Due
to limitations in space it will be beyond the scope of
this review to present all cutaneous manifestations
of rheumatic diseases. The major connective tissue
disorders are in the centre of this review followed
by more often encountered rheumatic diseases with
systemic involvement.
Major systemic connective tissue disorders
Systemic lupus erythematosus
Changes of the skin, mucous membranes and hair
are common signs in patients with systemic lupus
erythematosus (SLE). Approximately 72-85% of patients with SLE suffer from those changes. Moreover, they may represent the first sign of the disease
in 23-28% of the patients with SLE.1 The traditional
criteria of the American College of Rheumatology
(ACR) for SLE included four dermatologic manifestations: malar rash, photosensitivity, discoid lesions, and oral ulcers. However, patients may fulfil
four of these criteria based solely on dermatologic
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Cutaneous manifestations of rheumatic diseases
Table I.—Classification of LE-specific skin lesions.
A.Acute cutaneous LE (ACLE)
1. Localized ACLE
2. Generalized ACLE
3. Toxic epidermal necrolysis-like ACLE)
B.Subacute cutaneous LE (SCLE)
1. Annular
2. Papulosquamous
C.Chronic cutaneous LE (CCLE)
1. Discoid LE (DLE)
a) localized
b) generalized
2. Hypertrophic/verrucous LE
3. Lupus panniculitis/profundus
4. Chilblain LE
5. DLE-lichen planus overlap
D.Intermittent cutaneous LE
1. LE tumidus
Modified from Kuhn et al.1
findings without having other signs for a systemic
involvement. In order to improve the specificity and
clinical relevance of these cutaneous symptoms, the
Systemic Lupus International Collaborating Clinics
(SLICC) revised the ACR criteria in 2012 and proposed 17 clinical and immunological criteria. Importantly, non-scarring alopecia was added, whereas
“photosensitivity” is no longer included.2 However,
the SLICC criteria still have to be evaluated in routine clinical practice.
Figure 1.—Malar rash with typical butterfly distribution in a
young woman with SLE.
484
Classification of cutaneous lupus erythematodes
(CLE) remains complex. Notably, similar types of
skin lesions may occur in both SLE and patients with
non-systemic forms of LE. The most widely accepted classification of CLE distinguishes 3 major subtypes based on disease activity: acute CLE (ACLE),
subacute CLE (SCLE) and chronic CLE (CCLE).3
Moreover, extent of skin involvement (local versus
generalized) and localization of the inflammatory
infiltrate in the skin is indicated (e.g. LE panniculitis indicating LE-specific infiltration of the adipose
tissue). Intermediate CLE, formerly known LE tumidus has been suggested as another distinct subtype
and a revised classification system has been proposed accordingly (Table I).4 Importantly, patients
with SLE or CLE may carry simultaneously different LE-specific skin lesions, e.g. a butterfly rash plus
chilblain LE, the latter a variant of CCLE (v. i.). To
better monitor the type and extent of CLE lesions the
Cutaneous Lupus Area and Severity Index (CLASI)
has been proposed. Albeit time-consuming in routine
daily practice it may be especially helpful for systematic epidemiologic and therapeutic studies.
The hallmark lesion of ACLE in patients suffering
from SLE is malar dermatitis (malar rash, butterfly
rash). It describes a reddish maculopapular eruption
in a characteristic butterfly distribution of the face
(Figure 1). The eruption often extends symmetrically onto both cheeks and the nose. The forehead may
be involved but the nasolabial folds are typically
spared. Patients frequently report induction or exacerbation of this type of CLE by ultraviolet (UV) light
exposure indicating photosensitivity as an important
diagnostic clue as well as a pathogenetic component.
Lesions are often transient and last from hours to
weeks. Healing is without scarring. ACLE may become generalized involving the trunk with accentuation of the UV-exposed areas (Figure 2) but may be
localized elsewhere including the dorsal parts of the
hands and fingers. Knuckles are typically spared. A
life-threatening variant of generalized ACLE is toxicepidermal necrolysis (TEN)-like ACLE.5 Here, massive epidermal injury occurs due to severe alterations
of the dermoepidermal junction with subsequent keratinocyte damage. Another variant is Rowell’s syndrome. It was originally described as an erythema
multiforme-like eruption in patients with DLE and
positive anti-Ro/La antibodies.6 However, similar
skin lesions may also develop in patients with SLE,
SCLE and in presence or absence of anti-Ro/La anti-
October 2014
Figure 2.—Disseminated ACLE. Note accentuation in the UVexposed “V” area.
bodies. Oral lesions are another common cutaneous
manifestation in patients with SLE. They are part of
the classical ACR as well as SLICC criteria. These
oral lesions consist of painful aphthoid lesions and
ulcerations especially on the lips, buccal and palatal mucosa (Figure 3). Other areas of the oral cavity
may be affected as well. In a recent study, oral ulcers
were found to represent an independent predictor for
the development of SLE.7
Patients suffering from SCLE have usually anti-Ro
and anti-La antibodies and the human leucocyte antigen (HLA) B8 and DR3 haplotype.8 There are two
variants: the annular variant consisting of slightly
raised erythemas with central clearing, and the papulosquamous variant consisting of psoriasis-like or
eczematous-like lesions. Both variants are typically
Figure 3.—Oral aphthoid lesions in SLE.
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GKOGKOLOU
located in UV-exposed skin including the lateral aspects of the face: the “V” of the neck as well as of
the upper ventral and dorsal part of the trunk, and
the dorsolateral aspects of the forearms (Figure 4).
SCLE lesions may heal with residual hypo- or depigmentation and the resulting picture may be mistaken for vitiligo. Scarring, on the other hand, is not
a feature of SCLE. Many patients with SCLE may
have mild systemic symptoms including arthralgias
and musculoskeletal complaints. Accordingly, the
percentage of patients with SCLE fulfilling four or
more ACR criteria for SLE ranges from 30% to 62%.
A recent study in a Swedish population revealed that
about 38% of SCLE cases may be associated with
certain drugs. The most common agents include terbinafine, tumor necrosis factor-α (TNF-α) inhibitors,
antiepileptics, proton-pump inhibitors, thrombocyte
inhibitors, angiotensin-converting enzyme (ACE)
inhibitors and non-steroidal anti-inflammatory drugs
(Figure 5).9 Importantly, drug-induced SCLE resolves after discontinuation of the triggering medication.
The key features of skin lesions of CCLE, also
known as discoid LE (DLE) are erythema, hyper-
Figure 4.—Papulosquamous SCLE variant with typical UV-accentuated distribution.
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keratosis, atrophy and scarring (Figures 6, 7). Lesions tend to be discoid initially with a tendency for
coalescing that often results in a disfiguring clinical
appearance especially of the face. Hypo- and hyperpigmentation are common. The lesions have a predilection for the face, ears and neck but may be widespread without a relation to UV exposure. Mucosal
membranes including the lips, mucosal surfaces of
the mouth, nasal membranes, conjunctivae and genital mucosa may also be affected. These mucosal lesions resemble leukoplakia. Although most patients
with DLE do not fulfil the criteria for SLE up 5-10%
of them will develop SLE in the course of their disease. Therefore, long-term follow-up is strongly advised for all patients with DLE.
There are additional subtypes of CLE as listed in
Table I. Epidermal hyperkeratosis is the hallmark
feature in hypertrophic/verrucous CCLE and results
in thick scaly lesions. LE panniculitis describes an
intense inflammation of the adipose tissue of the skin
leading to indurated plaques and lipatrophy. Often
these lesions are encountered in the face, proximal
parts of the extremities, upper trunk and buttocks.
When the overlying dermis and epidermis is also
involved this is referred to as LE profundus. As
shown by a retrospective study of 40 patients with
this CCLE variant only 10% of patients fulfilled the
ACR criteria for SLE.10 Another variant of CCLE is
chilblain LE. Lesions consist of red to violaceous
plaques located on the distal parts of the extremities (fingertips, toes but also occasionally on other
parts of the body). They are typically induced and
aggravated by cold exposure but are also found during the summer time (Figure 8). Patients with this
CLE subtype should be carefully followed-up as up
to 24% of them will develop SLE.11 Finally, the term
LE tumidus has been applied for photosensitive erythematous, sometimes urticarial plaques and nodules
without epidermal hyperkeratosis or follicular plugging (Figure 9). These lesions are often transient for
which the term intermediate CLE has been proposed.
Lesions are often found on the face, upper trunk and
extremities. Most patients with LE tumidus do not
have antinuclear antibodies and diagnosis relies on
the clinical and histomorphological picture. Rarely
patients with LE tumidus develop SLE.1, 12
The exact pathogenesis of the various LE-specific
skin manifestations is complex and incompletely understood. A complex interplay between a predispos-
Figure 6.—CDLE. Note erythema, hyperkeratosis and scarring.
Figure 7.—CDLE of the scalp.
Figure 5.—Terbinafine-induced SCLE.
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GKOGKOLOU
Figure 9.—LE tumidus.
Figure 8.—Chilblain LE.
ing genetic background, epigenetic mechanisms and
environmental factors may lead to chronic immune
activation and manifestation of LE.13 At least 38 genetic susceptibility loci for SLE have been identified
including sequence polymorphisms within the major
histocompatibility complex (MHC), hereditary deficiencies of complement components and allelic variants for the Fc portion of IgG (FCGR) genes.14-16 Although genetic analyses have primarily concentrated
on SLE, a recent genetic study of CCLE patients
identified various skin-associated chromosomal loci
and genes, with only some overlap with known SLEloci and 87% of independent genes, indicating that
there may be a shared genetic background with also
distinctive CLE-specific genetic susceptibility.17 In
familial forms of chilblain LE mutations of TREX1,
a gene coding for a protein responsible for degradation of ds-DNA autoantibodies has been identified.18
At the molecular, genetic and epigenetic level, the
potential role of microRNAs (miRNAs) as modulators of the immune response and key components
in autoimmune diseases has emerged. MiRNAs are
fragments of single-stranded RNA and can regulate
gene expression via messenger RNA (mRNA) degradation and modulation of translation. Specifically,
Vol. 149 - No. 5
miR-146a, a negative regulator of the interferon
(IFN) pathway, has found to be significantly underexpressed in patients with SLE and be inversely correlated with disease activity.19 MiR-146a regulates
the type I IFN pathway through interaction with
various key molecules, e.g. the interferon regulatory
factor 5 (IRF-5), signal transducer and activator of
transcription (STAT)-1, interleukin (IL)-1 receptorassociated kinase 1 (IRAK1) and tumor necrosis
factor receptor-associated factor 6 (TRAF6). Interestingly, a haplotype of IRF-5 is associated with increased susceptibility to LE in multiple ethnic backgrounds.20 Moreover, an altered DNA-methylation
of T-cells, triggered from drugs, UV light or diet,
may induce a flair of LE in susceptible individuals.21
Estrogens as well as the presence of two X chromosomes seem to mediate an increased susceptibility
for LE in women.22 In those, one X chromosome
may be inactivated via epigenetic DNA methylation.
Demethylation of specific sequences in the X chromosome in women with LE may alter gene expression and contribute to the female predominance of
the disease.
Several studies suggest multiple factors including dysregulated innate and adaptive immune
mechanisms as well as chemokine and cytokine
imbalances in the etiopathogenesis of LE. Activation of toll-like-receptors (TLRs), such as TLR-7,
through recognition of endogenous ligands seems
to induce proinflammatory signals including type
I IFN pathways. Type I as well as type III IFN and
myxovirus protein A seem to play a key pathogenetic role in UVB-induced and genuine CLE
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lesions.23, 24 Decreased numbers of regulatory Tcells (Tregs) may further contribute in weakening
immune tolerance. An increased susceptibility of
keratinocytes to UV-induced cell death in combination with decreased clearing of apoptotic debris
due to impaired phagocytic capacity of macrophages may mediate the development of cutaneous LE
lesions by sun exposure.25 Interestingly, data from
in vitro studies demonstrate that UVB irradiation
of human keratinocytes is capable of translocating
autoantigens such as Ro to the plasma membrane
possibly making them accessible for circulating autoantibodies and leading to activation of apoptotic
pathways.26 Several other lines of evidence suggest that autoantibodies detected in patients with
LE appear to play an important role in the development of LE-specific skin lesions. Accordingly, it is
well known that pregnant women with circulating
anti-Ro antibodies may deliver babies with SCLElike lesions (neonatal LE) that are indistinguishable from the skin lesions seen in adults.27 Another
crucial pathogenetic factor that is closely related
to the occurrence of skin lesions of LE is complement C1q. Complete deficiency of C1q is a major
risk factor for the development SLE and most individuals with homozygous congenital deficiency
of C1q develop early-onset SLE with cutaneous
LE lesions.28 Accordingly, deficiency in C1q may
result in altered clearance of autoantigens and immune complexes associated with UVB-exposed or
cytokine-stimulated epidermal keratinocytes. Finally, there is also some recent evidence for a role
of TNF-α in the pathogenesis of LE. Anti-TNF-α
treatment of patients with other immune-mediated
inflammatory diseases can result in the occurrence
of autoantibodies, lupus-like syndrome and in rare
cases even to the development of LE or dermatomyositis.29, 30
In addition to UV light, smoking is considered
a potential trigger factor for CLE. Smoking alters
the metabolism of the aminochinolene antimalarials (chloroquine and hydroxychloroquine), the
most frequently used therapeutics against CLE.31
Other studies have shown that low but measurable
amounts of UVB can be emitted from compact
fluorescent lights, suggesting covering of these by
patients with lupus.32
A skin biopsy specimen may be helpful to establish the diagnosis of CLE and to rule out other
differential diagnoses (v.i.). However, the correct
488
classification of the various CLE subtypes relies
primarily on the clinical picture and laboratory
parameters. Notably, histological changes may be
subtle during the initial phase of patients with CLE.
Histopathologically, ACLE shows various degrees
of cellular damage of scattered epidermal keratinocytes (either hydropic change or eosinophilic
appearance) together with edema and a sparse
lymphohistiocytic infiltrate of the upper dermis.
The dermal blood vessels are often dilated with
extravasation of erythrocytes. SCLE displays hydropic and eosinophilic changes of basal epidermal
keratinocytes often with epidermal atrophy. There
is a lymphohistiocytic infiltrate in the upper dermis
with an interface and perivascular pattern. DCLE
lesions have additional epidermal hyperkeratosis
and thickening of the dermal-epidermal and follicular basement membranes. The lymphohistiocytic
infiltrate is often prominent involving hair follicles.
Dermal deposition of mucin is a frequent finding.
Deeper forms of CCLE are characterized by lymphohistiocytic infiltrates in the lower dermis (LE
tumidus) or within while subcutaneous fat (LE panniculitis).
Depending on the subtype of CLE the differential diagnoses include erythema solare, photoallergic and phototoxic drug eruptions, dermatomyositis, atopic eczema, seborrheic dermatitis, contact
eczema and rosacea, annular erythemas (erythema
annulare centrifugum, erythema gyratum repens),
granuloma annulare, eczema, psoriasis, and tinea.
There are a number of non-specific skin signs
and associated skin diseases which may occur in
patients with LE, especially SLE. These skin signs
encompass harmless vascular changes such as nail
fold abnormalities (large and tortuous capillaries
together with areas of avascularity) but also more
serious complications such as vasculitis (leucocytoclastic vasculitis, urticarial vasculitis, nodular vasculitis) and vasculopathy (atrophie blanche,
livedo reticularis, Degos’ disease-like lesions, ulcerations, thrombosis). The latter may develop
more often in patients with concomitant antiphospholipid syndrome. Non-scarring alopecia (“lupus
hair”) is sometimes encountered in SLE but often
remains underdiagnosed. Scarring alopecia is a
symptom of DLE involving the scalp. The presence
of Raynaud’s phenomenon, calcinosis cutis, scleroderma-like changes, or rheumatoid nodules in patients with LE points towards an overlap syndrome.
October 2014
Dermatomyositis
Involvement of the skin is an essential criterion
for the diagnosis of dermatomyositis (DM).33, 34
Importantly, skin manifestations may precede the
clinical symptoms of myopathy (muscle weakness,
muscle pain, electromyopathic abnormalities or increased levels of creatine phosphokinase) in about
1/3 of patients with DM. In 10-20% of all patients
with DM-specific skin changes occur longer than 6
months before systemic involvement (DM sine myositis or amyopathic DM).
The heliotrope rash is the most commonly encountered specific skin sign of DM (Figure 10). It consists
of a violaceous, confluent erythema resembling the
colour of the heliotrope, a red/purple-coloured flower tracking the course of the sun. The heliotrope rash
Figure 10.—DM with heliotrope rash.
Figure 11.—Gottron’s papules in DM.
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of DM has a characteristic distribution involving especially the periorbital area. Patients often complain
of a burning sensation but photosensitivity is rarely
recognized. Other sites of this rash are the malar
area of the face, the posterior neck and shoulders
(referred to as “shawl sign”) and the scalp. Moreover, DM very often involves the extensor surfaces of
the extremities, the knuckles and the dorsal aspects
of the interphalangeal joints and the periungual area
of the fingers in a symmetric fashion (Figure 11). In
contrast to distributed ACLE lesions the dorsal finger sites between the interphalangeal joints are often
spared. Moreover, violaceous colour and the periorbital distribution of the heliotrope rash distinguish
DM from the malar rash in patients with ACLE.
If left untreated early DM lesions develop into
plaques covered with a fine silvery scale especially
on the knees and elbows. Once encountered on the
knuckles, interphalangeal joints and in the periungual area they are called Gottron’s papules (Figure
11) while violaceous macules developing over the
knuckles and the elbows and/or knees are known as
the Gottron’s sign (Figure 12). Occasionally inflamed
skin lesions of DM may develop into erosions, subepidermal blisters and ulcers (Figure 13). Less frequently patients with DM may develop poikiloderma
atrophicans vasculare, a combination of violaceous
erythema, hyperpigmentation, hypopigmentation,
telangiectasia and atrophy.
In addition to these specific skin signs patients
with DM may suffer from non-specific skin signs including nail fold telangiectasias (Figure 14) and dystrophic (“ragged”) cuticles. The mucosal membranes
Figure 12.—Gottron’s sign in DM.
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GKOGKOLOU
Figure 13.—Skin ulcerations in DM.
Figure 14.—Dilated nail fold capillaries in DM.
may also be affected by teleangiectasia.35 Other less
frequently found skin signs of DM include panniculitis with lipatrophy,36 papular and pustular lesions,37
and centripetal flagellate erythema.38 Originally, the
term “mechanic’s hands” was reserved for chronic
eczematous skin lesions located on the fingers in
patients with myositis.39 However, similar changes
were described in other connective tissues diseases
as well.40 Finally, calcinosis cutis may occur in patients with DM and tends to be an extremely painful
and devastating skin manifestation. It is more prevalent in juvenile than in adult DM. Sites of friction
and trauma (elbows, trochanters, knees and fingers)
are predilection sites. Clinically, calcinosis cutis is
characterized by hard irregular nodules. Chalky material may drain to the skin surface. Recently, activated macrophages and TNF-α have been implicated
in the pathogenesis of calcinosis cutis in JDM.41
Notably, calcinosis is also a key feature of a limited
form of systemic sclerosis, the so-called CREST
syndrome (v.i.) or can be a skin manifestation of an
overlap syndrome.
The overall pathogenesis of DM is still poorly understood. The intense B-cell infiltrate together with
CD4+ and CD8+, CD 28 null T-cells in the muscle
perivascular areas strongly suggest an abnormal immune response. Recently, increasing evidence suggests the activation of type I IFN pathway as an
important pathomechanism in DM.42, 43 Antinuclear
antibodies are very frequently found in DM and
approximately 20% of the patients have anti-Mi-2
antibodies. In addition, the occurrence of several
antisynthetase autoantibodies has been described,
which are highly specific for DM and polymyositis
but do not occur in other connective tissue diseases.44 However, the precise role of these antibodies
in eliciting the characteristic skin manifestations of
DM is unknown. Activation of complement cascades
leading to formation and deposition of the membranolytic attack complex in endomysial capillaries
has been implicated in muscle ischemia and destruction although the specificity of these events in DM
has been recently set under question.44
Histopathology of the heliotrope erythema reveals
an interface dermatitis with a sparse lymphocytic
infiltrate, epidermal atrophy, vacuolar alteration of
the basal keratinocytes, basement membrane degeneration, and interstitially deposited mucin. More advanced lesions demonstrate lichenoid infiltrates consisting mainly of CD8+ lymphocytes and acanthosis
of the epidermis.
The differential diagnoses of DM include SLE,
psoriasis, atopic dermatitis, photoallergic- and -toxic
drug eruption, contact dermatitis, cutaneous T-cell
lymphoma, systemic sclerosis and trichinosis.
490
Systemic sclerosis
Sclerosis describes an induration of tissue due to
an altered extracellular matrix turnover, especially
collagen type I, which resembles fibrosis. Indeed,
sclerosis cannot be considered a specific skin sign
of systemic sclerosis (SS) since several other diseases may mimic this indurative reaction patterns of
the skin. The diagnosis systemic sclerosis (SS) is by
October 2014
GKOGKOLOU
Figure 15.—Raynaud’s phenomenon in SS.
extremities. However, in many cases overlaps exist
between these two widely accepted clinical forms of
SS. Recent studies correlate severity and course of
skin fibrosis with overall prognosis.46 Furthermore,
an evaluation of 1200 patients enrolled in the German
Systemic Sclerosis Network showed that patients
with increased mRSS have a higher prevalence of
dysphagia, pulmonary fibrosis, reflux, digital ulcers
and joint contractures, but not other systemic complications.47 A subtype of the limited form SS with
induration of the fingers (“sclerodactyly”) is CREST
(Calcinosis, Raynaud’s phenomenon, Esophageal
hypomotility, Sclerodactyly, Telangiectasia) syndrome. These patients typically have detectable anticentromer antibodies and an overall favourable prognosis compared with patients suffering from diffuse
SS. Finally, scleroderma sine scleroderma is a rarely
encountered entity, in which affected patients have
evidence for SS due to SS-related antibodies and internal organ involvement but no skin involvement.
The prognosis of these patients appears similar to
those with limited SS.
The majority of patients with SS recall Raynaud’s
phenomenon many years before the onset of skin
induration (Figure 15). Albeit a non-specific sign
which is seen in patients with other connective tissue
diseases Raynaud’s phenomenon is present in 9099% of patients with diffuse or limited SS. When cutaneous involvement proceeds there is often an edematous phase of the affected skin areas, especially
on the fingers (“puffy fingers”) (Figure 16). Similar
changes can occur on the forearms, legs, feet, face
and trunk. This is followed by thickening of the skin
Figure 16.—Puffy fingers in SS.
Figure 17.—Sclerodactyly in SS.
definition a multisystem disorder involving the skin
plus internal organs often associated with a typical
serological antinuclear antibody profile. Clinically,
the extent of sclerosis of the skin can be easily assessed by the modified Rodnan skin score (mRSS),
although its sensitivity for detecting small but clinically significant changes has been questioned.45 Alternative but less routinely used tools are 25 MHz
ultrasonography and the durometer device.
There is striking heterogeneity within the clinical
spectrum of cutaneous thickening in patients with
SS. Two main subtypes of SS with distinct clinical and prognostic features have been identified. In
patients with diffuse SS, skin thickening involves
the trunk and proximal portions of the extremities
while in patients with limited SS, the skin induration is confined to the face and distal portions of the
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due to interstitial fibrosis (indurative phase) resulting on the fingers in sclerodactyly and dermatopathic
contractures (Figure 17). Impaired acral blood flow
under these circumstances may finally lead to digital
pits and ulcers (Figure 18).
Among the other common cutaneous key signs
of SS are telangiectasias. They are also a diagnostic cornerstone in patients with CREST syndrome.
These telangiectasias are most often located in the
face including the lips but may also be present on
the neck, volar aspects of the fingers and palms (Figure 19). Another helpful skin sign of SS are dilated
nail fold capillaries, often alternating with areas of
loss of capillaries. They can be easily assessed by
dermatoscopy or in more detail by nail fold capillary microscopy. Calcinosis a further key feature of
CREST syndrome. It tends to be located on the extremities, especially at the finger tips and over joints
(Figure 20).
Diffuse hyperpigmentation of the skin is not a rare
phenomenon in patients with SS. However, its role
as a potential indicator of disease severity and/or
prognosis remains unknown. It mostly occurs as a
diffuse brownish discoloration resembling a sun tan.
In other patients with SS a combination of hyperand hypopigmentation (“salt and pepper”) may develop especially on the upper trunk.
The pathogenesis of SS is incompletely understood. However, recent advances in our knowledge
on the molecular mechanisms of fibrosis have shed
more light into this fascinating field of research.
Many investigators believe that endothelial cell damage is crucial in initiating an inflammatory response
that subsequently leads to the fibrotic stage of the disease.48 In early disease, vascular injury may lead to
tissue hypoxia which triggers the induction of several
proinflammatory cytokines including transforming
growth factor-β1 (TGF-β1).49, 50 TGF-β1 is considered
a master regulator of collagen metabolism and a key
profibrotic cytokine that upregulates collagen synthesis in dermal fibroblasts at the transcriptional and
Figure 19.—Telangiectasias in SS.
Figure 20.—Calcinosis cutis in SS.
Figure 18.—“Rat-bite” fingertip necrosis in SS.
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non-transcriptional level.51 Ex vivo studies on dermal
fibroblasts from patients with SS as well as in situ
studies on lesional skin of SS have unravelled alterations in TGF-β1 function and/or canonical TGF-β1 signalling including the transcription factor Smad.50, 52
In addition, expression of non-Smad signal transduction intermediates, e. g. the immediate-early response
transcription factor EGR-1, have been found to be
stunted in SS.53 Other cytokines such as endothelin-1
and hepatocyte growth factor appear to be involved
in the development of diffuse hyperpigmentation but
also of vascular alterations in patients with SS.54, 55
Recent studies have implicated a pathological activation of the morphogenic pathways Wnt, Hedgehog
and Notch, key regulators of organ development and
tissue homeostasis, in this chronic disease stadium.
In experimental fibrosis models, activation of these
pathways induced collagen type I synthesis, transdifferentiation into myofibroblasts and tissue fibrosis
while their blockade could inhibit these effects.56-59
Specifically, β-catenin is a key pro-fibrotic mediator
of the canonical Wnt pathway in SS and its modulation could be of novel therapeutic relevance.60 Furthermore, a decrease in PPAR-γ, an endogenous antifibrotic mediator, has been identified in a subset of SS
patients and may further abrogate fibrosis.61
There is recent evidence that distinct neuroendocrine pathways are also involved in the pathogenesis
of SS and/or may be exploited as future therapies
against this disease. Serotonin (5-hydroxy-tryptophan, 5-HT) has long been speculated to contribute to Raynaud’s phenomenon in patients with SS
but only recently its role as a direct fibrotic mediator
has been elucidated in more detail. Being stored in
platelets but released upon activation of these cells it
directly acts via 5-HT2B receptors in fibroblasts and
promotes tissue fibrosis. Pharmacological blockage
of 5-HT2B receptors ameliorated experimentally induced fibrosis.62 In addition, endocannabinoids seem
to have a stimulatory effect on cutaneous fibrosis via
signalling of the cannabinoid receptor CB1 while the
cannabinoid receptor CB2 seems to mediate antifibrotic effects.63,64 On the other hand, neuroendocrine
pathways exist which act in an antifibrotic direction and which include melanocortin peptides and
agonists of the α7 nicotinic acetylecholine receptor
(α7nAchR). Our own laboratory could demonstrate
that α-melanocyte-stimulating hormone (α-MSH),
a prototype of melanocortin peptides, antagonizes
TGF-β1-mediated collagen type I synthesis in vitro
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and in vivo.65 In the bleomycin mouse model of SS
α-MSH also attenuated skin fibrosis presumably via
antioxidative pathways.66 Interestingly, a functionally active melanocortin 1 receptor (MC1) binding
α-MSH and related peptides protects from bleomycin-induced fibrosis in mice.67 In this context it is interesting to note that insufficient MC1 expression and
signalling has been noted in keloids suggesting that
α-MSH-mediated pathways may also be disturbed in
SS.68 In addition, we could recently demonstrate that
targeting the α7nAch, e.g. by tropisetron, directly attenuates TGF-β1-mediated fibroblast activation. In
vivo treatment with this agent not only suppressed
experimentally induced skin fibrosis but also had an
antifibrotic effect.69
With regard to autoantibody production in SS the
precise pathogenetic role of anti-topoisomerase and
anti-centromere antibodies still remains unclear. In
addition to the presence of the former autoantibodies
antifibroblast antibodies have been detected in 46%
of SS patients. They were found to be internalized
into dermal fibroblasts and induce a proadhesive and
proinflammatory cellular phenotype.70-72 Moreover,
antibodies against endothelial cells and PDGF receptors may lead to endothelial cell activation and
tissue damage.72
On the genetic level, micro-array based genomewide expression profiling in skin biopsies from SS
patients identified more than 2000 genes with altered
expression in SS.61 Both HLA- and non-HLA-genes
have been identified.73 Finally, epigenetic mechanisms, e.g. DNA methylation, histone modification
and altered miRNA expression have been displayed
in SS.73 Differential miRNA expression profiles in
diffuse and localized disease underline the potential
role of these as biomarkers in SS. MiRNAs seem to
induce or attenuate fibrosis by targeting the canonical TGF-β1/Smad pathway.74
Finally, adaptive and innate immunity pathways
seem to play an important role in SS pathogenesis. In
initial stages, perivascular mononuclear cells secrete
profibrotic cytokines and chemokines.72 Furthermore, an imbalance of Th1 and Th2 cytokines with
shift towards Th2 cytokines seems to promote fibrosis.71 Finally, type I IFN pathways and activation of
TLRs are implicated in pathogenesis of SS.75, 76
Histopathology of sclerotic skin from patients
with SS typically shows excessive collagen deposits
within the dermis and subcutaneous tissue. Adnexal
structures are often entrapped. In early lesions (oede-
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matous phase) a dense lymphocytic infiltrate is seen
at the interface of the deep dermis and adipose tissue.
The differential diagnosis of SS includes scleromyxedema, eosinophilic fasciitis (Shulman syndrome), scleredema adultorum and diabeticorum,
diabetic thick skin, sclerosizing chronic graft-versus-host disease, sclerosizing forms of porphyria,
POEMS syndrome, nephrogenic fibrosing dermopathy, eosinophilia myalgia syndrome, toxic oil syndrome, carcinoid syndrome pansclerotic localized
scleroderma (morphea), exposure to bleomycin,
aromatic chlorinated hydrocarbons or vinyl chloride,
phenylketonuria, various progeria syndromes, and
reflex sympathetic dystrophy.
Figure 21.—Xerostomia in SjS.
Sjögren’s syndrome
Mucocutaneous symptoms are often the leading
clinical symptom in patients with Sjögren’s syndrome (SjS), also known as Mikulicz disease, or
sicca syndrome, a systemic autoimmune disorder
primarily affecting the salivary glands. SjS primarily affects women, with a female to male ratio of
9:1. The disease may present alone as primary SjS
or as secondary SjS in the context of almost every
other autoimmune disease. Compared with the
former major connective tissue diseases CLE and
dermatomyositis there are no specific skin lesions.
Upon histopathology of affected salivary glands
a lymphocytic infiltration including mononuclear
cells, T- and B-lymphocytes is seen. Although a nonspecific sign dryness (xerosis) of the mucous membranes in context with the other diagnostic criteria
is a key component for establishing the diagnosis of
this multisystem disease. Xerosis may not only involve the mouth (xerostomia, eyes leading to keratoconjunctivitis sicca, Figure 21), but also the vagina.
Patients typically complain of dryness and soreness
with burning sensations. Vaginal xerosis may result
in dryness, burning and dyspareunia. Due to diminished salivary production angular stomatitis (Perlèche) is common. Surprisingly, increased awareness
and dental care does not lead to a higher incidence of
dental and gingival problems in patients with SjS.77
The pathogenesis of the mucocutaneous changes
in patients with SjS is incompletely understood,
however immune-mediated and not immune-mediated mechanisms seem to be involved.78 A widely accepted model of pathogenesis of SjS suggests that in
494
genetic predisposed individuals environmental factors such as viral infections may cause epithelial cell
activation, which leads to induction of proinflammatory pathways, infiltration of immune cells and subsequently glandular dysfunction.
A genetic disposition is suggested by the increased
prevalence of specific HLA-haplotypes. Among
them, HLA-DR5 was also related to the presence
of anti-Ro and anti-La antibodies.79 Non HLA-gene
polymorphisms such as STAT-4, IL-12A, TNIP-1,
IRF-5, BLK and CXCR-5 seem also to mediate a
predisposition to disease.80 Furthermore epigenetic
mechanisms including defective DNA methylation
and altered miRNA expression has been shown to
modulate gene expression and the inflammatory response in SjS.78 Interestingly, viruses have for a long
time been considered as potential triggers for the immune response in SjS. Some reports have found an
association between SjS and HTLV-1, Epstein-Barr
virus, human immunodeficiency virus and hepatitis
C virus.79 Viral infections may trigger epithelial activation via binding to TLRs. Recently, TLR 3 activation and induction of type I interferon pathways have
been identified in early SjS stages and seem to play
a decisive role in immune attack and dysfunction of
glandular tissues.81
As demonstrated by the histopathologic picture
of specimens from minor salivary glands the interaction between lymphocytes and salivary gland epithelia appears to in the centre of the pathogenesis
of SjS. The term “epithelitis” has been created to
describe an epithelial cell activation leading to aberrant expression of molecules crucial for lymphocyte
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recruitment and activation thereby resulting in apoptosis of salivary gland epithelia in patients with
SjS.82, 83 Apoptosis in epithelial cells in SjS may occur in a Fas/Fas ligand-dependent pathway or after
direct interaction with cytotoxic T-lymphocytes. Apoptosis of epithelial cells leads to release of cellular
constituents, which are recognised from antigen presenting cells, further potentiating activation of T- and
B-lymphocytes.83
Periductal immune cell infiltrates in SjS consist of
activated T- and B-cells, macrophages and dendritic
cells. The infiltrating lymphocytes show elevated levels of the apoptotic regulators bcl-2 and bcl-x which
may favour increased survival of the cells and eventually development of marginal B-cell lymphoma in
the salivary glands.84 Moreover abnormal expression
of B-cell activating factor (BAFF) from monocytes
and epithelial cells, as well as of its receptor promote
B-cell survival and are related to lymphoproliferative complications such as B-cell lymphoma in SjS
patients.
The female predominance points to sex specific
predisposing factors, and recently evidence is accumulating about the role of estrogens in autoimmunity. Androgens seem on the other hand to be protective. An imbalance of the androgen/estrogen ratio
has been discussed in pathogenesis of SjS, as peak
age of the disease is the premenopausal period. Low
systemic and salivary levels of dehydroepiandrosterone (DHEA) and its metabolite DHEA sulfate
(DHEA-S) have been observed in SjS.81
It is well known that patients have positive antiRo (30-95%) and anti-La (15-60%) antibodies but
their precise role in the pathogenesis of the disease
remains unknown. Furthermore, autoantibodies
against muscarinic receptors have been identified in
up to 90% of patients with SjS.81 These could lead
to autonomic nervous system dysfunction and thus
contribute to xerostomia and xerophthalmia in SjS,
although their exact role remains controversial.
In addition to the afore-mentioned key signs of
the mucous membranes there other non-specific skin
manifestations that frequently occur in patients with
SjS. Xerosis cutis is present in 50% of SjS patients
and may lead to generalized pruritus. Another frequent sign is palpable and non-palpable purpura often located on the legs (Figure 22). It is typically induced or aggravated by physical exertion. Additional
forms of cutaneous vasculitis in patients with SjS
include lymphocytic vasculitis, and urticarial vascu-
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Figure 22.—Cutaneous vasculitis in SjS.
litis (either hypocomplementemic or less commonly
normocomplementemic). By definition, urticarial lesions of urticarial vasculitis last longer than 48 hours
(in contrast to common urticaria) and often have a
purpuric component. Patients frequently complain of
burning and painful sensations. Lesions often heal
with hyperpigmentation. Upon histology, there is a
mononuclear cell infiltration with disruption of the
architecture of the small blood vessels. Finally, an
unusual skin manifestation of SjS has been described
initially in Japanese children and coined annular
erythema of SjS.85 It appears to be highly associated
with the presence of anti-Ro antibodies. Clinically
and histologically, these lesions are indistinguishable from annular SCLE. Regarding other cutaneous
manifestations it is important to differentiate SjS as
a primary sicca syndrome from secondary sicca syndromes which are most commonly associated with
SLE, DM, SS, rheumatoid arthritis, primary biliary
cirrhosis or fibromyalgia.
Other systemic rheumatic diseases
Rheumatoid arthritis
Rheumatoid arthritis (RA) is often associated with
skin changes. They can be RA-specific, non-specific
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or associated skin diseases. Rheumatoid nodules
and nodulosis, accelerated rheumatoid nodulosis,
rheumatoid neutrophilic dermatosis and rheumatoid
vasculitis are considered RA-specific skin manifestations.
Rheumatoid nodules (RN) are the most commonly encountered extra-articular manifestation of patients with RA. About 25% of RA patients develop
these lesions. They are more frequent in white males
and in patients with rheumatoid factor (RF)-positive RA.86-88 Patients with an HLA-DR4 haplotype
and those with heterozygosity for HLADRB1 are
at increased high risk for rheumatoid nodules.89, 90
Clinically, RN are subcutaneous, firm, and painless
papules or nodes measuring from a few mm to some
cm in size. Predilection sites are the periarticular
regions of the extensor surfaces of the fingers. At
the histological level, RN consist of palisading
macrophages around an area of central collagen
degeneration, surrounded by an area of perivascular T-lymphocytes, plasma cells and macrophages.
The pathogenesis of RN remains obscure. Recent
studies suggest endothelial damage at areas prone
to mechanical trauma leading to immune complex
aggregation and focal vasculitis, Th1-cytokines like
TNF-α and IL-1β as well as macrophage chemotaxis and activation in RN formation.90, 91 Complications include infection, ulceration, gangrene, bursitis and synovial rupture. RN must be differentiated
from chronic tophaceous gouty arthritis, rheumatic
fever nodules, subcutaneous nodules found in systemic lupus erythematosus, nodular or keloidal
scleroderma, as well as nodules seen in necrobiosis lipoidica and granuloma annulare. In addition,
tumoral calcinosis, fibromas, xanthomas, subcutaneous sarcoidosis, metastatic tumors, amyloidosis,
ganglion cysts, foreign body granuloma, basal cell
carcinoma, epidermoid cysts and synovial cysts
most be executed.
Rheumatoid nodulosis is characterized by multiple subcutaneous rheumatoid nodules, recurrent
joint symptoms, frequently cystic involvement of
small bones and no or mild systemic manifestations
of RA. The disease usually is self-limited and well
controlled by non-steroidal anti-inflammatory drugs.
Accelerated rheumatoid nodulosis was initially reported in patients treated with methotrexate (MTX)
for RA or juvenile RA.92 Affected patients develop
painful nodules mainly on the hands (Figure 23).
RA patients receiving in addition to MTX hydroxy-
496
Figure 23.—Accelerated rheumatoid nodulosis in RA.
chloroquine, D-penicillamine, colchicine, and sulfasalazine did not develop accelerated rheumatoid
nodulosis. Similar nodules have been observed in a
patient with psoriatic arthritis during MTX challenging the view that accelerated rheumatoid nodulosis
is RA-specific.93 Recently, accelerated rheumatoid
nodulosis also has been described in patients receiving etanercept.94 Mechanistic studies revealed that
MTX enhances multinucleated giant cell formation
in monocytes in an adenosine-1 receptor-dependent
pathway. Blockade of this pathway by colchicine led
to regression of nodulosis in vitro and in vivo.95
Rheumatoid neutrophilic dermatosis is also regarded as a rare but RA-specific skin sign. Patients
with severe and seropositive RA appear to be affected.96 It manifests with asymptomatic erythematous
urticarial papules and plaques. Ulceration is possible. Lesions are typically located on the forearms
and hands.
Rheumatoid vasculitis is regarded as a late complication of RA. It may not only involve skin as but
also internal organs and is thus a potentially lifethreatening extra-articular manifestation of RA. In
the skin it can result in a variety of cutaneous skin
signs (Table II). It mostly occurs in seropositive and
mainly male patients with longstanding RA and is
often associated with presence of autoantibodies
against citrullinated peptides.97, 98 If small vessels
are affected there are palpable and non-palpable purpura, localized petechiae, splinter hemorrhages, nail
fold infarctions (Bywaters lesions), and peripheral
neuropathy. If medium-sized vessels are affected cutaneous findings include nodules, ulcerations, livedo
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Table II.—Skin manifestations of rheumatoid vasculitis.
Allergic venulitis
Atrophie blanche
Digital infarcts
Erythema elevatum et diutinum
Gangrene
Hemorrhagic blisters
Livedo reticularis
Nail fold teleangiectasias and infarctions
Necrotizing granulomatous vasculitis
Non-specific maculopapular or nodular erythema
Petechiae or pupura
Urticaria vasculitis
reticularis, or digital infarcts. Vascular deposition of
IgG-RF immune complexes activating complement
cascades or binding to leucocyte Fc receptors are
implicated in the pathogenesis of rheumatoid vasculitis.99, 100 Particularly, activation of Fc receptors
induces leucocyte degranulation, expression of adhesion molecules and secretion of proinflammatory
cytokines like TNF-α, IL-1 and IL-6. Furthermore,
TNF-α and IL-1 may exert a procoagulant activity as
well as release of MMPs further aggravating vascular occlusion and vascular wall degeneration.100 The
course of rheumatoid vasculitis is associated with a
high morbidity as well as mortality. Thus, early diagnosis is crucial in order to initiate an intensive immunosuppressive therapy. Since peripheral neuropathy is common in cases where vasculitis cannot be
identified nerve conduction studies and sural nerve
or muscle biopsies should be performed. The differential diagnosis of rheumatoid vasculitis includes
polyarteritis nodosa, pyoderma gangrenosum, SLE,
and Wegener granulomatosis.
Another highly characteristic complex of symptoms in patients with RA is Felty syndrome. It develops in about 1% of patients with RA and is clinically
characterized by arthritis, leukopenia and splenomegaly. Rheumatoid nodules (76%), hyperpigmentation and therapy-resistant leg ulcers (22%) may also
occur.101 Notably, Felty syndrome is associated with
an increased risk for cutaneous and systemic infections. These patients may be difficult to treat and
have an increased risk for sepsis. The differential
diagnosis of Felty syndrome includes SLE, druginduced leukopenia, viral infection, amyloidosis,
leukemia, lymphoma, subacute bacterial endocarditis, aplastic anaemia, splenic abscess, haemolytic
anaemia, tuberculosis, and SjS. It should be noted
that skin ulcerations and hyperpigmentation can also
occur in patients receiving MTX.
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Table III.—Non-specific skin manifestations and associated skin
disorders in RA.
Alopecia areata
Atrophic and fragile skin
Erythema multiforme
Erythema nodosum
Erythromelalgia
Hyperpigmentation
Intralymphatic histiocytosis of the skin
Livide (Raynaud-like) fingertips
Noninflammatoy purpura
Nonmelanoma skin cancer
Onycholysis
Onychorrhexis and clubbing of the nails
Pale and transparent skin
Palisaded neutrophilic and granulomatous dermatitis
Palmar erythema
Periungual erythema
Pressure ulcers
Pyoderma gangrenosum
Rheumatoid neutrophilic dermatosis
Splinter hemorrhages and nail fold thromboses
Transient macular erythema
Urticaria
Vitiligo
Yellow nail syndrome
There is a large number of non-specific skin signs
and associated skin diseases in patients with RA (Table III). Pyoderma gangrenosum (PG) is commonly
associated with RA both in RF-positive and negative patients. Lesions start it as a tender erythematous or violaceous papule and rapidly expand into a
hemorrhagic or purulent necrotic ulcer with ragged
edematous edges (Figure 24). Lesions are painful
and are most often located on the lower extremities.
The Koebner and pathergy phenomena are positive.
Since PG does not only occur in RA chronic relaps-
Figure 24.—Pyoderma gangrenosum in a patient with RA.
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ing lesions or those located in unusual sites such as
the face, upper extremities, or abdomen may indicate another underlying disease or immune-mediated inflammatory disease, e.g. inflammatory bowel
diseases, diabetes or a haematological disorder.102
Histological examination of early lesions reveals a
neutrophilic infiltrate and small abscesses the latter
mostly induced by elevated levels of IL-8, which can
attract neutrophils. Differential diagnosis for PG includes venous or arterial ulcers, vasculitis, drug reactions, antiphospholipid syndrome, halogenodermas,
factitial diseases, deep fungal infections, mycobacterial infections, gummatous syphilis, viral infections,
amebiasis, arthropod bites and tumors.
Palisaded neutrophilic and granulomatous dermatitis was originally described by Winkelmann (“Winkelmann’s disease”) as an unusual skin sign of unknown
cause with a variety of clinical pictures in the context
of systemic rheumatic diseases. Skin-coloured, erythematous or violaceous papules, nodules and plaques,
sometimes with central umbilication and crusts or perforation, develop symmetrically on the extensor surfaces of elbows, lower arms and fingers.103, 104
Another more recently appreciated skin sign in
patients with RA is interstitial granulomatous dermatitis (Figure 25).105 In a large proportion of cases
erythematous to violaceous indurated linear cords
(“rope sign”) develop in the trunk, however, other
configurations may occur and lesions may also perforate with extrusion of the necrobiotic collagen.
Histology reveals palisading histiocytes around basophilic collagen in the dermis and superficial subcutis. There is a dermal interstitial and perivascular
mixed infiltrate, in which neutrophils predominate,
leukocytoclasis, histiocytes, and lymphocytes and
sometimes eosinophils are present. Like PG and
Winkelmann’s disease interstitial granulomatous
dermatitis occurs in other autoimmune disorders
than RA and also neoplastic diseases. It must be also
distinguished from granulomatous diseases including granuloma annulare, necrobiosis lipoidica, granulomatous slack skin and interstitial granulomatous
drug reactions.
The recent years have witnessed major advances in the understanding of the pathogenesis of RA
which also broadens our insight into skin manifestations of the disease. Macrophages as well as
resident joint cells including synovial fibroblasts
are considered to be major effectors of synovial inflammation, secreting proinflammatory cytokines
including TNF-α, IL-1 and IL-6 as well matrix
degrading enzymes.106 Activation of autoreactive
T-cells and suppression of Tregs further promote
inflammation. B-lymphocytes contribute to RA progression through production of proinflammatory
cytokines and generation of autoantibodies characteristic of disease.106 Although the presence of RF
and its value in predicting the development of the
disease have been early recognised in patients with
RA it remains unclear if this molecule plays an active role in disease pathogenesis. RFs are autoantibodies against the Fc fraction of immunoglobulins.
Anti-citrullinated protein antibodies have been also
recently recognised as important diagnostic markers of RA. Recent genome-wide association studies have revealed around hundred associated genetic
loci. The best established genetic association with
RF-positive RA is the “shared epitope” MCH class
II alleles. A deficient epigenetic control, specifically
a reduced DNA methylation, is found in RA synovial fibroblasts.107 Moreover, altered expression of
miRNA seems also to modulate inflammation in the
posttranslational level in patients with RA.108, 109
In experimental murine arthritis models, there is
an emerging role of endosomal TLRs (TLR-3, -7,
-8 and -9) which recognise self and foreign nucleic
acid structures, in pathogenesis of RA.106
Systemic onset juvenile rheumatoid arthritis
Figure 25.—Interstitial granulomatous dermatitis in RA.
498
Systemic onset juvenile rheumatoid arthritis is
also called juvenile rheumatoid arthritis, juvenile
chronic arthritis, and Still’s disease.
Since skin manifestations can precede arthralgias
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in patients with systemic onset juvenile rheumatoid
arthritis (SOJRA) for years knowledge of these signs
is important for both dermatologists and rheumatologists to make an early diagnosis. There are two
clinical variants of SOJRA. In the acute onset febrile
systemic 90% of the patients develop a non-pruritic
transient exanthema that recurs with fevers.110 Lesions consist of a pinkish macular or maculopapular rash distributed over the trunk. Koebnerization is
common. Histopathology reveals a discrete perivascular mixed infiltrate with edema of the upper dermis. In the chronic oligoarticular variant of SOJRA
with low-grade persistant fever rheumatoid nodulelike lesions may develop. They have a predilection
for the extensor surfaces of the extremities and can
be both clinically and histologically indistinguishable from those of RA patients.111
In the last decade important steps in understanding the pathogenesis of SORJA have been made.
Elevated levels of IL-6, IL-1β and IL-18 as well as
the marked effects of anti-IL-1 and anti-IL-6 strategies in disease control indicate that these cytokines
are important players in its pathogenesis.112-114 It
was shown that serum from patients with SOJRA
can induce release of various IL-1-related genes in
peripheral blood mononuclear cells of control patients.115 In addition, polymorphisms in the IL-6
gene promoter, leading to changes in IL-6 levels
have been identified and may confer a genetic predisposition to the disease.116 Finally various circulating autoantibodies have been detected in patients
with SORJA but it is unclear whether these observations are of pathogenetic relevance or represent an
epiphenomenon.
The typical exanthema of SORJA in combination with fever and arthralgias must be distinguished
from rheumatic fever, familial Mediterranean fever,
hyper-IgD syndrome, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), familial
Hibernian fever, autosomal dominant periodic fever
with amyloidosis and benign autosomal dominant
familial periodic fever.
Adult onset Still’s disease
Adult onset Still’s disease (AOSD) is a rare multi-systemic inflammatory disease which is today
considered as a polygenic autoinflammatory syndrome.117 Clinical features include high fever, neutrophilic leukocytosis, arthralgias and skin rash.118
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Patients may also develop sore throat, myalgias,
generalized lymphadenopathy, hepatosplenomegaly,
pleuritis and pericarditis. Laboratory examinations
reveal a systemic inflammatory constellation with
increased C-reactive protein, erythrocyte sedimentation rate and ferritin. Based on clinical presentation,
two subtypes may be distinguished. In the first variant systemic symptoms with fever prevail while in
the second arthritis is the leading symptom without
systemic symptoms.117 The disease affects usually
young adults with a predominance of women. Viral
or bacterial infections have been proposed to trigger
the disease. Moreover an association with malignancies, mainly solid cancers of breast and lung as well
as hematologic malignancies has been reported. Due
to unspecific systemic manifestation and the wide
range of differential diagnoses definite diagnosis of
AOSD is difficult. Of the various proposed diagnostic criteria these of Yamaguchi or Fautrel are today
most widely used.117
The typical skin manifestation of AOSD is a salmon-pink, maculopapular exanthema predominantly
affecting the proximal extremities and trunk. Lesions
characteristically appear during fever spikes and
resolve with resolution of fever. Persistent pruritic
papules and plaques are another skin sign of AOSD,
characterized by slight scaly papules and plaques
with a linear configuration on the trunk.118 Furthermore, patients have typically an urticarial dermographism.
Histopathology of the typical skin lesions reveals
a mild inflammatory infiltrate of mononuclear leucocytes and neutrophils in the upper dermis. Biopsies
of persistent pruritic papules and plaques show on
the contrary specific histological features, including
dyskeratotic keratinocytes on the upper epidermal
layers and areas with focal hyperkeratosis.
The exact pathogenesis of the disease remains unclear. Recent reports underline the role of NLRP3
inflammasome activation, leading to production
of IL-1β and IL-18 and initiating a Th1 inflammatory response.117 This results in activation of macrophages and neutrophils, which is the hallmark of
the disease. Interestingly, elevated levels of TNF-α,
IL-1β, IL-6, IFN-γ have been identified in serum of
affected patients.118 IL-6 is considered as the major
cytokine leading to liver synthesis and release of ferritin. Finally, specific HLA alleles as well as polymorphisms in the IL-18 gene may confer a genetic
susceptibility for the disease.
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Relapsing polychondritis (Atrophic polychondritis,
systemic chondromalacia, polychondropathia)
Relapsing polychondritis (RP) is a chronic inflammatory multisystem disorder leading to significant
morbidity due to destruction of the cartilaginous tissue in many organs. Importantly, cutaneous involvement is the first clinical sign in many patients with
RP.
The most specific skin sign of RP consists of erythema, swelling, and pain of the cartilaginous part of
the ear. The earlobe is most characteristically spared
(Figure 26). The majority of RP patients suffer from
such auricular involvement during the course of their
disease. If left untreated persistent inflammation of
the outer ear will lead to destruction of the auricular
cartilage (“cauliflower ears”). If RP involves nasal
cartilage nose deformity may result (“saddle nose
deformity”).119
The presence of autoantibodies recognising the
cartilage matrix proteins type II collagen and matrillin-1 implicates an autoimmune process in the pathogenesis of RP.120-122 The association with MCH Class
II alleles, among them HLA-DR4, HLA-DQA1 and
HLA-DQB1 also suggests an immunologic mechanism responsible for the destruction of cartilaginous
tissue.121, 123 Today it is believed that various noxa,
such as trauma and infections, may lead to exposure
of connective tissue self-epitopes in predisposed individuals and trigger an aberrant immune response.
Key effector cells of tissue destruction are macrophages and neutrophils via production of matrix
metalloproteinases, elastases and reactive oxygen
species. Increased cytokine- and chemokine-levels,
such as MCP-1, IL-8, TNF-α and IFN-gamma further
amplify and sustain the inflammatory response.124
At the histological level, inflamed cartilage shows
a loss of its basophilic staining due to destruction of
glycosaminoglycans and a pleomorphic infiltrate of
macrophages, neutrophils, lymphocytes and plasma
cells.124 At later stages the cartilage is replaced by
granulation tissue and fibrosis.
About one third of patients with PR suffer from
other non-specific signs.125 Since RP can be associated with other systemic diseases, e.g., myelodysplastic syndromes, Behçet’s disease or an underlying
neoplasm it is often difficult to attribute these skin
changes to RP per se. Moreover, some of these skin
signs may be related to systemic treatment. Various
forms of vasculitis including palpable purpura, livedo reticularis and erythema elevatum et diutinum,
non-inflammatory vasculopathies such as livedo reticularis, panniculitis, and aphthosis (oral or complex) have been observed in patients with RP.
The differential diagnosis of painful erythema and
swelling in the context of RP must be distinguished
from physical trauma, erysipelas and Wegener’s
granulomatosis, the latter which can also result in
cartilage destruction especially of the nose.
References
Figure 26.—Erythema and swelling of the ear in RP. Note sparing
of the earlobe.
500
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E-pub ahead of print on July 31, 2014.
503

Cutaneous signs of classical dermatomyositis
M. AURIEMMA, A. CAPO, G. MEOGROSSI, P. AMERIO
Idiopathic immune myopathies (IIM) are an heterogeneous
group of autoimmune muscle disorders characterized by
progressive muscle involvement. Dermatomyositis (DM) is
the most common form of IIM. It is a multisystem disorder
characterized by symmetric proximal, extensor, inflammatory myopathy, vascular involvement and a characteristic
cutaneous eruption. Six types of DM have been identified:
idiopathic, juvenile (JDM), cancer-related other autoimmune diseases-related, iatrogenic DM and amyopathic DM.
Cutaneous manifestations of DM are the most important aspect of this disease and can precede from several months to
years muscle or systemic involvement. Three groups of signs
have been described: pathognomonic, highly characteristic
and compatible. Although differences exist among the different clinical presentation of skin lesions, they share common histological findings including the presence of interface
dermatitis with epidermal atrophy, basement membrane degeneration, vacuolar alteration of basal keratinocytes, and
dermal changes consisting of interstitial mucin deposition
and a sparse lymphocytic infiltrate. DM is a serious disease;
the correct evaluation of any skin lesion suggesting an early
diagnosis is of utmost importance. Skin signs may, also, represent a marker of treatment efficacy even though systemic
symptoms worsening may not always be followed by more
severe skin lesions.
Key words: Dermatomyositis - Skin manifestations - Muscular
diseases.
I
diopathic immune myopathies (IIM) are an heterogeneous group of autoimmune muscle disorders
characterized by progressive muscle involvement.
Dermatomyositis (DM) is the most common form
Corresponding author: M. Auriemma, Dermatologic Clinic, SS Annunziata Hospital, XII Livello corpo B, Via Dei Vestini, 66100 Chieti,
Italy. E-mail: [email protected]
Vol. 149 - No. 5
Department of Medicine and Aging Science
Dermatologic Clinic
G. d’Annunzio University of Chieti‑Pescara, Italy
of IIM. It is a multisystem disorder characterized by
symmetric proximal, extensor, inflammatory myopathy, vascular involvement and a characteristic cutaneous eruption. The pathogenesis of this disease is
still under investigation however several trigger factors have been identified including: infections (e.g.
HIV, EBV, HBV), drugs (e.g. anti-TNF), and environmental factors (especially ultra-violet radiations
[UV-r]);1 instead no correlations have been proposed
with vaccinations.2
Six types of DM have been identified (Table I):
idiopathic, juvenile (JDM), associated to cancer
(paraneplastic), associated to other autoimmune
diseases (overlap syndromes), iatrogenic DM, and
amyopathic DM (ADM).
DM may affect both children and adults. Children
under 18 years of age (JDM) and adults between 4060 year old are more frequently affected. The overall female/male ratio for the classical form of DM is
about 2:1.3
Paraneoplastic DM usually develops in older patients (45-74 years old).1, 4 Its frequency is very variable, since it has been described in 6-60% of DM
cases.5 The development of cancer usually follows
DM presentation in almost two thirds of cases. Thus
the early recognition of cutaneous DM signs is very
important.
AMD is usually described as the presence of typi-
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AURIEMMA
CUTANEOUS SIGNS OF CLASSICAL DERMATOMYOSITIS
Table I.—Classification of the different DM types.
Types of dermatomyositis
1
2
3
4
5
6
Idiopathic DM
Juvenile DM (JDM)
DM associated to cancer (paraneoplastic DM – PDM)
DM associated to other autoimmune diseases
Iatrogenic
Amyopathic DM (ADM)
cal dermatomyositis cutaneous signs without any
sign of muscular disease for at least 6 months.
Clinical symptoms
DM diagnostic criteria have been established by
Bohan and Peter in 1975 6, 7 and include: symmetric
proximal muscle weakness, elevation of serum skeletal muscle enzymes (CK) and lactate dehydrogenase
(LDH); electromyographic specific signs; muscle biopsy abnormalities and typical skin rash of DM.
Muscular symptoms are characterized by weakness and myalgia of the proximal limbs, a decrease
of strength in the proximal muscles associated to
contractures leading to muscular atrophy, respiratory and oro-pharyngeal muscle involvement causing
dysphagia, respiratory difficulties and ab-ingestis
pneumonia.8 Muscle’s disease activity is frequently
discordant from skin lesions presentation,9 thus DM
diagnosis can be challenging when muscle weakness
is not obvious or missing and when skin lesions are
similar to other autoimmune connective tissue diseases.10
Systemic symptoms and involvement of other
organs may also be present such as: fever, malaise,
weight loss, arthralgias, interstitial lung disease and
cardiac dysfunction.
Elevation of CK levels, which is indicative of muscle damage, is the most sensitive enzyme test and
usually parallel disease activity so, CK levels, can be
used to monitor DM therapy response. Muscle biopsies and electromyography can be used as confirmatory tests; beside, noninvasive diagnostic procedures
such as magnetic resonance imaging and ultrasound
are helpful in finding muscle inflammatory lesions.10
Cutaneous signs may precede muscular involvement by several months or years and have been classified in: pathognomonic, highly characteristic and
DM compatible skin lesions.11
506
Cutaneous manifestations of DM
Cutaneous manifestations of DM are the most important aspect of this disease, being the hallmark of
disease definition and diagnosis; moreover they are
consistent throughout the various subtypes of disease. Skin signs can proceed of several months to
years, muscle or systemic involvement.
DM skin signs are important since they lead to
early recognition of the disease; this in turn favors
an early treatment and strict follow-up to improve
patient quality of life (QoL). In fact, skin lesions reduce QoL in DM patients.12 However, skin lesions,
are not always simultaneous to DM systemic symptoms or they may appear as atypical presentations.
Skin lesions identification is of ultimate importance
in paraneoplastic and amyopathic DM to ensure
a higher and better life expectancy. Skin signs of
DM are not always easily recognizable. Classical
skin DM signs like malar erythema and Gottron’s
papulae may assume atypical aspects. These atypical manifestations may present concomitantly to
less frequent but specific signs of DM like cuticular
hyperkeratosis, periungueal erythema, the “V sign”
(presence of erythemato-violaceus skin in the upper chest and anterior neck), the “Shawl sign” (the
presence od poikilodermic skin on the shoulders
and upper back), the “Holster sign” (the presence of
poikilodermic skin on tha antero-lateral aspects of
thigs), non scarring alopecia, hyperkeratotic lesions
on the hands (mechanic’s hands), and oral erosions.
The association of these lesions may characterize
specific clinical presentation of DM associated to
autoantibody. Here follows the description of some
unusual presentation of classical skin DM signs and
the more frequent non-specific lesions associated to
DM.
Three groups of signs have been described: 1)
pathognomonic (typical of DM); 2) highly characteristic (which may suggest the diagnosis of DM);
and 3) compatible (which may be present in DM).
Most of the lesions appear in sun-exposed areas
since DM is classically defined as a photoaggravated disease.
Pathognomonic DM lesions
Gottron’s papules, together with Gottron’s sign
represent the pathognomonic DM lesions, present in
almost 70% of patients.13
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AURIEMMA
Gottron’s papules
Gottron’s sign
Gottron’s papules consist of violaceous slightly
scaly papules and plaques symmetrically found over
bony prominences, particularly over the metacarpophalangeal, proximal interphalangeal and/or the
distal interphalangeal joints (Figure 1). However
they can be found also over other joints (elbows and
knees). In late stages Gottron’s papules can be characterized by the presence of telangiectasias, hyperhypopigmentation, ulceration (Figure 2).8, 14, 15 Active lesions tend to resolve with dyspigmentation,
atrophy, and scarring.16 Sometimes iperkeratosis
may be present resembling psoriasis lesions (Figure
3).
Gottron’s sign is a symmetrical macular violaceous erythema with or without edema overlying the
dorsal aspect of the inter-phalangeal or metacarpophalangeal joints (Figure 4), olecranon processes,
patellae, and medial malleoli.
Figure 1.—Gottron’s papules.
Figure 2.—Gottron’s papules with ulceration.
Figure 3.—Hyperkeratotic Gottron’s papulae resambling psoriasis lesions.
Figure 4.—Gottron’s sign.
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Highly characteristic DM skin lesions
Heliotrope rash
Heliotrope rash is a lilac discoloration or a violaceous to dusky erythematous rash in a symmetric
distribution involving the periorbital skin (Figures 5,
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Figure 6.—Heliotrope rash.
Figure 5.—Heliotrope rash.
Figure 7.—Heliotrope rash with telangiectasia.
Figure 8.—Heliotrope rash sparing the nasolabial folds.
Figure 9.—Heliotrope rash consisting in discrete areas of erythema.
6), which is also considered a pathognomonic sign
of DM. The term heliotrope refers to the purplish
color of the petals of the flower Heliotropium peru‑
vianum.17 Edema and telangiectasia may accompany
the rash or be present in a late stage sign (Figure 7).
Usually the Heliotrope rash spares the nasolabial
folds (Figure 8).18 However a more widespread ery-
thema can affect the perioral area, the forehead, and
the lateral face and ears. In those cases, erythema
often involves the cartilaginous portion of the helix
of the ear, sparing of the earlobe. In rare cases, the
rash may consist in discrete areas of erythema (Figure
9).12 In darker skin types this erythema may be subtle
and overlooked, and itch, pain or a burning sensation
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October 2014
may lead the diagnosis.18 All those lesions can evolve
forming scales, crusts or ulcerations.19 The heliotrope
rash can parallel the course of myositis and the intensification of the erythema may represent the first sign
of a disease flare-up, suggesting the need for a further
evaluation of systemic and muscular involvement.
Nailfold erythema
Erythema overlying the periungueal areas is usually due to periungual telangiectasias which represent
the dilated and tortuous “bushy capillaries” typical
of DM capillaroscopy. This lesions are often associated with 16 small hemorrhagic infarcts and cuticular
hypertrophy (Figure 10). Periungual erythema is not
pathognomonic of DM since may be present in other
connective tissue diseases such as Lupus erythematosus and systemic scleroderma. The presence of this
lesion parallels disease activity.20
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DM compatible skin lesions
Poikilodermatous skin lesions
Poikilodermatous skin lesions are characterized
by telangiectasias, atrophy, depigmentation, and
papules that can be observed on the dorsum of the
hands and forearms, on the upper back (Figure 12)
and posterior neck. They can be described as:
—— V sign: erythematous lesions, which usually
are followd by crusts and discolorations. Those lesions are present in a V shape around the anterior
neck sparing non sun-exposed areas (Figure 13).
The V signs is particularly present in patients with
anti Mi-2 positivity.
—— Shawl sign: it is characterized by the confluence of different grade of erythematous maculae
with a specific distribution resembling a shawl distribution on the shoulders, posterior neck and on
upper back; seldomly it involves the lateral aspects
Confluent macular areas of erythema
This presentation may affect symmetrically the
dorsal aspect of the hands like a macular violaceous
erythema, or it can affect the extensor aspects of the
arms and forearms and deltoids (Figure 11). Confluent erythema involving over 50% of the body surface area is rare in case of DM. Rarely, patients can
present with a more ichthyotic variant of erythroderma, which appears as dry and cracked skin.16
Figure 10.—Nailfold erythema with small hemorrhagic infarcts
and cuticular hypertrophy.
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Figure 11.—Confluent macular areas of erythema.
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AURIEMMA
Figure 12.—Poikilodermatous skin lesions.
Figure 13.—V sign.
Figure 14.—Shawl sign.
of the arms (Figure 14). The shawl sign, like the V
sign, is associated to the presence of anti Mi-2 antibody, although in a lesser frequency.21
—— Holster sign: it represents a simmetric erythema of skin of the thighs (Figures 15, 16). A
similar erythema, called “Gottron’s sign” can be
present on the skin overlaying the extensor tendons
of hands, forearms, foots and legs.12 This sign is not
DM specific; it can be, in fact, recognized in different immuno mediated dermatoses, although less
frequently.18
Scalp involvement
Non-pathognomonic signs may be present on the
scalp of DM patients frequently associated with
disease flare up.14 A diffuse erythematous lilaceous
510
Figure 15.—Holster sign.
macular presentation, presenting on the nuchal area
(Figure 17) or a scaly psoriasis-like process may be
present leading in some cases to moderate non-scarring alopecia (Figure 18).14 Usually these manifestation may be associated with very intense pruritus
that is resistant to antihistaminic and corticosteroid
therapy.18
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Figure 16.—Holster sign.
Figure 17.—Diffuse erythematous lilaceous maculae in the nape
area.
Figure 18.—Non-scarring alopecia.
Figure 19.—Calcinosis cutis resulting in an ulcerate nodule with
surrounding erythematous skin.
Calcinosis cutis
a surrounding erythematous skin.9, 22, 23 Calcinosis,
in the context of JDM, generally develops within
a few years from diagnosis. Lesions are frequently
located at sites exposed to trauma (e.g., knees, elbows, and buttocks). Four characterized patterns of
calcinosis exist: cutaneous or subcutaneous plaques
or nodules; deposits that extend to muscle; calcinosis
Calcinosis can be present in the course of DM
(Figure 19) especially in JDM. Usually calcinosis
involves the skin, subcutaneous tissue, fascia, or
muscle, consisting in tender, firm papules or nodules
which can eventually ulcerate in the center and show
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along fascial planes that may lead to contractures,
and widespread calcium deposition.23
of DM, eventually being the sign of a concomitant
Sjögren Sindrome (SS).26
Excoriations
Lipodystrophy
Pruritus is usually an accompanying symptom that
can precede of several months the onset of skin or
muscle symptoms. It usually determines excoriations and the development of linear streaks in the upper back (flagellate erythema – Figure 20). It represents one of the major stressor inducing a reduction
in the quality of life (QoL) in DM patients.12
Lipodystrophy is increasingly recognized in patients with JDM. Rarely seen at presentation, these
changes develop later in the course of the disease in
up to one-fourth of the patients.27
Ulcers
Ulcers are serious manifestations of DM. These lesions presumably reflect significant vasculopathy in
Mechanic’s hands
Mechanic’s hands consist in the presence of
rough and cracked, hyperkeratotic, lichenoid lesion and papules on the lateral (Figure 21) and palmar areas of the fingers. Frequently such lesions
are misinterpreted as eczematous lesions, however
they are refractory to any form of topical treatment.
These lesions may be associated with the presence
of anti Jo-1 antibodies in particular subtypes of DM
(t-istidil synthase syndrome).
Oral manifestations
Oral manifestations consist in oral mucosal ulcers,
white patches, and gingival telangiectasias and erythema as well as tongue involvment.24, 25 Xerostomia
and salivary hypofunction can be found in the course
Figure 20.—Flagellate erythema.
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Figure 21.—Mechanic’s hands.
October 2014
the skin leading tissue hypoxia thus being predictors
of a more severe disease course.28 Moreover according to several papers, ulcers may be associated with
interstitial lung disease and/or concomitant cancer.29
Follicular hyperkeratosis lesions
A rare form of DM, called Wong’s DM, has been
described in the last years as the coexistence of DM
with pityriasis rubra pilaris lesions; this subtype of
DM shows histopathologic features of both pityriasis
rubra pilaris and DM depending on the biopsy specimen site.30
Raynaud phenomenon
This vascular parossistic ischemic sign is common to other collagen immune mediated diseases,
it is frequently present in DM.16 Some authors have
associate its presence with an higher risk of malignancy. Moreover this sign is typically present in the
so called “antisynthetase syndrome,” which is characterized by myositis, interstitial lung disease (ILD),
fever, Raynaud’s phenomenon, arthritis, and mechanic’s hands.31
Vesicles and bullae
It is a rare presentation. The lesions more frequently appear in flexural areas such as antecubital
and popliteal fossae, however they may appear also
on the lower eyelid or on the dorsum or over pressure
points. Bullous lesion may develop due to severe
edema, mucine deposition and friction action. These
lesions have been seldomly associated with peripheral neuropathy or cancer in DM patients. Bullous
detachment is localized at the basal membrane level
and immunofluorescence is frequently negative.32
Vasculitis
Expression of a localized and or more diffuse vasculitidies,37 livedo reticularis, erosive lesions, urticarial, exfoliative erythroderma represent other rare
presentation of DM.14, 34, 35
Of notice, in the course of DM, specific signs of
the disease with a segmental distribution have been
only rarely described. This kind of skin manifestation
seems to be exclusively present in juvenile DM.36, 37
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Particular DM subsets
Classical DM with Mi-2 positive antibody
In case of anti Mi-2 antibody (a nuclear helicase
protein) positivity, classical DM can be considered
with a favorable course. The positivity of anti Mi-2
identifies a reduced propension to ILD and a better
responce to therapy. Skin sign frequently associated
to anti Mi-2 positivity are Gottron’s papulae, the V
sign, the Shawl sign and cuticular hyperkeratosis.38, 39
Classic DM with Jo-1 antibody positivity (tistidil synthase syndrome)
The association of anti Jo-1 positivity to DM describes a subset of the disease which aften presents
ILD and pour response to therapy. Beside, the t-istidil synthase syndrome is accompanied by myositis,
non-erosive arthritis less frequently and by constitutional symptoms, skin rash or sicca syndrome. Main
skin lesions are mechanic’s hands and Raynaud phenomenon.39, 40
Amyopatic DM
Amyopatic DM (ADM) is a DM characterized by
the absence of muscle involvment and muscle enzyme elevation for at least of six months. ADM has
a lower correlation with neoplasm compared to classical DM. Typical skin lesion in ADM are Gottron’s
papulae, heliotrope rash, nail abnormalities and
poikiloderma.41
Paraneoplastic DM
Different clinico-laboratoristic characteristics
have been associated to paraneoplastic DM (PDM)
to favor an early diagnosis.42 Among the different
PDM characteristics that suggest the presence of a
neoplasm there are: necrotic lesions, vasculitidies,
pruritus, erythroderma (more than 90% of body surface area involved) end the presence of Gottron’s papulae.43, 44
Iatrogenic DM
Iatrogenic DM is usually induced by different
types of drugs of which some induce skin and muscle symptoms (chloroquine, cimetidine clofibrate,
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cholchicine, corticosteroids, ε-aminocaproic acid,
ethanol, gemfibrozil, heroin, hydrazine, levodopa,
lovastatin, penicillamine, nicotinic acid, rifampicin,
sulfonamide, vincristine, tamoxifen, terbinafine, isoniazide, minocyclin, alpha-INF, anti-TNF-beta) or
skin symptoms alone (idroxiurea, ethoposide, cyclofosfamide, diclofenac, acetylsalicylic acid, imatinib mesilate). Common signs of drug induced DM
are the same of classical DM including: Gottron’s
papules, heliotrope rash, nailfold changes and a
widespread sun induced erythema.45
Histology of cutaneous DM lesions
The main characteristics of DM skin lesions are:
the presence of interface dermatitis with epidermal
atrophy, basement membrane degeneration, vacuolar
alteration of basal keratinocytes, and dermal changes consisting of interstitial mucin deposition and a
sparse lymphocytic infiltrate.46 Perivascular inflammation with CD4-positive T-cells in the dermis and
in chronic stages a dilatation of superficial capillaries, may also be present.8
Gottron’s papules are characterized by hyperkeratosis, mild papillomatosis, acanthosis or, epidermal
atrophy and interface dermatitis. The poikilodermatous lesions usually show hyperkeratosis, mild epidermal atrophy with loss of the epidermal ridge pattern, and basal cell liquefactive degeneration seldom
resulting in subepidermal vesiculation.47 The dermis
is edematous, often contains increased mucin, and
characteristically shows conspicuous dilated vascular vessels.
Figure 22.—Hyperkeratotic Gottron’s papulae mimicking psoriatic hand lesions.
Differential diagnosys
Therapy
DM can be underdiagnosed in case of Gottron’s
papule being the unique manifestation of the disease.
Whenever Gottron’s papulae are hyperkeratotic, can
mimic psoriasiform hand lesions (Figure 22). Mechanic’s hands may usually be confused with allergic or irritative hand dermatitis as well as heliotrope
rash may be confuse with an allergic dermatitis or
Lupus Erythematous. Some T cell lymphomas may
resemble poikylodermic lesions of DM, especially
on the scalp, face and on the extensor joint surface.
Atopic dermatitis may mimic juvenile DM for the
common presence of pruritus.45
Treatment of DM skin lesions is difficult. Therapies need to be individualized, also, on the base of
muscle and systemic involvement. While muscle
symptoms usually respond to systemic corticosteroid, skin lesions may persist. In some cases, skin lesions recede during the treatment of the underlying
pathology (e.g. cancer); if it’s not the case, a specific
therapy should be suggested.
Both UV-A and UV-B light may trigger or worsen
skin lesions;48 thus the avoidance of sun exposure,
the diligent use of sunscreens (SPF≥50) as well as
the use of sun protective clothing and wide-brimmed
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October 2014
hats are mandatory.8 Vitamin D level should be investigated and supplementation is warranted.49
Management of pruritus and burning sensation
is a special aspect of DM treatment. In moderate
cases associated with xerosis, emollients and moisturizing creams are often useful.50 In more severe
cases, oral sedating antihistamines, such as hydroxyzine 10-50 mg or non-sedating antihistamines in
day-time or Doxepin and amitriptyline (long-acting
tricyclic antidepressants with potent antihistaminic
effects) as well as gabapentin and pregabalin can
be used.48
Topical corticosteroid drugs (class I and II) twicedaily may be recommended when pruritus and burning sensation are present.14 The usage of occlusive
dressing usually enhances the therapeutical efficacy.48 To avoid side effects, in case of prolonged use,
a cyclic therapy is recommended.
Also topical calcineurin inhibitors (CNIs) such
as tacrolimus and pimecrolimus can be used for the
treatment of cutaneous DM signs in a twice-daily
bases, for 6-8 weeks. These agents have been proved
to be safe and effective in combination with systemic
therapies rather than alone,14, 48 or for long term therapies in atrophogenic areas.51
In more refractory cases of skin DM lesions systemic antimalarials have been used. Their mode of
action is still under investigation; however they exert
immunomodulatory, antinflammatory and anti proliferative effect together with sun protective activities.52 Hydroxychloroquine sulfate in best used at a
dose of 200-400 mg/day while chloroquine phosphate in a dose of 250-500 mg/day.53 Antimalarians
can be used as sole therapy or in combination with
other systemic or topical therpies.14
Although systemic corticosteroids are the first option in case of myositis, the discordant response to
therapy between muscle and cutaneous manifestations and their adverse effects, limit their use to concomitant or alternative therapy for skin DM lesion.
Usually prednisone is used at a dosage of 1 mg/kg/
day tapered over 2-3 months for particularly symptomatic skin DM lesions. In the course of JDM, corticosteroid can be of interest in preventing or rapidly
reducing lesions like calcinosis cutis.54
Methotrexate (MTX) is a useful therapy in patients
with more resistant cutaneous DM and may control
DM-associated myositis. For that reason MTX can
be considered as first line steroid sparing agent. The
efficacy of MTX has also been reported in cutane-
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AURIEMMA
ous disease in JDM. The typical starting dose is 10
mg/week orally or subcutaneously with folic acid
supplementation 1 mg daily.14, 48
Mycophenolate mofetil (MMF) has been shown to
be an alternative steroid-sparing agent at the dosage
of 1000 mg twice daily, in course of DM, for both
systemic and cutaneous involvement.14, 46, 55
Azathioprine (AZA) is a steroid-sparing agent
widely used in dermatologic conditions. However
the lack of data on AZA in DM skins disease seems
not to suggest its use for cutaneous DM.48
High dose of intra venous immunoglobulin (Ig)
are a therapeutical option in refractory DM, in fact
their use seem not to be superior to corticosteroids in
course of myositis.56 Low dose intravenous immunoglobulinhave been also shown to be useful in course
of ADM.57
Other drugs have been reported to be useful in
case of DM: retinoids, dapsone, thalidomide, leflunomide, sirolimus, rituximab and TNF-α inhibitors;
however their usage is not standardized and conflicting evidence exists.14
A special attention should be taken for cutaneous
calcinosis, which affects the great part of patients
with JDM. Suggested therapies are: aluminum hydroxide, diltiazem, surgical excision, colchicine,
probenecid, bisphosphonates, intralesional steroid
injection and IVIg. However best results seem to
be reached when and aggressive corticosteroid
therapy is used in case of JDM since calcifications
appear to be related to long-term chronic inflammation.48
Conclusions
Although DM represents the most common subtype of IIM is actually a great masquerade. Skin
signs are the hallmark of the disease and usually lead
the correct diagnosis. DM related skin signs could be
classified as pathognomonic, highly characteristics
and compatible.
Skin signs usually precede the onset of general
symptoms or can represent the only manifestation of
DM (amiopathic DM). Actually DM has to be addressed as a probable paraneoplastic syndrome and
those skin signs are important not only for diagnosis,
being sometimes correlated with diseases course.
However treatment of cutaneous signs of DM is
sometimes difficult ad a combination of topical and
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AURIEMMA
system agents is necessary. Some other, the avoidance of sun exposure and the use of a sun filter cream
is enough to reduce skin manifestation.
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telangiectases: an underappreciated physical sign of dermatomyositis. Arch Dermatol 1999;135:1370-4.
25. Gonçalves LM, Bezerra-Júnior JR, Gordón-Núñez MA, Libério
SA, de Fátima Vasconcelos Pereira A et al. Oral manifestations as
important symptoms for juvenile dermatomyositis early diagnosis:
a case report. Int J Paediatr Dent 2011;21:77-80.
26. Iaccarino L, Gatto M, Bettio S, Caso F, Rampudda M, Zen M et
al. Overlap connective tissue disease syndromes. Autoimmun Rev
2013;12:363-73.
27. Batthish M, Feldman BM. Juvenile dermatomyositis. Curr Rheumatol Rep 2011;13:216-24.
28. Spencer CH, Hanson V, Singsen BH, Bernstein BH, Kornreich HK,
King KK. Course of treated juvenile dermatomyositis. J Pediatr
1984;105:399-408.
29. Ishigaki K, Maruyama J, Hagino N, Murota A, Takizawa Y, Nakashima R et al. Skin ulcer is a predictive and prognostic factor of
acute or subacute interstitial lung disease in dermatomyositis. Rheumatol Int 2013;33:2381-9.
30. Haro R, Revelles JM, Fariña Mdel C, Martín L, Requena L. Wong’s
dermatomyositis: a new case and review of the literature. Int J Dermatol 2013;52:466-70.
31. Hamaguchi Y, Fujimoto M, Matsushita T, Kaji K, Komura K,
Hasegawa M et al. Common and distinct clinical features in adult
patients with anti-aminoacyl-tRNA synthetase antibodies: heterogeneity within the syndrome. PLoS One 2013;8:e60442.
32. Ayhan E, Baykara SN, Ozekinci S, Aytekin S. Vesiculobullous dermatomyositis with sensory motor neuropathy. Skinmed
2013;11:185-7.
33. Cao H, Pan M, Kang Y, Xia Q, Li X, Zhao X et al. Clinical manifestations of dermatomyositis and clinically amyopathic dermatomyositis patients with positive expression of anti-melanoma differentiation-associated gene 5 antibody. Arthritis Care Res (Hoboken)
2012;64:1602-10.
34. Pipkin CA, Lio PA. Cutaneous manifestations of internal malignancies: an overview. Dermatol Clin 2008;26:1-15.
35. Maoz CR, Langevitz P, Livneh A, Blumstein Z, Sadeh M, Bank I et
al. High incidence of malignancies in patients with dermatomyositis and polymyositis: an 11-year analysis. Semin Arthritis Rheum
1998;27:319-24.
36. Torchia D. Superimposed segmental dermatomyositis. Allergol Int
2011;60:401.
37. Takahashi Y, Murota H, Tarutani M, Sano S, Okinaga T, Tominaga
K et al. A case of juvenile dermatomyositis manifesting inflammatory epidermal nevus-like skin lesions: unrecognized cutaneous
manifestation of blaschkitis? Allergol Int 2010;59:425-8.
38. Rider LG, Miller FW, Targoff IN, Sherry DD, Samayoa E, Lindahl M
et al. A broadened spectrum of juvenile myositis. Myositis-specific autoantibodies in children. Arthritis Rheum 1994;37:1534-8.
39. Targoff IN, Reichlin M. The association between Mi-2 antibodies
and dermatomyositis. Arthritis Rheum 1985;28796-803.
40. Iaccarino L, Gatto M, Bettio S, Caso F, Rampudda M, Zen M et
al. Overlap connective tissue disease syndromes. Autoimmun Rev
2012;3:363-73.
41. Caproni M, Cardinali C, Parodi A, Giomi B, Papini M, Vaccaro M
et al. Amyopathic dermatomyositis: a review by the Italian Group of
Immunodermatology. Arch Dermatol 2002;138:23-7.
42. Amerio P, Girardelli CR, Proietto G, Forleo P, Cerritelli L, Feliciani C et al. Usefulness of erythrocyte sedimentation rate as tumor marker in cancer associated dermatomyositis. Eur J Dermatol
2002;12:165-9.
43. Santmyire-Rosenberger B, Dugan EM. Skin involvement in dermatomyositis. Curr Opin Rheumatol 2003;15:714-22.
October 2014
44. Nousari HC, Kimyai-Asadi A, Spegman DJ. Paraneoplastic dermatomyositis presenting as erythroderma. J Am Acad Dermatol
1998;39(4 Pt 1):653-4.
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46. Jorizzo lj. Rheumatologic diseases. Dermatomyositis 155-63.
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50. Sontheimer RD. Skin disease in dermatomyositis – what patients
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AURIEMMA
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in the manuscript.
E-pub ahead of print on July 11, 2014.
517

An update on juvenile dermatomyositis
V. BOCCALETTI, S. DI NUZZO, C. FELICIANI, G. FABRIZI, C. PAGLIARELLO
Juvenile dermatomyositis (JDM) is a rare, severe, autoimmune disease characterized by a small-vessel vasculopathy
that primarily affects skin and muscle, but also lung, joints,
gut and heart. Nowadays prompt recognition of this entity
and aggressive treatment, when needed, improves outcomes
and has decreased mortality that, before corticosteroid became a mainstay in therapy, could reach 40%.
Key words: Dermatomyositis - Autoimmune diseases - Vascular diseases.
I
ncidence of juvenile dermatomyositis (JDM) varies between 2 and 4 children per million per year
with some minor variations between ethnic groups 1
and is more frequent in females with a male:female
ratio of 1:2.3,1 even if it could be lower in younger
age groups.2 Median age of onset is around 7 years,
although 1 case out of 4 starts before 4 years of age,
indicating a worst prognosis.3
Typical rashes in JDM include a generalized photosensitive erythema, periorbital heliotrope rash (Figures
1, 2) and Gottron’s papules over the extensor surfaces
(Figure 3), that are diagnostic and pathognomonic.
Proximal muscle weakness may precede, follow or be
present at the same time of the cutaneous rash and is
fundamental for the diagnosis. Actually, in the majority of children, a number of minor systemic signs can
be present such as fever, anorexia, malaise, abdominal
pain, irritability, weight loss.
A diagnosis of definite JDM, based on classic criteria of Peter and Bohan,4, 5 consisted of typical skin
rash and, at least three of the following: 1) muscle
Corresponding author: C. Feliciani, Clinica dermatologica, Università
di Parma, 43126 Parma, Italia. E-mail: [email protected]
Vol. 149 - No. 5
Clinica Dermatologica
Università degli Studi di Parma, Parma, Italia weakness; 2) elevation of muscle enzymes; 3) abnormal EMG suggestive of myopathy; 4) abnormal
muscle biopsy sample suggestive of inflammatory
myopathy (Table I) even if the Childhood Arthritis
and Rheumatology Research Alliance (CARRA) has
recently proposed to introduce MRI study of muscles instead of biopsy as an acceptable tool to assess
myositis and its good correlation with disease activity (Table II).6, 7
Pathogenesis
While the pathogenesis of JDM still remains unclear, the most recent hypothesis is that the interactions between environmental factors (infections,
vaccinations and drugs) 8 and an immune dysfunction in a genetically susceptible patient could generate the disease.9 Recent studies show that the
ancestral haplotypes HLA-B*08, DRB1*0301 and
DQA1*0501 may confer extended risk to develop
myositis in Caucasian children and adults,10 and
also JDM.
The clinical manifestations of JDM are mainly
due to a small-vessel angiopathy in which deposition and activation of the complement cascade determines a perivascular inflammation and endothelial
dysfunction and finally in a depletion of capillaries.
Consequently, this will determine tissue damage (in
519
BOCCALETTI
Update on juvenile dermatomyositis
Figure 1.—Periorbital erythema without edema.
Figure 2.—Typical picture of dermatomyositis on the hands.
Table I.—Bohan and Peter criteria (1975).
Major: typical cutaneous rash
Minor: proximal muscle weakness
–– ↑ CPK, ↑ LDH, ↑ transaminasis, ↑ aldolasis
–– abnormal EMG and histology suggestive for dermatomyositis
Diagnosis: 1 major criteria + 3 minor criteria
Uncertain diagnosis if: 1 major criteria + 2 minor criteria
Figure 3.—Gottron’s papules.
520
skin, in muscles) with dilated capillaries and fiber
atrophy.11 There is mounting evidence of a strong
role for type I Interferons in both adult and JDM,12
for which a major source are activated plasmocytoid
dendritic cells. These cells in the skin could be activated by toll-like receptors after various stimuli (viral infections, UV, tissue damage) while the resident
October 2014
BOCCALETTI
Table II.—Diagnostic criteria.
Typical cutaneous manifestations + 3 signs:
a. muscle weakness
b. ↑ muscle enzymes
c. abnormal EMG
d. muscle histology suggestive for dermatomyositis
e. myositis signs using magnetic resonance
Modified by CARRA 2006 (Childhood Arthritis and Rheumatology Research Alliance).
ones in muscle may be activated after endothelial
damage and vasculopathy. Plasmocytoid dendritic
cells also secrete chemokines which may contribute
to the formation of lymphocyte aggregates, tipically
perivascular.11 Auto-antibodies may contribute to the
formation of immunecomplexes that are chemoattractants for other inflammatory cells and enhance
inflammation with overexpression of type I interferons.13
Table III.—Antibodies myositis-specific (MSAs) and Antibodies myositis-associated (MAAs)
Antobodyes
MSAs
Anti-ARS
Anti-JO-1
Anti-PL-12
Anti-PL-7
Anti-EJ
Anti-OJ
Anti-KS
Anti-Ha
Anti-Zo
Other MSAs
Anti-MI-2
Anti-SRP
New autoantibodies
Anti-p155/140 o
Anti-p155
Anti-p140 (MJ)
MAA-s
Anti-U1-RNP
Anti-U3-RNP
Anti-PM-Scl
Anti-Ro
Anti-La
Anti-Ku
Anti-Topo
Antigen
Aminoacyl-tRNA synthetase
Clinical picture associated to JDM
Weakness, arthritis, Raynaud, fever, interstitial
lung fibrosis
Histidyl-tRNA synthetase
Alanyl-tRNA synthetase
Threonyl-tRNA synthetase
Glicyl-tRNA synthetase
Isoleucyl-tRNA synthetase
Asparaginyl-tRNA synthetase
Tyrosyl-tRNA synthetase
Phenylalanyl-tRNA synthetase
DNA helicase
Signal Recognizing Proteins
JDM with severe and recalcitant polymyositis
Severe cutaneous manifestations, generalized
γ subunit of trascriptiona intermediate factor
lipodystrophia
(TIF)-1-γ
MJ autoantigen (?), Nuclear matrix protein NXP2 Calcinosis
Ribonucleoprotein U1 (snRNP)
Ribonucleoprotein U3 (fibrillarin)
Ribonucleoprotein 52 o 60 kD (hYRNA)
Eterodimer p70/p80, DNA associated protein
Overlap with sclerodermia
DNA topoisomerase I
IMACS
Medical evaluation
Patient / parents evaluation
Muscle condition
Functional ability
Laboratory tests
Overall activity
Non-muscle activity
Quality of life
Global medical assessment using VAS or Likert
scale
Patient / parents assessment using VAS or Likert
scale
MMT
CHAQ o CMAS
2 between CK, LDH, aldolasis, ALT, AST
Not included
MDAAT
Not included
PRINTO
Global medical assessment using VAS or Likert
scale
Patient / parents assessment using VAS or Likert
scale
MMT, CMAS
CHAQ
Not included
DAS or MDAAT
Not ioncluded
CHQ global physical score
PRINTO, Paediatric Rheumatology International Trials Organisation; IMACS, International Myositis Assessment and Clinical Studies Group; IIM, Idiopathic inflammatory myopaty; JDM, Juvanile dermamyositis; VAS, Visual analogical scale; MMT, Manual Muscle test; CMAS, Childhood Myositis Assessment Scale; CHAQ, Childhood Health Assessment Questionnaire; CK, creatine kinase; LDH, lactate dehydrogenase; ALT, alanine aminotransferasis
AST, aspartate aminotransferase; DAS, Disease Activity Score; MDAAT, Myositis Disease Activity Assessment Tool, including MYOACT (Myositis
extra-skeletal muscle disease activity assessment by VAS) and MITAX (Myositis intention to treat activity index); QOL, quality of life; CHQ, Child
Health Questionnaire.
Vol. 149 - No. 5
521
BOCCALETTI
Autoantibodies are common in JDM and classically can be divided into two categories: myositis-specific Ab (MSA) directed at nuclear or cytoplasmic
components that are involved in protein synthesis
(aminoacyl-tRNA synthetase) or nuclear transcription and myositis-associated Ab (MAA), which are
found in other autoimmune conditions and overlap
syndromes (Table III). Around 70% of children affected by JDM are positive to some MSA or MAA
with similar clinical characteristics to adults, according to the positive autoantibody: e.g., lung involvement is more frequent in anti-Jo-1 positive patients
while anti-Mi-2 patients run a less severe course.14
Analysis of the same data tells us that about 30%
of the same cohort of patients with JDM and ANApositivity are ENA-negative, pointing out the fact
that research of new autoantibodies is still needed to
better define more patients subgroups. Recently antip155/140 was described that confers a higher risk to
develop lypodistrophy and a more severe cutaneous
involvement, and others are under study.
Long-term outcome
Based on clinical course, DMG patients are divided in three different groups:
1. monocyclical, patients who present complete
remission within two years;
2. polycyclical, patients who shows several episodes of recurrence of disease;
3. patients with continuous chronic disease.
Due to recurrence or continuous symptomatic
disease, patients included in the second and third
group present a more severe cumulative skin damage compared to the first one. However, severe
course leading to death, nowadays, is a rare event
(1% to 3% of the patient population) and occurs
as consequence of severe infection in patients with
heavy immunosuppressive treatment. On the other
hand, overall morbidity of disease is not neglectable. Anecdotal report on the occurrence of malignancies in DMG patients does not suggests a routine follow-up, which must be considered in case
of specific symptoms and signs of disease, such as
splenomegaly. During infancy, skin ulcers, soft tissue damage and calcynosis due to vascular flogosis are reported. Studies on the long-term outcome
showed that after eight years of continuous disease,
10% and 40% of patients had severe and moderate
522
muscular weakness, respectively. In these patients
involvement of any organ occurs in almost 70% of
them: skin (calcynosis 23%, which is more frequent
than adults; lypoatrorphy around 10%) and muscles
more frequently; bone (ankilosis, and osteoporosis),
endocrine glands (delayed growth and hirsutism),
gastrointestinal tract (dysphagia). In literature, involvement of respiratory tract in children is scarcely
reported, sometimes an asymptomatic reduction of
respiratory function occur.24, 25 Female are more
prone to severe prognosis.
JDM treatment
A definitive treatment strategy for JDM patients
remain elusive because of lacking of clear, evidence
based prognostic factors. Many studies have shown
that deferring treatment onset as well as a low dose
treatment are linked to worse outcomes and could
also promoting calcinosis development.26, 27
Systemic corticosteroids are the mainstay of JDM,
at least at its onset. A standard therapeutical approach is represented by prednisone 1-2 mg/kg/day
for at least four weeks, tapering by 20% each two
weeks if a favorable response is achieved. When the
dosage of 0.5 mg/kg/day is reached, treatment could
be reduced by about 20% per fortnight till its complete discontinuation.28
Other authors suggest to induce a clinical remission through high dose intravenous methylprednisolone bolus therapy at dosage of 5-30 mg/kg/day
for three days and then using the aforementioned
oral prednisone treatment.29 If a complete remission
could not be achieved with this regimen, it was suggested to introduce steroid sparing agents such as
methotrexate (MTX) or cyclosporine (Cya). When
choosing to use MTX, the dose should be increased
in order to reach the full dosage of 15 mg/m2 and
then maintained for at least two years.30 Intravenous
immunoglobulin (IVIG) administration could not be
routinely recommended because of limited evidence
of its effectiveness and its high cost.
Biologic drugs for JDM treatment have also limited evidence of effectiveness. Some case series
have suggested that infliximab could be useful for
the management of refractory cases of JDM at the
dosage of 6 mg/kg per week, administered at week
0, 2 and 6 and then every 4-6 weeks. Nevertheless,
JDM seems a IFN-1 driven pathology and there is
October 2014
conflicting evidence about the role of TNF-α in its
pathogenesis.31
A promising drug is rituximab, which acts through
selective cd20 positive B lymphocytes depletion.
Recently, a study involving 200 refractory myositis
including 48 adult and childhood DM have shown a
relevant effectiveness after 44 weeks of treatment,
although adverse events were acknowledged as a potential issue.32
Finally, another study by Levy et al.33 suggests
that for early diagnosed JDM (symptoms onset from
less than 8 weeks) IVIG monotherapy without systemic steroids administration represents a safe and
effective alternative devoid of severe side effects.
Conclusions
JDM should be regarded as a systemic disease affecting mainly skin and muscles as principal targets.
The course of JDM could also progress to a severe
form, therefore, its early diagnosis is of paramount
importance. JDM diagnosis could be supported by
imaging techniques such as MRN, that for selected
cases in appropriate clinical setting could replace
the EMG and even muscle biopsy. Clinical course of
the disease and treatment response should be evaluated by validated and disease specific clinical scores.
Besides of systemic corticosteroids, new biologic
drugs (such as monoclonal antibody against the protein CD20) and IVIG seems promising and deserve
consideration for recalcitrant cases. Future studies
should better assess the role of these new and expensive treatments as steroid sparing agents in the
routine clinical practice.
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October 2014

Cancer risk in dermatomyositis:
a systematic review of the literature
D. DI ROLLO 1, D. ABENI 2, M. TRACANNA 1, A. CAPO 1, P. AMERIO 1
The association between idiopathic inflammatory myopathy
(IIM) and cancer has been extensively studied in adults. Many
epidemiological studies demonstrated this association, which
appears stronger for dermatomyositis (DM) than for polymyositis (PM). The first case suggesting an association between
cancer and DM was reported in 1916. At present the reported
incidence of cancer association with DM varies widely, from
less than 7% to over 30%. Many early evidences came from
case reports, but this association was later confirmed in casecontrol as well as in population-based studies. Ovarian cancer
or breast cancer in females and lung cancer in males are the
main malignancies associated with DM. Given the frequency
of the association of dermatomyositis with cancer, for costeffectiveness reasons it might be important to develop simple
and appropriate diagnostic tests for identification of patients
with DM, who may be at higher risk of developing a malignancy. Clinicians should plan follow-up schedules to optimize both
cancer detection and treatment, and thus to improve patient
survival. Many different clinical and serological signs have
been suggested as possible predictive factors for malignancy
in dermatomyositis: age, increased erythrocyte sedimentation
rate (ESR), presence of cutaneous leukocytoclastic vasculitis,
cutaneous rash and skin lesions as cutaneous necrosis and
periungueal erythemas, neoplastic markers or dysphagia. The
results of the different studies are quite discordant. Therefore,
we conducted a systematic review of the scientific literature
to evaluate the level of the risk of cancer in patients with dermatomyositis and to explore whether certain patient characteristics may be linked to different levels of cancer risk.
Key words: Dermatomyositis - Neoplasms - Skin diseases.
D
ermatomyositis (DM) is an autoimmune disease
characterized by a symmetric proximal, exten-
Corresponding author: D. Di Rollo, Department of Dermatology and
Venereology, University of Chieti-Pescara, viale Vestini, 66100 Chieti,
Vol. 149 - No. 5
1Department of Dermatology and Venereology
University of Chieti‑Pescara, Chieti, Italy
IDI‑IRCCS, Rome, Italy
2Health Services Research Unit,
sor, inflammatory myopathy and a characteristic
cutaneous eruptions. Several subtypes of DM have
been described such as: classical, juvenile, overlap,
amiopathic, drug induced and cancer associated. The
association between idiopathic inflammatory myopathy (IIM) and cancer is well demonstrated in adults
and several epidemiological studies have confirmed
this association, as well as that cancer risk is greatest in patients with DM. The reported incidence of
cancer varies widely in the published literature from
less than 7% to over 30%.1, 2
The first reports suggesting this association were
published in 1916, when Sterz and Kankeleit described the first case of DM and gastric cancer. Early
studies were limited by the absence of diagnostic criteria for DM. The criteria established in 1975 by Bohan and Peter for diagnosis of dermatomyositis are
presently considered the “gold standard” in clinical
studies and in trials, although the authors themselves
stated that failure to fulfill these criteria cannot completely exclude a diagnosis of dermatomyositis or
polymyositis (PM). The frequency of cancer in myositis detected by Bohan and Peter was 8.5%, with a
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Cancer risk in dermatomyositis
higher risk of malignancy in patients with dermatomyositis.3
The heterogeneity of the data reported in the literature depends on the heterogeneity of the samples
(e.g., from the ethnicity of the study population, the
different criteria for the diagnosis of DM/PM, the inclusion of patients with tumors temporally unrelated
to DM, the diverse duration of the follow-up periods)
and the lack of appropriate control groups.
Sigurgeisson et al.4 estimated the percentage of
cases of malignancy in the course of myositis, analyzing within a population-based study in Sweden, a
sample of 788 DM/PM patients, utilizing data from
a national register. He found 392 patients with DM,
61 of whom had a malignancy, and 59 of these were
diagnosed at the same time or shortly after the diagnosis of DM. Airio et al.,5 in 1995, revised a national registry of diseases in Finland, which covered
a period between 1969 and 1985, and described 175
cases of PM and 71 patients with DM, finding 34
cases of malignancy associated with myositis (30
with DM and 4 with PM). Patients at higher risk
were those with DM and aged more than 50 years,
and in whom the diagnosis of DM was made within
one year.
Stockton et al.6 selected patients with an initial
diagnosis of DM or PM from the Scottish hospital
registry between 1982 and 1996 and identified malignancies in their cohort through a cross search in
the National Cancer Registry. They concluded that
there was an overall increased risk of malignancy for
DM with a standardized incidence ratio (SIR) of 7.7
(95% confidence interval [CI]=5.7 to 10.1).
Buchbinder et al.7 identified all patients with biopsy-proven IIM diagnosed in the state of Victoria,
Australia, from 1981 to 1995 from the Victorian
Neuropathology Service, which has reviewed all
muscle biopsies performed in that state since 1981.
The State Cancer Registry and National Death Registry were used to identify malignant disease to the
end of 1997 or death, if earlier. Also these authors
observed an increased risk for malignant disease in
DM (SIR=6.2;95% CI=3.9-10.0). This risk remained
elevated even when the first year of follow-up after
diagnosis of myositis was excluded from the statistical analysis (SIR=4.3; 95% CI=2.3-8.1).
Many other case-control and cohort studies are
reported in the scientific literature. However, even
though they all include an appropriate control group,
and adopt a more strict disease definition, these stud-
526
ies have reached conflicting conclusions regarding
the association between myositis and cancer.
Two meta-analyses examine the results of epidemiological studies. The first is from Zantos et al.,8
who in 1994 reviewed 4 case-control or cohort studies. Taken together, these reports provided 565 cases
of PM and 513 cases of DM for a total of 1078 myositis cases. There were 97 cancers diagnosed in the
DM group and 56 cancers in the PM group over a
period of 10 years, from 5 years prior the diagnosis
of myositis though 5 years after it. The pooled odds
ratios (OR) for the association with cancer were 4.4
for DM (95% CI, 3.0-6.6) and 2.1 for PM (95% CI
1.4,3.3). Since the risk of cancer in DM was high
both before and after the diagnosis of DM, the authors concluded that the DM may be regarded as a
paraneoplastic phenomenon.
The second pooled analysis was performed by
Hill et al.9 They analyzed the published national data
from Sweden, Denmark and Finland concerning DM
and cancer. They found 618 cases of DM of whom
198 had cancer, 115 of these had developed after the
diagnosis of DM.
Several features have been reported as possible prognostic indicators for cancer development.10, 11 Anyway, most of the previous studies were
small in size and failed to draw sound conclusions.
Wang et al.12 published in 2013 a meta-analysis of 20
previously published observational studies and suggested that age, gender, cutaneous necrosis, dysphagia, arthritis and lung complication may influence to
cancer development in DM/PM patients.
In order to confirm these data and to possibly identify other clinical and laboratory characteristics associated with malignancy in DM, we performed a
deeper literature search including more case-series
studies. We report here the results concerning the
information about signs and symptoms that may be
associated with a higher risk of cancer in DM.
Methods
Our systematic review of the English literature
covered the period from 1969 through March 2011.
According to the criteria described in detail here below, we identified all the original studies (i.e., whether retrospective, prospective, case-control, cohort
studies, and case series) evaluating the association of
DM with and malignancies. We also included previous reviews as well as letters to the editor.
October 2014
Information source and search strategy
The search for relevant articles was conducted on
the following electronic database: Pubmed/Medline,
Ovid and Embase. Search terms included: dermatomyositis and malignancy, dermatomyositis and cancer, dermatomyositis and tumor, dermatomyositis
and neoplasia. Articles published before 1969 were
excluded because of lack of detailed data and of the
difficulty in assessing the validity of the diagnoses,
due to the lack of established diagnostic criteria at
that time.
From these simpler search terms a combined strategy was developed, as shown in Figure 1.
The four “single search terms” yielded preliminary
lists including 1260, 1243, 1297 and 1171 articles,
respectively yielding a total of 4971 potentially relevant articles. Subsequently, duplicate articles were
excluded and after this phase the number of selected
items was reduced to 1207 titles. In a further phase,
articles in non-English languages, case reports, and
studies that included patients affected by amyopathic
dermatomyositis, polymyositis, juvenile myositis,
inclusion body myositis, myositis and tissue connec-
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tive diseases (CTD) and overlap syndrome were also
excluded.
Two reviewers, independently screened these articles for inclusion. Articles were read in full text if at
least one of the two reviewers considered an abstract
to be potentially relevant. This phase of the screening process identified 208 items, which underwent
a full text appraisal. Of these, only the studies that
fulfilled the following prespecified eligibility and ineligibility criteria were chosen for the analysis.
Eligibility criteria were: case series of at least ten
patients affected by classic dermatomyositis and in
whom the association with cancer was studied; articles in English language; articles published after
1969.
Ineligibility criteria were: case reports and case
series with fewer than ten classic DM patients; studies of patients with amyopathic DM, polymyositis,
juvenile myositis, inclusion body myositis, myositis
and tissue connective diseases (CTD) and overlap
syndrome; articles in languages other than English;
articles published before 1969.
Conflicts were resolved through discussion.12-77
A flow diagram (Figure 2) illustrates the selection
process for the articles included in the review. Exceptionally, 4 studies 25, 41, 43, 77 reporting less than 10
patients affected by DM were included, because they
were considered of particular interest for our review,
given the presence of data concerning paraneoplastic
DM. A total of 85 articles were assessed for quantitative and qualitative analysis and underwent data
extraction.
Data collection process
Figure 1.—Search strategies.
Vol. 149 - No. 5
Data extraction from reports on DM concerned:
authors, date of publication, duration of follow-up,
study location, data collection period, sample size,
number of patients with associated malignancy, sex,
weighted mean age. Patients were divided in two
study-groups, “paraneoplastic dermatomyositis”
and “classic dermatomyositis”, and the following
data were also recorded: cutaneous signs such as
skin necrosis, Raynaud’s phenomenon, periorbital
erythema, heliotrope erythema, Gottron’s papules,
Gottron’s sign, periungual erythema and/or nail fold
telangiectasia, cutaneous ulceration, poikiloderma,
cutaneous vasculitis, and capillaroscopy signs such
as megacapillaries. Moreover systemic involvement signs such as dysphagia and/or dyspnea, rapid
527
DI ROLLO
Figure 2.—Flow diagram.
onset, fever, interstitial lung disease, arthtalgia, resistance to treatment, distal muscle weakness and
serological signs such as positivity for different
autoantibodies like antinuclear antibodies (ANA),
extractable-nuclear antibodies (ENA), myositisspecific antibody (MSA), anti Jo-1 antibodies, anti
155/140 antibodies, anti-RNP antibodies were recorded.
528
Data synthesis
The frequency (%) of malignancy in DM patients
was obtained for the different studies, in order to input in the calculation of the pooled estimates. Frequency (%) of cutaneous, systemic and serological
signs in both patient study groups were calculated.
Relative risk (RR) and 95% confidence interval (CI)
October 2014
were computed using EpiInfo (version 3.5.1). Classically, the RR is a dimensionless number resulting
from the ratio of two risks.
Results
Eighty-five reports evaluating the association of dermatomyositis and malignancy were retrieved.3-7, 9, 13-91 Simple size ranged from 6 to 1059
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patients. When pooled, these reports provided 8712
cases of dermatomyositis. We found 1784 cases of
DM associated with malignancy, yielding a rate of
20.5%. The highest cancer rate in a single study was
10/11, or 90.9%, while a case series reported a rate
of 2.5%, or 1/40. The results of the literature review
are summarized in Figure 3.
None of the studies reported all the characteristics we wanted to analyze. On the other hand, each
selected study showed only few characteristics we
Figure 3.—Description of all retrieved records: number of cases (%) of DM associated with malignancy.
Vol. 149 - No. 5
529
DI ROLLO
were interested in. In order to overcome this issue
each time we chose studies within the 85 original
papers that recorded the variable to be examined.
Relative risk (RR) of malignancy in DM by gender
Data about gender of patients was available only
in 44 out of the 85 studies retrieved.4, 6, 13-16, 18-20, 2224, 26-31, 34, 37, 41-45, 49, 57-60, 62, 63, 66, 68, 72, 73, 76-79, 84, 85, 88
This refinement yielded 6152 DM patients of which
4195 were female and 1957 male. The pooled rate of
cancer in male patients was 476/1957, or 24.3%. The
highest reported malignancy rate, in three different
studies, was 100%. Of the 4195 female patients, 629
were associated to malignancy, with a rate of 15%.
The relative risk of cancer in DM was significantly
elevated in the male vs. female patients (RR 1.6; CI
95% 1.44-1.78) (Figure 4).
Figure 4.—Relative risk of cancer in dermatomyositis in male vs. female patients.
530
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Clinical and serological features and risk of malig‑
nancy
We selected within the 85 original reports different
studies that analyzed the following characteristics:
cutaneous necrosis (N.=6),16, 20, 26, 32, 40, 70 Raynaud’s
phenomenon (N.=9),13, 21-24, 26, 45, 49, 67 periorbital
erythema (N.=9),13, 20, 22, 40, 45, 62, 64, 67, 73 heliotrope
erythema (N.=18),3, 13, 20, 22-26, 29, 40, 41, 43, 45, 59, 64, 65, 67,
73 Gottron’s papules (N.=13),13, 20, 22, 26, 29, 40, 41, 43, 45,
64, 65, 67, 73 Gottron’s sign (N.=8),17, 22, 23, 24, 29, 45, 62, 67
periungual erythema and/or nail fold telangiectasia
(N.=10),13, 16, 17, 20, 23, 24, 40, 45, 62, 65 cutaneous ulceration
(N.=7),13, 22, 40, 41, 45, 62, 67 poikiloderma (N.=6),13, 26, 29,
45, 65, 73 cutaneous vasculitis (N.=5),29, 34, 37, 41, 42 capillaroscopy signs such as megacapillaries (N.=6),20, 26,
29, 40, 49, 73 dysphagia (N.=17),13, 16, 21, 22, 26, 27, 34, 41, 44,
45, 49, 55, 59, 62, 65, 67, 79 dyspnea (N.=7),16, 17, 21, 27, 41, 46, 67
rapid onset (N.=3),16, 21, 66 fever (N.=5),17, 21, 22, 45, 67
interstitial lung disease (N.=18),13, 20, 22-25, 34, 44, 45, 49,
57, 62, 67, 68, 72, 81, 85, 86 arthralgia (N.=14),3, 13, 16, 17, 22-26,
34, 40, 41, 45, 67 resistance to treatment (N.=13),22, 24, 31, 33,
37, 40, 41, 49, 57, 59, 62, 67, 83 distal muscle weakness (N.=17)
17, 22-24, 29, 40, 41, 43, 45, 57, 62, 64, 65, 67, 73, 74, 77 and
positivity
for different auto-antibodies like antinuclear antibodies (ANA) (N.=18),13, 16, 20-22, 24-26, 29, 34, 40, 41, 45, 47, 53, 59,
67, 68 extractable-nuclear antibodies (ENA) (N.=9),22,
26, 29, 40, 42, 59, 67, 68, 81 myositis-specific antibody (MSA)
(N.=2),68, 84 anti Jo-1 antibodies (N.=10),13, 22, 24, 26, 29,
57, 67, 68, 84, 85 anti 155/140 antibodies (N.=5) 84-87, 90
and anti RNP antibodies (N.=3).34, 84, 85
The pooled results from the literature review, concerning the rates of clinical and serological signs in
DM patients with and without malignancy are summarized in Tables I-III.
Paraneoplastic DM was more frequently associated with cutaneous necrosis, compared to Classic
DM patients (34% vs. 5%; RR 6.1; P<0.001). In
addition, DM presenting with dysphagia, muscle
weakness, arthralgia and anti-155/140-Ab positivity was associated with a higher risk of cancer. The
RR for dysphagia, arthralgia, and anti -155/40 Ab
positivity was of 1.8 (95% CI 1.5-2.2; P<0.001), 1.3
(95% CI 1.2-1.5; P<0.001), and 5.4 (95% CI 3.7-8.1;
P<0.001), respectively, for paraneoplastic DM patients vs. classic DM.
Table I.—Frequency (%) of clinical cutaneous signs in paraneoplastic DM patients and RR vs. classic dm patients.
Classic DM
Cutaneous necrosis
Ulceration
Heliotrope erythema
Gottron’s papules
Periungual erythema
Megacapillaries
Gottron’s sign
Periorbital erythema
Cutaneous vasculitis
Poikiloderma
Raynaud’s phenomenon
Total of
patients
N. of cases
260
189
565
446
224
254
238
283
117
199
531
13
20
391
244
98
99
134
213
24
113
117
Paraneoplastic DM
%
Total of
patients
N. of cases
%
RR
95% CI
P<0.05
5%
10.6%
69.2%
54.7%
43.8%
39%
56.3%
75.3%
20.5%
56.8%
22.0%
94
192
489
210
425
116
400
230
45
120
340
32
38
404
131
212
51
230
165
8
51
35
34%
19.8%
82.6%
62.4%
49.9%
44%
57.5%
71.7%
17.8%
42.5%
10.3%
6.08
1.9
1.2
1.1
1.1
1.1
1.0
0.95
0.9
0.8
0.5
3.7-12.4
1.1-3.1
1.1-1.3
1.0-1.3
0.96-1.4
0.9-1.5
0.9-1.2
0.86-1.06
0.4-1.8
0.6-0.95
0.3-0.7
<0.001
0.012
< 0.001
0.064
0.137
0.365
0.768
0.367
0.695
0.013
<0.001
Table II.—–Frequency (%) of clinical systemic signs in paraneoplastic DM patients and RR vs. classic DM patients.
Classic DM
Total of
patients
Dysphagia
Dyspnoea
Muscle weakness
Arthralgia
Rapid onset
Refractory to therapy
Fever
Intertstitial lung
Vol. 149 - No. 5
557
136
439
422
108
218
252
468
N. of cases
146
32
209
194
29
110
82
140
Paraneoplastic DM
%
26.2%
23.5%
47.6%
46.0%
26.9%
50.5%
32.5%
29.9%
Total of
patients
318
44
496
319
52
255
75
495
N. of cases
153
17
323
195
13
83
9
62
%
48.1%
38.6%
65.1%
61.1%
25.0%
32.5%
12.0%
12.5%
RR
1.8
1.6
1.4
1.3
0.9
0.7
0.4
0.4
95% CI
P<0.05
1.5-2.2
1.02-2.6
1.2-1.5
1.2-1.5
0.5-1.6
0.5-0.8
0.2-0.7
0.3-0.6
<0.001
0.050
<0.001
<0.001
0.803
<0.001
<0.001
<0.001
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Table III.—Frequency (%) of antibodies positivity in paraneoplastic DM and RR vs. classic DM patients.
Classic DM
Anti 155/140 Ab
Anti RNP Ab
ANA
Anti MSA* Ab
ENA
Anti Jo-1 Ab
Paraneoplastic DM
Total of
patients
N. of cases
%
237
129
714
138
294
390
29
9
318
65
72
62
12.2%
7%
44.5%
47.1%
24.5%
15.9%
Interestingly, instead, Raynaud’s phenomenon
(10.3% vs.22%; RR 0.5; P<0.001), fever (12%
vs.32.5%; RR 0.4; P<0.001), interstitial lung disease
(12.5% vs. 29.9%; RR 0.4; P<0.001), and anti Jo-1
Ab positivity (1.5% vs. 15.9%; RR 0.09; P<0.001)
were inversely correlated with cancer presence.
Discussion
DM is a rare inflammatory myopathy which has
been associated with an increased risk of cancer development. The association of DM with malignancy
was first reported in 1916 but only confirmed with
recent large, population-based, retrospective cohort
studies.1-9, 11, 14, 17, 18, 20. The risk of malignancy is
highest at the time of or within 1 year of myositis
diagnosis. Cancer of the ovary, lung, and gastrointestinal tract are most often associated with DM,
particularly in Western nations, while nasopharyngeal carcinoma is commonly associated in Southeast
Asia, Southern China, and Northern Africa.11
Several studies suggested that specific features of
DM occur in association with internal malignancy
and may be used to identify patients who may benefit from an extensive evaluation for malignancy.10
Most authors recommended a cancer screening
specific for patient’s age, gender and ethnic background. So colon cancer may be over-represented
in patients with DM aged 65 years or more,49 while
ovarian carcinoma may be easier to detect in women
with DM.92
These recommendations were based on population-based cohort studies examining cancer risk in
white populations.6, 7, 9 In Southeast Asia the risk of
nasopharyngeal carcinoma is clearly increased, and
thus a cancer type-specific screening according to
the different population may be required.17, 18, 29, 64
532
Total of
patients
48
36
260
6
106
134
N. of cases
32
4
119
0
3
2
%
RR
95% CI
P<0.05
66.7%
11.1%
45.8%
0%
2.8%
1.5%
5.4
1.6
1.02
0.3
0.12
0.09
3.7-8.1
0.5-4.9
0.9-1.2
0.05-1.9
0.04-0.4
0.02-0.4
<0.001
0.416
0.732
0.088
<0.001
<0.001
Paraneoplastic DM presents also relevant features
when considering age and gender of patients. In the
Finnish and Danish population-based cohort studies, an increased risk of malignancy was evident in
patients older than 45 to 50 years of age at the time
of myositis diagnosis.5, 38 In the Scottish populationbased study there was a increased risk of malignancy
for DM patients 45 to 74 years of age.6 In the Taiwanese population-based study a significantly risk
was evident in DM patients 40 to 59 years of age.
While gender was never considered a consistent risk
factor for malignancy.14 However, in several studies,
as in three of four European studies, in one American
study and in one Asian study there were higher standardized incidence ratios for men.4, 5, 6, 12, 17, 18, 20, 29, 68
The recently, published meta-analysis by Wang et
al. on the association of DM and Polymyositis with
cancer included twenty studies with 380 patients and
1575 controls. The factors that may increase the risk
of cancer were older age (WMD 11.41, 95% CI 9.8412.98), male sex (OR 1.92, 95% CI 1.49-2.48), cutaneous necrosis (OR 5.52, 95% CI 3.49 -8.74) and
dysphagia (OR 2.41, 95% CI 1.50-3.86). Their results showed that the factors that may provide protection against cancer were arthritis (OR 0.38, 95% CI
0.24-0.61) and ILD (OR 0.32, 95% CI 0.20-0.51).12
In our review we were able to retrieve 1784 cases
of paraneoplastic DM and 6928 controls, and our estimated rate of paraneoplastic DM was 20.5% in the
overall sample. These data are similar to the most
precise reports from the population studies which
estimated that the cases of paraneoplastic DM are
approximately 25% of the total DM cases.4-7, 14, 38.
Also our review of the literature, similarly to
Wang’s meta-analysis,12 suggested that the relative
risk of cancer in DM was significantly elevated in
the male compared to female patients (RR 1.6; CI
95% 1.44-1.78).
October 2014
Throughout the literature several prognostic or
predictive markers or clinical signs have been proposed to assess the presence of paraneoplastic DM:
age,5, 6, 12-14, 29, 32, 38 ESR,21, 32, 63 cutaneous rash and skin
lesion, as cutaneous necrosis,12, 16, 20, 21, 32, 40, 70, 76 periungueal erythemas 13, 20, 32, 76 and ulceration,13, 22, 45, 67
neoplastic markers,67, 72 and dysphagia.12, 13, 27, 32
However, most studies were able to demonstrate
the significance of only one of these factors, or were
not coherent with other studies and failed to demonstrate the relevance of one or more of the proposed
factors as a predictive feature of malignancy in DM.
For example in our previous work, only ESR, out of
many proposed clinical and laboratory features, was
found to be statistically associated with the presence
of malignancy in DM patients.63
Also the assessment of classical tumor markers
is debated. Amoura et al.72 proposed the diagnostic
value of several circulating tumor markers for the
detection of solid cancers in DM. They found that
cancer antigen (CA) 125 and CA 19-9 were useful
in detecting cancer in patients with DM without interstitial lung disease (ILD). However, other authors
have not supported this finding.43
Interstitial lung disease (ILD),12, 13, 17, 22, 67, 68 arthritis,12, 13, 22, 25, 67 Raynaud’s phenomenon,13, 21, 22, 26, 45, 67
fever 22, 67 and high titer of antinuclear antibodies 13, 22, 67
were all proposed as features of reduced risk of a
coexisting malignancy. In our study we were able to
retrieve and pool a vast set of clinical an serological
characteristics form a large set of reports. Our results showed that thirteen characteristics were likely
to be associated (positively or negatively) with a risk
of neoplasm in DM.
Seven characteristics were associated with an
increased risk: cutaneous necrosis, heliotrope erythema, dysphagia, dyspnea, muscle weakness, arthralgia and positive anti- 155/140 antibodies. On
the other hand, six factors were consistently estimated to have a relative risk lower than 1, thus indicating that they may provide some degree of protection
against developing a malignancy. These putative
protective factors were: Raynaud’s phenomenon,
interstitial lung disease, refractory to therapy, fever
positive anti Jo-1 antibody and positive ENA antibodies.
Paraneoplastic DM had higher rates of cutaneous
necrosis compared with classic DM patients (i.e.,
34% vs. 5%; RR 6.1; P<0.001), which is in agreement with the findings from several previous reports.
Vol. 149 - No. 5
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In addition, cases of DM with dysphagia, muscle
weakness, arthralgia, and anti-155/140-Ab positivity had an increased risk of cancer with a RR of
dysphagia, arthralgia, and anti-155/40 Ab positivity
of 1.8 (95% CI 1.5-2.2; P<0.001), 1.3 (95% CI 1.21.5; P<0.001) and 5.4 (95% CI 3.7-8.1; P<0.001),
respectively for paraneoplastic DM patients vs. patients with classic DM.
In addition, we confirmed the results of some previous reports, when we observed that paraneoplastic
DM patients, compared to Classic DM patients, had
lower rates of Raynaud’s phenomenon (10.3% vs.
22%; RR 0.5; P<0.001), fever (12% vs.32.5%; RR
0.4; P<0.001), interstitial lung disease (12.5% vs.
29.9%; RR 0.4; P<0.001), and anti Jo-1 Ab positivity (1.5% vs. 15.9%; RR 0.09; P<0.001).
A study by Feldman et al.41 suggested the presence of a possible association of cutaneous vasculitis with tumor in DM patients, and Hunger et al.,42 in
a retrospective study of 23 patients with DM, found
that 4 of the 5 cases with an associated malignancy
had a histologically-confirmed vasculitis in lesional
skin, and their statistical analysis showed that this
association was significant (P<0.05), indicating that
vasculitis in lesional skin biopsies has a predictive
value for the presence of underlying malignancy. In
contrast with these findings, our analysis showed no
statistically significant difference (P=0.695) for cutaneous vasculitis between two patient study groups,
thus suggesting that vasculitis may not be taken into
consideration as a malignancy predictive sign.
Recently, several studies examined the role of autoantibodies as potential predictive factors of cancer
risk in patients with idiopathic inflammatory myopathies (IIM).10, 83, 85, 89, 93-96
A new hypothesis proposed that in cancer associated myositis, an immune reaction to the tumor may
cross-react with antigens in the skin and muscle,
leading to DM.94, 95
Myositis autoantigens, Mi-2 and Jo-1 were expressed at high levels in myositis muscle, particulalry in regenerating muscle fibers, as well as in
adenocarcinomas of the lung and breast, but not in
the corresponding healthy tissue, demonstrating that
tumor cells and undifferentiated myoblasts were antigenically similar.87
Myositis-specific and myositis associated autoantibodies (MSA, MAA) were present in about 40%
of patients with myositis, and they played specific
immunopathogenic roles in myositis. MAA include
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Figure 5.—Proposed strategy for the identification of DM patients at increased risk of malignancy.
anti-PM-Scl, anti-Ku, anti-components of the U1
small nuclear RNP (snRNP) or the cytoplasmic Ro
antibodies such as Ro60/SSA, La/SSB, and Ro52.93
Among MSAs anti-synthetases were frequently
used in screening test and of these the anti-histidyl
tRNA synthetase (Jo-1) antibody was the most common. In patients with myositis the anti-Jo-1 antibodies were frequently associated with ILD, Raynaud’s
phenomenon, arthopathy and “mechanic’s hands”.
A negative association had been noted with this antibody and paraneoplastic DM.85, 93 More recently,
a new antibody has recently been reported in DM
patients with malignancy in in the absence of ANA.
Targoff et al.90 first described anti 155/140 antibody
534
in six of eight adult patients with myositis and malignancy. In a further small study, Kaji et al.86 described anti 155/140 antibody in five of seven adult
patients with paraneoplastic myositis. In both studies, none of the anti-155/140 antibody-positive patients had ILD, confirming the proposed negative association between ILD and cancer. Trallero-Araguas
et al.90 recently confirmed that anti 155/140 auto-antibody may be strictly linked with cancer in patients
with DM. Their analysis included 312 adult patients
with DM pooled from six studies. The sensitivity
and specificity of anti-155/140 for diagnosing cancer-associated DM were 78% (95% CI 45-94%) and
89% (95% CI 82-93%), respectively. Anti 155/140
October 2014
had positive and negative predictive values of 58%
and 95%, respectively. In a study by Chinoy et al.,10
the anti 155/140 antibody was DM-specific and had
50% sensitivity and 96% specificity for cancer associated myositis. When combined with negative results of hospital-based routine testing for Jo-1, Ku,
PM-Scl, U1-RNP antibodies, a positive anti 155/140
antibody result had 94% sensitivity and 99% negative predictive value.
Our pooled analysis confirmed these data of the
literature, since we observed that patients with a
positive anti-155/140 antibody test have a 5.4 RR
of having cancer compared to anti-155/140 antibody
negative patients (95% CI 3.7-8.1; P<0.001).
Other statistically significant results we obtained
concerned the positivity of ENA and anti-Jo-1 antibodies. The presence of these antibodies is negatively associated with cancer, indicating a possible
protective effect, with a RR of 0.12 (95% CI 0.040.4; P<0.001) and 0.09 (95% CI 0.02-0.4; P<0.001),
respectively in paraneoplastic DM compared to the
non-malignant variant. Our analysis did not show an
association between ANA auto-antibodies and cancer development.
Unfortunately, we were not in a position to examine others relevant laboratory tests (e.g., ESR,
aldolase, creatine chinase, lactate dehydrogenase)
because of the excessive heterogeneity in the type of
reported factors in the different studies.
In accordance with data already reported in the
literature, a proposed strategy for the identification
of patients with DM, who may be at increased risk
of developing a malignancy, is in Figure 5. This
strategy includes a very careful clinical history and
physical examination, as well as the performance of
laboratory tests (mainly, a comprehensive serological screening), and CT scan of the chest to exclude
ILD.
Limitations of the study
We acknowledge that our review may have some
limitations. For instance, some studies considered in
the analysis were retrospective case-control studies
for which selection bias could not be excluded. Several of the included studies adopted different criteria
for the diagnosis of paraneoplastic DM and/or considered different time periods before and after the
diagnosis of DM for evaluation of the association
with cancer.
Vol. 149 - No. 5
DI ROLLO
Conclusions
However, in conclusion, the results of our comprehensive review of the literature and the metaanalysis have pointed out a subgroup of factors that
would require particular clinical attention and that,
taken together, should help clinicians in identifying
DM patients that may be at increased risk of having
or developing a malignancy.
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537

The Italian version of the systemic sclerosis questionnaire:
a comparison of quality of life in patients with systemic
sclerosis and with other connective tissue disorders
C. URAS 1, S. TABOLLI 1, P. GIANNANTONI 1, G. ROCCO 2, D. ABENI 1
aim. Aim of the present study was to measure disability
among patients with systemic sclerosis or other connective
tissue disorders, using the specific Systemic Sclerosis Questionnaire (SySQ) and the Skindex-17.
Methods. Cross-sectional survey on hospitalized and dayhospital female patients in a dermatological setting, during
March-May 2013. Comparison of disability and quality of
life scores between patients in the two diagnostic groups.
Results. The use of these questionnaires in a clinical setting
was well accepted. The levels of disability were slightly greater among women with systemic sclerosis in terms of general
and musculoskeletal symptoms, while women with other connective tissue disorders had higher cardiopulmonary scores.
The correlation between SySQ and Skindex-17 scores was
low-moderate, indicating that the instruments indeed measure related but distinct constructs.
Conclusion. The Italian version of the SySQ may provide an
additional tool for dermatologists, both in the research and
clinical setting. Furthermore, its use may be extended to the
medical as well as to the nursing clinical practice. Results
from SySQ can be very useful for dermatological nursingcare for the implementation of educational plans targeted to
patients, with the objective of enabling the patients to selfmanage the disability of this severe chronic condition also
outside of the strictly clinical setting.
Key words: Scleroderma, systemic - Connective tissue diseases - Disability evaluation - Quality of life.
T
he connective tissue diseases (CTD) constitute a
group of chronic, inflammatory, immuno-mediated diseases which cause extensive tissue damage
with frequent involvement of internal organs, and in
particular of the respiratory system. Rheumatoid arCorresponding author: D. Abeni, MD, MPH, Health Services Research Unit, IDI-IRCCS, via dei Monti di Creta 104, I-00167 Rome,
Italy. E-mail: [email protected]; [email protected]
Vol. 149 - No. 5
1Health Services Research Unit,
IDI‑IRCCS, Rome, Italy
e di Studi Sanitari
Padre Luigi Monti, Rome, Italy
2Centro di Formazione
thritis (RA), systemic sclerosis (SSc), polymyositis
(PM), dermatomyositis (DM), Sjogren’s Syndrome,
and systemic lupus erythematosus (SLE) are among
the most significant connective tissue diseases seen
in the clinical units of dermatological institutes.
Systemic sclerosis is a multisystem disorder which
affects the connective tissue and results in a generalized thickening of the skin, internal organ involvement, weakening of microcirculation, and of musculoskeletal tissue.1 Symptoms may vary greatly,
depending on the degree of involvement of the skin
and of the other affected organs.2
Like many chronic conditions that impose a lifelong presence and concern to the patients, SSc, as
well as other CTD, is associated with depression, a
worsening of the quality of life (QoL) 3, 4 and physical disabilities.3, 5, 6
In the recent past, disability among patients with
SSc has been assessed using the Health Assessment
Questionnaire (HAQ),7 which is not exhaustive, and
sufficiently specific when measuring functional limitation in people affected by connective tissue disorders.8
Therefore, there is a need for a tool to comprehensively measure the level of physical disability
for patients affected by SSc, both in discriminative
terms (i.e., in order to distinguish cross-sectional
differences between patients with different levels of
539
URAS
Systemic sclerosis questionnaire
disability) and evaluative terms (i.e., to measure the
change in physical disability during the course of the
illness as the disease progresses and as it modifies
due to on going treatment).
Such a tool could be useful both in the clinical routine as well as in the clinical research setting, since it
could be utilized for the screening and identification
of the specific areas on which to focus the diagnostic
investigations and then the specific therapeutic interventions, monitoring both the progression of the
condition and the possible effect of treatment.
Furthermore, tools of this kind could be useful for
dermatological nursing purposes, as they would allow to identify specific issues of care, due to physical disability, so that it would be possible to propose
interventions to improve the patients’ well-being and
also to increase patients’ ability for self-care.
In our study we use the Italian version of a questionnaire designed to measure disability among patients with SSc, the Systemic Sclerosis Questionnaire (SySQ),8 with the joint objective to evaluate
and compare the disability level among women with
SSc or other CTD.
Materials and methods
This study is part of a larger project to evaluate the
degree of disability among patients with CTD and
to test educational activities aimed at reducing, or
slowing down, the progression of such disabilities.
The study protocol was approved by the Institutional Ethical Committee of IDI-IRCCS.
Study population
During the period March-May 2013 we consecutively enrolled in this study 115 patients with SSc
(ICD-9-CM code 710.1), and 35 with other connective tissue diseases (ICD-9-CM codes 710.0 and
710.2 through 710.9). This latter group was composed of systemic lupus erythematosus (SLE), dermatomyositis, and undifferentiated connectivitis,
who were hospitalized either in the dermatological
wards or were seen in the outpatient or the day-hospital clinics of IDI-IRCCS in Rome, Italy, were invited to participate in this study.
Inclusion criteria were: a diagnosis of connective
tissue disease according to the criteria of the American College of Rheumatology, ability to read and to
540
understand the Italian language, 18 years of age or
older, signing the written informed consent form.
Gender was not an inclusion/exclusion criterion;
however, during the study period, only two males
had been seen who had agreed to participate in the
study, so that the decision was made to limit the
study to women.
Data collection
Socio-demographic characteristics (i.e., age, education, and marital status) were self-reported by the
patients. Organ involvement and duration of disease
were also self-reported, and were then cross-validated by nurses who abstracted information from the
clinical records.
Questionnaires
The SySQ is a self-administered questionnaire that
evaluates several aspects of the patients’ experience
with the disease: functional disability, organ involvement, and general conditions.8
It is composed of 32 items, each scored 0-3, with
a possible total score ranging from 0 to 96. However,
the original paper as well as a preliminary analysis
on the psychometric properties of the Italian version,
indicates that the more meaningful scores are those
of the four main categories of the questionnaire:
general symptoms, musculoskeletal symptoms, cardiopulmonary symptoms, and upper gastrointestinal
symptoms.8
The score for each category is obtained by summing the scores for all items pertaining to the same
category. Higher values indicate worse disability.
The Italian version of the SySQ is reproduced in
Appendix 1.
We also used a dermatology-specific questionnaire, to better describe the burden of disease deriving from skin involvement, and to study the relationship between the disease-specific and this
specialty-specific instrument.
The Skindex-17 9 is a dermatology-specific healthrelated QoL instrument that was derived from the
Skindex-29 10 using Rash analysis. It consists of 17
items, and the answers are given on a three-point
scale. The answers options are: never, rarely/sometimes, often/always. The answers are scored on
two scales, one for the symptoms and the other for
the psychosocial domain. The scores of each scale
October 2014
can be also categorized, with cut-offs at 50 for the
symptoms (i.e., thus subdividing the scale in “mildmoderate” vs. “severe” impact) and 21 and 38 for the
psychosocial scale (i.e., thus subdividing the scale
in “mild”, “moderate”, and “severe” impact). Higher
values indicate worse QoL on both scales.
The evaluation of the clinical severity of the disease was assessed using the Physician Global Assessment (PGA). It consists of a 5-point scale about
diseases severity, with scores ranging from 0 to 4,
corresponding to very mild, mild, moderate, severe,
very severe.11 Due to the scarce numerosity in each
of the five classes the PGA was dichotomized into
“mild-moderate” and “severe”.
Translation of the SySQ
The Italian translation of the SySQ was conducted from the original German version using also the
English version provided by the authors in the original paper.8 The translation/adaptation process was
conducted according to the guidelines for the process of cross-cultural adaptation of patient-reported
outcomes.12, 13
Statistical analysis
Descriptive analyses were conducted with standard statistical methods and tests, using the STATA
statistical package, Release #9. For the categorization of the symptoms and psychosocial scales of the
Skindex-17 we utilized the cut-offs published in the
original validation paper. For the single-item analysis of the SySQ we dichotomized each item, separating the “lower impairment levels” (i.e., answers
coded as “0” and “1”) from the “higher impairment
levels” (i.e., answers coded as “2” and “3”).
Results
We collected data on 150 patients, 115 with SSc
e 35 with CTD. This latter group was composed of
SLE (3 patients), dermatomyositis (3), and undifferentiated connectivitis (29). The patients, as specified
in the Methods section, were all females. The age
range was 23-83 years, with a mean age of 58 years
(standard deviation [SD] 1.4 years). The mean duration of the disease was 8.6 years (SD, 0.63 years).
Table I summarizes the main characteristics of the
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study population, also showing separately the characteristics of the two diagnostic groups under study.
Overall, it is interesting to note that while the dermatologists classified as severe or very severe only
17.9% of all patients, we observed only 16% of the
study population without internal organ involvement,
and approximately 50% of the women were in the
“Severe” category of both scales of the Skindex-17.
As for the general socio-demographic characteristics, only few differences were observed between the
women with SSc and those with other CTD: SSc patients were more likely to have a lower educational
level (P value=0.042), and they had a longer disease
duration (P value=0.045). A slight difference was
observed in the clinical disease severity, as assessed
by the physician: 20.3% of patients with SSc were
classified as severe, compared to only 9.4% of the
women with other CTD. However such difference
did not reach statistical significance, due to the small
number of patients with CTD.
In Table II we provide a comparison between patients with SSc or CTD, for all the levels of all the
variables of interest, summarizing the mean values
of the General Symptoms category of the SySQ and
of the Symptoms scale of the Skindex-17 questionnaire. In general, average scores, both for the SySQ
and the Skindex-17, tend to be higher among women
with SSc compared to those with CTD, although
very seldom such differences reach, or even come
close to, a statistically significant level.
For the SySQ it is interesting to note that the levels
of impairment are higher for women with internal
organ involvement, and that the scores are progressively higher with the number of organ-systems involved. Also of interest, is that practically no differences are seen – for both women with SSc or CTD
– according to the dermatologist’s evaluation of the
clinical severity.
We also looked at the psychosocial scale of the
Skindex-17, and here we noticed the same pattern
with a few notable exceptions: among patients with a
disease duration >10 years the impairment was much
higher among women with CTD (70.8 vs. 38.9 for
women with SSc), and this was also true for women
without comorbidities (53.1 for CTD patients vs.
27.7 for SSc patients).
In Table III we summarize the mean scores and the
95% confidence intervals for the Categorical Scales
and all the Subscales of the SySQ, to compare such
scores between SSc and CTD patients. Also when
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Table I.—Patient’s characteristics: complete sample, and patients with systemic sclerosis (SSc) or other connective tissue diseases
(CTD).
Overall
N. 150
Variables
Age (years)
<50
50-64
65+
Education
Elementary
Middle or high school
College or higher
Marital status
Single
Married
Separate/widow
Duration of illness
<3 years
3-9 years
10+
Number of organ-systems involved
0
1
2
3
Organ involvement
Cardiorespiratory No
Yes
Gastrointestinal No
Gastrointestinal Yes
Musculoskeletal No
Musculoskeletal Yes
Skindex-17 symptoms
Mild-moderate
Severe
Skindex-17 psychosocial
Mild
Moderate
Severe
Physician Global Assessment
Milde-moderate
Severe
SSc
N. 115
CTD
N. 35
P value
N.
%
N.
%
N.
%
44
52
54
29.3
34.7
36.0
31
39
45
27.0
34.0
39.0
13
13
9
37.1
37.1
25.8
0.306
35
49
64
23.7
33.1
43.2
31
32
50
27.4
28.3
44.3
4
17
14
11.4
48.6
40.0
0.042
23
75
50
15.5
50.7
33.8
17
61
35
15.0
54.0
31.0
6
14
15
17.1
40.0
42.9
0.329
48
57
41
32.9
39.0
28.1
38
38
36
33.9
33.9
32.2
10
19
5
29.4
55.9
14.7
0.045
24
35
56
35
16.0
23.3
37.3
23.4
19
25
46
25
16.5
21.7
40.0
21.8
5
10
10
10
14.2
28.6
28.6
28.6
0.553
59
91
89
61
50
100
39.3
60.7
59.3
40.7
33.3
66.7
45
70
67
48
41
74
39.1
60.9
58.3
41.7
35.7
64.3
14
21
22
13
9
26
40.0
60.0
62.9
37.1
25.7
74.3
0.927
70
64
52.2
47.8
53
51
51.0
49.0
17
13
56.7
43.3
0.582
33
36
65
24.6
26.9
48.5
25
28
51
24.0
26.9
49.1
8
8
14
26.7
26.7
46.6
0.955
119
26
82.1
17.9
90
23
79.7
20.3
29
3
90.6
9.4
0.153
0.628
0.275
Totals may vary because of missing values
considering these summary scores, women with SSc
have in general a slightly greater level of impairment
than women with the other CTD. Such differences
are more evident in the General Symptoms Category, but they also relevant for the Musculoskeletal
542
Category and for the Eating subscale. The only exception, although without scales reaching statistical
significance, is that women with CTD tend to have
higher scores in the Cardiopulmonary Category as
well as in the two Subscales of this category (i.e.,
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Table II.—Mean values of the General Symptoms scale of the SySQ and of the Skindex-17 Symptoms scale: comparison between
scores of patients with SSc and patients with other CTD.
SySQ
General Symptoms
Variables
Overall
Age (years)
<50
50-64
65+
Education
Elementary
Middle or high school
College or higher
Marital status
Single
Married
Separate/widow
Duration of illness
<3 years
3-9 years
10+
Number of organ-systems involved
0
1
2
3
Organ involvement
Cardiorespiratory No
Cardiorespiratory Yes
Gastrointestinal No
Gastrointestinal Yes
Musculoskeletal No
Musculoskeletal Yes
Physician Global Assessment
Milde-moderate
Severe
SSc
N.=115
CTD
N.=35
Mean
Mean
1.43
1.25
1.89
1.48
1.42
SSc
N.=115
CTD
N.=35
Mean
Mean
0.130
43.9
41.3
0.620
1.22
1.30
1.24
0.460
0.427
0.539
42.5
49.1
39.9
43.0
44.4
34.7
0.956
0.586
0.576
1.61
1.76
1.10
0.07
1.30
1.36
0.049
0.025
0.205
39.1
52.2
41.8
35.0
42.3
41.7
0.808
0.219
0.993
1.01
1.47
1.53
0.81
1.14
1.62
0.509
0.158
0.672
36.2
42.9
50.5
31.7
52.8
38.7
0.732
0.235
0.170
1.34
1.45
1.55
1.48
1.06
1.55
0.620
0.072
0.993
49.6
43.1
36.6
37.8
37.8
58.8
0.207
0.464
0.122
1.30
1.20
1.46
1.72
1.08
1.15
1.37
1.32
0.591
0.855
0.741
0.129
30.7
43.0
47.6
46.8
52.5
30.0
47.8
40.0
0.109
0.188
0.982
0.494
1.29
1.53
1.36
1.55
1.27
1.52
1.11
1.35
1.18
1.38
1.28
1.24
0.423
0.339
0.318
0.504
0.988
0.089
39.3
46.8
43.3
44.7
36.0
47.7
36.4
44.2
41.7
41.7
50.0
38.2
0.732
0.698
0.754
0.696
0.124
0.125
1.45
1.44
1.28
1.21
0.306
0.569
41.4
53.2
44.8
16.7
0.549
0.022
Shortness of breath and Upper airway involvement).
In Figure 1 an example of single-item analysis is
shown, regarding the General Symptoms Category.
Each bar represents the percentage of women, in the
two disease groups, who have reported for that question a higher impairment level, i.e., have answered
with a score of either “2” or “3”. The questions about
the extremities, and in particular those regarding the
hands, are the ones that show a greater proportion of
“higher impairment”. This proportion is almost in-
Vol. 149 - No. 5
Skindex-17
Symptoms
P value
P value
variably more substantial for women with SSc compared to those with CTD.
In Figure 2 we use the same approach to illustrate
the results about selected items from the three other
main Categories of the SySQ. In this case, the proportion of women with higher impairment is overall
lower, but the differences are sharper for the items
of the Musculoskeletal and Upper Gastrointestinal
categories, with a higher impairment for the women
with SSc. Also of note, is the confirmation that for
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Table III.—Mean scores, and 95% confidence intervals, for the categorical scales and the 12 subscales of the SySQ: comparison
between scores of patients with SSc and patients with other CTD.
Categorical scales
SSc N.=115
CTD N.=35
Subscales
Mean
CI 95%
Mean
CI 95%
General symptoms
1.43
1.30 -1.60
1.25
1.00-1.50
Pain
1.45
1.29-1.61
1.43
1.15-1.70
Stiffness
1.15
1.01-1.30
1.01
0.72-1.29
Coldness
1.61
1.44-1.78
1.37
1.08-1.67
Musculoskeletal symptoms
0.80
0.68-0.92
0.73
0.52-0.93
Complex function
0.79
0.65-0.93
0.57
0.33-0.81
Strength of hands
0.93
0.80-1.06
0.92
0.69-1.15
Rising
0.56
0.43-0.69
0.52
0.29-0.77
Walking
0.68-1.23
0.79
0.66-0.93
0.73
Cardiopulmonary symptoms
0.75
0.64-0.85
0.81
0.6 -0.99
Shortness of breath
0.88
0.75-1.01
0.91
0.72-1.11
Upper airway
0.59
0.49-0.70
0.70
0.49-0.91
Upper gastrointestinal symptoms
0.78
0.66-0.89
0.71
0.48-0.95
Eating
0.94
0.80-1.10
0.78
0.51-1.06
Swallowing
0.51
0.39-0.63
0.60
0.34-0.86
Heartburn/regurgitation
0.88
0.74-1.02
0.86
0.57-1.15
1) Painful hands
2) Painful fingers when touching or holding
objects
3) Stiffness of hands
4) Stiffness of arms
CTD
5) Stiffness of legs
SSc
6) Coldness of hands
7) Painful hands if they are cold
8) Painful feet if they are cold
0
20
40
60
80
%
Figure 1.—Single-item analysis for the General Symptoms category of the SySQ: proportion of patients scoring “2” or “3”, separately
for patients with SSc or CTD.
544
October 2014
URAS
9) Ability to cut meat w ith a knife
10) Ability to w ash and dry oneself
11) Ability to put on socks
12) Ability to cream oneʼs ow n body
CTD
21) Shortness of breath w hen climbing stairs
SSc
23) Coughing
26) Ability to eat an apple
27) Ability to eat large pieces of food w ithout cutting
them up
28) Difficulty w ith sw allow ing
0
10
20
30
40
50
%
Figure 2.—Single-item analysis for selected items of musculoskeletal, cardiopulmonary, and upper gastrointestinal categories of the
SySQ: proportion of patients scoring “2” or “3”, separately for patients with SSc or CTD.
the Cardiopulmonary category the women with CTD
have a greater proportion of “higher impairment”.
The Italian version of the questionnaire, with the
complete list of items and the appropriate response
modality, is shown in Appendix 1. The solid horizontal lines separate the four main Categories; the dotted lines separate the twelve subscales. The sequence
of the subscales is in the same order as they are listed
in Table III.
Discussion
In our study we have shown the feasibility to use in
a clinical setting a specific instrument for the standardized measurement of disability among women
with SSc or other CTD. The SySQ provides a quantitative assessment of important issues in these diseases, and allows a comprehensive evaluation at the
level of the main categories of involvement (such as
Vol. 149 - No. 5
the General Symptoms, the Musculoskeletal, Cardiopulmonary, and Upper gastrointestinal systems),
but also may give detailed insight when the subscales
and the single items are analyzed.
Our cross-sectional survey indicates that disability and quality of life impairment are very common
in dermatological patients with SSc and CTD. Our
results are in accordance with previous reports,
where in particular the general and musculoskeletal
symptoms 3 were found to have the higher impact
on the disability, specially among women with SSc.
Such impairment, for instance coldness and pain in
the hands, has a direct impact daily activities such
as cutting food, getting dressed, wash and dry onself, etc. In turn, disability has an effect on quality of
life, and in a very general way we notice that higher
levels of disability on the SySQ may correspond to
higher scores on the Skindex-17.
However, while such correlation exists, it is of a
low-to-moderate level, usually in the 0.3-0.4 range
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for the correlation coefficients, indicating that the
two instruments are indeed measuring different constructs, and that the skin manifestations – as measured by the Symptoms scale of the Skindex-17 – may
only be a component of the wider problems encountered by the patients.
In fact, we should also consider that the Skindex-17 is intended to measure the skin-related QoL
of patients, whereas the SySQ is oriented to assess
the level of physical disability and limitation. Moreover, the Skindex-17 is a specialty-specific instrument, targeted to patients with any dermatological
disease, whereas the SySQ is a questionnaire specifically designed for patients with scleroderma. In
the light of such results and considerations, it would
seem advisable to use both instruments to achieve a
really comprehensive description of the experience
of each patient in their illness.
The acceptability of the Italian version of SySQ
confirms, as it was true for the original study of
Rouf et al.,8 that it is a good tool in assessing the
level of disability in patients with systemic sclerosis, but also for patients with other connective tissue conditions. The Italian version of the SySQ did
not show substantial differences between patients
in the two clinical diagnostic groups of scleroderma or CTD. In fact, scores in each of the variables
we considered were comparable for the SSc and
the CDT. However, when looking at the subscales,
differences emerged, specially for the categories of
the General and of the Musculoskeletal symptoms,
for which there seems to be a worse disability in
patients with scleroderma. This finding could be
explained by the fact that the General Symptoms
category includes items assessing pain, stiffness,
and coldness of extremities, and that these characteristics are more extremely pronounced in patients
with scleroderma. This supports also the construct
validity of the SySQ.
Interestingly, patients with systemic sclerosis
were classified as having a higher clinical severity, according to the PGA, and the scores are significantly higher for the Skindex-17, but not for the
SySQ: this could be due to the fact that the clinicians assessing the global situation of the patients
were dermatologists, so that their evaluation might
have been somewhat driven by the level of skin involvement – and this would be reflected, as noted
above, by the two different natures of the SySQ and
the Skindex-17. Furthermore, when looking at the
546
PGA of women with SSc, again there is little difference in SySQ scores between patients with “mildmoderate” or “severe” clinical severity, while the
difference is more marked in the Skindex-17 symptoms score for these two groups. This observation
is also in line with the previous reports of a certain
level of discrepancy between the way clinicians and
patients evaluate the actual impact of skin diseases
on patients.14
Finally, it is interesting to note that the Skindex-17
scores in this sample are quite similar to those previously reported by our group,15, 16 confirming the
measurements obtained from this instrument are
quite stable even when different groups of patients,
enrolled in different clinical settings (e.g., outpatients vs. inpatients) and in different time-periods,
are considered.
Conclusions
The Italian Version of the SySQ may provide an
additional tool for dermatologists, both in the research and clinical setting. As stated in a recent
editorial,17 accurate and comprehensive measures
of clinical phenomena provide dermatologists and
nurses with tools that should help them improve the
quality of their care. The SySQ could be used for
an initial assessment of the patient and for the follow up, in clinical studies or during the treatment of
the SSc. In both cases it will allow the evaluation
and the monitoring of the patients’ disability and the
possible influence of treatment and general care on
the progression of the disease. Results from SySQ
could also be useful for dermatological nursing-care
in guiding the implementation of educational plans
targeted to patients, with the objective of enabling
the patients to self-manage the disability of this severe chronic condition also outside of the strictly
clinical setting.
References
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TA Jr et al. Scleroderma (systemic sclerosis): classification, subsets
and pathogenesis. J Rheumatol 1988;15:202-5.
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sclerosis identifies CD247 as a new susceptibility locus. Nat Genet
2011;42:426-9.
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3. Müller H, Rehberger P, Günther C, J Schmitt. Determinants of disability, quality of life and depression in dermatological patients with
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4. Hudson M, Thombs B, Steele R, Panopalis P, Newton E, Baron M.
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(HAQ) to determine physical disability in systemic sclerosis. Arthritis Care Res 1991;4:27-31.
6. Lawrence E, Pope J, Al Zahraly Z Lalani S, Baron M. The relationship between changes in self-reported disability (measured by the
Health Assessment Questionnaire, HAQ) in scleroderma and improvement of disease status in clinical practice. Clin Exp Rheumatol
2009;3:32-7.
7. Steen VD, Medsger TA Jr. The value of the Health Assessment
Questionnaire and special patient-generated scales to demonstrate
change in systemic sclerosis patients over time. Arthritis Rheum
1997;40:1984-91.
8. Ruof J, Brühlmann P, Michel BA, Stucki G. Development and
validation of a self-administered systemic sclerosis questionnaire
(SySQ). Rheumatology 1999;38:535-42.
9. Nijsten TE, Sampogna F, Chren MM Abeni D. Testing and reducing skindex-29 using Rasch analysis: Skindex-17. J Invest Dermatol
2006;126:1244-50.
10. Abeni D, Picardi A, Pasquini P, Melchi CF, Chren MM. Further evidence of the validity and reliability of the Skindex-29: an
Italian study on 2,242 dermatological outpatients. Dermatology
2002;204:43-9.
11. Sampogna F, Picardi A, Chren MM, Melchi CF, Pasquini P, Masini
C et al. Association between poorer quality of life and psychiatric
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morbidity in patients with different dermatological condition. Psycosom Med 2004;66:620-4.
Guillemin F, Bombardier C, Beaton D. Cross-cultural adaptation
of health-related quality of life measures: literature review and proposed guidelines. J Clin Epidemiol 1993;46:1417-32.
13. Beaton DE, Bombardier C, Guillemin F Ferraz MB. Guidelines
for the process of cross-cultural adaptation of self-report measures.
Spine (Phila Pa 1976) 2000;15:3186-91.
14. Sampogna F, Picardi A, Melchi CF, Pasquini P, Abeni D. The impact of skin diseases on patients: comparing dermatologists’ opinions with research data collected on their patients. Br J Dermatol
2003;148:989-95.
15. Sampogna F, Tabolli S, Abeni D. Impact of different skin conditions
on quality of life. G Ital Dermatol Venereol 2013;148:255-61.
16. Sampogna F, Spagnoli A, Di Pietro C, Pagliarello C, Paradisi
A, Tabolli S et al. Field performance of the Skindex-17 quality
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2013;133:104-9.
17. Abeni D, Sampogna F. Why measure quality of life in dermatology?
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12.
Funding.—The study was financially supported by the “Progetto
Ricerca Corrente 2013” of the Italian Ministry of Health, Rome, Italy;
and by the “Centro di Eccellenza per la Cultura e la Ricerca Infermieristica” (CECRI), Rome, Italy.
in the manuscript.
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Appendice 1
QUESTIONARIO SULLA SCLEROSI SISTEMICA
Questo questionario ha lo scopo di misurare quanto la sua malattia l’abbia condizionata nel corso dell’ULTIMA SETTIMANA. Per favore scelga con una crocetta una sola risposta a ogni domanda.
Modalità di
risposta
Items
1.
2.
3.
4.
5.
Con che frequenza ha sentito dolore alle mani nell’ultima settimana?
Nell’ultima settimana, quanto le facevano male le dita delle mani quando toccava o stringeva un oggetto?
Nell’ultima settimana, quanto erano rigide le sue braccia?
Nell’ultima settimana, quanto erano rigide le sue gambe?
Con che frequenza ha sentito freddo alle mani nell’ultima settimana?
A
B
B
B
A
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
Nell’ultima settimana, se aveva le mani fredde, quanto le facevano male le mani?
Nell’ultima settimana, se aveva i piedi freddi, quanto le facevano male i piedi?
Nell’ultima settimana, riusciva a tagliare la carne con il coltello?
Nell’ultima settimana, è stato/a in grado di lavarsi e di asciugarsi da solo/a?
Nell’ultima settimana, è stato/a in grado di mettersi le calze da solo/a?
Nell’ultima settimana, è stato/a in grado di spalmarsi sulla pelle le creme (e/o le pomate) da solo/a?
Nell’ultima settimana, è stato/a in grado di aprire e chiudere i rubinetti dell’acqua?
Con che frequenza ha sentito debolezza alle mani quando prendeva in mano un oggetto nell’ultima settimana?
Con che frequenza le sono caduti di mano degli oggetti nell’ultima settimana?
Nell’ultima settimana, è stato/a in grado di alzarsi da una sedia senza braccioli?
Nell’ultima settimana, è stato/a in grado di sdraiarsi e alzarsi dal letto da solo/a?
Nell’ultima settimana, è stato/a in grado di camminare su un percorso in pianura?
Nell’ultima settimana, è stato/a in grado di fare le scale a piedi?
Nell’ultima settimana, le mancava il fiato quando camminava per strada?
Nell’ultima settimana, le mancava il fiato quando faceva le scale a piedi?
Nell’ultima settimana, le mancava il fiato quando si vestiva?
Quanto ha tossito nell’ultima settimana?
Quanto ha espettorato nell’ultima settimana?
Nell’ultima settimana, si sentiva incapace di far entrare aria nei polmoni?
Nell’ultima settimana, è (o sarebbe) stato/a in grado di mangiare una mela?
Nell’ultima settimana è (o sarebbe) stato/a in grado di mangiare bocconi di cibo abbastanza grandi?
Nell’ultima settimana ha provato difficoltà a “mandare giù” il cibo?
Nell’ultima settimana ha provato dolore quando “mandava giù” il cibo?
Nell’ultima settimana, quando “mandava giù” il cibo, le si fermava in gola?
Nell’ultima settimana, ha sentito bruciore alla bocca dello stomaco?
Nell’ultima settimana, ha avuto rigurgiti?
B
B
C
C
C
C
C
A
A
C
C
C
B
B
B
B
B
B
C
C
A
A
A
A
A
A
Modalità di risposta- A
0
1
2
3
Mai
A volte
Spesso
Sempre
Modalità di risposta- B
0
1
2
3
Per nulla
Poco
Molto
Moltissimo
Modalità di risposta- C
548
0
1
2
3
Senza difficoltà
Con poca difficoltà
Con molta difficoltà
Non in grado di farlo
October 2014

A. PARODI, E. COZZANI
Cutaneous involvement in case of lupus erythematosus (LE)
is very frequent and can present both specific or non-specific
manifestations. LE specific lesions can be classified in acute,
subacute and chronic cutaneous LE lesions. All of them can
be localized and generalized. The LE non specific lesions
are not exclusive to LE disease but are often seen in patients
with active systemic LE. All the cutaneous lesions are often
induced or aggravated by ultraviolet light, in fact they are
usually localized in sun-exposed areas. Acute cutaneous LE
is associated with systemic disease, subacute cutaneous LE
has been considered a subset of its own since 1979 when it
was first described, chronic cutaneous LE is the most common subtype of LE. Although less frequently also the chronic
cutaneous lesions can be an aspect of systemic LE (25%).
Key words: Lupus erythematosus, cutaneous - Skin diseases Autoimmune diseases.
L
upus erythematosus (LE) is a chronic autoimmune disease characterized by cutaneous and
systemic symptoms. According to Gilliam and
Sontheimer 1 cutaneous lesions can be divided into
two groups: LE-specific and LE-non specific lesions.
LE-specific skin manifestations have a typical histopathological picture with interface changes. LEspecific lesions can be subdivided into acute cutaneous LE (ACLE), subacute CLE (SCLE) and chronic
CLE (CCLE) where discoid LE is the most common
form. Among CCLE, lupus erythematosus tumidus
(LET) has been described, even though some authors
include LET as a separate subgroup called intermittent subtype of CLE (ICLE).2 The LE-non specific
Corresponding author: A. Parodi, Di.S.Sal., Section of Dermatology,
University of Genoa, IRCCS AOU San Martino-IST Genova, largo Rosanna Benzi 10, 16132 Genoa, Italy. E-mail: [email protected]
Vol. 147 - No. 5
Di.S.Sal., Section of Dermatology
University of Genoa
IRCCS AOU San Martino-IST Genova, Genoa, Italy
lesions are not exclusive of LE and include a wide
range of symptoms with different histopathological
findings.
Chronic LE
Discoid LE is the most common form of chronic
LE (CLE). The lesions are erythematous maculae
or plaques with a hyperkeratotic surface (Figure 1).
These plaques grow peripherically into larger plaques
that heal with atrophic scars and pigmentary changes
in particular of the external edges. Often keratin accumulates in the hair follicle and when peeled back, a
keratotic spike can be seen protruding from the under
surface of the scale (carpet-tack sign).3 The lesions are
localized above the neck in 60-80% of cases (localized DLE, L-DLE) and below the neck in 20-40% of
cases (disseminated DLE, D-DLE), usually on the
trunk. Mucosal discoid lesions are also frequent 25%.
They are asymptomatic and are characterized by a
violaceous erythema with white striae 4 (Figure 2).
Also the lower lip can be involved with erythema and
striae. Mutilations with tissue loss can be seen especially when the lesions affect the ears and the tip of
the nose 5 (Figure 3). In some patients the keratotic aspect is very important (verrucous DLE) or the lesions
appear nodular (hypertrophic DLE). Very rarely some
549
PARODI
Figure 2.—Discoid lesions in the mouth.
Figure 1.‑—Discoid lesions.
Figure 3.—Scars and comedonic lesions.
comedo-like lesions can be present on the discoid skin
manifestations (lupus comedonicus) (Figure 3). When
the lesions are localized on the scalp on hairly areas a
cicatricial alopecia develops (Figure 4). The 70-80% of
patients suffer from photosensitivity.6, 7 A recent study
has shown that 17% of DLE patients receive a diagnosis of systemic LE (SLE) during the following three
years from the development of cutaneous lesions.8
Lupus erythematosus tumidus (LET) is characterized by erythematous-edematous skin manifestations
without hyperkeratosis and atrophic scars. The lesions
most commonly involve the face and 80% and more of
the patients suffer from photosensitivity 9 (Figure 5).
Lupus profundus is a panniculitis where the in-
550
Figure 4.—Scarring alopecia.
flammation is primarily located in the lower dermis
and subcutaneous tissue. The UV exposure seems to
be of minor importance in this subset. The lesions
are subcutaneous nodules which develop chronic
deep scars 10, 11 (Figure 6).
Subacute cutaneous LE
12
It was described by Gilliam and Sontheimer
and has been considered as a subset of its own
October 2014
PARODI
Figure 5.—Lupus tumidus.
since 1979. This form is more common in Caucasian, the majority of patients (90%) is photosensitive and the lesions are located on the upper back,
shoulders, dorsal part of the arms; less frequently
face and scalp are involved. Two groups of lesions
are described: a psoriasiform and an annular form. In
the psoriasiform form, papulosquamous lesions resembling psoriasis are present (Figure 7), in the annular form, erythematous plaques or papules which
become widespread annular and polycyclic clearing centrally are seen (Figure 8). The combination
of these two forms is possible.11-14 SCLE is strongly
associated with the anti-Ro/SSA antibodies.15 About
20% of SCLE patients present other types of CLE
lesions and about 50% fulfill the American College
of Rheumatology criteria for SLE. About 1/3 of all
SCLE cases, particularly those diagnosed in older
ages, can be attributed to previous drug exposure 16
(non-steroidal anti-inflammatory drugs, angiotensinconverting enzyme inhibitors, anti epileptic, terbinafine, TNF-α inhibitors and diuretics).
Figure 6.—Lupus profundus.
Acute CLE
It is usually associated with systemic disease. The
most common lesion is malar rash or butterfly erythema. It is a typical localized lesion with erythema
and edema over the malar eminence and the nose with
a tendency to spare the naso-labial folds (Figure 9).
Postinflammatory hyperpigmentation can occur, on
the contrary, scars never develop. An exanthematic
Vol. 147 - No. 5
Figure 7.—Psoriasiform lesions of SCLE.
generalized form of acute CLE can occur and is localized on the trunk. All the lesions are usually associated with a previous sun exposure.17 Typically, patients
551
PARODI
Figure 9.—Malar rash.
Figure 8.—Annular lesions of SCLE.
are critically ill due to SLE and present underlying
manifestations in various organs, as well as high titers of antinuclear antibodies, frequently anti-dsDNA
antibodies. Mucosal involvement is usual. Most often
the buccal mucosa is involved with erosions of the
lower lip and palatal mucosa, clinically different from
the lichenoid aspect of DLE. Hair loss is one of the
most common cutaneous signs of SLE. Alopecia can
be the presenting manifestation of SLE and may affect
the scalp, eyebrows, eyelashes, beard and body hair.
Sometimes it can occur or be aggravated because of
the medications used to treat lupus. Acute lupus alopecia is usually non scarring and it is characterized
by diffuse hair loss or by sparse thin hairs (lupus hair)
with clusters of newly regrown hairs.18
LE non-specific lesions
Figure 10.—Papular mucinosis.
552
They are diagnosed in about 45-50% of the LE
patients, in particular in SLE patients. The most fre-
October 2014
PARODI
and arms, but the face and other areas of the body
may also be affected 20 (Figure 10). Bullous SLE is
a subepidermal blistering disorder that primarily affects young women. This form responds dramatically to Dapsone. The lesions are widespread vesicobullous lesions that heal without scarring. Mucosal
involvement is relatively common. Histologycally it
is characterized by subepidermal blisters with neutrophilic infiltrate in the dermal papillae (Figure 11).
The basement membrane split is located below the
lamina densa and often anti type VII collagen (noncollagenous domain) antibodies but no antinuclear
antibodies are detected.21
Conclusions
LE is characterized by a wide range of cutaneous
lesions which occur in about 85% of the patients.
In SLE they represent the first sign of the disease
in about 30% of the patients. Cutaneous lesions are
important for providing information about the diagnosis and prognosis of the disease, in fact discoid
or tumidus LE lesions are usually associated with a
non-systemic disease, on the contrary malar rash, cutaneous mucinosis or vasculitis are an aspect of systemic lupus. However, any cutaneous lesions deserve
attention as lupus is, in some cases, a severe disease.
References
Figure 11.—Hystologycal aspect of bullous systemic lupus erythematosus resembling dermatitis herpetiformis.
quently reported are Raynaud’s phenomenon (30%)
and livedo reticularis (13%), which is usually present
in patients with antiphospholipid antibodies. Periungual telangiectasia and ulcers are found in about
6% of the patients. Vasculitis can appear as palpable
necrotic purpura or urticarial leukocytoclastic vasculitis especially in hypocomplementemic forms,
thrombophlebitis, anetoderma, erythema multiforme, rheumatic nodules, sclerodactyly, calcinosis
cutis, papulonodular mucinosis and bullous lesions
occurred in less than 2% of the patients.19 Papulonodular mucinosis is associated with increased glycosaminoglycan production by dermal fibroblasts.
It presents clinically as asymptomatic skin colored
papules and nodules that typically involve the trunk
Vol. 147 - No. 5
spectrum of lupus erythematosus. J Am Acad Dermatol 1981;4:4715.
2. Kuhn A, Bein D, Bonsmann G. The 100th anniversary of lupus erythematosus tumidus. Autoimmun Rev 2009;8:441-8.
3. Kuhn A. Cutaneous manifestations of lupus erythematosus. Handbook Syst Autoimmun Dis 2006;5:49-59.
4. Obermoser G, Sontheimer RD, Zelger B. Overview of common,
rare and atypical manifestations of cutaneous lupus erythematosus
and hystopathological correlates. Lupus 2010;19:1050-70.
5. Kuhn A, Lehmann P, Ruzicka T, editors. Cutaneous lupus erythematosus. Dusseldorf: Springer; 2005.
6. Cardinali C, Caproni M, Bernacchi E, Amato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosus. The Italian experience. Lupus 2000;9:417-23.
7. Obermoser G. Lupus erythematosus and the skin. A journey at time
perplexing, usually complex, often challenging and evermore exhilarating. Lupus 2010;19:1009-11.
8. Gronhagen CM, Fored CM, Granath F, Nyberg F. Cutaneous lupus
erythematosus and the association with systemic lupus erythematosus: A population based cohort of 1088 patients in Sweden. Br J
Dermatol 2011;164:1335-41.
9. Cozzani E, Christana K, Rongioletti F, Rebora A, Parodi A. Lupus
erythematosus tumidus: clinical, histopathological and serologi-
553
PARODI
cal aspects and therapy response of 21 patients. Eur J Dermatol
2010;20:797-801.
10. Martens PB, Moder KG, Ahmed I. Lupus panniculitis: clinical perspective from a case series. J Rheumatol 1999;26:68-72.
11. Callen JP. Cutaneous lupus erythematosus: A personal approach to
management. Australas J Dermatol 2006;47:13-27.
12. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus
erythematosus: A cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409-15.
13. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: Issues
in diagnosis and treatment. Am J Clin Dermatol 2009;10:365-81.
14. Rothfield N, Sontheimer RD, Bernstein M. Lupus erythematosus: Systemic and cutaneous manifestations. Clin Dermatol
2006;24:348-62.
15. McCauliffe DP. Cutaneous diseases in adults associated with antiRo/SS-A antibody production Lupus 1997;6:158-66.
16. Gronhagen CM, Fored CM, Linder M, Granath F, Nyberg F. Subacute cutaneous lupus erythematosus and its association to drugs:
554
a population-based matched case control study of 234 patients in
Sweden. Br J Dermatol 2012;167:296-305.
17.Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol 1996;135:355-62.
18. Nico MMS, Bologna SB, Lourenço SV. The lip in lupus erythematosus. Cl Exp Dermatol 2014;39:563-9.
19. Gronhagen CM, Gunnarsson I, Svenungsson E, NybergF. Cutaneous manifestations and serological findings in 260 patients with systemic lupus erythematosus. Lupus 2010;19:1187-94.
20. Rongioletti F, Parodi A, Rebora A. Papular and nodular mucinosis
as a sign of lupus erythematosus. Dermatologica 1990;180:221-3.
21. Ludgate MW, Greig DE. Bullous systemic lupus erythematosus responding to dapsone. Austral J Dermatol 2008;48:91-3.
in the manuscript.
Epub ahead of print on July 31, 2014.
October 2014

Hair disorders associated
with autoimmune connective tissue diseases
N. CASSANO 1, P. AMERIO 2, R. D’OVIDIO 3, G. A. VENA 1
Hair disorders are frequently observed in various systemic diseases, including autoimmune connective tissue
diseases (CTDs), with predilection of lupus erythematosus (LE), followed by dermatomyositis (DM) and scleroderma. Hair disorders in CTDs may manifest as various clinical patterns, such as telogen hair loss, diffuse
thinning or fragility of hair, and scarring alopecia. Less
common hair disorders include anagen effluvium, alopecia areata, and trichomegaly. Some drugs used to treat
CTDs may cause hair loss in a drug-related manner or
hyperthrichosis. In the assessment of common hair loss
patterns, such as telogen effluvium, the possible association with CTDs must be borne in mind and should not be
overlooked. Alopecia appears to be a significant sign in
the course of LE and especially systemic LE. In DM, the
involvement of the scalp is common, and is often characterized by a diffuse, violaceous, scaly, non-scarring and
symptomatic hair loss. Linear scleroderma en coup de
sabre is an uncommon localized form of morphea with involvement of the paramedian forehead and frontal scalp,
where it is associated with cicatricial alopecia. The most
important variant of scarring alopecia in the context of
CTDs is that associated with discoid lupus erythematosus
(DLE). In the diagnostic work-up of DLE-related cicatrical alopecia, histopathological and immunopathological
studies are useful, and a relevant role has been attributed
to dermatoscopy (trichoscopy) over the last years. Hair
loss has been reported in several other CTDs, including
mixed and undifferentiated CTDs, and primary Sjögren’s
syndrome, although it is likely to be underestimated in
such diseases.
Key words: Hair diseases - Alopecia - Lupus erythematosus,
cutaneous - Dermatomyositis - Scleroderma, diffuse - Connective tissue diseases.
Corresponding author: N. Cassano, Dermatology and Venereology
Private Practice, Bari and Barletta, via Fanelli, 206/16, 70125 Bari, Italy.
E-mail: [email protected]
Vol. 149 - No. 5
1Dermatology and Venereology Private Practice
Bari and Barletta, Italy
2Department of Dermatology
“G. D’Annunzio” University, Chieti, Italy
Associazione Italiana
Dermatologi Ambulatoriali (AIDA), Bari, Italy
3Trichology Group of
H
air disorders are frequently observed in numerous systemic pathological conditions, including
autoimmune diseases and connective tissue diseases
(CTDs), with predilection of lupus erythematosus
(LE), followed by dermatomyositis (DM) and scleroderma.1
Hair disorders in CTDs may manifest as various
clinical patterns, such as telogen hair loss, diffuse
thinning or fragility of hair, and the scarring alopecia associated with discoid lupus erythematosus
(DLE).2 Less common hair loss patterns in LE and
autoimmune systemic diseases encompass anagen
effluvium, alopecia areata, and other variants that
will be briefly discussed below.
Trichomegaly is instead a rare condition that has
been associated with various medical conditions,
and also systemic LE (SLE) and DM.3
Alopecia appears to be a significant sign in the
course of LE and especially SLE. Several studies
have been carried out in patients with SLE to assess
the frequency and characteristics of clinical signs
and only a part of these studies also examined alopecia among the manifestations. Unfortunately, the
clinical type of hair loss was rarely specified, and
most data refer to the prevalence of alopecia as a
whole, without distinction between scarring and
555
CASSANO
HAIR DISORDERS ASSOCIATED WITH AUTOIMMUNE CONNECTIVE TISSUE DISEASES
noncicatricial subtypes, apart from very few exceptions. In an international survey of SLE, malar rash
(40%), alopecia (24%), and oral ulcers (19%) were
the most frequent cutaneous signs.4 Skin lesions
found to be associated with a worse prognosis include photosensitivity, oral ulcers, Raynaud’s phenomenon, and alopecia.5 In a cohort of patients with
early undifferentiated CTDs, those who evolved to
SLE were more likely to have alopecia and discoid
lupus, along with other clinical and immunological criteria.6 In general, clinical studies in SLE patients have shown that alopecia is more frequent in
women.7, 8 In a Chinese study, adult-onset SLE male
patients, when compared with adult-onset females,
presented more frequently with discoid rash, but
less frequently with alopecia.9 A lower prevalence
of alopecia has been repeatedly confirmed in SLE
patients with late onset of the disease (beyond the
age of 50 years).10-12 In SLE, alopecia tends to be
less common in children than in adults.7, 13 A lower
frequency of alopecia was detected in patients with
subacute cutaneous LE compared to patients with
chronic cutaneous LE.14 However, alopecia has been
reported in several other CTDs, including mixed
and undifferentiated CTDs,6, 15,16 and primary Sjögren’s Syndrome.17 The prevalence of hair disorders
in such diseases is likely to be underestimated, also
considering the relative paucity of specific clinical
and epidemiological studies on this topic in CTDs
other than LE. For instance, considering our routine
experience, primary Sjögren’s syndrome can have an
association with telogen effluvium, especially in cases with extra-glandular manifestations, and less frequently with cicatricial alopecia secondary to lichen
plano-pilaris, but large studies are needed to test and
verify these hypotheses.
In this article, special attention will be focused
on the most important hair disorders associated to
CTDs, with a revision of general, clinical and diagnostic aspects, and with special emphasis on LE-related hair disorders. Cicatricial alopecia and telogen
effluvium will be discussed more in depth because
of their frequency and relevance. The diagnostic
methodology of hair loss consists of multiple steps,
depending on the clinical form, and may take into
account physical and dermatoscopic examination of
the scalp and hairs, the assessment of hair density,
the pull test, the wash test, the modified wash test,
and, in selected cases often represented by cicatricial
alopecia, scalp biopsy and histopathology.18, 19 In the
556
assessment of common hair loss patterns, such as telogen effluvium, the possible association with CTDs
must be borne in mind and should not be overlooked.
Scarring alopecia
Scarring alopecia or cicatricial alopecia is the result of the irreversible damage of hair follicles with
the obliteration of follicular orifices and progressive
replacement with fibrous tissue responsible for permanent hair loss. The degree of damage and fibrosis
of this disfiguring disease is variable among patients
according to the intensity of the offending process.
The most paradigmatic examples of cicatricial alopecia are represented by lichen plano-pilaris and discoid LE (DLE).
In certain systemic diseases, permanent destruction of hair follicles may be caused by blood supply abnormalities, direct compression, or release of
proinflammatory cytokines. These events may take
place, for example, in sarcoidosis, systemic amyloidosis, and scleroderma. Scarring alopecia has
infrequently been reported in DM.20, 21 The typical
DM-related hair loss is in fact non-cicatricial, but
it may overlap with the scarring alopecia of other
CTDs, particularly scleroderma and LE.22
Other mechanisms that potentially, even if rarely,
can lead to cicatricial damage and largely involve
patients with SLE are immunologically mediated
vasculitic lesions or microthrombotic vasculopathic
lesions triggered by procoagulant and/or hyperviscosity states associated with LE (antiphospholipid
antibody syndrome). Such lesions may be characterized by either a severe pandermal vasculitis with
thrombosis and cutaneous infarction, or luminal
thrombi occluding vessels in the reticular dermis or
subcutis with necrosis of the epidermis and dermis,
with a compensatory dilatation of superficial vessels.23 When the vasculitic or vasculopathic processes are limited, however, the resulting injury might
result in reversible and non-scarring hair loss.
Linear scleroderma “en coup de sabre” is an uncommon localized form of morphea with onset
typically in childhood or adolescence.24 It generally
presents as a dyschromic, atrophic, linear depression located on the paramedian forehead and frontal
scalp, where it is associated with cicatricial alopecia.
It can present with more than one lesion, typically
following Blaschko’s lines.20 It is not microscopical-
October 2014
ly distinguishable from other forms of scleroderma.
The histopathology of alopecia in linear morphea is
characterized by dense dermal sclerosis with marked
reduction in the number of follicular units and with
atrophy of eccrine and sebaceous glands. In earlier
lesions, an intense infiltration of lymphocytes and
plasma cells, extending deeply into the reticular dermis up to the subcutis and even to the fascia, has
been described, sometimes with a perineural distribution.25 On histopathology, the atrophic follicular
remnants in linear scleroderma were found to have
morphologic aspects similar to those observed in
chemotherapy-induced permanent alopecia but not
in alopecia secondary to morphea or other cicatricial
alopecias.26
Scarring alopecia associated with chronic cutaneous discoid lupus erythematosus
Cicatricial alopecia associated with DLE is reported as a LE-specific skin lesion in the Gilliam
classification,27, 28 as it shows LE-specific histologic
features. According to the provisional classification
for primary cicatricial alopecia created in 2001 by
the North American Hair Research Society,29 alopecia caused by DLE is included among the primary
acquired lymphocytic scarring alopecias and is considered to be the most common form in this group.
Cicatricial alopecia is a frequent complication of
DLE and is estimated to occur in at least one third
of patients with DLE, showing correlation with a
prolonged disease course.30, 31 Scalp may be the
only area affected in approximately 10% of DLE patients.23 Scalp DLE affects women more often than
men.30, 32, 33 Progression to systemic involvement
with SLE is described as an uncommon event in DLE
patients with isolated involvement of the scalp.34
Scalp DLE is present in up to 14% of patients with
SLE, and can often be the presenting manifestation
of SLE.23, 35
In LE, the injury of hair follicles, as well as that of
other target structures, is mediated by inflammatory
immune mechanisms, recruiting T cells, cytokines,
autoantibodies, and immune complexes. Among the
major proinflammatory events implicated in DLE
and related scarring alopecia, there are type I interferon-associated cytotoxic inflammation, loss of hair
follicle immune privilege, and loss of immunosuppressive signals.36 Like other cicatrical alopecias,
there is the permanent damage to the pluripotent hair
Vol. 149 - No. 5
CASSANO
follicle stem cells in the bulge area of hair follicles,37
and the loss of the sebaceous gland is a frequent
associated finding.38 In scalp DLE, a relevant role
for the induction of the inflammatory response has
been attributed to the Langerhans cells, whose infundibulocentric distribution below the entry of the
sebaceous glands into the follicle corresponds to the
pattern of mid-follicular inflammation involving the
follicular bulge that is typically revealed by the histopathological examination of lesional skin.39
In cutaneous LE, the antigenic stimulus triggering the immune response is thought to be ultraviolet
radiations, although this hypothesis may be hardly
adapted to the hair-bearing scalp, a site relatively
protected from the sunlight.23, 40 Interestingly, patients with concomitant androgenetic alopecia were
found to be less prone to develop DLE lesions in
bald areas,30 possibly because of the depletion of
immunogenic target structures. Mechanical stimuli,
such as intense rubbing and scratching, thermal injury, or infection can favor the occurrence of new lesions in affected patients. Koebner phenomenon may
also arise from other dermatoses, such as contact
dermatitis, infection,41 or even after hair transplantation (Figure 1). However, the relation of exposure
to the offending stimulus (e.g., ultraviolet radiations)
with the development or exacerbation of lesions can
be not easily recognized because of the lag time between the events. Smoking has been shown to have a
pronounced influence on cutaneous LE, and appears
also capable of diminishing the effectiveness of antimalarials.42
Figure 1.—Koebner phenomenon in scalp DLE after autograft
hair transplantation.
557
CASSANO
Clinically, early DLE lesions present as scaling
erythematous or violaceous papules or well-demarcated, erythematous, oval or roundish patches with
adherent follicular hyperkeratosis. Later, the lesion
progresses centrifugally to form a nummular (discoid) white ivory, atrophic, depressed plaque with
follicular plugging and adherent scale. Telangiectasias are usually present. After removal of the adherent scale, which can be difficult and painful, keratotic
spikes corresponding to the follicular plugging can
be seen (“carpet tack” sign).40 The acronymn PASTE
has been created to summarize the key clinical features: plugging, atrophy, scale, telangiectasia, and
erythema.20 Lesions may sometimes be pruritic or
tender, although they are often asymptomatic and,
at the most, when symptoms are complained, they
are usually of mild-to-moderate severity. Pigmentary changes may be observed especially in darkerskinned individuals, with hypopigmentation in the
central area and hyperpigmentation at the periphery
of the patches. In a study performed in 36 patients
with DLE scarring alopecia, 33.3% presented a
single lesion and 52.7% presented multiple lesions,
while 13.8% exhibited a picture resembling pseudopelade of Brocq.43
Squamous cell carcinoma has been described as a
rare late sequel in chronic lesions.44
A lichen plano-pilaris and LE overlap condition
has been recently described in a male presenting with
frontal fibrosing alopecia, in whom biopsies from the
scalp and other sites demonstrated features consistent with lichen plano-pilaris, but direct immunofluorescence studies showed a positive lupus band test.45
DLE-related alopecia is usually irreversible if not
treated early to control the inflammatory process and
to prevent the damage of the stem-cell-containing
midfollicle area. Classic treatment includes topical,
systemic or intralesional corticosteroids, and topical
calcineurin inhibitors, but antimalarial drugs, thalidomide, oral cyclosporin and sulfones may be active
as well.18, 46-48 Oral isotretinoin can be also considered for refractory cases.49 Other therapeutic options
are gold, methotrexate, mycophenolate, azathioprine,
and cyclophosphamide.40, 48
plano-pilaris, tinea capitis, morphea, early phases
of squamous cell carcinoma, and actinic keratoses
(Figure 2).1, 20
In the diagnostic work-up, the initial approach
should include the assessment of the entire scalp and
a complete physical examination in order to detect
other cutaneous or systemic pathological signs, such
as the presence of discoid lesions elsewhere or other
LE-related features. Histopathological and immunopathological studies are helpful in confirming the
diagnosis. Two biopsy specimens, one for standard
hematoxylin-eosin sections and the other for direct
immunofluorescence, should be taken. Ideally, two
distinct biopsies can be performed for standard histopathology, one examined for transverse sectioning
and one for vertical sectioning.1 Punch or excisional
scalp biopsy specimens should be obtained from the
border of early clinically active lesions (anyhow from
inflammatory areas), and extend into the fat, avoiding
to choose end-stage cicatricial areas which are likely
to provide nonspecific and useless findings.1, 20
The major histopathologic features found in active
scalp DLE lesions are: follicular hyperkeratosis, epidermal atrophy, superficial and deep patchy interstitial and periadnexal lymphocytic infiltrate, thickened
basement membrane, basal vacuolar degeneration at
the dermal-epidermal junction, mucin deposition in
the papillary dermis, and extravasation of red blood
Diagnostic aspects
As concerns differential diagnosis, DLE scalp
lesions must be differentiated by a large variety of
cutaneous disorders, such as alopecia areata, lichen
558
Figure 2.—A patient with diffuse scalp DLE lesions (resembling
actinic keratoses) in association with alopecia areata.
October 2014
cells around the inflamed blood vessels. In the late
stages, fibrosis and a reduction of pilosebaceous
units are characteristic findings.43, 50 Direct immunofluorescence reveals deposition of immunoglobulins (most frequently IgG) and C3 in a granular or
homogeneous band-like pattern at the interface between the dermis and the follicular epithelium or the
epidermis.1 A study demonstrated that histopathology alone was able to support a correct diagnosis
only in 68.5% of cases; in the other cases, the diagnosis was made through the additional evaluation of
immunopathologic findings.43 In the final phase, in
the absence of clinically evident inflammatory signs,
alopecic patches can be difficult to differentiate from
alopecia areata or pseudopelade of Brocq. On histopathology, these lesions usually lack superficial
inflammation, but show deeper inflammation with
perifollicular lymphocytic infiltrates or infiltrates
within fibrous tracts. In the late-stage pseudopeladelike lesions, the absence of hair follicles and fibrosis
are detected.23
In the last years, dermoscopy (dermatoscopy) has
become a popular diagnostic method among dermatologists, and may represent a relevant diagnostic
tool not only for pigmentary skin lesions but also
for other skin conditions. Trichoscopy, or dermoscopy and videodermoscopy of the scalp, may shows
features of a specific pattern of hair loss.51, 52 Dermoscopic examination may be useful to guide scalp
biopsy in scarring alopecia, allowing the selection of
the optimal biopsy site.53 In cicatricial alopecia, trichoscopy can reveal reduced hair density and loss of
follicular openings. Dermoscopic findings associated
with scalp DLE include: scattered dyschromia, follicular plugs, telangiectasias, and irregularly distributed blue-gray dots in a speckled pattern between the
hair follicles, and in more advanced stages, fibrosisrelated white central plaques and milky-red areas,
along with a reduced number of follicular ostia.
Follicular keratotic plugs are a marker of DLE and
correlate with follicular hyperkeratosis and plugging
of the ostia with keratotic material.54 Moreover, scalp
DLE may be differentiated from lichen plano-pilaris
thanks to the presence of follicular red dots (Figure
3), that are erythematous, polycyclic, concentric
structures, regularly distributed around the follicular ostia.55 These dots are present in active DLE and
seem to be a good prognostic factor for hair regrowth.
Among the characteristic trichoscopic features of
DLE of the scalp, there are particular types of yel-
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Figure 3.—Dermatoscopic assessment of scalp DLE lesions: follicular red dots (x40 magnification).
low dots, that correspond to hyperkeratotic plugs,
and are different from those classically observed in
alopecia areata. In scalp DLE, in fact, yellow dots
are large and surrounded by radial, thin arborizing
vessels emerging from the dot, arranged as a “red
spider in yellow dot”.56 Long-lasting, inactive DLE
lesions differ from active lesions by the presence of
structureless milky-red areas, and lack of follicular
orifices.52, 56
As concerns the multiple blue-grey dots, they correspond histopathologically to melanophages in the
papillary dermis. This finding results from interface
dermatitis and the subsequent pigment incontinence,
and may be associated also with lichen plano-pilaris. However, some authors highlight some possible
peculiarities in the distribution pattern of such dots,
described as “speckled” in DLE, and as a “target”
pattern in lichen plano-pilaris.57 In the latter case,
there is a circular arrangement around the follicular
structures and follicular white dots, thus preserving
the interfollicular epidermis.
Non-scarring alopecia
Lupus erythematosus
The skin findings in cutaneous LE have been
divided into two groups, LE-specific and LE-non-
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specific skin changes.20 Biopsy of LE-specific skin
lesions shows LE-specific histology, as happens in
DLE, thus permitting the confirmation of LE diagnosis, while LE nonspecific skin lesions are not histopathologically distinct for LE and/or may be seen
as a feature of another disease process.
Non-scarring alopecia is included among LE-nonspecific skin disorders in the modified Gilliam classification of LE-related skin lesions and seems to be
very frequently encountered in SLE patients, especially during the active phases of the disease.58, 59
Diffuse, non-scarring hair loss can be the presenting
manifestation of SLE.20 Polyarthralgia, fever and
hair loss have been mentioned as the most common
presentation of SLE in some reports.60 This clearly
highlights the importance of hair loss as a diagnostic
clue of LE. Hair loss may affect not only the scalp,
but also eyebrows, eyelashes, beardhair, or body
hair.20
A study in Pakistani patients with SLE specified
the association with non-cicatricial diffuse alopecia
in 22% of patients.61 In an Italian case series,62 nonscarring alopecia was observed in 31% of SLE patients, usually in the active phases of the disease.
A cross-sectional study tried to identify cutaneous
manifestations that could be used as a marker of
systemic involvement in LE. A highly significant association was found between SLE and non-scarring
alopecia, while no significant association was noted
between SLE and scarring alopecia.63
There are several etiologies for the non-cicatricial
alopecia, as already declared in the modified Gilliam
classification,58 but the main types correspond to lupus hairs, telogen effluvium, and alopecia areata.
Telogen effluvium, which will be examined in depth
in a distinct paragraph, is likely to be the predominant non-scarring alopecia associated with LE.
An interesting pilot study analyzed the dermoscopic and histopathological features of diffuse
non-scarring hair loss in four women suffering from
SLE.64 Scalp dermoscopy showed scaling, perifollicular telangiectasia, increased numbers of short
vellus hairs, focal atrichia, and decreased hair shaft
pigmentation. Of note, scalp tissue histopathology
revealed typical changes of LE. These preliminary
results seem therefore to suggest that non-scarring
alopecia in SLE might sometimes display more LEspecific findings than expected.
In a prospective, multicenter European study,
clinical and laboratory characteristics were exam-
560
ined in 1002 patients with different subtypes of
cutaneous LE: acute cutaneous LE, subacute cutaneous LE, chronic cutaneous LE, and intermittent
cutaneous LE.65 LE-nonspecific skin lesions were
diagnosed in 45.2% of patients with cutaneous LE,
with the most frequently reported manifestation being diffuse alopecia (55.8%). Diffuse alopecia was
recorded significantly more often in patients with
chronic cutaneous LE and acute cutaneous LE than
in patients with subacute cutaneous LE or intermittent cutaneous LE.
Another form of transient alopecia in chronically
active SLE patients is the so called “lupus hairs”,
which consist in thin, dry, weakened hairs, especially at the periphery of the scalp, with possible evident
recession.66 Lupus hairs have been substantially related to telogen effluvium, although the true telogen
hair loss is generally more extensive, and overlap
between the two entities exists. It is hypothesized
that the hair growth disruption in this circumstance
is due to the induction of a negative nitrogen balance.23
A possible variant of non-scarring alopecia seldom encountered consists in a band-like alopecia
along the posterior occipital and temporal margins,
resembling the ophiasis pattern of alopecia areata.20
Another hair loss pattern that is considered fairly common and important in SLE patients, despite
the relatively scarce number of literature reports, is
patchy, non-cicatricial alopecia. This form of hair
loss seems to occur in patients with severe disease.
In a cross-sectional study of 122 SLE patients, the
overall prevalence of non-scarring patch alopecia
was 14.8%.67 In patients who experienced hair loss
after SLE diagnosis, non-scarring diffuse hair loss
was the most common pattern (65.1%) followed by
non-scarring patchy alopecia (15.1%). In patchy
non-cicatricial hair loss, there are scattered patches
of partial hair loss, with mild erythema and without
scarring. Gentle traction reveals that hairs remaining in the alopecic patches are almost all telogen
hairs, or dystrophic anagen hairs.23 SLE-associated
non-scarring patchy alopecia should be carefully
differentiated from alopecia areata. Histopathological features are similar to those shown in alopecia
areata, with peribulbar infiltrate of lymphoid cells
surrounding anagen hair bulbs, many of which are
miniaturized. The diagnosis of LE might be suggested by the greater density of inflammatory infiltrate,
presence of dermal mucin, and further clinical and
October 2014
serological findings.23 For the differential diagnosis,
dermatoscopy may be successfully used, as demonstrated by a recent study.68 While exclamationmark hairs, black dots, broken hair and yellow dots
are helpful for diagnosis of alopecia areata, common dermoscopic features in SLE patchy alopecia
were hair shaft thinning and hypopigmentation, teleangiectasias, peripilar sign, perifollicular red dots,
white dots and honeycomb pigment patterns. Interfollicular polymorphous vessels were the most common vascular pattern in the SLE alopecia patches.
In exceptional cases, non-scarring hair loss in LE
may derive from vascular lesions of mild severity
when they are not capable of irreversible damage
and spare the stem cell-rich follicular area.23 Other
histopathological substrates described in anecdotal cases of LE patients with non-scarring alopecic
patches are lupus panniculitis and tumid lupus (papulo-nodular mucinosis).69, 70 The literature also
contains a report of a lupus panniculitis of the scalp
occurring along Blaschko’s lines and presenting as a
reversible linear alopecia.71
Non-scarring alopecia is usually responsive to
treatment of the lupus, and hair regrowth is expected
after LE is well controlled and becomes quiescent,
although some drugs usually used to treat lupus can
cause hair loss.23
riasis or psoriasiform dermatitis is not possible.
Histopathological changes can be similar to those
detectable in lupus and comprise epidermal atrophy, basement membrane degeneration, vacuolar
changes in the basal keratinocytes, and a perivascular lymphocytic infiltrate, which is less abundant
and less deep than in lupus. Accumulation of mucin
usually in the papillary dermis can be seen. Direct
immunofluorescence can show deposition of immunoglobulin at the dermal-epidermal junction, but of
less intensity than in lupus.20
As concerns serologic studies, circulating antibodies targeting melanoma differentiation-associated
gene 5 (MDA5), an antigen involved in innate immune responses also named CADM-140, have been
identified in DM patients with little or no myositis
and with an increased risk of interstitial lung disease. Patients with anti-MDA5 antibodies also were
found to have an increased risk of arthritis/arthralgia
and some cutaneous manifestations, including diffuse hair loss.77
According to some authors,76 scalp DM is a treatment-resistant disease, even when other cutaneous
lesions of DM show clinical response.
Special forms of non-scarring alopecia
Telogen effluvium
Dermatomyositis
In DM, the involvement of the scalp is common
and can be the presenting manifestation. It usually
manifests as diffuse, confluent, erythematous to
violaceous, atrophic, scaly plaques, resembling seborrhoeic dermatitis or psoriasis, and can be often
misdiagnosed.72 Unlike lupus, the eruption is frequently accompanied by intense pruritus or burning. Hair loss tends to be diffuse, although it is often
more subtle than in LE. This diffuse, violaceous,
scaly, non-cicatricial symptomatic alopecia is one of
the typical cutaneous signs of DM, without being
pathognomonic,20 especially in patients with adultonset classic DM and amyopathic and/or hypomyopathic DM, in whom it can accompany a disease
flare.73,74 Non-cicatricial hair loss has also been observed in juvenile-onset DM.75 In case series, scalp
involvement has been recorded in 63-82% of DM
patients, and alopecia in 33-43%.72, 76
Histopathology and dermoscopy can be helpful,
especially when differential diagnosis with pso-
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It is well known that the hair follicles have an intermittent activity, known as hair cycle, characterized by an ever-ending sequence of phases of growth
(anagen), involution (catagen), and rest (telogen).
In the scalp, telogen usually lasts for up 3 months,
catagen only a few weeks, while the anagen phase
duration, which influences the hair length, is estimated to be 2-7 years. Normally, up to 90% of hair
follicles on the human scalp are in anagen, 10-14%
are in telogen and 1-2% in catagen. A latency period may occur between hair shedding (teloptosis,
exogen) and the early emergence of the next anagen VI stage.19, 78, 79 Exogen corresponds to the programmed termination of telogen hair and finishes
with its shedding (teloptosis). Kenogen indicates the
physiological interval of the hair cycle in which the
hair follicle remains empty after the telogen hair has
been extruded and before a new anagen hair emerges.
Telogen effluvium is due to an abnormally high
number of hairs entering the telogen phase simul-
561
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taneously with loss of the usual asynchrony in normal hair loss. The consequent hair loss may vary in
severity with daily shedding of more than 100 hairs
even up to 300 hairs. Different pathomechanisms resulting in telogen hair loss have been recognized: a)
immediate anagen release, with premature start of
telogen after 2-3 months from a triggering event; b)
delayed anagen release caused by the prolongation
of anagen (i.e., postpartum hair loss or discontinuation of contraceptive pill); c) immediate telogen
release (i.e., shortening of telogen, sometimes observed at the beginning of therapy with minoxidil);
d) shortened anagen (idiopathic shortening of anagen duration, leading to mild persistent hair loss and
inability to grow the hair long); e) delayed telogen
release (prolonged telogen and delayed transition to
anagen, which can be responsible for seasonal shedding in humans).21, 80 Rebora has recently proposed
a simplified classification of telogen effluvium categorizing three main mechanisms: a) premature teloptosis; b) collective teloptosis; c) premature entry
into telogen.19 This last form can be further distinguished according to the etiology into three subcategories: medications, dietary deficiencies, and lymphotoxicity (autoimmunity).
Telogen effluvium is considered the most common form of hair loss seen in systemic disease.81 A
short-lived insult usually produces a sudden onset of
diffuse shedding, after time interval of 2-3 months.
This can be associated to physiologic stress, severe
illness, or drug-induced hair loss. When the insult is
prolonged or repeated, shedding can develop insidiously. Chronic telogen effluvium refers to telogen
hair shedding persisting longer than 6 months. A
shortening of anagen is the mechanism most commonly involved. Recently, chronic telogen effluvium has been related to a reduction in the variance of
anagen duration.82
Chronic telogen effluvium has been distinguished
into an idiopathic form and chronic diffuse telogen
hair loss secondary to a variety of organic causes.
To be a true cause of chronic diffuse telogen hair
loss, the relationship between the trigger and the
disease has to be reversible and reproducible. Common causes of chronic diffuse telogen effluvium are
thyroid disorders, profound iron deficiency, malnutrition, and treatment with some drugs (e.g., retinoids and cytoxic drugs).80 SLE and DM are included
among the documented causes of chronic diffuse
telogen hair loss.83 In SLE and other similar system-
562
ic inflammatory conditions, the telogen effluvium
is thought to derive from both severe catabolic effects and the action of high levels of proinflammatory cytokines during disease flare on hair growth
cycling.23 The “autoimmune” telogen effluvium, recently described by Rebora,19 actually corresponds
to an exogen effluvium, and is characterized by a
sudden onset and intermittent course. This condition
has been called “autoimmune” because of the common coexistence of circulating anti-thyroperoxidase
antibodies and full-blown Hashimoto thyroiditis, as
it happens in alopecia areata. Other less frequent associations reported by the authors are other thyroid
autoimmune disorders, and other autoimmune diseases, such as Sjögren’s syndrome, in accordance
with our clinical experience. Moreover, it should be
mentioned that autoimmune thyroid diseases have
in turn a significant association with various other
autoimmune disorders, including primary Sjögren’s
syndrome, rheumatoid arthritis, SLE, systemic sclerosis and DM.84
The hair loss in telogen effluvium occurs in a
diffuse pattern. Trichodynia is frequently complained and has been described as a possible
marker of disease activity corresponding to the
presence of an active inflammatory peripilar process.85 86 On examination, the scalp appears nonerythematous and without remarkable changes, and
the hair appears normal in thickness. The absence
of signs of hair miniaturization can be easily confirmed by dermatoscopy, allowing the differentiation from androgenic alopecia. Bitemporal thinning can be present along with a marked regrowth
of smaller hair in the frontal and bitemporal areas.
Hair pull test is commonly positive, with many
hairs coming out easily from their roots, with an
elongated hair bulb visible to the naked eye.21, 80
The modified wash test can be a simple and useful
diagnostic tool.19
Differential diagnoses comprise androgenic alopecia, alopecia areata incognito, and other causes of
non-scarring alopecia.
Anagen effluvium
Anagen effluvium results from an abrupt cessation
of the metabolic and mitotic activity of the follicular
epithelial compartment is rapidly suppressed.23, 87
Dramatic hair loss occurs shortly after the insult,
within days or weeks. Although anagen effluvium is
October 2014
commonly associated with chemotherapy and radiation to the head and neck, other causes of anagen
effluvium are: severe protein energy malnutrition,
pemphigus vulgaris, and exposure to toxic agents
and some medications. Certain inflammatory diseases are also capable of diminishing the metabolic activity of hair follicles, resulting in anagen effluvium.
The paradigmatic case is represented by alopecia areata, in which the anagen arrest is the consequence
of an autoimmune T cell-mediated insult against hair
follicle antigens. Occasionally, patients with severe
systemic disease, such as secondary syphilis and
SLE, may experience dystrophic anagen effluvium.
In such diseases, an anagen arrest occurs through
the development of peribulbar inflammation, and a
temporary shutdown of the hair matrix, analogous to
Beau’s lines in the fingernails.23
Alopecia areata
Alopecia areata is known to be associated with
atopic and autoimmune disorders, and has been
recorded in a small percentage of patients with
rheumatoid arthritis, SLE, scleroderma, and other
CTDs.88, 89 An increased incidence of alopecia areata was revealed in patients with LE.88 A significant
association between LE and alopecia areata was recently confirmed by a nationwide population-based
study from Taiwan.90 Figure 2 shows a case of coexistence of alopecia areata and DLE.
Drug-induced hair disorders
Some drugs used to treat CTDs (i.e., azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, gold) may cause hair loss in a
drug-related manner.91, 92 The medication-induced
hair loss is usually diffuse, non-scarring, and limited to the scalp. Women are more commonly affected than men.92 Systemic retinoids, occasionally
used in the treatment of cutaneous LE, may cause
reversible alopecia, hair greying and hair curling/
kinking.23, 91, 92 Antimalarial therapy has long been
recognized as a cause of hair depigmentation and
graying, especially in people with blonde or reddish
hair.23, 93 Hypertrichosis is a well-established side effect of cyclosporine, topical and systemic corticosteroids, and has been also reported with methotrexate and penicillamine.91
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2013;5:217-9
46. Oremović L, Lugović L, Vucić M, Buljan M, Ozanić-Bulić S. Cicatricial alopecia as a manifestation of different dermatoses. Acta Dermatovenerol Croat 2006;14:246-52.
47. Holm AL, Bowers KE, McMeekinm TO, Gaspari AA. Chronic cutaneous lupus erythematosus treated with thalidomide. Arch Dermatol 1993;129:1548-50.
48. Walling HW, Sontheimer RD. Cutaneous lupus erythematosus: issues
in diagnosis and treatment. Am J Clin Dermatol 2009;10:365-81.
49. Vena GA, Coviello C, Angelini G. Impiego dell’isotretinoina orale
nel trattamento del lupus eritematoso cutaneo. G Ital Dermatol Venereol 1989;124:311-5.
50. Sperling LC, Cowper SE. The histopathology of primary cicatricial
alopecia. Semin Cutan Med Surg 2006;25:41-50.
51. Tosti A, Torres F. Dermoscopy in the diagnosis of hair and scalp
disorders. Actas Dermosifiliogr 2009;100(Suppl 1):114-9.
52. Rudnicka L, Olszewska M, Rakowska A, Slowinska M. Trichoscopy update 2011. J Dermatol Case Rep 2011;5:82-8.
53. Miteva M, Tosti A.Dermoscopy guided scalp biopsy in cicatricial
alopecia. J Eur Acad Dermatol Venereol 2013;27:1299-303.
54. Lanuti E, Miteva M, Romanelli P, Tosti A. Trichoscopy and histopathology of follicular keratotic plugs in scalp discoid lupus erythematosus. Int J Trichology 2012;4:36-8.
55. Tosti A, Torres F, Misciali C, Vincenzi C, Starace M, Miteva M et
al. Follicular red dots: a noveldermoscopic pattern observed in scalp
discoid lupus erythematosus. Arch Dermatol 2009;145:1406-9.
56. Rakowska A, Slowinska M, Kowalska-Oledzka E, Warszawik O,
Czuwara J, Olszewska M et al. Trichoscopy of cicatricial alopecia.
J Drugs Dermatol 2012;11:753-8.
57. Duque-Estrada B, Tamler C, Sodré CT, Barcaui CB, Pereira FB.
Dermoscopy patterns of cicatricial alopecia resulting from discoid
lupus erythematosus and lichen planopilaris. An Bras Dermatol
2010;85:179-83.
58. Sontheimer RD. The lexicon of cutaneous lupus erythematosus—a
review and personal perspective on the nomenclature and classification of the cutaneous manifestations of lupus erythematosus. Lupus
1997;6:84- 95.
59. Werth VP. Clinical manifestations of cutaneous lupus erythematosus. Autoimmun Rev 2005;4:296- 302.
60. Adelowo OO, Oguntona SA. Pattern of systemic lupus erythematosus among Nigerians. Clin Rheumatol 2009;28:699-703.
61. Rabbani MA, Shah SM, Ahmed A. Cutaneous manifestations of
systemic lupus erythematosus in Pakistani patients. J Pak Med Assoc 2003;53:539-41.
62. Cardinali C, Caproni M, Bernacchi E, Amato L, Fabbri P. The spectrum of cutaneous manifestations in lupus erythematosus--the Italian experience. Lupus 2000;9:417-23.
63. Das NK, Dutta RN, Sengupta SR. Skin lesions in lupus erythematosus: a marker of systemic involvement. Indian J Dermatol
2011;56:537-40.
64. Gong Y, Ye Y, Zhao Y, Caulloo S, Chen X, Zhang B et al. Severe diffuse non-scarring hair loss in systemic lupus erythematosus - clinical and histopathological analysis of four cases. J Eur Acad Dermatol Venereol 2013;27:651-4.
65. Biazar C, Sigges J, Patsinakidis N, Ruland V, Amler S, Bonsmann
G et al. Cutaneous lupus erythematosus: First multicenter database
analysis of 1002 patients from the European Society of Cutaneous
Lupus Erythematosus (EUSCLE). Autoimmun Rev 2013;12:44454.
66. Alarcon-Segovia D, Cetina JA. Lupus hair. Am J Med Sci
1974;267:241-2.
67. Yun SJ, Lee JW, Yoon HJ, Lee SS, Kim SY, Lee JB et al. Crosssectional study of hair loss patterns in 122 Korean systemic lupus
erythematosus patients: a frequent finding of non-scarring patch
alopecia. J Dermatol 2007;34:451-5.
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68. Ye Y1, Zhao Y, Gong Y, Zhang X, Caulloo S, Zhang B et al. Nonscarring patchy alopecia in patients with systemic lupus erythematosus differs from that of alopecia areata. Lupus 2013;22:1439-45.
69. Kossard S. Lupus panniculitis clinically simulating alopecia areata.
Australas J Dermatol 2002;43:221-3.
70. Singh AH, Werth VP. Alopecia associated with papulonodular mucinosis (tumid) lesions of lupus erythematosus. J Clin Rheumatol
1997;3:343-5.
71. Chen YA, Hsu CK, Lee JY, Yang CC. Linear lupus panniculitis of the
scalp presenting as alopecia along Blaschko’s lines: a distinct variant of lupus panniculitis in East Asians? J Dermatol 2012;39:385-8.
72. Kasteler JS, Callen JP. Scalp involvement in dermatomyositis. Often overlooked or misdiagnosed. JAMA 1994;272:1939-41.
73. Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol
2006;24:363-73.
74. Santmyire-Rosenberger B, Dugan EM. Skin involvement in dermatomyositis. Curr Opin Rheumatol 2003;15:714-22.
75. Palero TM, Miller OF, Hahn TF, Newman ED. Juvenile dermatomyositis: a retrospective review of a 30-year-experience. J Am Acad
Dermatol 2001;45:28-34.
76. Tilstra JS, Prevost N, Khera P, English JC 3rd. Scalp dermatomyositis revisited. Arch Dermatol 2009;145:1062-3.
77. Fiorentino D, Chung L, Zwerner J, Rosen A, Casciola-Rosen L.
The mucocutaneous and systemic phenotype of dermatomyositis
patients with antibodies to MDA5 (CADM-140): a retrospective
study. J Am Acad Dermatol 2011;65:25-34.
78. Piérard-Franchimont C, Petit L, Loussouarn G, Saint-Léger D,
Piérard GE. The hair eclipse phenomenon: sharpening the focus on
the hair cycle chronobiology. Int J Cosmet Sci 2003;25:295-9.
79. Rebora A, Guarrera M. Teloptosis and kenogen: two new concepts
in human trichology. Arch Dermatol 2004;140:619-20.
80. Grover C, Khurana A. Telogen effluvium. Indian J Dermatol Venereol Leprol 2013;79:591-603.
81. Sperling LC. Hair and systemic disease. Dermatol Clin 2001;19:71126.
82. Gilmore S, Sinclair R. Chronic telogen effluvium is due to a re-
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duction in the variance of anagen duration. Australas J Dermatol
2010;51:163-7.
83. Dawber RP, Simpson NB. Hair and scalp in systemic disease. In:
Dawber RP, editor. Diseases of the Hair and Scalp. Oxford: Blackwell Science; 1997. p. 483-527.
84. Lazúrová I, Benhatchi K. Autoimmune thyroid diseases and nonorganspecific autoimmunity. Pol Arch Med Wewn 2012;122(Suppl
1):55-9.
85. Kivanç-Altunay I, Savas C, Gökdemir G, Köslü A, Ayaydin EB. The
presence of trichodynia in patients with telogen effluvium and androgenetic alopecia. Int J Dermatol 2003;42:691-3.
86. Baldari M, Montinari M, Guarrera M, Rebora A. Trichodynia is a
distinguishing symptom of telogen effluvium J EurAcad Dermatol
Venereol 2009;23:702-38.
87. Ramos-e-Silva, Kanwar AJ, Narang T. Anagen effluvium. Indian J
Dermatol Venereol Leprol 2013;79:604-12.
88. Werth VP, White WL, Sanchez MR, Franks AG. Incidence of alopecia areata in lupus erythematosus. Arch Dermatol 1992;128:36871.
89. Seetharam KA. Alopecia areata: an update. Indian J Dermatol Venereol Leprol 2013;79:563-75.
90. Chu SY, Chen YJ, Tseng WC, Lin MW, Chen TJ, Hwang CY et
al. Comorbidity profiles among patients with alopecia areata: the
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91. Tosti A, Pazzaglia M. Drug reactions affecting hair: diagnosis. Dermatol Clin 2007;25:223-31.
92. Patel M, Harrison S, Sinclair R. Drugs and hair loss. Dermatol Clin
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in the manuscript.
565

Skin cancer risk
in autoimmune connective tissue diseases
D. KOSTAKI 1, A. ANTONINI 1, K. PERIS 2, M. C. FARGNOLI 1
Cutaneous malignancies have been significantly associated
with autoimmune connective tissue diseases (ACTDs). This
review focuses on the current state of knowledge on skin
cancer risk in the most prevalent ACTDs in dermatology including lupus erythematosus, scleroderma, dermatomyositis
and Sjögren syndrome. Potential pathogenetic mechanisms
for the association between ACTDs and malignancy involve
disease-related impairment of immune system, sustained
cutaneous inflammation, drug-associated immune suppression and increased susceptibility to acquired viral infections.
An additional causal role might be played by environmental
factors such as UV exposure and smoking. The occurrence
of skin cancer can have a profound impact on the already
compromised quality of life of ACTD patients. Therefore, effective screening and monitoring strategies are essential for
ACTD patients as early detection and prompt therapeutic
intervention can reduce morbidity and mortality in these patients.
Key words: Connective tissue diseases - Lupus erythematosus,
cutaneous - Skin diseases - Carcinoma, squamous cell.
M
alignancies have been widely reported as comorbidities of autoimmune connective tissue
diseases (ACTDs). Patients with ACTDs have an increased risk of secondary hematological malignancies and solid tumors including cutaneous malignancies, mostly non melanoma skin cancers (NMSC),
melanoma and lymphoma.1-6
ACTDs are polygenic clinical disorders of unclear etiology with heterogeneous and overlapping
features characterized by abnormal immune system
activity and autoimmunity, leading to tissue inflamCorresponding author: M. C. Fargnoli, MD, Department of Dermatology, University of L’Aquila, via Vetoio-Coppito 2, 67100 L’Aquila,
Vol. 149 - No. 5
University of L’Aquila, L’Aquila, Italy
Catholic University, Rome, Italy
mation. The most prevalent ACTDs in dermatology include lupus erythematosus (LE), scleroderma,
dermatomyositis and Sjögren syndrome (SS). An
increased risk of skin cancer might be expected in
ACTDs patients due to the prevalence of ACTDs in
the population, the long disease duration and the improved care and life expectancy of patients.1
Skin cancer is a multistep process and, as such,
many events can contribute to its occurrence in
ACTDs. Impaired immune system, mainly due to active disease and ACTD-associated immune dysfunction, seems to be one of the major risk factors for
cancer. Similarly, chronic cutaneous inflammation,
hallmark of ACTDs, is likely to contribute directly
to the pathogenesis of malignancy through increased
susceptibility to cell mutagens and DNA changes.7 In
addition, a number of drugs used for the treatment of
ACTDs have been reported to increase the incidence
of cutaneous malignancies, due to direct mutagenesis of DNA or iatrogenic-induced immunosuppression with interruption of immunosurveillance.2, 4, 6, 8
However, the role of these drugs is debated as their
strong anti-inflammatory and disease-modifying
properties slow down disease progression and, thus,
may even have a favorable influence on the risk of
malignancies. It may be also difficult to differentiate
whether the increased risk of skin cancer is linked
567
KOSTAKI
Skin cancer and autoimmune connective tissue diseases
to disease-related or treatment-related immune dysfunction.2 Patients with ACTDs may also exhibit a
higher risk of infections because of treatment and
underlying impairment of the immune system.9
Moreover, ACTD patients have greater exposure to
infectious pathogens, owing to continuous seeking
medical advice in outpatient and/or inpatient departments. Given the well-known oncogenic potential
of several virus,10 an increased risk of infection in
ACTD patients may, thereby, enhance the probability
to develop skin cancer. Finally, common genetic and
environmental background (UV exposure, smoking)
for ACTDs and cancer may also play an additional
role.11
This review focuses on the current state of knowledge concerning the risk of skin cancer in the most
common ACTDs seen in dermatological clinical
practice.
Lupus erythematosus
A significantly elevated overall cancer risk has
been reported in patients with LE compared to the
general population.1, 12, 13 Squamous cell carcinoma
(SCC) appears as the most frequent skin cancer in LE
patients (Figure 1), although few cases of melanoma and basal cell carcinoma (BCC) have been described.1, 12, 14, 15
A Swedish population-based study evaluated the
association between systemic LE (SLE) and malignancy in 5715 patients identifying 443 cancer cases.
SLE patients were shown to be at increased risk of
SCC (standardized incidence rate [SIR] =1.53, 95%
CI 0.98-2.28), which was more pronounced after more
than 15 years of follow-up.16 In a large study investigating the association between SLE and malignant
diseases in an unselected cohort of Icelandic patients,
SCC was the only individual cancer type to be statistically increased with an observed/expected ratio of
6.43 (95% CI 1.31-18.5, P=0.012).17 The incidence of
potentially virus-induced malignancies, mainly HPVassociated cancers, was investigated in 576 Danish
patients with SLE. Twelve NMSC were diagnosed in
46 cancer patients confirming a higher risk for NMSC
among SLE patients compared to the general population (SIR=2.0, 95%, CI 1.2-3.6).12 In contrast to the
abovementioned studies, in a Hungarian cohort, the
SIR for skin cancer was significantly decreased in
SLE patients (SIR=0.04, 95% CI 0.001-0.236).18
568
Figure 1.—Cutaneous squamous cell carcinoma of the ear in a
young patient with systemic lupus erythematosus.
In a Swedish cohort of cutaneous LE (CLE) patients, 21 SCCs out of 183 incident cancers were observed in 3663 patients with a 4-fold higher risk of
SCC in CLE patients compared to a control cohort
from the general population.13 The general hazard
ratio (HR) for SCC was 3.6 (95% CI 1.8-7.2) with
greatest HR for the first year after CLE diagnosis
(HR 5.2, 95% CI 1.3-21.1). The risk estimates remained elevated even after excluding patients also
diagnosed with SLE (HR 2.8, 95% CI 1.2-6.2).
SCC is a well recognized complication of discoid
LE (DLE) with an incidence ranging from 2.3% to
3.3%.19, 20 More than 100 cases of SCC in DLE lesions have been described, mainly arising in longstanding lesions,13, 21 although cases of SCC can also
develop in DLE plaques of recent onset.22, 23 DLE-related SCC appears as solitary lesions, less frequently
as multiple lesions, in sun-exposed skin areas with
October 2014
lips, forearms, back of hands, cheek and scalp being the preferential anatomic locations.24, 25 Interestingly, SCCs in DLE lesions have a more aggressive
behavior compared to non DLE-related SCC with
recurrence rates of 29%, metastatic rates of 16% and
death ratios of 19.4%.19, 24-26
Concerning mechanisms linking LE with cutaneous malignancies, disease-related and/or treatmentrelated impairment of the immune system may play
a significant role in cancer development. In DLE,
predisposing factors are also related to chronic inflammation, scarring, actinically damaged epidermis and decrease in protective melanin at the lesion
site.27 The role of sun exposure in the development
of NMSC in LE is still debated: about two-thirds of
LE patients have been reported to be photosensitive,
such people should avoid the sun and have fewer
NMSC.13 However, despite advices, they might not
change their exposure habits and/or inappropriately
use suncscreens. Therefore, additional environmental factors should be considered in LE as driving
stimuli including HPV infection 28-30 and tobacco
use, in cases of SCC of the lips.23
Surveillance bias may, to some extent, also explain
the significantly increased occurrence of NMSC in
the LE population, mainly during the first year after
diagnosis, since they can be more readily diagnosed
in patients subjected to close medical attention because of chronic disease.1, 12, 13
Scleroderma
Current evidences support an increased risk of
malignancy in scleroderma patients compared to the
general population, with an overall prevalence of
3.6-10.7%.31
SCC is the most common skin cancer observed in
scleroderma patients, mainly in patients with generalized or pansclerotic morphea, although all variants of scleroderma can be interested.32 Additional
cutaneous neoplasia include melanoma, dermatofibrosarcoma protuberans and BCC.33-39 A Swedish national population-based study reported an increased
risk of NMSC in scleroderma patients with a SIR
of 4.2 (95% CI 1.4-9.8), especially among women.40
Increased NMSC risk was limited to the subset of
patients with diffuse or limited scleroderma. In a
larger Danish population-based study, cancer was diagnosed in 222 out of 2040 sclerodema patients and
Vol. 149 - No. 5
KOSTAKI
comprised 28 NMSCs (BCC and SCC) and 6 melanomas with an increased risk of NMSC (SIR=1.3, 95%
CI 0.9-1.9), especially among men (SIR=2.4, 95%
CI 1.2-4.4), and of melanoma (SIR=1.7, 95% CI 0.63.6) in the absence of gender difference.41 A SIR of
26.6 for NMSC was reported in a Hungarian cohort
of 218 scleroderma patients.42 Nine melanomas out
of 90 cancer cases were identified in 441 scleroderma patients of a population-based cohort from South
Australia. In this study, NMSC could not be evaluated since they were not included in the registry.37
Regarding clinical characteristics of sclerodermarelated SCC, the current knowledge relies on isolated case reports or small case series.32, 38, 43, 44 It is
well established that SCC can arise on chronically
inflamed wounds and, as such, burns, scars and skin
ulcers may precede malignant transformation. Since
it is not uncommon for patients with scleroderma to
develop ulcers and scars, it is conceivable that scleroderma patients have a high risk to develop SCC
within these lesions. The most common reported
sites of scleroderma-related SCC are legs followed
by feet and scalp. Patients consistently suffer from
scleroderma for years prior to developing a tumor
and multiple primaries within confluent sclerotic
plaques are a feature in adult onset cases.32 Finally,
patients with scleroderma are likely to develop more
aggressive SCC, probably due to a difficult and delayed recognition of the tumor at diagnosis since it
arises in already damaged skin.38, 45, 46
The increased risk of skin cancers in scleroderma
may be related to the primary immune suppression
of the disease itself or may be secondary to the immunosuppressive effect of therapies (drugs, UVA1
and PUVA therapy).41, 42 Since tumor location corresponds to sites commonly affected by fibrosis and
ulceration, persistent inflammation, local lymphatic
ablation, poor nutrient and vascular delivery at these
sites may also facilitate the development of skin cancer in scleroderma patients.38
Sjögren’s syndrome
Lymphoproliferative malignancies are a well-established life-threatening comorbidity of Sjögren’s
syndrome (SS). A high incidence of lymphomas,
mainly B-cell lymphomas, has been reported in primary SS patients with an estimated 16-fold increased
risk as compared to the general population.47-50 A
569
KOSTAKI
higher relative risk of 44.4 has been previously reported but probably related to the highly selected
population of patients with severe disease included
in the original study.51 Skin vasculitis, low peripheral
CD4+ counts, reduced CD4+/CD8+ ratio≤0.8, monoclonal B-cell proliferation and low serum complement levels have been suggested as clinical predictors of lymphoma in SS patients.49, 52 Waldenström’s
macroglobulinemia, chronic lymphocytic leukemia
and multiple myeloma are additional lymphoproliferative disorders described in SS patients.53
Limited evidence is available on the development
of primary cutaneous lymphomas in SS patients. Isolated cases of pleomorphic T-cell lymphoma, primary cutaneous large B-cell lymphoma of the legs and
cutaneous IgGk plasmocytoma have been indeed reported in association with primary SS.54-56
Underlying causes for the development of lymphoma in SS patients potentially include persistent
antigenic stimulation, impaired apoptosis, mutagenicity of B cells, T-cell modulation and the effects
of BLys or type 1 interferon.49, 52 Although disease
activity is difficult to assess in SS, localized chronic
inflammation might also contribute to SS-related increased risk of malignancy.
Regarding cancers other than lymphoproliferative diseases, studies failed to demonstrate any significant association between SS and solid tumors
including skin cancers.49, 50, 57 The observation that
NMSC might be a risk factor for the development of
B-cell lymphoma in SS patients is worthy of further
investigations.49
Dermatomyositis
The association between dermatomyositis (DM)
and risk of malignancy has been extensively reported
in epidemiological studies, occurring in about 30%
of cases with a higher incidence in elderly individuals and within the first year of DM diagnosis.59-62
Cancer diagnosis can precede, parallel or follow
DM diagnosis. The reported highest risk for cancer
within the first year of DM diagnosis suggests the
paraneoplastic nature of DM.61 However, a more aggressive cancer screening after the diagnosis of DM
could influence detection of malignancy. A parallel
clinical course between DM and malignancy has
been reported in some patients, with disappearance
of DM cutaneous and muscle manifestations after
570
treatment of the tumor and recurrence of DM symptoms after recurrence of cancer. Although the underlying mechanisms of this association are unclear, it
has been suggested that the presence of a cross-reaction between antigenic epitopes in the muscle and
tumor antigens generate an inflammatory response
against muscle.63 The lifelong use of immunosuppressive medications in DM may also contribute to
an elevated risk of cancer after years of observation.
The types of malignancy detected in patients with
DM generally reflect those found in age- and sexmatched general population, further supporting the
paraneoplastic process in DM that can happen with
any kind of cancer. Newly diagnosed patients with
DM should receive age- and gender-appropriate malignancy evaluations although the optimal strategies
and length of cancer screening are still a matter of
debate.
Melanoma has been rarely reported in association
with DM, mainly as metastatic disease. Occurrence
of DM during the course of melanoma has been regarded as a poor prognostic marker leading to death
of patients within a few months.64, 65 However, a
more recent literature review revealed that DM occurring in patients with stage IV melanoma is associated with a poorer prognosis as compared to stage
IV melanoma patients without DM while stage III
melanoma patients with and without DM retain similar prognosis.66
In a single-center retrospective study assessing
malignancies up to 12 months after the diagnosis of
DM, 3 NMSCs (2 SCCs and 1 BCC) were identified out of 12 cancer cases in 139 newly diagnosed
DM patients.60 However, few data are available on
NMSC in DM patients, since data on NMSC are not
included in all studies.67
Occurrence of cutaneous lymphomas has been
exceptionally described in DM patients. Isolated reports of mycosis fungoides,68, 69 angiotropic T-cell
lymphoma 70 or nasal type NK/T cell lymphoma 71
as well as of cutaneous B cell lymphoma have been
described in patients with DM.72, 73
Final considerations
Patients with ACTDs exhibit a higher risk of developing skin tumors, especially SCC. The occurrence of skin cancer has a profound impact on their
already compromised quality of life and their life ex-
October 2014
pectancy. Awareness of this association can guide effective screening and monitoring strategies in ACTD
patients since early detection and rapid therapeutic
intervention can reduce morbidity and mortality.
Continuing interest in this field may help to understand the underlying biological mechanisms linking
skin cancer to ACTDs and, thus, to identify risk factors in such patients.
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33. Abu-Shakra M, Guillemin F, Lee P. Cancer in systemic sclerosis.
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2000;20:39-40.
36. Westermann GW, Buerger H, Kappes U, Matzkies F, Kisters K.
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with progressive systemic sclerosis. South Med J 2002;95:363-5.
37. Hill CL, Nguyen AM, Roder D, Roberts-Thomson P. Risk of cancer
in patients with scleroderma: a population based cohort study. Ann
Rheum Dis 2003;62:728-31.
38. Saleh DB, Williams AM, Smith IM. Cutaneous squamous cell carcinoma arising within generalized morphea. J Plast Reconstr Aesthet
Surg 2011;64:e149-52.
39. Siau K, Laversuch CJ, Creamer P, O’Rourke KP. Malignancy in
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40. Rosenthal AK, McLaughlin JK, Gridley G, Nyrén O. Incidence of
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41. Olesen AB, Svaerke C, Farkas DK, Sørensen HT. Systemic sclerosis
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MG, Poppema S. Sjögren’s syndrome with specific cutaneous
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1989;92:357-61.
55. Jubert C, Cosnes A, Clerici T, Gaulard P, André P, Revuz J et al.
Sjögren’s syndrome and cutaneous B cell lymphoma revealed by
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56. Selva-O’Callaghan A, Perez-López J, Solans-Laque R, Lopez-Peig
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in the manuscript.
October 2014

A. VERDELLI, E. ANTIGA, V. BONCIOLINI, D. BONCIANI, W. VOLPI, M. CAPRONI
Connective tissue diseases (CTDs) are defined as a group
of acquired disorders resulting from persistent immunomediated inflammation. Several classes of drugs seem to be
capable of inducing or exacerbating CTDs. A drug-induced
(DI) syndrome is defined as a condition temporally related
to continuous drug exposure, which resolves upon drug
discontinuation. Among CTDs, lupus erythematosus is the
most widely known and investigated DI syndrome. However,
in recent years, the association between the onset of other
CTDs, such as dermatomyositis (DM) and morphea/systemic sclerosis (SSc) has increased in patients with preceding
exposure to particular substances. Herein, we conducted a
review of published case reports including DM and morphea/SSc, evaluating the real causality among drugs and
these syndromes.
Key words: Connective tissue diseases - Dermatomyositis Scleroderma, systemic.
C
onnective tissue diseases (CTDs) are defined
as a group of acquired disorders resulting
from persistent immuno-mediated inflammation.
The classic autoimmune CTDs include systemic
lupus erythematosus (SLE), dermatomyositis/
polymyositis (DM/PM), systemic sclerosis (SSc),
Sjögren’s Syndrome (SS), undifferentiated CTD
(UTCD) and overlap syndromes e.g. mixed CTD
(MCTD).1
Many CTDs related to drug therapies have been
described in literature. Moreover, the introduction of
new therapeutic agents in recent years has been acCorresponding author: A. Verdelli, Section of Dermatology, Department of Surgery and Translational Medicine, University of Florence,
Viale Michelangiolo 41, 50125 Florence, Italy.
E‑mail: [email protected]
Vol. 149 - No. 5
Department of Surgery and Translational Medicine
Section of Dermatology, Section of Dermatology
University of Florence
Florence, Italy
companied by an increase in such reported associations. By definition, drug-induced (DI) syndromes
are temporally associated with the use of a drug and
the symptoms and signs generally regress with its
discontinuation.2 The most common DI-syndrome
is DI-lupus erythematosus (DILE) 3 but cases of
DI-dermatomyositis (DI-DM) have also been described.4 Furthermore, several reports point out a
possible association between the onset of cutaneous
scleroderma-like lesions and the preceding, usually
long term, exposure to different drugs.5, 6 However,
the pathogenesis of most of these syndromes remains
unclear.
In this article, we reviewed the literature on commonly DI-CTDs, focusing on the main aspects of
DM and morphea/SSc. DILE is not included, since
Marzano et al.2 published an exhaustive review in the
previous volume.
Materials and methods
We carried out a review of the Medline/PubMedcited literature on DI-DM and morphea/SSc until the
1950s. Regarding DM, we only included cases of
classic and amyopathic DM, while cases of DI-PM
were excluded.
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VERDELLI
Results
Drug-induced dermatomyositis
DM is a rare autoimmune disease characterized by
proximal muscle weakness, elevated serum creatine
kinase (CK), abnormal electromyogram and abnormal muscle biopsy.
Pathognomic cutaneous findings include Gottron’s
papules, Gottron’s sign and heliotrope rash. Until now, different DM subsets have been identified.
These subsets include classic DM, amyopathic DM
(without muscle involvement), hypomyopathic DM,
post-myopathic DM and DM sine dermatitis.7
In the past, DM caused or exacerbated by drugs
has also been described as drug-induced dermopathy, pseudo-DM, DM-like eruption or DM associated with a specific drug.
The search yielded 72 articles reporting a possible
association of drugs with DM. We identified a total
of 91 DI-DM reported cases.
DM was described both in male and female patients
with no sex prevalence. The median age at diagnoses
was 56 (ranging from 29 to 82 years). The median
duration of treatment before the onset of DM was 24
months ranging from 2 days after a carticaine injection
to 11 years in association to penicillin. The majority of
patients had underlying disease (65%). Malignancies
were present in 37 out of 91 patients (40%) and the
most common one was chronic myelogenous leukemia (CML). Other haematological disorders included:
acute lymphocytic lymphoma, acute myeloid leukaemia, follicular lymphoma, essential thrombocythemia,
polycythemia vera and myelofibrosis.8-10 The neoplasms also included two cases of gastrointestinal adenocarcinomas 11, 12 and one case of melanoma which
developed after interferon α-2b treatment.13
Autoimmune diseases were present in 22 out of
91 patients (24%). The most common one was rheumatoid arthritis (RA) (17 out of 22 patients) 14-16 followed by juvenile idiopathic arthritis (JIA) 17, 18 and
psoriasis.19, 20 In one case, DM developed in a patient
treated with anti TNF-α for Crohn’s disease.21
A cytoreductive agent, hydroxyurea (HU), used in
the treatment of neoplastic myeloproliferative disorders (chronic myeloid leukaemia, polycythemia rubra
vera, essential thrombocythemia and myelofibrosis),
was the most common drug involved.8, 10, 22-34 Other
medications such as D-penicillamine, non-steroidal
anti-inflammatory drugs, anti-infective agents, anti-
574
neoplastic, lipid lowering drugs and anti TNF-α have
also been associated with DI-DM (Table I).35-65 For
some of these agents, only sporadic or unique cases
were reported.
Most of the patients showed clinical and histologic findings similar to those of the idiopathic form.
However, compared with the other DI-DM,4 the HUinduced DM seems to be associated with a distinct
dermopathy. The HU reaction had typical dermal
features of dermatomyositis, like scaly erythematous
patches, papules and plaques of the dorsal hands,
with atrophic and telangiectatic changes. Pruritic
erythematous patches developing on the extremities
and dorsa of the feet, and poikiloderma in photosensitive areas have also been rarely described. The face
may be involved, with edema and heliotrope rash in
some cases.8
HU-induced DM cases were uniformly negative for systemic involvement, with no antinuclear
autoantibodies (ANA)-positive patients. It was not
reported any proximal muscle weakness and the
muscle enzyme level and electromyography were
normal. In most patients, clinical manifestations imTable I.—Drugs reported to be the trigger of drug-induced dermatomyositis.
Cytotoxics/antitumor antibiotics Hydroxyurea
HMG Co-A reductase inhibitor Atorvastatin
Lovastatin
Pravastatin
Simvastatin
Chelator
Penicillamine
Local anesthetic (Amide)
Carticaine
Nonsteroidal anti-inflammatory Niflumic acid
Phenylbutazone
Alkylating agent
Cyclophosphamide
Cytotoxic agent
Capecitabine
Topoisomerase inhibitor (Podo- Etoposide
phyllum)
Kinase inhibitor
Imatinib mesylate
Interferon
Interferon alfa-2b
Antidote
Ipecac
Proton pump inhibitor
Omeprazole
Anticonvulsant
Phenytoin
Sulfa antimicrobial
Sulphacetamide sodium10%
eye drops
Antimetabolite (5-fluorouracil)
Tegafur
Alpha-blocker
Alfuzosin
Fibrate
Gemfibrozil
Vaccine
BCG vaccine
Bisphosphonate
Zoledronic acid
Tumor necrosis factor alpha
Etanercept
inhibitor
Adalimumab
Infliximab
October 2014
proved within the 1 to 12 months that followed the
discontinuation of HU therapy without recurrence.26
On the other hand, with ANA positivity (80%),4 the
non-HU-DM commonly displayed muscle weakness
or evidence of myositis The HU group had a longer
time to onset (>5 years) and it was invariably associated with other cutaneous signs of HU therapy
including: leg and oral ulcers, stomatitis, melanonychia, palmoplantar keratoderma and ichtyosiform
lesions.28 As a result of these distinct features, DM
induced by HU is most commonly termed HU-induced DM-LE, but has also been known as DM-like
lesions, pseudo-DM, Gottron’s papules-like rash or
HU dermopathy. Nofal et al recently proposed the
term “HU-induced amyopathic DM” to identify this
subset of patients because the skin lesions are identical to the one of classic DM, but without the clinical
or laboratory evidence of myositis.8
Several cases of statin-induced DM among nonHU-DM were described 35-38 These 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors, commonly used in the treatment of hypercholesterolaemia and prevention of cardiovascular
events, are known to produce a skeletal muscle myopathy with symptoms ranging from mild myalgias
to frank rhabdomyolysis. In literature there are 14
reports of statin-associated DM 37 mostly characterized by typical cutaneous lesions, elevated CK levels
and proximal muscle weakness during or after statin
therapy. DM manifested between 2 months and up to
5 years after the initiation of treatment. The disease
occurred either after intake of first-generation (simvastatin, lovastatin and pravastatin) or of second-generation HMG-CoA reductase inhibitors (atorvastatin
and fluvastatin).38 Apart from one fatal outcome due
to DM-associated lung fibrosis, statin-associated
DM shows a relatively benign course. However,
most cases required systemic treatment with glucocorticoids to control the disease.36
In recent years, as anti-tumor necrosis factor
(TNF)-α treatment has increased, especially in severe psoriasis, and side effects associated to this
class of drug have increased. Anti- TNF-α associated DM/PM is rare, consisting in less than 1% of
reported cases of anti- TNF-α induced autoimmune
phenomena.39-44 We found 14 publications describing a total of 21 patients who were treated with
anti-TNF-α agents in the setting of dermatological
or rheumatologic conditions such as RA, Crohn’s
disease, ankylosing spondilytis (AS), JIA and seron-
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VERDELLI
egative arthritis with a familiar history of psoriasis
who developed DM. Anti-TNF-α therapy included
etanercept, adalimumab, infliximab and lenercept.
In two cases both infliximab and adalimumab were
administred while in one case etanercept and adalimumab determined a new onset and an exacerbation
of DM. An improvement of DM after withdrawal of
the anti-TNF-α agents was recorded in more than
94% of cases.21
Drug-induced morphea/systemic sclerosis
The term scleroderma refers to thickening of the
skin as a result of increased collagen deposition. It
is classified as two separate, but related entities, a
localized form and a systemic form.
The localized scleroderma, also known as morphea, is a sclerotic condition limited to the skin. It
is divided into five categories: plaque, generalized,
bullous, linear, and deep.66
SSc is a heterogeneous disease which pathogenesis is characterized by small vessel vasculopathy,
production of autoantibodies and fibroblast dysfunction leading to increased deposition of extracellular
matrix.67 The clinical manifestations and the prognosis of SSc vary with the majority of patients having
skin thickening and variable involvement of internal
organs. SSc is divided into limited and diffuse disease based on the extent of skin involvement.
In literature, there are various syndromes and anecdotal cases in which patients have features similar
to, or the same as, those in “classic” scleroderma after being exposed to drugs.6
These syndromes can be triggered or exacerbated
by many drugs such as taxanes, bleomycin, pentazocine, D-pencillamin, anti-neoplastic agents, cathepsin K inhibitor balicatib, and injections (vitamin K1
e K12) (Table II).68-97 Recently, 4 cases of anti TNF-α
induced morphea have also been reported. Two cases
were associated to adalimumab, one to infliximab
and the last one to etanercept.68-71
Totally, 82 cases of DI morphea/SSc were found.
Patients’ median age was 40 years (ranging from 12
to 79 years) mainly female. Skin lesions appeared
after a mean period of 12.5 months (from 1 to 36
months) after the beginning of the drug treatment
which was believed to be responsible for the lesion
development. Most reactions occurred during active treatment, but in few cases after the therapy was
stopped.5, 72, 73
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VERDELLI
Table II.—Drugs reported to be the trigger of drug-induced
scleroderma.
Chemotherapeutics
Bleomycin
Peplomycin
Miotmycin
Docetaxel
Paclitaxel
Carboplatin
Capecitabine
Hydroxyurea
Pentazocine
Analgesics
Ergot, methylsergide
Bromocriptine
Ketobemidone
Morphine
Vitamin
Vitamin B12
Vitamin K1
Amino acids
L-Triptophan
Neurological drugs
Carbidopa and L-5-hydroxy-tryptophan
Ethosuximide
Valproate sodium
Chelant
D-penicillamine
Interferon
Interferon-alpha
Interferon 2b
Anti-hypertensive agents Beta-blocking agents (bisoprolol)
Angiotensin converting enzyme
(ACE) inhibitors (fosinopril)
Corticosteroids
Triamcinolone
Cathepsin K inhibitor
Balicatib
Tumor necrosis factor
Adalimumab
alpha inhibitor
Infliximab
Etanercept
Most of the cases described showed morphea,
characterized by oval or round areas of induration
confined to the dermis, while a minority of the patients developed SSc, with confluent plaques involving different cutaneous sites and systemic involvement. Linear scleroderma was described only
in children. In two cases bullous lesions were also
present.5 Vitamin K1, vitamin B12 and pentazocineinduced morphea was always limited at site of injection.74-77 Sclerotic lesions were usually preceded
by erythematous lesions, variably itchy or associated
with tingling or burning sensation.5, 6
Many chemotherapeutic agents have been associated to scleroderma-like lesions.78-90 Currently, taxanes (docetaxel and paclitaxel) are the most common
drugs involved.79-85 These antimicrotubule agents
are widely used in the treatment of metastatic breast
cancer and other solid tumors. In literature, a total
of 16 cases of taxanes induced scleroderma were reported. The female prevalence can be explained by
the frequent use of taxanes in the treatment of breast
and ovarian cancer. In most patients, skin sclerosis
developed mainly on the extremities, especially on
576
the lower parts of the legs.81 In all the cases, oedema
developed a few months before skin sclerosis, and
appears to be one of the preceding factors for skin
sclerosis itself. Systemic involvement including
Raynaud’s phenomenon and pulmonary fibrosis, as
well as immunological abnormalities, was not detected in any of the patients. The discontinuation of
the drug was associated to oedema and sclerosis improvement, but steroids were necessary in most of
the cases to control the disease.79
So far, a total of 11 cases of bleomycin-induced
scleroderma have been reported.6, 88, 89
Bleomycin, administered intravenously or intramuscularly, is an antitumor antibiotic with a mild
myeolosuppressive effect. It is used to treat several
types of cancer, including testicular neoplasm, as
well as Hodgkin and non-Hodgkin lymphoma. Pulmonary fibrosis is the most severe toxicity associated with belomycin injection.88 The cutaneous adverse reactions included erythema and infiltrations
with marked hyperpigmentation. Nine out of 11
patients showed localized scleroderma while only
2 patients developed diffuse plaques. Sclerodactyly
with swelling and induration of the hands and forearms was present in all the patients, while Raynaud’s
phenomenon and digital pitting scar were described
in few patients. ANA were detected in five cases, but
no patients showed SSc-specific antibodies. Visceral
involvement was reported only in two patients with
lung damage. In many instances, withdrawal of the
culprit drug was not sufficient to obtain complete
remission, suggesting that the drug was the trigger
exacerbating an underlying scleroderma.89
Few patients with metastatic melanoma treated
with interferon-alpha (INF-α), developed vitiligo
and morphea or SSc.86 There have also been reports
of cases in patients receiving pegylated INF-α combined with ribavirin for treatment of hepatitis C infection.
Nine patients treated with balicatib, an inhibitor of
the osteoclastic enzyme cathepsin K under evaluation
for the treatment of osteoporosis, developed dose related morphea-like lesions.5 Skin hardening affected
mostly the trunk and the neck with diffuse morphea.
No systemic involvement was detected and none of
the patients showed Raynaud’s phenomenon. In only
one case there was swelling of the fingers with paraesthesia and slight sclerodactytly. ANA positivity
was demonstrated only in four patients.91
Finally, 17 patients under ergot treatment have
October 2014
been reported with scleroderma and typical migraine
headaches. Most of the patients developed stage I
or II vascular scleroderma, Raynaud’s phenomenon
and systemic involvement including pleural and myocardial damage.6
For all the other drugs, only sporadic cases have
been described with scleroderma-like lesions, usually in the limited variant. Interestingly, few cases
associated with L-5-hydroxytryptophane and carbidopa showed hypereosinophilia with an eosinophilia
myalgia-like syndrome.94
Discussion
Drug-induced dermatomyositis
Several cases of DI-DM were described in the past
decades. The majority of cases (85%) had pathognomic skin findings for DM with or without muscle
involvement, associated to compatible histology. Serologies, including ANA and anti-Jo1, were mostly
negative.
There is uncertainty whether DI-DM exists, particularly as the majority of patients have underlying diseases that are possibly associated with DM.
Moreover, the identification of an offending drug or
attributing causality may be challenging in patients
taking multidrug therapy.5
As reported previously, 22 of the suspected cases
of DI-DM showed an association between DM and
RA. Such an association has long been well known,
but its real incidence is unknown.40 RA can precede
myositis or it can develop after the diagnosis of
DM.39 However, no uniform criteria or detailed case
records can be found regarding these cases. Furthermore, patients with DM may also have joint manifestations that can be misinterpreted as RA, even if
these manifestations rarely lead to joint deformities
and destruction.42
To our knowledge, there is no clear and confirmed
relation between RA and DM, even if there is a significant increase in the frequency of autoimmune diseases (also including RA) in first-degree relatives of
patients affected by idiopathic inflammatory myopathies. This association between many autoimmune
diseases can be explained by the fact that many disorders share genes that together act as polygenic risk
factors for autoimmunity.98
In the whole, 40% of the patients reported in our
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VERDELLI
Table III.—DI-DM: diagnostic criteria.
1. A plausible time relationship to drug administration
2. No other concurrent disease or drugs that could have caused
the DM
3. Remarkable improvement of the skin lesions after withdrawal
(dechallenge)
4. Reappearance of the skin lesions upon rechallange
revision had underlying malignancies. The most
common one was CML. In a recent review,4 evaluating a total of 70 DI-DM patients, authors pointed
out that the presence of an associated disease alone,
especially malignancy, may not provide a strong argument for the onset of DM in the majority of patients. DM occurred after a long period (> 3 years)
and nearly in all patients there was an improvement
of DM with discontinuation of the drug and/or additional treatment (84.3%).30 Moreover, adenocarcinomas, the most common DM associated malignancies 99 were present only in two DI-DM patients. All
these data suggest a possible pathogenetic role of
these drugs in developing DM.
Recently, Seidler et al proposed a classification
system for DI-DM composed of four criteria, shown
in Table III. If all the 4 criteria were present DI-DM
was considered certain. probable if 3 criteria were
fulfilled, and possible only if a plausible time relationship was shown. According to these criteria, no
cases of certain causality have been reported yet,
since most of patients satisfied only one criterion,
i.e. time relationship.
The pathomechanism of DI-DM is not well understood yet. It is postulated that the main mechanisms,
by which these drugs induce autoimmunity, are the
promotion of apoptosis and the enhancement of the
innate immune response. This causes the displacement of various cellular antigens resulting in a state
of neo-antigenicity and anti-endothelial cell antibody formation.
DI-morphea/SSc
Different categories of drugs have been implicated
in DI-scleroderma. In many cases, discontinuation of
the culprit agent alone was not sufficient to obtain
complete remission, suggesting that the drug was the
trigger exacerbating an underlying scleroderma.
A direct role for some classes of drugs in the pathogenesis of scleroderma is well demonstrated. As an
example, the bleomycin-induced mouse model has
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VERDELLI
been established and used extensively to investigate
the pathogenesis of SSc. It has also been used to
seek new therapeutic agents, since the subcutaneous
injection of bleomycin to mice induces fibrosis and
inflammatory infiltration in the dermis and lung and
stimulated autoantibody production, which mimics
SSc.100
A profibrotic effect due to the collagen synthesis
and/or fibroblast growth, has also been documented
for peplomycin, dopaminergic drugs and beta-blocker agents.5
The role of chemotherapeutic agents is still controversial since scleroderma has been associated
with various cancers. However, the onset of the disease in most patients appears to be in a closer temporal relationship with the administration of chemotherapy (mean period 16 months) than with the onset
of neoplasia (mean period 42 months). Furthermore,
the underlying cancer was in remission in most of
patients, making a paraneoplastic nature of scleroderma unlikely. From this point of view, immune
modulating activities of chemotherapeutic drugs
may be responsible, together with their direct chemical effect, for triggering the immune cascade that activates fibroblasts.
An ischemic damage has been postulated for ergot
derivatives and pentazocine.5
Vitamin K1 and vitamin B12 may induce morphea-like lesions locally, possibly in relation to a
toxic effect of the vehicle or the preservative, or to a
hypersensitivity reaction.75-77
Balicatib is a selective cathepsin K inhibitor, but
some studies have showed that it can also inhibit
cathepsins B, L and S, which are all expressed by
skin fibroblast.5 Cathepsin K is a key enzyme in osteoclastic bone resorption. At the same time, it is
able to degrade type I and type III collagen as well as
elastin. It is plausible that the observed skin fibrosis
in the described patients was a result of the inhibition of matrix-degrading functions of cathepsins in
the skin.91
Finally, anti TNF-α seems to be implicated in rare
cases of morphea.68 As a consequence of TNF-α suppression, TNF blockers may act on tumour growth
factor beta 1 (TGF-β1), a pro-fibrotic cytokine involved in skin thickening, inducing an accumulation of the extracellular matrix through its actions
on fibroblasts and endothelial cells.70 Another study
points out the role of Th2 cells in the regulation of
fibrosis reducing type I collagen synthesis by dermal
578
fibroblasts. TNF-α, inhibition may dysregulate the
balance between pro-fibrotic and anti-fibrotic triggers, promoting collagen deposition.
Conclusions
Our review was limited by the small number of
cases reported. Not all the information regarding
each patient were uniform. Moreover, for most of the
cases described, only sporadic association with an
offending drug was shown. No clinical or histological differences among DI- DM or DI-morphea/SSc
and the idiopathic counterpart were found either.
Thus, no uniform diagnostic criteria have been developed until now. Clinical improvement after withdrawal of the drug seems to be the only criterion that
can help us in making diagnosis. Furthermore, an
additional treatment was often necessary to control
the disease.
In conclusion, DI- DM and DI-morphea/SSc
seem to be rare. The patients must be monitored to
exclude underlying diseases, such as neoplasms or
autoimmune diseases. If the clinical possibility of a
DI syndrome is encountered, drug discontinuation
is recommended. Improvement of the lesions would
support a pathogenic role for the guilty drug.
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in the manuscript.
October 2014

ORIGINAL ARTICLES
The use of skin needling
for the delivery of a eutectic mixture of local anesthetics
G. FABBROCINI, V. DE VITA, R. IZZO, G. MONFRECOLA
Aim. The use of skin needling is believed to aid the transdermal delivery of drugs, even if it is mostly used for skin collagen induction. The aim of this paper was to use skin needling,
combined with a local anesthetic EMLA (eutectic mixture of
lidocaine and prilocaine), as a way to enhance transdermal
drug penetration and optimize the analgesic effects of common local anesthesia.
Methods. We recruited 15 patients. For each patient of our
study we defined a skin area of 3 cm2 from two forearms: on
one side, we used skin needling first and immediately thereafter applied the EMLA in occlusion for 60 minutes; on the
other one, we only applied EMLA in occlusion for 60 minutes. Then, pain was induced in each patient’s forearm by introducing a 27 G needle into the skin 4 mm deep three times.
Lastly, pain sensation measures were registered and a middle
value was calculated.
Results. When skin needling is used in conjunction with
EMLA applied in occlusion for 60 minutes on skin forearms,
the level of pain sensation registered was significantly reduced on a Visual Analogue Scale compared to the application of EMLA alone.
Conclusion. The use of skin needling can improve the transdermal delivery of an emulsion-like eutectic mixture of local
anesthetics (EMLA) and can introduce the use of this method
for delivering topical molecules in dermatology.
Key words: EMLA - Anesthesia, local - Dermatology.
T
he stratum corneum (SC), the outermost layer
of the skin, is the main barrier for transdermal
drug delivery.1, 2 This thin stratum ranges from 10
to 20 μm and can be considered a highly differentiated structure that controls the diffusion of comCorresponding author: V. De Vita, Section of Dermatology, Department of Clinical Medicine and Surgery, Via Sergio Pansini 5, 80133 Naples, Italy. E-mail: [email protected]
Vol. 148 - No. 5
Section of Dermatology
Department of Clinical Medicine and Surgery
Federico II University of Naples, Naples, Italy
pounds across the skin. The transdermal delivery of
drugs is significantly restricted for the presence of
the stratum corneum. To penetrate into the skin, drug
molecule must be of small size and/or low molecular
weight. Lipophilic molecules, which can carry a low
therapeutic dose, can penetrate the skin deeper than
hydrophilic ones.3-5 In the last few years transdermal
delivery of active substances has become an important therapy used to treat a large number of skin diseases.
Skin penetration enhancement can be achieved
either physically or chemically.6-9 Many techniques
have been developed to improve transdermal drug
delivery, such as electroporation,10, 11 sonophoresis
12, 13 and iontophoresis.14, 15 These techniques have
shown to improve the permeability of the stratum
corneum layer and enhance penetration of topical
agents across the skin.
Recently the use of microneedles has been proposed as another strategy to dramatically increase
drug delivery through the skin. Several authors have
used microneedle injections with topical application
to investigate if microneedles enhance in-vivo drug
delivery through the stratum corneum: microneedle-injected sites showed a significantly higher
transdermal penetration.16-23 Microneedles are also
of most interest because they could offer painless
drug delivery due to the absence of nerves in the
581
FABBROCINI
SKIN NEEDLING FOR LOCAL ANESTHETICS DELIVERY
skin’s stratum corneum. In current practice, there
is no evidence of microneedles penetrating 10-20
µm across the stratum corneum without entering
the viable epidermis, where nerves are found. Instead, microneedles are inserted into the epidermis
and sometimes into the superficial dermis. Nevertheless, microneedles are still reported as painless,
probably because their small size reduces the odds
of encountering a nerve or of stimulating it to produce a painful sensation.24
EMLA cream, an eutectic mixture of local anesthetics with lidocaine 2.5% and prilocaine 2.5% has
been shown to decrease the discomfort of such procedures, particularly in pediatric patients. Although
it is considered to be effective, its penetration is low
and the onset of anesthesia is slow. Topical anesthesia for more invasive procedures such as split-thickness skin graft harvesting may require 1 to 2 hours
EMLA application. This delay in onset of topical anesthesia is generally considered problematic.
Objective
The purpose of our study was to evaluate the use
of microneedles in order to improve the transdermal
delivery of EMLA used for superficial anesthesia in
skin surgical procedures.
Patients
Fifteen patients were recruited for this study from
relatives of in-patients of the Dermatology DivisionUniversity of Naples Federico II from patients who
have to receive an excision treatment. All patients
enrolled into the study gave an informed consent
to partake in the study. The participants were recruited between October and December of 2011 and
the sample was stratified by sex (10 females and 5
males) and by age (between 18 and 45 years, with
an average of 23 years). Exclusion criteria included:
patient refusal, contraindication to EMLA (allergy
to any of its components, congenital methemoglobinemia, porphyria), concomitant use of an analgesic
within the previous 24 hours, diabetes, neurologic
sensorimotor disorders, infection localized to the
site of puncture, damaged skin at the designated
site, psychiatric disorder and dementia. The study
was conducted in accordance with the Declaration
of Helsinki and approved by the local ethics committee.
582
Procedure
EMLA Cream (lidocaine 2.5% and prilocaine
2.5%) is an emulsion in which the oil element is a
eutectic mixture of lidocaine and prilocaine in a ratio
of 1:1 by weight. It is used as a local skin anesthetic
and applied to the skin before superficial surgical
procedures or prior to the insertion of intravenous
needles. For each patient of our study we defined a
skin area of 3 cm2 from two forearms: on one side,
we used skin needling first and immediately thereafter applied the EMLA in occlusion for 60 minutes;
on the other one, we only applied EMLA in occlusion for 60 minutes (Figures 1-3). Then, pain was
induced in each patient’s forearm by introducing a
27 G needle into the skin 4 mm deep three times.
Lastly, pain sensation measures were registered and
a middle value was calculated.
For the microneedling we used a skin needling tool
(Dermaroller ™ - Model CIT 8) that consists of a 12
cm plastic handle at the end of which lies a cylinder,
like a small paint-roller, of 20 mm diameter and 20
mm length. On the surface of the cylinder are 24 circular arrays of 8 needles each (total 192 needles), with
a needle length of only 0.05±0.02 mm and a diameter
of 0.02 mm. Needles and disks are firmly bound together with a special medically approved adhesive.
Needles create microtrauma, microinflammation
and very little damage in the epidermis and in the
deep dermis. The healing phase is short: the skin
appears mildly redness and swollen only for 24-48
hours. No side effects were observed.
Pain evaluation grading
The evaluation of pain sensation, an indirect expression of EMLA penetration, was performed by
using a Visual Analogue Scale (VAS) (Figure 3).
The level of personal pain experienced can only be
indirectly measured by self-reported ratings, often
by using a one-dimensional pain rating scale.25, 26
According to this measurement scale, the levels
of pain ranges across a continuum from “none” to
“worst” possible pain. Operationally a VAS is usually a horizontal line, 100 mm in length, with 0 on
one end, representing no pain, and 10 on the other,
representing the worst pain ever experienced. Patients mark on the line the point that they feel represents their perception of pain. The VAS score is
determined by measuring in millimeters from the
October 2014
Figure 1.—A device with microneedles is rolled back and forth ten times
in four directions, applying a slight pressure.
left end of the line to the point that the patient marks
on the scale.27
FABBROCINI
Figure 2.—EMLA cream is applied to a skin area of 3 cm2 from two
forearms in occlusion for 60 minutes to increase its transdermal delivery: on one side, we used skin needling first and immediately thereafter
applied the EMLA cream; on the other one, we only applied EMLA
cream without previously using the microneedles device.
Statistical analysis
Data were analyzed using SPSS version 13.0 for
Windows. Student’s t-test was performed to determine the difference among VAS value with and without needling. Significant level were set at P<0.05.
Results
The results of our study have shown that, when skin
needling is used in conjunction with EMLA applied in
occlusion for 60 minutes, the level of pain experienced
by each patient was significantly reduced (Figure 4).
Patients recruited for the trial reported a mean reduction in pain of 31.2 (51.3±6.7 vs. 20.1±4.2) mm on the
Visual Analogue Scale (VAS): the mean score obtained
on the side treated by microneedling compared to the
side not treated by microneedling, was significantly
lower (Student’s t paired test; P<0.05). Our results have
showed a statistically significant difference between
the two groups and suggest that the use of microneedling can improve the transdermal delivery of EMLA.
These results, even if preliminary, offer an important contribution to local anesthesia and pain management of human skin and suggest that microneedles can be a useful approach to enhance transdermal
drug delivery in dermatology.
Vol. 148 - No. 5
Figure 3.—Visual Analogue Scale (VAS): a horizontal line, 100 mm in
length, with 0 on one end, representing no pain, and 10 on the other, representing the worst pain ever experienced; patients were asked to mark
on the line the point that they feel represents their perception of pain.
Discussion and conclusion
EMLA cream, an eutectic mixture of local anesthetics with lidocaine 2.5% and prilocaine 2.5% has
been shown to decrease the discomfort of such procedures, particularly in pediatric patients. Although
it is considered to be effective, the onset of anesthesia is slow. The depth of penetration and degree of
topical anesthesia attained following EMLA application depends on the duration of the application.
McCafferty et al. have shown that following a 60
minutes EMLA application to the skin, only 45% of
the subjects demonstrated complete loss of pin prick
sensation at the site.28 Topical anesthesia for more
invasive procedures such as split-thickness skin graft
harvesting may require up to 2 hours EMLA application. This delay in onset of topical anesthesia is
583
FABBROCINI
Figure 4.—Pain reduction comparison: the mean score obtained on the side treated by microneedling compared to the side not treated by microneedling was significantly lower.
inconvenient as well as impractical in some clinical
settings.29
Recent reports have tried to identify the mechanisms involved in the enhancement of transdermal drug
delivery and several hypotheses have been proposed,
though none is completely exhausted.
To understand the mechanism by which microneedles increase skin permeability, McAllister
et al. theoretically modeled transdermal transport
as diffusion through holes of known geometry
made by insertion of microneedles. All scientific
data is based on a repetitive rolling, of 10 to 15
times, on the same area of the skin.30 Kalluri et
al. have investigated the pore closure kinetics for
the microchannels created by these stainless steel
microneedles. The time taken for skin to restore its
barrier function and to complete pore closure was
investigated by calcein imaging studies. Calcein
dye binds only living cells which are exposed upon
disruption of the skin barrier, thereby indicating
presence or absence of pores. In skin sites treated
with microneedles, complete pore closure occur
12-18 h after poration, depending on the length of
microneedles. Traditionally, chemical agents such
as esters, azones, cyclodextrins, etc. have been
employed in formulations as a means to alter the
584
barrier properties of the stratum corneum layer
of skin and aid in better permeation of the active
agent. These permeation enhancers tend to disrupt
the lipid structure of the SC layer, thereby causing damage which takes a long recovery time. The
reversible nature of microchannels is very advantageous for controlled delivery of cosmetic agents/
therapeutic compounds.31, 32
The results of our study confirm the findings from
previous reports and show that microneedles can be a
useful approach in enhancing skin permeability and
transdermal drug delivery. The potential advantages
of this procedure include the significantly increased
accumulation of a skin drug depot, short delivery lag
times, simplicity and better penetration. Our study
represents an interesting tool for further in-depth research and additional experimentation on the use of
skin needling as a procedure improving the transdermal delivery of drugs.
References
1. Hadgraft J. Skin, the final frontier. Int J Pharm 2001;224:1-18.
2. Trommer H, Neubert RHH. Overcoming the stratum corneum: the
modulation of skin penetration. Skin Pharmacol Physiol 2006;19:
106-21.
October 2014
3. Forslind B. A domain mosaic model of the skin barrier. Acta Derm
Venereol 1994;74:1-6.
4. Norlen L. Skin barrier formation: the membrane folding model. J
Invest Dermatol 2001;117:823-9.
5. Norlen L. Skin barrier structure and function: the single gel phase
model. J Invest Dermatol 2001;117:830-6.
6. Kalbitz J, Neubert R, Wohlrab W. Modulation of drug penetration in
the skin. Pharmazie 1996;51:619-37.
7. Walker RB, Smith EW. The role of percutaneous penetration enhancers. Adv Drug Deliv Rev 1996;18:295-301.
8. Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv
Rev 2004;56:603-18.
9. Mitragotri S. Synergistic effect of enhancers for transdermal drug
delivery. Synergistic effect of enhancers for transdermal drug delivery. Pharm Res 2000;17:1354-9.
10. Denet AR, Vanbever R, Préat V. Skin electroporation for transdermal and topical delivery. Advanced Drug Delivery Reviews
2004;56:659-74.
11. Hui SW. Overview of drug delivery and alternative methods to electroporation. Methods Mol Biol 2008;423:91-107.
12. Santoianni P, Nino M, Calabrò G. Intradermal drug delivery by low
frequency sonophoresis (25KHz) Dermatol Online J 2004;10:24.
13. Mitragotri S, Kost J. Low-frequency sonophoresis-A review. Advanced Drug Delivery Reviews 2004;56:589-601.
14. Rastogi SK, Singh J. Effect of chemical penetration enhancer and
iontophoresis on the in vitro percutaneous absorption enhancement of insulin through porcine epidermis. Pharm Dev Technol
2005;10:97-104.
15. Le L, Kost J, Mitragotri S. Combined effect of low-frequency ultrasound and iontophoresis: applications for transdermal heparin
delivery. Pharm Res 2000;17:1151-4.
16. Henry S, McAllister DV, Allen MG, Prausnitz MR. 1998 Microfabrication microneedles: a novel approach to transdermal drug delivery. J Pharm Sci 2006;87:922-5.
17. Teo AL, Shearwood C, Ng KC, Moochhala S. Transdermal
microneedles for drug delivery applications. Mater Sc Eng
2006;132:151-4.
18. Lv YG, Lie J and Xu B. Modeling of transdermal drug delivery with
a microneedle array. J Micromech Microeng 2006;16:2492-501.
19. Vandervoort J, Ludwig A. Microneedles for transdermal drug delivery: a minireview. Front Biosci 2008;13:1711-5.
20. Wermeling DP, Banks SL, Hudson DA, Gill HS, Gupta J, Prausnitz MR et al. Microneedles permit transdermal delivery of a skin-
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impermeant medication to humans. Proc Natl Acad Sci U S A
2008;105:2058-63.
21. Wu Y, Qiu Y, Zhang S, Qin G, Gao Y. Microneedle-based drug delivery: studies on delivery parameters and biocompatibility. Biomed
Microdevices 2008;55:1063-71.
22. Wu XM, Todo H, Sugibayashi K. Enhancement of skin permeation
of high molecular compounds by a combination of microneedle pretreatment and iontophoresis. J Control Release 2006;118:189-95.
23. Fabbrocini G, De Vita V, Fardella N, Pastore F, Annunziata MC,
Mauriello MC et al. Skin needling to enhance depigmenting
serum penetration in the treatment of melasma. Plast Surg Int
2011;2011:158241.
24. Kaushik S, Hord AH, Denson DD, McAllister DV, Smitra S, Allen
MG et al. Lack of pain associated with microfabricated microneedles. Anesth Analg 2001;92:502-4.Von Korff M, Jensen MP, Karoly
P. Assessing global pain severity by self-report in clinical and health
services research. Spine 2000;25:3140-51.
25. Scott J, Huskinsson EC. Graphic representation of pain. Pain
1976;2:175-84.
26. Wewers ME, Lowe NK. A critical review of visual analogue scales
in the measurement of clinical phenomena. Res Nurs Health
1990;13:227-36.
27. McCafferty DF, Woolfson AD, Boston V. In vivo assessment of percutaneous local anaesthetic preparations. Br J Anaesth 1989;62:1721.
28. Bjerring P, Arendt-Nielsen L. Depth and duration of skin analgesia
to needle insertion after topical application of EMLA cream. Br J
Anaesth 1990;64:173-7.
29. McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen
MG et al. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport
studies. Proc Natl Acad Sci USA 2003;100:13755-60.
30. Kalluri H, Banga AK. Formation and closure of microchannels in
skin following microporation. Pharm Res 2011;28:82-94.
31. Kalluri H, Kolli CS, Banga AK. Characterization of microchannels created by metal microneedles: formation and closure. AAPS J
2011;13:473-81.
in the manuscript.
Received on February 4, 2014.
Accepted for publication February 4, 2014.
585

REVIEWS
Pyoderma gangrenosum: a systematic review
E. COZZANI, G. GASPARINI, A. PARODI
Pyoderma gangrenosum (PG) is a rare, chronic neutrophilic
dermatosis of unknown etiology. The world wide incidence is
estimated to be around 3-10 cases per million population per
year. In 50-70% of cases inflammatory bowel diseases, hematological malignancies or rheumatologic disorders are associated
to PG. Although the etiology is uncertain, the dysregulation of
the immune system appears to be implied. Pathergy is the most
important triggering factor of PG. Indeed, 20-30% of patients
report the onset of PG following trivial trauma. Four main
variants of PG have been described, namely classic, pustular,
bullous, and vegetative forms. The classic form of PG is characterized by ulcers with a raised, undermined, inflammatory
border. Intense pain is generally associated to PG. The diagnosis is mainly clinical and of exclusion. The differential diagnosis
should take into account infections, vascular disorders and malignancies. The clinical course can be explosive and rapidly progressive or indolent and gradually progressive. Often patients
develop only one episode and the overall prognosis is good but
extremely influenced by the underlying disorders. Local therapy, mainly with topic steroids is used for mild to moderate lesions. For severe forms of PG a systemic therapy with glucocorticoids and/or other drugs such as tacrolimus, cyclosporine, etc.
is needed. This paper is a systematic review of literature on PG.
Key words: Pyoderma gangrenosum - Inflammatory bowel diseases - Therapeutics.
P
yoderma gangrenosum (PG) is a rare, chronic neutrophilic dermatosis of unknown etiology, characterized by extremely painful nodules and pustules,
which evolve into ulcers with a raised, tender and
undermined border. The cutaneous lesions might be
the only manifestation of the disease, but in 50-70%
Corresponding author: E. Cozzani, Di.S.Sal., Section of Dermatology, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Genoa
16132, Italy. E-mail: [email protected]
Vol. 149 - No. 5
Di.S.Sal., Section of Dermatology
IRCCS Azienda Ospedaliera Universitaria San Martino
IST Genoa, Genoa, Italy
of cases, PG is associated to a systemic disease, such
as: inflammatory bowel diseases (IBD), hematological malignancies and rheumatologic disorders. Furthermore, pyodermic lesions are typically triggered
by pathergy, which is reported in 30% of patients.1
Epidemiology
The first description of PG was given by Brocq
in 1916, naming this condition “phagédénisme
géometrique”.2 However, it was thoroughly described for the first time as a nosographic entity in
1930 by Burnsting et al., at the Department of Dermatology of the Mayo Clinic.3 The authors coined
the term pyoderma gangrenosum and hypothesized a
possible infectious etiology.
The world wide incidence of PG is uncertain, but
it is approximately estimated to be around 3-10 cases
per million population per year.4 While, according to
other authors, the incidence of PG is about 1 case per
100,000 population per year.5, 6
PG occurs at any age, but the peak of incidence
is between the ages of 20-50 years.1, 7 Only 3-4% of
cases of PG occur during childhood or adolescence
5 and it’s only occasionally described in elderly
people.8 Females tend to be slightly more affected
than men.
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COZZANI
PYODERMA GANGRENOSUM
Etiology and pathogenesis
The etiology and pathogenesis of PG are not yet
completely understood. In the 1980s, Fulbright et al.
had already advanced the hypothesis, that an aberrant
immunological response to undefined factors could
be responsible for the clinical manifestations of PG.9
Indeed, systemic diseases, characterized by immunological alterations, are often associated with PG.
Furthermore, an exaggerated inflammatory response
to non-specific stimuli characterizes the pathergy
phenomenon, which consists in the onset of new lesions or the worsening of the existing ones following minimal trauma.1, 10 These elements suggest that
the dysregulation of the immune system is probably
implied in the pathogenesis of the cutaneous lesions.
Since IBD are frequently associated to PG, Van
den Driesche et al. hypothesized the possible crossreactivity between intestinal and cutaneous antigens,
which could explain the genesis of the cutaneous lesions as manifestations of the underlying disease.11
Other elements that support the immunological
pathogenesis are the ex adiuvantibus criteria. Indeed, lesions heal with immunosuppressant drugs
and anti-TNF-a biologics. Always according to this
criterion, a T-cell response was hypothesized, based
on the efficacy of T-cell inhibiting drugs12 and T-cell
apoptosis inducing agents.13
Chemotactic defects and hyperactivity of neutrophils
might play a role in pathogenesis. In particular, abnormal neutrophil trafficking, metabolic oscillations,14
aberrant integrins,15 and insufficient cutaneous protection from neutrophilic infiltration were described.
IgA gammopathies have been demonstrated to
alter in vitro the chemotaxis of neutrophils, setting
the basis to hypothesize that IgA might influence the
function of neutrophils in vivo as well. Furthermore,
PG is associated in 10% of patients to monoclonal
or polyclonal hypergammaglobulinemia, especially
IgA and less often IgG or IgM.6
Various studies 16-19 demonstrated an over-expression in skin biopsies taken from pyodermic ulcers of
IL-8, a powerful chemotactic factor for neutrophils.
Oka et al. obtained ulcers absolutely similar to the
pyodermic ones, on human skin xenografts, transplanted on immunodeficient mice, infected by a recombinant virus, able to induce an IL-8 over-expression in human fibroblasts.17 These clinical data and
experimental results suggest that IL-8 might play an
important role in pathogenesis of PG.
588
The deposition of proteins in the walls of cutaneous vessels in PG, has suggested a possible vasculitic
etiology, due to a type III hypersensitivity reaction.
Indeed, the direct immunoflorescence reveals IgM,
C3 and fibrin deposits in vessels of the reticular and
papillary derma in 55% of cases. Less frequently
IgA and IgG deposits are detectable. Furthermore,
Su et al.20 demonstrated a characteristic morphological and pathological evolution of the lesions on biopsy specimens obtained from the necrotic border of
the ulcer. The initial lesions present a mild to moderate perivascular infiltration of lymphocytes and
endothelium edema. The completely developed lesions show necrosis, a dense perivascular infiltration,
extravasated erythrocytes and thrombosis. While ulceration, infarction and abscesses are visible only in
later phases. The evolution of the lesions suggests
that the initial damage might have a vasculitic origin.
Certainly the most important triggering factor is
pathergy (Koebner phenomenon), reported in 2030% of patients affected by PG. Any kind of skin
trauma, due to surgery, injections, prick tests, insects
bites can induce a new lesion or worsen the preexisting ones. Interestingly sometimes patients refer
(especially in the USA) a spider bite, especially by
brown recluse spiders (Loxosceles reclusa).21, 22 Although, it’s uncertain whether the venom of the spider is only a triggering factor or if it is sufficient to
determine the lesion itself.
Durg-induced PG has been reported in literature
and the implied drugs are: propylthiouracil 23 potassium iodide, pegfilgastrim (granulocyte macrophage
colony-stimulating factor) 24 and gefitinib (epidermal growth factor receptor inhibitor). 25
Clinical features
Powell et al.26 classified PG into four major clinical variants: ulcerative, pustular, bullous and vegetative. The most frequent one is the ulcerative type,
also known as classic form. Generally one clinical
form predominates on the others, but sometimes different types might coexist in the same patient.27
Classic form
This form is characterized by an ulcer with a
raised inflammatory border and a wet necrotic base
(Figure 1).
The primary lesion starts as a painful nodule or
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COZZANI
a superficial follicular often hemorrhagic pustule.1
Necrosis causes a deep or shallow central ulceration,
discharging a purulent and hemorrhagic exudation,
easily detectable by applying pressure on the border
of the ulcer. The purulent and malodorous exudation
can be attributable to a bacterial colonization 28 or
to an actual superinfection.8 The base of the ulcer is
covered by necrotic debris and studded with small
sterile abscesses. The border is raised, undermined,
irregular and dusky red or purplish.29
An erythematous, edematous and infiltrated halo
extends up to 2 cm from the border of the ulcer.8
The lesion enlarges starting from the undermined
borders or from the newly aroused pustules on the
border of the ulcer.1
The ulcer can propagate rapidly and occasionally
it spreads faster in one direction rather than in another, showing a serpentine configuration (Figure 2).
The ulcer might remain limited in the dermis, but
more frequently deepens in adipose tissue and muscle fascia.1 57% of patients present more than one
lesion (Figure 3).30 Very rarely the PG originates as
a painful panniculitis, which shows its true nature
when purulent blisters appear and the ulcer expands
in a concentric manner until it reaches the typical
pyodermic aspect.6
The lesions may be single or multiple and sometimes single lesions coalesce into a bigger ulcer with
irregular borders.
Intense pain is generally associated to PG.3, 11, 31
Even though the whole body surface can be affected, ulcers typically localize on the lower extremities,
especially on the pretibial region or on the trunk.1, 8
Generally mucosas are not involved, but occasionally aphthous lesions or broad ulcerations of
the mouth, larynx, pharynx, eyes or vulva might be
seen.1
These atypical lesions resemble the purplish plaques
found in Sweet’s syndrome, making the differential
diagnosis quite difficult between these two diseases.6
Since this type of PG is frequently associated to
underlying hematological disorders (i.e. myeloid
leukemia and myeloproliferative disorders), the
work up to rule out a possible underlying malignancy
should always be done in these patients. Bullous PG
often has a poor prognosis due to the underlying neoplasia. Koester et al. have reported a mortality rate of
82.6%, with death occurring on the average 7 months
after the diagnosis. Moreover, they hypothesized that
a possible neutrophilic infiltration of the inner organs
could be the cause of the elevated mortality rate.33
Atypical or bullous form
Vegetative form
Bullous PG is a superficial variant of PG that
mainly regards the face and the upper limbs (especially the back of the hands). This form of PG is frequently associated with hematological malignancies
and it was described for the first time by Perry and
Winkelmann in 1972.32 The lesion is characterized
by hemorrhagic blisters or plaques in concentric expansion, that might break causing an ulcer, usually
much more superficial than the classic pyodermic
lesions, but still presenting an undermined border.7
The vegetative form is a superficial, more localized
and less aggressive variant of PG. It also responds
better than other forms to local treatment. Perry et
al.35 initially considered it as a separate entity, defining it malingnant pyoderma; while Gibson et al.36
have more recently classified it as an atypical manifestation of Wegener’s granulomatosis. The lesions
are verrucous and shallow ulcers, without the typical
undermined border and erythematous halo. The most
frequently affected areas are the head and neck.
Vol. 149 - No. 5
Pustular form
It’s a rare variant of PG, described for the first
time by O’Loughlin and Perry in patients with active
IBD.34 Indeed, this form is almost exclusively associated to IBD. It’s a forme fruste of PG, since the lesions stop at the pustular phase, without evolving into
ulcers.22 The clinical presentation is characterized by
multiple sterile pustules, surrounded by an erythematous halo, with possible systemic symptoms such as
fever, arthralgias and myalgias. The lesions localize,
often symmetrically, on the extensor surfaces of the
limbs and on the trunk. The pustular eruption can regress by treating the underlying condition.1 Pyostomatitis vegetans and subcorneal pustular dermatosis are
neutrophilic diseases reported in association with PG
and at times with monoclonal IgA gammopathies. Pyostomatite vegentans is probably the oral expression
of the pustular PG and it is characterized by a vegetative proliferation and also by superficial “snail-tracklike” ulcerations. Albeit, according to other Authors it
should be considered a different variant itself of PG.6
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COZZANI
Figure 1.—Classic pyoderma gangrenosum of the leg: cribriform
ulcer with a raised and undermined inflammatory border and a
wet, necrotic base.
Figure 2.—Classic pyoderma gangrenosum of the of pubis: the
ulcer can propagate rapidly and occasionally spreads faster in one
direction, showing a serpentine configuration linear ulcers.
other penile PG in a HIV positive patient described
by Ecra et al.39 The differential diagnosis should be
performed between PG and sexually transmitted diseases and Behçet’s disease.
Extracutaneous PG
Figure 3.—Severe pyoderma gangrenosum with exposure of underlying structures.
Besides the four major variants described by Powell et al., other particular forms of PG have been reported in literature.1, 8
Genital PG
This form generally regards the vulvar region and
doesn’t have an erythematous halo. A similar condition has been described for the penis and scrotum.
Very few cases are reported in literature, including
a case reported by Ho et al.37 of a Chinese patient
affected by Crohn’s disease with a scrotal PG, a
case of penile PG reported by Kim et al. 38 and an-
590
The extracutaneous localizations rarely complicate PG. The lesions are sterile abscesses, in which
no pathogens can be detected. Lungs are the most
commonly involved extracutaneous site,40 however
sterile infiltrates have been described in the heart,41
skeletal muscles,42 bones, central nervous system,43
spleen, liver, lymphonodes,44 gastrointestinal tract
and cornea.45 The bone lesions are commonly defined as recurrent sterile multifocal osteomyelitis.46, 47
Peristomal PG
This condition occurs around abdominal stomas
and comprises about 15% of all cases of PG.7 Almost all of these patients are affected by IBD, especially Crohn’s disease,21 and underwent surgery
for the placement of an ileostomy or a colostomy.
However, some cases have been described following
a ileo- or colostomy performed because of intestinal
malignancies, diverticular disease 7 or after an urinary diversion following a radical cystectomy.8
October 2014
COZZANI
Based on a large study, peristomal PG occurs in
about 0.6% of patients with abdominal stomas.48 Generally the lesions appear from 2 months to 25 years
after the enterostomy.1 The continuous trauma of
the skin surrounding the stoma, the irritation caused
by fecal loss and the stoma bag adhering to the abdominal wall may evocate the pathergy phenomenon
and trigger new lesions. Furthermore, a vicious cycle might begin: the lesion can reduce the adherence
of the stoma-bag to the peristomal skin, so more irritating fecal material might spill out, worsening the
wound even more. Surgical debridement, grafting or
replacing of the stoma might as well induce new lesions. Commonly the peristomal PG is mistaken for a
surgical site infection, therefore a precise differential
diagnosis is vital, in order to start as quickly as possible the steroid therapy and to guarantee the healing of
the wound, as a Japanese study demonstrates.49
PG and surgery
In literature PG is also reported to be a complication of different kinds of surgery, probably due to
the pathergy phenomenon. It is often described as
a complication of additive or reductive mastoplasty
and to a lesser extent of other types of surgery such
as hernioplasty, heart-surgery, and head and neck
surgery. Wollina advanced the hypothesis that the
areas with thicker subcutaneous fat tissue, are the
ones with a higher risk of developing PG as a complication of surgery; this would explain why mastoplasty is so frequently involved.8 In international
literature only 400 cases of PG of the breast can be
found, most of which following breast surgery.50 As
the peristomal forms also these forms of PG are often initially misdiagnosed, since they are mistaken
for surgical site infections. However, it is extremely
important to recognize it promptly in order to avoid
surgical debridement, which would only worsen the
lesion, and to start a steroid therapy. As in the other
cases of PG, these patients generally have underlying systemic diseases and surgery is only the triggering factor for the skin lesion.
If patients with a history of PG must undergo surgery, excessive skin trauma should be avoided, surgery should be as fast as possible, the surgical wound
should be kept as small as possible, suturing ought
to be performed carefully and all in all prophylactic
systemic perioperative steroids or cyclosporine are
recommended.1, 10, 51
Vol. 149 - No. 5
Associated diseases
Fifty-seventy percent of cases of PG are associated with an underlying systemic condition; most
frequently IBD (30%), arthritis (25%) and lymphoproliferative disorders (10%) (i.e. myeloid leukemia,
hairy cell leukemia, myelofibrosis and monoclonal
gammopathy).1
After erythema nodosum, PG is the second most
common extraintestinal manifestation of IBD. PG is
reported in 2-12% of patients 52 with IBD and the
30% of all cases of PG are associated to an underlying IBD, of which 10-15% 11 are attributable to ulcerative colitis and a similar amount to Crohn’s disease.
The lesions of PG generally appear after the clinical
onset of ulcerative colitis, however a few cases were
reported in which the cutaneous lesions would precede the bowel disease or even occur after the removal of the affected intestinal tract. In most patients intestinal flares go hand in hand with the worsening of
the cutaneous lesions, but in many other cases there
is no correlation between the clinical course of the
two conditions. Sometimes, PG persists during the
quiescent phases of the ulcerative colitis. PG has also
been described in association to Crohn’s disease, but
to a lesser extent.1 The ulcerative and pustular form
are most frequently associated forms to IBD.22 Furthermore, PG-like lesions are reported in the aseptic
abscesses syndrome, a new entity within the spectrum of Neutrophilic Dermatoses which frequently
occurs in association with IBD and is characterized
by deep abscesses mainly involving the spleen and
skin and by polymorphic cutaneous manifestations.53
PG is sometimes associated with: classical seropositive arthritis, seronegative rheumatoid-like arthritis, Felty’s syndrome, osteoarthritis, and sacroiliitis.1
In other patients PG is associated to IBD related arthritis: seronegative, acute, oligoarticular, and nondestructive arthritis and spondylitis.
Other particular associations with SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis,
osteitis) and with psoriatic arthritis have been described.1, 26 The rheumatological manifestations generally precede the cutaneous lesions.
High titers of IgA and less frequently IgG and
IgM are found up to 15% of patients with PG.1 Even
though most of patients with paraproteinemia over
short-term don’t show a progression to malignancy,
some patient already have myeloma at the diagnosis
or develop it afterwards.1 Myeloma usually appears
591
COZZANI
after the PG itself. Interestingly, it was demonstrated
that in vitro IgA are able to inhibit neutrophil function and this could translate into neutrophil dysregulation also in vivo.
Fifteen-twenty-five percent of all cases of PG, both
in adults and in children, were observed in patients
with hematological malignancies. Most commonly associations were described with myeloid acute
leukemia, but also with chronic myeloid leukemia,
hairy cell leukemia, polycythemia vera, erythroid
hypoplasia, myelofibrosis and Hodgkin lymphoma.10
Other associated conditions are: chronic hepatitis,
HCV and HIV infections, primitive biliary cirrhosis,
paroxysmal nocturnal hemoglobinuria, systemic lupus erythematousus, diabetes and occasionally other
gastrointestinal disorders such as duodenal ulcers,
polyposis, and diverticulitis. Some studies have reported probably fortuitous associations with solid
tumor, including carcinoids, colon-rectal adenocarcinomas, adrenal carcinoma, bladder carcinoma,
breast cancer and lung cancer.10, 26
Other neutrophilic dermatosis, such as Behçet syndrome, subcorneal pustular dermatosis and Sweet’s
syndrome have been reported in association with
PG. PG was observed contextually with vasculitis,
erythema elevatum diutinum, conglobate acne, ance
fulminans, and Wegener’s granulomatosis.1
In Japanese case series up to 30% of patients with
Takayasu’s disease present PG, but these data are not
confirmed in European studies, since the incidence is
only 1 out 80 cases. 1,10
It is a rare form of PG, since only 3-4% of all cases
of PG occur during childhood. The skin lesions in
children have overall a similar aspect and localization to the ones reported in adults, but especially in
newborns the genital and perianal regions might be
involved. The correlated systemic disorders are the
same as those described in adults: 40% of children
with PG are affected by IBD, 18% by leukemia and
occasionally by AIDS.22 Most of the time children
have a favorable prognosis.
Familial PG
Histopathology
In literature familial forms of PG have been reported in the context of the so-called pyogenic arthritis,
pyoderma gangrenosum and acne (PAPA) syndrome.
The PAPA syndrome is a rare autoinflammatory disease characterized by recurrent episodes of sterile inflammation in the affected organs, in absence of high
titers of circulating autoantibodies and autoreactive
T cells.54, 55 It is an autosomal dominant genetic disease, described for the first time in 1997 by Lindor et
al.56 and until now only other five affected families
were reported. In PAPA syndrome, point mutations in
the CD2BP1/PSTPIP1 (CD2-binding protein1/proline, serine, threonine phosphatase-interacting protein1) gene on chromosome 15q25 are responsible
for an increased binding affinity of PSTPIP1 for pyrin, which induces the assembly of inflammosomes.
There is no specific histopathological hallmark
for PG, therefore the diagnosis is mostly clinical.
However, a skin biopsy should always be performed,
in order to rule out other possible causes of ulceration (malignancies and vasculities). The histological presentation changes according to evolutionary
stages of the lesion and to the site of the biopsy.60
In early lesions and in biopsies taken from the erythematous halo, the inflammation tends to be confined to the dermis and causes vasculitic-like lesions
in blood vessels, in which a lymphocytic infiltration
predominates and fibrinoid necrosis in the walls of
vessels is visible. Occasionally thrombosis and extravasation of red blood cells are detectable.
In the later phases and in biopsies taken from the
border closer to the center of ulcer, neutrophilic infil-
592
Inflammosomes are molecular platforms responsible
for the activation of the caspase 1, a protease cleaving the pro-interleukin-1 to functionally active IL1-beta.57 The overproduction of IL-1-beta triggers
the release of more pro-inflammatory cytokines and
chemokines,58 inducing the recruitment and activation of neutrophils and leading to a neutrophil-mediated inflammation which is the pathophysiological
hallmark of the neutrophilic dermatoses.54
PG and pregnancy
PG is extremely rare during pregnancy and puerperium. Less than 20 cases are reported in international literature, although pregnancy, according to
Wollina et al. might be a triggering factor for neutrophilic dermatosis, due to high G-CSF levels and
pathergy.50, 59
PG and childhood
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tration, necrosis, hemorrhage and abscesses clearly
predominate.60
During the resolution phase granulation tissue is
visible; but the presence of granulomas is incompatible with the diagnosis of PG.
In early lesions IgM, C3, fibrin and less commonly IgA and IgG deposits are detectable in blood
vessels by direct immunoflourescence (DIF), supporting the vasculitic hypothesis. Nether less, not all
Authors agree on defining these lesions as properly
vasculitic.21, 61
Sometimes in biopsies obtained from patients affected by myeloid leukemia or preleukemic conditions, atypical cells infiltrates are visible, revealing
the underlying hematological disorder.62
The pustular variant is characterized by a pustular necrotizing folliculitis, subepidermial edema,
neutrophilic infiltration in the dermis and in the subcorneal layer.
In the bullous form a mixed infiltrate of eosinophils and plasmacells is detectable and subepidermal blisters are visible.
In the vegetative form the histological characteristics include an infiltration of neutrophils, histiocytes
and eosinophils, that determines the formation of
subepidermal granulomas.
Compared to Sweet’s syndrome, PG has a deeper
neutrophilic infiltration, that reaches deep dermis
and subcutanoues fat tissue.
Diagnosis
In approaching a patient with a suspected PG, it
must be kept in mind that the diagnosis is mainly
clinical and of exclusion.
Patient’s history and physical examination should
focus on defining the features of the skin lesion and on
discovering underlying systemic diseases, especially
researching symptoms and sings of gastrointestinal,
rheumatological and hematological diseases.63
The most remarkable historical data are: minor
trauma or insect bite preceding the development of
a pustule or papule, rapid progression of ulceration,
markedly or exaggeratedly painful ulcer, symptoms
of an associated disease and drug history (e.g. bromides, iodide, GM-CSF, etc.).64
The characteristic features of the ulcer on physical examination are: tenderness, necrosis, irregular
violaceous and undermined border.
Vol. 149 - No. 5
Even though there are no specific histological characteristics of PG and despite the risk to
determine the enlargement of the ulcer, a biopsy
of lesional skin should always be performed. In
the biopsy protocol, suggested by Weenig et al.64
an elliptical incision is preferable to a punch biopsy in order to include subcutaneous fat in the
biopsy specimen. On specimen from the erythematous halo routine hematoxylin and eosin
staining and special staining for microorganisms
(Gram’s, methenamine silver and Fite) should be
performed; while with the material taken from the
center of the ulcers cultures in appropriate media
to detect bacteria, fungi and atypical mycobacteria must be performed.64
Laboratory investigations should include complete blood count, erythrocyte sedimentation rate,
blood chemistry (liver and kidney function), and
coagulation panel (including antiphospholipidantibody screening).64 A full blood workup will
probably show high inflammatory indices and
leucocytosis. At times sideropoenic anemia and
hyperglobulinemia might be reported. No pathognomonic auto-antibodies are titrable for PG. Circulating immune complexes are not detectable and
complement fractions are not consumed. As well
as no significant HLA-association has been demonstrated.
Further exams should comprise: ANA, ANCA,
rheumatoid factor and cryoglobulin titration.
Gastrointestinal evaluation should always be considered in patients with PG. The gold standard exam
in order to asses IBD is a colonoscopy with biopsies
for the histological confirmation.
If hematological malignancies are suspected, in
addition to a complete blood count, peripheral blood
smear, bone marrow aspiration and biopsy might
be useful. While blood and urinary protein electrophoresis can identify monoclonal gammopathies or
a myeloma.
A chest X-ray is necessary to exclude pulmonary
infections or systemic vasculities with lung involvement.
Ultrasounds or an angiography should be performed, if circulation issues are suspected in lower
extremities.
Su et al. proposed diagnostic criteria for classic PG, 65 might be useful in clinical practice, even
though they are not universally accepted.21 The following are Su et al.’s criteria revised by Callen et al.
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Major criteria:
—— rapid progression (margin’s expansion 1-2 cm/
day or a 50% increase of ulcer size in 1 month) of
a painful (pain is generally out of proportion to the
size of the ulceration); necrolytic ulcer with an irregular, violaceous, and undermined border;
—— exclusion of other causes of cutaneous ulceration.
Minor criteria:
—— history suggestive of pathergy or clinical finding of cribriform scarring;
—— systemic diseases associated with PG;
—— histopathologic findings (sterile dermal neutrophilia ± mixed inflammation ± lymphocytic vasculitis);
—— treatment response (rapid response to systemic glucocorticoid treatment) (generally responds to
a dosage of 1-2 mg/kg/day, with a decrease in size
within 1 month).
Differential diagnosis
The differential diagnosis can be rather complex,
due to the wide variety of possible causes of cutaneous ulceration. Dabade et al. report that in the Mayo
Clinic case series, 10% of patients diagnosed with
PG, were actually misdiagnosed.63 The same authors
underline the importance of a correct diagnosis in
patients with unusual ulcerations. On the one hand
not recognizing a PG means the relentless enlargement of the lesion, while a correct diagnosis and a
prompt therapy can rapidly heal the wound. On the
other hand over diagnosing PG entails an inappropriate use of immunosuppressive drugs with relative
side effects and since the treatment is not effective
the patient might be exposed to further risks, especially if the real cause is infectious. The differential
diagnosis is mainly clinical and all of the other possible causes of ulcerative and erosive skin lesions,
including above all infections, vascular disorders
and malignancies should be considered.
Infectious disease that resemble PG are:
—— bacterial infections: pyogenic infections such
as erysipelas, cellulitis, necrotizing fasciitis, ecthyma gangrenosum;21 systemic infections by Pseudomonas aeruginosa 66 and syphilitic gummas;
—— viral infections: herpetic (HSV) ulcers;
—— mycobacterial infections: including cutaneous
tuberculosis, Buruli ulcer (caused by Mycobacterium ulcerans) and atypical mycobacterial infections;
594
—— parasitic infections: cutaneous leshmaniosis
and amoebiasis;
—— fungal infections: deep infections mainly sporotrichosis but also blastomycosis, cryptococcosis,
coccidioidomycosis, histoplasmosis and aspergillosis.21
In order to out rule infections, cultures from swabs,
exudation or biopsies should be performed. Cultures
should be kept at least for six weeks, since some microorganisms might have slow growth rates.
The vascular disorders, both venous and arterial,
are a major cause of cutaneous ulceration and must
be appropriately excluded.64
Some types of systemic vasculitis, such as polyarteritis nodosa, mixed cryoglobulinemia (generally
associated with hepatitis C) and ANCA (antineutrophil cytoplasmic antibodies) associated vasculities, might cause ulcerative lesions similar to the
ones seen in PG.
Veno-occlusive disease should be ruled out by
evaluating all of the risk factors for such disease. In
particular, a few thrombophlic conditions might be
mistaken for PG, such as livedo reticularis, antiphospholipid syndrome, factor V Von Leiden mutation,
methyl-tetrahydrofolate-reductase polymorphism,21
protein C and protein S mutations and antithrombin
III deficiency.
Other than the veno-occlusive disorders, peripheral
arterial occlusive disease should be always be taken
in consideration. Within this context atherosclerotic
and traumatic artheropathy and cholesterol microembolization syndrome should be kept in mind.
Malignancies that can emulate PG include: squamous-cell carcinoma, cutaneous lymphoma,64 leukemia cutis, metastasis of carcinoma, melanoma, Kaposi sarcoma and angiosarcoma.
A very difficult differential diagnosis should be
made between PG and self induced skin lesions,
which are also diagnosed by using exclusion criteria.
Histopathology is completely nonspecific and the
injected or applied substances (urine, disinfectants,
detergents) are not identifiable.22 Perfectly straight
lines and lesions forming acute angles, should alert
the clinician, for it might be a self induced lesion.21
Since diabetic ulcerations are quite common, they
should always be taken in account in the differential
diagnosis of PG.
Moreover, autoimmune disorders, which can result in cutaneous lesions, such as bullous diseases
and connectivitis including lupus erythematousus,
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COZZANI
polyartheritis nodosa and Wegener’s granulomatosis
must be ruled out. Extremely relevant is the differential diagnosis with Sweet’s syndrome, another neutrophilic dermatosis, characterized by sudden onset
of fever and a papulo erythematous eruption.7
Patients affected by Crohn’s disease might present
non-caseous granulomas typically localized at the
upper limbs as a rare cutaneous metastatic complication of the underlying disorder. These manifestations
ought not be mistaken for PG.67
Insects bites, especially spider bites, might lead to
necrotizing lesions; this hypothesis should be carefully considered if the lesions are on an extremity.
However, in spider bites, the expansion of the lesion
is faster and is commonly associated with systemic
symptoms (e.g. disseminated intravascular coagulation).22
Course and prognosis
The clinical course can follow two different patterns:1
1) explosive onset with fast progression, clinically
characterized by fever, toxicity, pain, hemorrhagic
pustules, wide areas of necrosis and an intensely inflammatory halo;
2) indolent and gradually progressive: granulation
tissue at the base of the ulcer, crusts and hyperkeratosis of the margin are clinically seen. The growth
of the ulcer is slow over months and it regards broad
skin areas and it is characterized by resolution in one
spot and progression to another.
In both cases there can be a spontaneous resolution of the lesions, resulting in an atrophic, cribriform and hypopigmented scar.6, 10 A promptly
made diagnosis can avoid disfiguring scarring.7 An
objective evaluation of the ulcer, done by measuring its depth, width and length, as well as sequential photography represent excellent parameters
for the assessment of the evolution of the ulcer in
time and of the efficacy of therapy. The extent of
the inflammatory component is evaluated by the
dimensions of the erythema and by expansion of
the ulcer. In fact, when the border flattens and the
erythema reduces therapy can be gradually reduced.68
Many patients with PG develop only one isolated
episode, that resolves with a short course therapy,
Vol. 149 - No. 5
with no other relapse. Some times after the first
episode, the disease remains silent for months or
even for years, but then it may relapse after trivial
trauma, surgery or without any clear triggering factor. Moreover, other patients have a chronic relapsing course, which requires a long term therapy.21 In
spite of the progress made in therapy, the long term
outcome for patients with PG remains uncertain.
PG is a potentially mortal disease, with a mortality rate that reaches 30% in a few case series. Poor
prognostic factors are: male gender, onset in old age
and the bullous form of PG, especially if it’s associated to underlying hematological malingnancies.1
The prognosis is more easily predictable in those patient with a systemic underlying disorder, that can be
identified and cured. Although, even in these cases
prognosis might be poor according to the type of
systemic disease, especially if the immune system
is involved.
If PG is associated to IBD, the clinical course
of both diseases can be parallel and the regression
of the cutaneous lesions is possible by treating the
enteropathy. However, the skin ulcers might have a
completely different and independent course compared to the activity of IBD. Even if some Authors
have suggested the correlation between the cutaneous onset and the flares of IBD, 69 others didn’t report this relationship.51
A quick response to treatment suggests a good
course of PG.
Management and therapy
Probably because PG is a very rare, only a few
clinical trials were made on the treatment of this pathology. There is no gold standard therapy for PG.28
Since the pathogenesis is not perfectly known, the
therapeutic approach is mostly empirical and there
is no specific and constantly effective therapy. 1 The
therapy is chosen based on multiple factors, including the extension and depth of the ulcer, the associated systemic diseases and the patient’s performance
status.1 Other elements that influence the therapeutic
choice are the side effects of drugs, since in more
than 50% of cases of classic PG long term-therapy
is required in order to obtain and maintain a longlasting remission.28 The goals of therapy are to: turn
off inflammation, reduce pain and to control the underlying disorder.
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Local therapy
The local treatment requires cleaning and avoiding bacterial over-infections. However, a more invasive surgical debridement is always discouraged, in
order not to induce a further extension of the ulcer,
due to the pathergy phenomenon.
Topical therapy is the first choice treatment for
mild to moderate lesions in early stages (papules,
pustules, nodules or superficial ulcers) and includes
dressings, topical agents and intralesional injections.22 Topical agents might be useful as additional
treatment to the systemic therapy in more severe
forms of PG. Many topical agents were demonstrated to be effective in small studies, however, no large
trials have confirmed it.
The most commonly used topical agents are potent, super-potent steroids 70 and tacrolimus.71 Tacrolimus is particularly effective on peristomal PG, in
monotherapy or associated with other drugs.72 Systemic absorption of topical agents is possible and its
entity should be controlled. Indeed, a few cases were
reported of patients, who by daily applying topical
tacrolimus, reached high blood levels of this drug,
resulting in a systemic immunosuppressant effect.73
Anyhow, this side effect is very rare (only two cases
were reported in literature) and there were no severe consequences for the patients.73 As Schadt and
Callen suggested this event might be related to the
extent of the treated area and to the severity of the
ulceration.74
In some patients 5-aminosalicylic acid,75 pimecrolimus 1% (associated with prednisone),76 nicotine,77 cromoglycate sodium,78 nitrogen mustards
79 and benzoyl peroxide 80 were proven effective.
In other patients, with healing lesions but with slow
re-epithelization the topical use of platelet-derived
growth factor was helpful.81 Other treatment options
are intralesional injections in the border of the ulcer twice a week of steroids, cyclosporine or triamcinolone acetonide (5 mg/mL), which was the most
effective above all.82 Although, not all authors agree
on using intralesional injections as first line therapy,
because of the possible worsening of the lesion as a
consequence of pathergy.21
Even though the ulcer is not caused by infection,
there might be a colonization by bacteria producing
malodorous substances; in this case an antibiotic
therapy with metronidazole can reduce the odor.28
Autologous split-graft surgery gave variable out-
596
comes. New developments were made in skin bioengineering, for example dermal regeneration template,
hair follicle stem cell-derived autologous keratinocyte sheets 83 or hyaluronic acid-based autologous
keratinocyte delivery system were successfully used
for the treatment of PG.84
Systemic therapy
In patients with severe forms of PG in rapid expansion and resistant to topical treatment, a systemic
therapy is needed. Glucocorticoides, tacrolimus, cyclosporine, dapsone, sulfapyridine,84 azathioprine,
mycophenolate mofetil,86 methotrexate,87 chlorambucil,88 thalidomide,89 colchicine 90 cyclophosphamide 91 minocycline are all possible options for the
systemic therapy of PG.
Corticosteroids and cyclosporine are the first line
drugs. Steroids are used in the acute phase of the disease and generally give predictable and tangible effects.82 The initial dose is generally quite high (100200 mg/day of prednisone),1 that has to be reduced
as the inflammation shuts down and then gradually
suspended when the complete resolution occurs. In
order to avoid excessive toxicity it is necessary to
reduce the doses of steroids, by using steroid sparing
drugs already in the initial phases, if the lesions therapy resistant.74 The initial oral prednisone dose of
0.5-2 mg/kg/day ought to be reduced gradually over
4-6 weeks by using steroid-sparing drugs.74 Pulse
therapy with high doses of methylprednisolone (1 g/
day for five consecutive days) is the most effective
treatment for severe, aggressive and rapidly expanding forms of PG.1
Cyclosporine is another first line option in treating PG by inhibiting T-cells. Various retrospective
studies and plenty case reports have demonstrated
the efficacy of cyclosporine, however long term
therapy might be problematic.92, 93 Cyclosporine in
monotherapy induces a rapid remission of the disease at a dose of 3-6 mg/kg/day after a few weeks of
treatment and the complete resolution of the lesion
after 1-3 months.82 Furthermore, cyclosporine was
shown to be a valid steroid sparing agent for those
patients with skin lesions resistant to steroid therapy
and for those patients who present severe side effects
of such a therapy. Some patients require low maintenance dose, while others can stop the treatment completely. Some patients might need an associated low
dose steroid therapy. Not even cyclosporine is free
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COZZANI
from side effects in long term therapy, in particular it
can induce hypertension, renal damage and secondary tumors.
Sulfa drugs, such as dapsone, sulfapyridin and
sulfasalazine are used in systemic therapy as well.
Ruocco et al. reported a higher efficacy of sulfasalazine both in patients with IBD and in patients without underlying disorders.1 The initial dose of sulfasalazine is in between 4-6 g/day, gradually reduce
to 0.5-1 g/day. An association with steroids might
be necessary especially in the early phases of the
disease, but in spite of that some patients don’t respond to therapy. The dosage of dapsone can be
brought up to 200 mg/day in monotherapy or associated to a steroid-sparing agent but generally the
dose ranges from 100-150 mg/day. The evaluation
of side effects of this therapy is very important, especially attention must be paid to the formation of
methemoglobin.
The exact mechanism of action of sulfa drugs in
PG is unknown, probably it induces the stabilization
of lysosomes and interferes with the function of neutrophilic myeloperoxidase reducing the ROS production and reduces the viscosity of glycosaminoglycans.1, 10
Usually Clofazimine is very effective at the dosage of 200-300 mg/day, only in some patients the
treatment is ineffective. An isolated case of splenic
infarction was reported,10 and more frequently hyperpigmentation is seen. Clofazimine at higher doses
(300-400 mg/day) is comparable to the efficacy of
sulfa drugs.8
Other used immunosuppressant agents are azathioprine, methotrexate and 6-mercaptopurine; although these drugs are not universally effective.
Azathioprine (100-150 mg/day) is a cytotoxic drug
used as a steroid-sparing agent. Its action is tangible
after 2-4 weeks. White blood cell count and transaminases need to be checked in patients undergoing
such therapy.8 Metabolization rates for this drug are
significantly different between individuals, because
of the polymorphism of the thiopurine methyltranferase, an essential enzyme in the detoxification of
azathioprine. Azathioprine and sulfasalazine are excellent choices in patients affected by Crohn’s disease or ulcerative colitis.8
Cyclophophamide is another cytotoxic agent
that can induce remission in some patients, however severe side effects such as infertility, hair loss,
secondary tumors, hemorrhagic cystitis, can de-
Vol. 149 - No. 5
rive from this therapy. Pulse therapy is practiced,
alternating methotraxete or azathioprine in Crohn
affected patients resistant to steroid therapy. With
such a regime remissions for more than 30 months
can be obtained.8
Mycophenolate mofetil is an inhibitor of purinic
synthesis, which reduces T-cell and B-cell proliferation. The dose of 2-4 g/day is used both in monotherapy or associated with topical or systemic agents
is effective in a few cases and shows a better safety
profile as far as renal function is concerned in long
term therapy compared to steroids or cyclosporine,
making this agent an excellent option in responsive
patients.74 Very few cases were reported of sepsis by
staphylococci or pseudomonas in patients undergoing this therapy.
Also chlorambucyl (4 mg/day) is a good steroidsparing agent.
Anecdotal reports
Thalidomide has an immunomodulatory activity
by inhibiting TNF-alfa, basic fibroblast growth factor (BFGF) and by reducing chemotaxis of neutrophlis. This agent has been successfully used associated
to steroid therapy.94
Colchicine inhibits the mitotic bundle and has
anti-inflammatory properties. Kontochristopoulos et
al. report the only case in which this drug was used
for the treatment of PG.89 Monotherapy or associations are possible and gastrointestinal side effects
might limit its use.8
Tacrolimus is a selective inhibitor of calcineurin,
used as a systemic treatment at the dose of 0.1 mg/
kg/day. During treatment serum levels of the drug
should range from 4-6 ng/L.8 Lesions completely
disappear in patients with underlying ulcerative colitis.
Due to the risks related to the immunosopressive
therapy, recently the intravenous immunoglobulin
therapy (IVIG) was experimented. In a retrospective
study out of 10 patients with classical PG, 7 showed
complete resolution of the lesions by using IVIG 2 g/
kg divided into 3 doses given in 3 consecutive days
in one month. The side effects of IVIG include nausea, headache and a case of aseptic meningitis was
reported. On the down side costs of this therapy are
very high. Associating IVIG to intravenous thalidomide was proven useful in cases of PG associated to
Beçhet disease.10
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Biologics
Generally TNF-a inhibitors are chosen if patients
are already affected by Crohn’s disease or rheumatoid arthritis. Endovenous infliximab is preferred to
subcutaneous injections of etanercept or adalinumab, which could evocate pathergy.21
It’s a third line therapy for patients who don’t respond either to steroids nor cyclosporine. Very recently Gisondi et al. underlined how monoclonal antibodies, infliximab and adalimumab were effective
in improving quality of life (QoL) in patients with
PG.95 Infliximab is the only biologic agent for which
randomized, double blind with placebo studies are
reported in literature, which means its efficacy is
evidence based.95 The maintenance dose is still to be
correctly determined. In various studies the whole
dose was divided into 3 doses (0, 2 and 6 weeks)
with a 5mg/kg infusion. This protocol allowed a dramatic cutaneous and intestinal improvement and as
maintenance therapy azathioprine was used in order
to reduce steroids and infliximab.96
In a few case series etanercept was used for PG.
In most cases 50 mg/weekly were given in only one
dose or two doses of 25 mg each. The results in all
studies were of a dramatic reduction of the dimensions of the ulcer or even complete resolution.97
Adalinumab is another TNF-a inhibitor, used in 8
patients with PG up till now.98 Independently from
the dose, most patients showed improvement or regression within 2 weeks or 2 months maximum. In
most cases the biological agent was not permanently
suspended, but was kept as maintenance therapy.
Very few cases were reported of effective treatment
with efalizumab (withdrawn in Italy), but Woodson
et al. described a case of a patient non responding to
any other therapy but responsive to this biologic after
6 weeks of treatment.99
Finally a recent study defined alefacept, a T-cell
immunomodulator, as a valid treatment option in
these patients.100 After 20 weeks of 15 mg/im/day
out of 4 patients, one obtained a complete resolution,
two showed dramatic improvement and the last one
had a moderate improvement. After 32 weeks two
patients were completely healed.
Therapeutic leukocytapheresis
The selective granulocyte/monocyte adsorption
apheresis (GMA) was demonstrated to be an extreme-
598
ly effective therapeutic approach for patients with
ulcerative colitis, as well as Behçet disease, pustular psoriasis, psoriatic arthritis and other neutrophilic
disorders, including PG.101 GMA is an extracorporeal
leukocyte apheresis device, filled with specially designed cellulose acetate beads as adsorptive carriers.
The adhesion of leukocytes to the cellulose acetate
beads is mediated by the Fcγ receptor, hence the adsorption is specific for Fcγ receptor bearing cells, i.e.
activated granulocytes and monocytes. Therefore
GMA reduces the production of TNF-α and removes
activated granulocytes and monocytes from peripheral blood. This non-pharmacological treatment has
an excellent safety profile and patients with PG or
psoriasis-like skin lesions are reported to be the best
responders to such therapy.102 Ikeda et al.101 report a
case of PG associated to IBD dramatically improved
by this therapy. These Authors report a significant decrease of serum levels of Il-8 and G-CSF in such patient, suggesting the relevant role of these cytokines
in the development of PG. While Hanai et al. underline that the response of PG lesions was more striking
than anything expected from GMA. These authors
also report that the CXCR3, a chemokine receptor
know to have an important role in skin inflammation,
was strongly down regulated by GMA.102
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59. Dinarello CA. A clinical perspective of IL-1beta as the gatekeeper
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in pregnancy]. Ann Dermatol Venereol 2010;137:225-9.
61. Powell FC, Schroeter AL, Su WP, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J MEd 1985;55:173-86.
62. Malone JC, Slone SP, Wills-Frank LA, Fearneyhough PK, Lear SC,
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patients. Arch Dermatol 2002;138:345-9.
63. Farina MC, Requena L, Dòmine M, Soriano ML, Estevez L, Barat A.
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72. Chiba T, Isomura I, Suzuki A, Morita A. Topical tacrolimus therapy
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76. Sanders CJ, Hulsmans RF. Successful treatment of pyoderma gangrenosum with topical 5-aminosalicylic acid. Cutis 1993;51:262-4.
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in the manuscript.
Received on April 30, 2013.
Accepted for publication on September 24, 2013.
October 2014

GUIDELINES
Spitz/Reed nevi: proposal of management
recommendations by the Dermoscopy Study Group
of the Italian Society of Dermatology (SIDeMaST)
P. BROGANELLI 1, S. TITLI 1, A. LALLAS 2, M. ALAIBAC 3, A. ANNETTA 4, V. BATTARRA 5, B. BRUNETTI 6
I. CASTAGNO 1, S. CAVICCHINI 7, A. FERRARI 8, G. GHIGLIOTTI 9, C. LANDI 10, A. MANGANONI 11
E. MOSCARELLA 2, G. PELLACANI 12, M. A. PIZZICHETTA 13, P. ROSINA 14, P. RUBEGNI 15, R. SATTA 16
M. SCALVENZI 17, I. STANGANELLI 18, G. STINCO 19, I. ZALAUDEK 2, P. ZAMPIERI 20, G. ARGENZIANO 2
S
pitz nevus is a benign melanocytic neoplasm
mostly appearing in the pediatric age and clinically consisting of a single, pink, red or brown papule, mainly observed on the face and limbs and
characterized by an initially rapid growth.1-6 Reed
nevus is the pigmented variant of Spitz nevus, which
appears more frequently on lower limbs and has
equally dynamic morpho-evolutive aspects.
Histopathologically, both Spitz and Reed nevi are
typified by a proliferation of large epithelioid and/or
spindle-like melanocytes.7, 8 Therefore, the 2 entities
will hereafter be referred to under the “umbrella”
term “Spitz/Reed nevus”.
The diagnosis of the most typical variants of Spitz/
Reed nevus does not generally pose any problems
of interpretation, especially in the pediatric age. On
the other hand, the diagnosis of atypical forms is
more complex, due to the morphologic overlap with
atypical Spitz/Reed tumor and Spitzoid melanoma.
The latter is particularly relevant for Spitz/Reed nevi
arising in adults.
Recent advances in the histopathologic classification of Spitz/Reed nevi have improved the reliability of microscopic diagnosis, narrowing the interpretative “grey areas”. Furthermore, the gradually
acquired experience in the use of dermoscopy and
videodermoscopy along with data provided from
longitudinal studies concerning the evolution of
Spitz/Reed nevi,9-11 facilitated the more accurate
Corresponding author: P. Broganelli, Department of Oncology and
Hematology, Section of Dermatology, City of Health and Science of Turin, via Cherasco 23, 10126 Turin, Italy.
Vol. 149 - No. 5
1Department of Oncology and Hematology,
Section of Dermatology, City of Health and
Science Hospital of Turin, Turin, Italy
2Skin Cancer Unit, Arcispedale Santa Maria
Nuova IRCCS, Reggio Emilia, Italy
3Unit of Dermatology, Department of Medicine,
University of Padua, Padua, Italy
4S. Maria Goretti Hospital, Latina, Italy
5Skin Cancer Unit, Azienda Ospedaliera
“Sant’Anna e San Sebastiano”, Caserta, Italy
6Dermatology Service, Ospedale Santa Maria
della Speranza, Battipaglia, Salerno, Italy
7Dermatology Unit, Fondazione IRCCS Ca’ Granda,
Ospedale Maggiore Policlinico, Milan, Italy
8Department of Oncologic Dermatology, San Gallicano
Dermatological Institute, IFO, Rome, Italy
9Unit of Dermatology
IRCCS AOU San Martino ‑ IST, Genoa, Italy
10Dermatologic Unit, Surgical Department
“Infermi” Hospital, Rimini, Italy
11Dermato‑Oncologic Unit, University Hospital
Spedali Civili of Brescia, Brescia, Italy
12Department of Dermatology, University of
Modena and Reggio Emilia, Modena, Italy
13Department of Medical Oncology, National
Cancer Institute, Aviano, Pordenone, Italy
14Department of Medicine, Section of Dermatology,
University of Verona, Verona, Italy
15Department of Dermatology,
University of Siena, Siena, Italy
16Dipartimento di Scienze Chirurgiche, Microchirurgiche
e Mediche, Università di Sassari, Sassari, Italy
17Dipartimento di Medicina Clinica e Chirurgia,
Università di Napoli Federico II, Naples, Italy
18Skin Cancer Unit ‑ IRCCS IRST Istituto
Scientifico Romagnolo per lo Studio e la Cura
dei Tumori, Meldola, Forlì‑Cesena, Italy
19Department of Experimental and Clinical Medicine,
Institute of Dermatology, University of Udine, Udine, Italy
20Department of Dermatology, General Hospital
“F. Tappeiner”, Merano, Bolzano, Italy
601
BROGANELLI
Spitz/Reed nevi
diagnosis and appropriate management of pediatric
Spitz/Reed nevi.12-14
By combining the existing evidence and our own
experience, our purpose was to provide a comprehensive summary on the clinical and dermoscopic
characteristics of Spitz/Reed nevi, aiming to allow
clinicians better diagnosis and management of Spitzoid lesions.
A still open debate
Spitzoid lesions are generally characterized by an
extremely dynamic clinical and dermoscopic evolution in the course of time. Their rapid morphologic
alterations often force clinicians to excise the lesions in order to resolve their diagnostic uncertainty
by histopathologic examination. The introduction
of confocal microscopy may constitute a valuable
and promising alternative to histopathologic examination, even if its use is still limited to a restricted
number of Italian hospitals. Despite the improvement of histopathologic and immunohistochemical techniques and the experience that pathologists
have acquired in evaluating Spitzoid lesions, the
debate about the accurate classification of Spitzoid
neoplasms is still open. In fact, several attempts to
reach a consensus on the “grey areas” – constituted
by Spitzoid lesions of more complex interpretation
– has so far resulted in the suggestion of a “case by
case” evaluation, integrating clinical and histopathologic information.
Spitzoid lesions represent an articulate complex
of entities with different biologic behavior, with
the completely benign Spitz/Reed nevus at the one
edge and Spitzoid melanoma at the other, while the
malignant potential of atypical Spitzoid lesions that
lay in between is uncertain and controversial. This
causes significant difficulties in their interpretation
and results in a great heterogeneity of management
strategies.
A recent paper 15 has shown that 95.8% of American dermatologists consider Spitz/Reed nevus a benign entity and recommend follow up in about 50%
of cases. However, the criteria warranting excision
were not clearly discussed, not allowing the development of a management plan applicable in the clinical
practice.
Our suggestions are based on existing evidence, as
well as on the experience our research team has ac-
602
quired over the years. Our aim was not to thoroughly
review the controversial topic of histopathologic
criteria, but mainly to focus on the “clinical” issue,
providing clinicians practical recommendations on
the interpretation of the clinical and dermoscopic
characteristics of Spitzoid lesions and on the management decision.
Age is crucial
As strongly supported by existing data, the most
crucial parameter in the evaluation of Spitzoid lesions
is age. Specifically, the possibility that a Spitzoidlooking lesion is a melanoma linearly increases after
puberty, while it is extremely low before 12 years
of age. This has led to the recommendation that a
Spitzoid-looking lesion developing in the postpubertal age should be excised to exclude melanoma. The
threshold of 12 years is supported from statistical
and epidemiological considerations. Particularly, by
applying Bayes’s rule to differentiate between Spitz/
Reed nevus and melanoma, Vollmer et al.16 showed
that the a priori possibility to diagnose Spitz/Reed
nevus vs melanoma is high in subjects under 12
years of age, sharply decreasing after this threshold.
Actually, the discrimination of patients with Spitzoid lesions in 2 age groups is also supported by different clinical and dermoscopic characteristics between them. In detail, Spitzoid lesions in prepubertal
children usually exhibit a more typical morphologic
aspect and clinical course. Nevi deviating the typical morphologic criteria or undergoing unexpected
evolution and, thus, prompting clinicians to excise
them, are uncommon in this age group. In contrast,
Spitzoid lesions in individuals after puberty are often more troublesome to interpret from a clinical
and dermoscopic point of view. Surgical excision of
Spitzoid lesions is the rule in the latter age group,
but even histopathologic examination may be insufficient to establish an accurate diagnosis.
Although age represents a crucial parameter in
the interpretation of Spitzoid lesions, this should
not mislead clinicians to underestimate cases of
prepubertal melanoma. Pediatric melanoma, albeit
uncommon, does exist and its early diagnosis and
appropriate management have a substantial impact
on patient’s health. Effectively, the dual goal of clinicians when evaluating spitzoid lesions under the
age of 12 is not to miss the rare cases of melanoma,
October 2014
Spitz/Reed nevi
BROGANELLI
while minimizing the rate of nevi misinterpreted and
managed as melanoma. The latter is particularly relevant since melanoma management includes surgical procedures with significant burden on patient’s
health, such as the complete lymph node dissection
following a positive sentinel lymph node biopsy. Especially in childhood, both under- and over-diagnosis of melanoma result in important physical, social,
ethical and legal consequences.
Dynamic of Spitzoid lesions
The benign natural evolution of Spitz/Reed nevus
is well-documented, while few described cases of
metastatic diffusion with deadly outcome were more
likely melanoma not accurately diagnosed.17, 18 Typically, after a rapid growth phase, Spitz/Reed nevus
stabilizes and gradually enters an involutive process.18, 19 This evolution characterizes both pigmented
and amelanotic forms and partially explains the reason why Spitz/Reed nevi are uncommon in adults,
making the detection of a Spitzoid lesion in the adult
age even more alarming. Effectively, given that a
Spitz/Reed nevus showing “typical” aspects in prepubertal age is likely to regress spontaneously, only
follow-up should be deemed necessary. A surgical
excision should be considered only in case of peculiar clinical and/or dermoscopic characteristics that
do not fit the typical aspect of a Spitz/Reed nevus.
Avoiding unnecessary surgical procedures is particularly useful in children, considering that the pediatric
patient generally shows little compliance to surgery,
often requiring general anesthesia or sedation. Moreover, surgery entails the risk of complications and
unaesthetic scars that may turn out to be problematic
in the adult age. Postsurgical complications might be
significantly more severe in case of sentinel lymph
node biopsy, which may result positive in Spitz/Reed
nevi, and especially in case of completion lymph
node dissection. Finally, legal consequences cannot
be ruled out if the surgical procedures were based
on no other indication than the diagnosis of a typical
Spitz/Reed nevus.
Size of the lesions
The decision to excise a Spitzoid lesion in the
pediatric age should be based on the presence on
Vol. 149 - No. 5
morphologic or evolutional parameters that exceed
standards of “relative normality”.
The first factor reported is the size, with lesions
exceeding 8 mm of larger diameter warranting excision. The diameter of Spitz/Reed nevi is usually
equal to or less than 6 mm,5 while a growth beyond
10 mm has been reported in the literature as uncommon and suspicious.20 An intermediate value of 8
mm constitutes an acceptable threshold and has been
considered a valid discriminant dimensional factor
in previous studies.21, 22
Palpability
Nodular spitzoid lesions merit special attention. A
nodular lesion of recent onset is by definition suspicious, especially when it dermoscopically lacks the
characteristic regular distribution of monomorphous
dotted vessels that typifies Spitz/Reed nevi. Although
large irregular, polymorphous and asymmetrically
distributed vessels have also been described in the
context of Spitz/Reed nevi,23 the presence of the latter criteria is generally suggestive of melanoma. The
presence of micro ulcerations is an additional warning sign, as they indicate a thinning of the epidermis
due to the rapid proliferation of the underlying lesion.
Dermoscopic patterns
Dermoscopically, Spitz/Reed nevi display two
predominant patterns, namely globular and starburst.
The former is more frequently associated with Spitz
nevi while the latter characterizes Reed nevi, even
though this distinction, as explained above, might
be practically irrelevant. Less common dermoscopic
patterns include the homogeneous black pattern, the
homogenous pink pattern (characterized by dotted or
irregular vessels), and the inverse network pattern.
The latter is characterized by interconnected hypopigmented serpiginous lines which form a network
that circumscribes irregular pigmented globular-like
structures or dotted vessels and which can be associated with crystalline or chrysalis structures.24 However, in about 20% of cases, Spitz/Reed nevi may
dermoscopically exhibit a multicomponent or atypical pattern, characterized by an asymmetric distribution of structures and colors and by pigmentation
603
BROGANELLI
Spitz/Reed nevi
structures similar to the white-blue veil.25, 26 The evidence of asymmetric growth is often considered an
indicator of histopathologic atypia.11
The frequency of different dermoscopic patterns
of Spitz/Reed nevi and their histopathologic correlation was investigated by Ferrara et al.11 The authors
found a higher frequency of the globular pattern in
the “classic-desmoplastic” Spitz nevus, while the
starburst pattern was more typical of pigmented
Spitz nevus, Reed nevus and Spitz/Reed nevus. An
important finding of the latter study was the high frequency of the “multicomponent” pattern among histopathologically atypical Spitz nevi. Pellacani et al.27
investigated the correlation among dermoscopic, histopathologic and confocal microscopic findings of
Spitz nevus, Clark nevus and melanoma. According
to their results, the most frequent dermoscopic patterns of Spitz nevi were the starburst, the globular,
and the multicomponent, followed by the reticular/
homogeneous and the inverse network pattern. Of
note, a reticular/homogeneous or a multicomponent
pattern was observed mostly in lesions suggestive of
melanoma by means of confocal microscopy.
Location
Although there is no evidence that the risk of
melanoma depends on the anatomical site, the management of Spitzoid lesions might also be influenced
by their localization on specific body sites. First, we
recommend the excision of lesions located on anatomical sites not typical for a Spitz/Reed nevus according to what has been reported in the literature and
observed in the clinical practice (head, neck, lower
limbs). Our recommendation is in agreement with
other investigators suggesting excision of scalp, acral
and genital Spitzoid lesions, because they are often
associated with cytologic and architectural atypias.21
Furthermore, in our experience, Spitzoid lesions on
special body areas often deviate the usual dermoscopic features of Spitz/Reed nevus, complicating
the clinical diagnosis and management. For instance,
the specific anatomic architecture of the acral skin
might result into an atypical dermoscopic pattern of
an acral Spitz nevus, posing significant problems in
its accurate diagnosis and regular follow-up.
In addition, early surgical excision of Spitzoid lesions located on surgically troublesome body sites,
such as the nose or the eyelids, might also be recom-
604
mended. This suggestion is based on the experience
of our group and aims to prevent more complicated
surgical interventions that would be required if the
lesion grows during follow up.
Special variants
Finally, we recommend excision of lesions whose
clinical and/or dermoscopic characteristics are suggestive of a “special” Spitz variant (i.e., verrucous,
desmoplastic, and angiomatoid). The clinical management of these subtypes might be troublesome,
as they often deviate from the “standard” diagnostic
criteria and natural course of Spitz/Reed nevus. In a
previous study, we excised a verrucous nevus showing several typical criteria (dotted vessels, inverse
network) but displaying a global architecture not
fitting the diagnosis of Spitz/Reed nevus. Similarly,
a combined lesion consisting of a Spitz/Reed nevus
and a common nevus described by Duncan et al.,28
was histopathologically characterized by a high degree of cytologic atypia, increased cellularity, loss of
symmetry and an increase of mitotic figures.
Conservative approach in children
According to our recommendations, a conservative management strategy should be applied in the
vast majority of Spitzoid lesions in childhood. However, we strongly recommend their regular follow-up
in order to enable the detection of spitzoid melanomas that may appear small and morphologically
regular at baseline visit, but exhibit signs of irregular
or excessive growth during monitoring. In line with
previous evidence, we suggest a 3 to 6 month period
as the optimal follow up interval.
An excessive dimensional growth (beyond 8 mm),
a tendency not to stabilize (typically, the appearance
of globules of different dimension and color), or the
detection of one or more of the previously described
morphologic features at any time during follow-up,
should warrant excision of the lesion.
As mentioned above, the expected evolution of
Spitz/Reed nevi includes a stabilization phase followed by a slow involution until their disappearance.
Therefore, in children younger than 12, a Spitz nevus
showing “typical” aspects should be dermoscopically monitored until its stabilization, which often
October 2014
Spitz/Reed nevi
BROGANELLI
coincides with the tendency to acquire a more homogeneous dermoscopic pattern. After stabilization,
we recommend prolonging the follow-up gradually
extending the interval to 6 and 12 months, as suggested also by Soyer et al.12, 13, 29
For Spitz/Reed nevi remaining stable and not
involuting after the transition to the adult age, the
decision for excision should be reconsidered on an
individual basis. Parameters to be taken into account
include the better compliance to surgery, the esthetic
impact of the intervention as well as psychological
and social factors.
Finally, even though we cannot examine in depth
the controversial question of the post-surgical therapeutic approach of a Spitzoid lesion diagnosed
histopathologically as an atypical Spitzoid lesion
(STUMP) or “Spitzoid tumor with uncertain malignant potential”, we intend to underline some conclusions that can be extracted from existing evidence.
The majority of investigators recommend complete
excision without performing sentinel lymph node
biopsy.30 In a study conducted on 24 patients who
had undergone only local excision, no local, regional
or distant recurrence after a long follow-up period
of 8.4 years was reported. Taken all the above into
account, we recommend clinicians to inform the
patient and relatives on the controversial nature of
these lesions and discuss the possibility of having a
sentinel lymph node biopsy, but in the light of its
doubtful prognostic value and of the hard decision to
be taken in case of a positive result. In contrast, the
importance of a regular clinical follow-up has to be
clearly communicated.31
Management flow-chart
Summarizing the aforementioned recommendations, which are based on existing evidence and
the experience of our group of experts, we present
a management flow-chart for Spitzoid lesions (Figure 1). Taking into account the subject’s age, history
and the lesion’s clinico-dermoscopic morphologic
characteristics, the chart could represent a practical
guide, helping dermatologists in the management of
Spitzoid lesions in daily practice.
It should be further underlined that, in order to be
useful in daily practice, our recommendations should
often be adjusted by the clinician in the context of
each individual patient.
Vol. 149 - No. 5
Figure 1.—Spitz/Reed nevi management recommendations
(flowchart).
Conclusions
Spitzoid lesions are a diagnostic challenge for
dermatologists, since they represent a group of morphologically similar entities whose biological behavior ranges between the benign Spitz/Reed nevus
and the potentially lethal spitzoid melanoma. The
studies carried out in the last few years have only
partially clarified the discrepances on interpretation
of atypical Spitzoid lesions. The advances of immunohistochemical and biomolecular techniques have
so far been able to shed light to the controversy and
provide clinicians with useful information for the diagnostic approach and appropriate management of
Spitzoid tumors.
Based on existing evidence and our experience,
we aimed to provide decision-making criteria that
could enhance clinicians to adopt a more homogeneous diagnostic and management path of Spitzoid
tumors.
605
BROGANELLI
Spitz/Reed nevi
References
1. Dal Pozzo V, Benelli C, Restano L, Gianotti R, Cesana BM. Clinical
review of 247 case records of Spitz nevus (epithelioid cell and/or
spindle cell nevus). Dermatology 1997;194:20-5.
2. Herreid PA, Shapiro PE. Age distribution of Spitz nevus vs malignant melanoma. Arch Dermatol 1996;132:352-3.
3. Weedon D, Little JH. Spindle and epithelioid cell nevi in children and adults. A review of 211 cases of the Spitz nevus. Cancer
1977;40:217-25.
4. Coskey RJ, Mehregan A. Spindle cell nevi in adults and children.
5. Luo S, Sepehr A, Tsao H. Spitz nevi and other Spitzoid lesions part
I. Background and diagnoses. J Am Acad Dermatol 2011;65:107384.
6. Schaffer JV. Pigmented lesions in children: when to worry. Curr
Opin Pediatr 2007;19:430-40.
7. Allen AC. Juvenile melanomas of children and adults and melanocarcinomas of children. Arch Dermatol 1960;82:325-35.
8. Spitz S. Melanomas of childhood. 1948. CA Cancer J Clin
1991;41:40-51.
9. Engasser HC, Warshaw EM. Dermatoscopy use by US dermatologists: a cross-sectional survey. J Am Acad Dermatol 2010;63:412-9.
10. Marchell R, Marghoob AA, Braun RP, Argenziano G. Dermoscopy
of pigmented Spitz and Reed nevi: the starburst pattern. Arch Dermatol 2005;141:1060.
11. Ferrara G, Argenziano G, Soyer HP, Chimenti S, Di Blasi A, Pellacani G et al. The spectrum of Spitz nevi: a clinicopathologic study
of 83 cases. Arch Dermatol 2005;141:1381-7.
12. Brunetti B, Nino M, Sammarco E, Scalvenzi M. Spitz naevus: a proposal for management. J Eur Acad Dermatol Venereol 2005;19:3913.
13. Nino M, Brunetti B, Delfino S, Brunetti B, Panariello L, Russo D.
Spitz nevus: follow-up study of 8 cases of childhood starburst type
and proposal for management. Dermatology 2009;218:48-51.
14. Ferrara G, Zalaudek I, Savarese I, Scalvenzi M, Argenziano G.
Pediatric atypical spitzoid neoplasms: a review with emphasis on
‘red’ (‘spitz’) tumors and ‘blue’ (‘blitz’) tumors. Dermatology
2010;220:306-10.
15. Tlougan BE, Orlow SJ, Schaffer JV. Spitz nevi: beliefs, behaviors, and experiences of pediatric dermatologists. JAMA Dermatol
2013;149:283-91.
16. Vollmer RT. Patient age in Spitz nevus and malignant melanoma:
implication of Bayes rule for differential diagnosis. Am J Clin
Pathol 2004;121:872-7.
17. Barnhill RL, Flotte TJ, Fleischli M, Perez-Atayde A. Cutaneous melanoma and atypical Spitz tumors in childhood. Cancer
1995;76:1833-45.
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18. Luo S, Sepehr A, Tsao H. Spitz nevi and other Spitzoid lesions
part II. Natural history and management. J Am Acad Dermatol
2011;65:1087-92.
19. Argenziano G, Agozzino M, Bonifazi E, Broganelli P, Brunetti
B, Ferrara G et al. Natural evolution of Spitz nevi. Dermatology
2011;222:256-60.
20. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol
2006;19(Suppl 2):S21-33.
21. Russak JE, Dinulos J. Pigmented lesions in children. Semin Plast
Surg 2006;20:169-79.
22. Ko CB, Walton S, Wyatt EH, Bury HP. Spitz nevus. Int J Dermatol
1993;32:354-7.
23. Argenziano G, Zalaudek I, Corona R, Sera F, Cicale L, Petrillo G
et al. Vascular structures in skin tumors: a dermoscopy study. Arch
Dermatol 2004;140:1485-9.
24. Haliasos EC, Kerner M, Jaimes N, Zalaudek I, Malvehy J, Hofmann-Wellenhof R et al. Dermoscopy for the pediatric dermatologist part III: dermoscopy of melanocytic lesions. Pediatr Dermatol
2013;30:281-93.
25. Argenziano G, Scalvenzi M, Staibano S, Brunetti B, Piccolo D,
Delfino M et al. Dermatoscopic pitfalls in differentiating pigmented Spitz naevi from cutaneous melanomas. Br J Dermatol
1999;141:788-93.
26. Argenziano G, Soyer HP, De Giorgi V, Piccolo D, Carli P, Delfino M
et al. Interactive atlas of dermoscopy. Milan: EDRA Medical Publishing and New Media; 2000.
27. Pellacani G, Longo C, Ferrara G, Cesinaro AM, Bassoli S, Guitera
P et al. Spitz nevi: In vivo confocal microscopic features, dermatoscopic aspects, histopathologic correlates, and diagnostic significance. J Am Acad Dermatol 2009;60:236-47.
28. Baran JL, Duncan LM. Combined melanocytic nevi: histologic
variants and melanoma mimics. Am J Surg Pathol 2011;35:1540-8.
29. Soyer HP, Argenziano G, Hofmann-Wellenhof R, Johr RH. Color
atlas of melanocytic lesions of the skin. Berlin-Heidelberg: Springer-Verlag; 2007.
30. Tom WL, Hsu JW, Eichenfield LF, Friedlander SF. Pediatric
“STUMP” lesions: evaluation and management of difficult atypical
Spitzoid lesions in children. J Am Acad Dermatol 2011;64:559-72.
31. Cerrato F, Wallins JS, Webb ML, McCarty ER, Schmidt BA, Labow
BI. Outcomes in pediatric atypical spitz tumors treated without sentinel lymph node biopsy. Pediatr Dermatol 2012;29:448-53.
in the manuscript.
Received on January 24, 2014.
Accepted for publication on February 6, 2014.
October 2014

CONSENSUS PAPER
Consensus on the use of cyclosporine
in dermatological practice
G. ALTOMARE 1, F. AYALA 2, F. BARDAZZI 3, G. BELLIA 4, S. CHIMENTI 5, D. COLOMBO 4
M. L. FLORI 6, G. GIROLOMONI 7, G. MICALI 8, A. PARODI 9, K. PERIS 10, G. A. VENA 11
Cyclosporine A (CsA) efficacy and safety have been proven
in various dermatoses both in adults and in children even
as long-term treatment. Over the last 25 years, Italian dermatologists have gathered relevant experience about CsA
treatment for psoriasis and atopic dermatitis. This paper has
been developed by an Italian Consensus Conference and it
is aimed at providing recommendations based on real-world
clinical experience in adult patients, consistent with efficacy
and safety data arising from the scientific literature. The paper is mainly focused on the analysis of the optimal therapeutic schemes for psoriasis and atopic dermatitis, in terms
of doses and treatment duration, according to individual
characteristics and to the severity of the disease. Moreover, it
overviews ideal management, taking into account pharmacological interactions, influence of comorbidities, and the most
common adverse events related to CsA treatment.
Key words: Cyclosporine - Skin diseases - Psoriasis - Dermatitis, atopic.
C
yclosporine (cyclosporine A, CsA), was first isolated from the soil fungus Tolypocladium infla‑
tum in 1970.1 Its antifungal activity was demonstrated to be poor, whereas a potent immunosuppressive
effect was found in 1976.1 For this reason, two years
later, CsA was successfully used in preventing kidney transplant rejection 2 and, in 1979, it was proven
effective in the treatment of rheumatoid arthritis and
psoriasis.3 The original orally administered formulation of CsA (Sandimmun, Novartis) was approved in
1983 by the Food and Drug Administration (FDA)
for the prevention of transplant rejection.
Corresponding author: Giampiero Girolomoni, Clinica Dermatologica, Università di Verona, Piazzale A. Stefani 1, 37126 Verona.
Vol. 149 - No. 5
1IRCCS Galeazzi,
University of Milan, Milan, Italy
2Department of Clinical Medicine and Surgery
Dermatology Clinic
University of Naples Federico II, Naples, Italy
3Dermatology Unit, Department of Specialist
Diagnostic and Experimental Medicine
S. Orsola‑Malpighi Hospital
University of Bologna, Bologna, Italy
4Novartis Farma, Italy, Origgio, Varese, Italy
University of Rome “Tor Vergata”, Rome, Italy
6Dermatology Unit
Department of Clinical Medicine and Immunology
University of Siena, Siena, Italy
7Section of Dermatology, Department of Medicine
University of Verona, Verona
8Dermatology Clinic, University of Catania
A.O.U. Policlinico Vittorio Emanuele, Catania, Italy
9Section of Dermatology
IRCCS University Hospital San Martino‑IST
Genoa, Italy
University of L’Aquila, L’Aquila, Italy 11Private Practitioner, Bari and Barletta, Italy
Despite the increased availability of new therapeutic options, CsA is still one of the most widely
used and effective systemic drugs for the treatment
of psoriasis and atopic dermatitis, worldwide.4-6 In
Italy, it has been found to be the most frequently
used systemic antipsoriatic therapy.7
It is noteworthy that the Italian experience in CsA
is broad, and often long lasting, for most of its therapeutic indications, starting from transplant with 25year experience. Moreover, several indications for
CsA have originated from clinical trials conducted
in Italy.
607
ALTOMARE
CONSENSUS ON THE USE OF CYCLOSPORINE IN DERMATOLOGICAL PRACTICE
Upon these grounds, an Italian Consensus Conference was held to provide recommendations based on
real-world clinical experience.
Pharmacokinetics
CsA is a cyclic endecapeptide,8 able to act directly
on cells of the immune system, primarily on T cells,
because of its inhibitory effects on calcineurine. It
targets the major T cell-driven pathways of immunemediated response and inflammation. These effects
explain its efficacy both in prevention of transplant
rejections and in immune-mediated dermatoses.9
CsA absorption occurs within 30 minutes and the
peak serum concentration (Cmax) is observed 2-4
hours after the administration.10-15
Due to its lipophilicity, CsA is widely distributed
throughout the body. In plasma, it is mostly bound to
lipoproteins (≥90%) and easily transferred between
different lipoproteins, and to or from albumin as
well.5 It has a first-pass effect of 27% in the liver.15
CsA metabolism is highly dependent on cytochrome P450 isoenzymes 3A4 (CYP3A4) and 3A5
(CYP3A5) in the liver and small intestine, and dependent on the efflux p-glycoprotein pump (PGP)
encoded by the multidrug resistance-1 gene (MDR1)
in the gastrointestinal tract and liver.5 The metabolites of CsA are mainly excreted in the bile; another
6% is eliminated in the urine, of which 0.1% remains
unchanged.12
A higher CsA serum concentration reflects higher
clinical efficacy and is obtained if the drug is administered before food intake.5,16
CsA dosage is established on a weight-per-weight
basis (mg/kg/day, see below for further details).
Drug interactions
By virtue of its almost complete hepatic metabolism by cytochrome P450 IIIA, the plasmatic levels
of CsA are increased or decreased by drugs that inhibit or stimulate cytochrome P450 activity, respectively (Tables I-III).5 The consequent change in CsA
bioavailability results in adverse effects that are potentially exerted on target-organ toxicity.17
Among patients with dermatoses, the use of some
systemic antibiotics as well as of NSAIDS could be
critical due to pharmacological interactions, leading
608
Table I.—Drugs and foods that inhibit the cytochrome P450 sys‑
tem, leading to a higher concentration of cyclosporine.5
–– Allopurinol
–– Amiodarone
–– Antifungals (fluconazole, itraconazole, ketoconazole and
voriconazole)
–– Bromocriptine
–– Calcium channel blockers (diltiazem, nicardipine, verapamil
and mibefradil)
–– Ciprofloxacin
–– Danazol
–– Doxycycline
–– Furosemide
–– Gentamicin and tobramycin
–– Grapefruit juice
–– Macrolide antibiotics (erythromycin, clarithromycin and
josamycin)
–– Methylprednisolone
–– Metoclopramide
–– Oral contraceptives and androgen steroids
–– Protease inhibitors
–– Ranitidine and cimetidine
–– Statins (especially atorvastatin and simvastatin)
–– Thiazide diuretics
–– Ticarcillin
–– Warfarin
Table II.—Drugs that stimulate the cytochrome P450 system,
leading to a lower cyclosporine level.5
–– Anticonvulsants (carbamazepine, phenobarbitone, phenytoin
and valproate)
–– Isoniazid
–– Metamizole
–– Nafcillin
–– Octreotide
–– Orlistat
–– Probucol
–– Rifabutin
–– Rifampicin
–– Selective serotonin reuptake inhibitors (sertraline)
–– St John’s Wort (Hypericum perforatum)
–– Sulfinpyrazone
–– Terbenafine
Table III.—Drugs that may impair renal function during cyclo‑
sporine treatment.5
–– Acyclovir
–– Aminoglycosides (gentamycin and tobramycin)
–– Amphotericin B
–– Cimetidine and ranitidine
–– Ciprofloxacin
–– Clotrimazole and ketoconazole
–– Colchicine
–– Fibrates
–– Melphalan
–– Methotrexate
–– Nonsteroidal antiinflammatory drugs
–– Trimethoprim with sulfamethoxazole
–– Vancomycin
October 2014
to higher CsA concentration and, consequently, toxicity.5
CsA may reduce the clearance of some HMG-CoA
reductase inhibitors. Thus, statins should be used
with caution because of the risk of rhabdomyolysis.5
It is important to underline that heavy alcohol intake increases CsA levels.18
Grapefruit juice avoidance must be recommended
during CsA treatment, since it inhibits the metabolism of CsA by suppressing cytochrome P450 enzyme activity.5, 18
Systemic CsA in dermatoses
CsA has been proven an effective therapeutic option for several dermatoses.4-6 Its systemic use is authorized in Italy for psoriasis and atopic dermatitis.19
Psoriasis
Among the available systemic treatments for psoriasis, CsA has a particularly favorable profile, due
to the rapid clinical response (4 weeks for the relief
of symptoms, 10-16 weeks for a PASI 75 response)
even in patients unresponsive to other therapies.4, 2022
CsA has been proven effective in all variants of
psoriasis (Table IV), where different schemes in
terms of doses and treatment duration have been
used.4, 6, 20
ALTOMARE
The clinical benefit of CsA therapy is related not
only to the clinical response, but also to the effects
on psychological distress, which are a common experience in patients with psoriasis (see below).29, 30
Many studies indicate a clear dose-dependent response, with higher doses producing higher rates of
remission.6, 31-35
To identify patients who may benefit from systemic treatments including CsA, the “rule of tens” has
been proposed: a body surface area affected >10%
or a Psoriasis Area Severity Index (PASI) >10 or a
Dermatology Life Quality Index (DLQI) >10.36
Dose-finding studies and current consensus guidelines have identified 2.5 mg/kg/day CsA as ideal starting dose, to be gradually increased up to 5 mg/kg/
day by 0.5-1 mg/kg/day at 2-4 weeks intervals.4, 21-32
Tachyphylaxis did not occur if regimens with progressive increases were prescribed.31 In patients who
are unresponsive, or who respond inadequately after
3 months (PASI 50 not achieved), CsA withdrawal is
recommended.4 Drug reduction should be performed
stepwise (0.5-1.0 mg/kg/day at 2 weeks intervals).4
Based on long-term clinical experience, six therapeutic strategies are currently used to treat moderateto-severe psoriasis with systemic CsA (I=induction;
M=maintenance; definition and treatment regimens
are illustrated in Table V): 1) intermittent shortterm therapy (I); 2) rescue therapy (I); 3) long-term
continuous therapy (I+M); 4) combination therapy
(I+M); 5) rotational therapy (I+M); and 6) week-end
therapy (M).4, 6, 37, 38
Table IV.—CsA in psoriasis variants.
Plaque psoriasis
Erythrodermic psoriasis
Palmoplantar pustular psoriasis
Generalized pustular psoriasis
Nail psoriasis
Lebwohl M et al. J Am Acad Dermatol 1998;39:464-75.23
Fradin MS et al. Br J Dermatol 1990;122(Suppl 36):21-5.24
Erkko P et al. Br J Dermatol 1998;139:997-1004.25
Ozawa A et al. J Dermatol 1999;26:141-9.26
Farber EM. Cutis 1993;51:29-32.27
Witkamp L et al. J Eur Acad Derm Vener 1996;7:49-58.28
Table V.—Systemic cyclosporine treatment schedules.
Intermittent short-term therapy
Rescue therapy
Long-term continuous therapy
Combination therapy
Rotational therapy
Week-end therapy
Vol. 149 - No. 5
–– Short course (12-16 weeks) until significant improvement is achieved, after which treatment
is withdrawn
–– If relapse occurs, treatment is reinstituted at the previously effective dose
–– Used in severe flares of disease until an alternative maintenance treatment is instituted
–– Clinical improvement maintained with the lowest effective dose
–– Cyclosporin can be combined with topical therapies, such as corticosteroids, anthralin, or
vitamin D3 analogues, and other systemic treatments, such as methotrexate, fumaric acid
esters and mycophenolate mofetil
–– Treatment with cyclosporine can be rotated with other systemic agents (see text)
–– Maintain remission (5mg/kg/day) for 2 consecutive days a week for 24 weeks
609
ALTOMARE
Moreover, CsA due to its fast therapeutic action,
represents an appropriate “bridging” therapy, which
is useful if associated with a new long term biological treatment which needs a certain time lapse to be
effective.4,21
Intermittent short-term therapy
The most common systemic CsA regimen is
represented by a short course (12-16 weeks) administration, followed by the withdrawal when a
significant improvement (PASI 75) or remission
(PASI≥90) is achieved. In case of relapse, a shortterm course may be repeated at the previously effective dose.4, 21, 23, 39-43
In patients with severe psoriasis, a 1-year remission is obtained in 80% of cases with 2 courses of
therapy, the remission after the first course lasting 4
months in 45% of cases.41, 42 A slight advantage in
terms of remission duration was observed with dose
tapering.41, 42
Rescue therapy
The rapid onset of effect with short-term CsA is
useful to control severe flares, particularly in severe
psoriasis variants.4 A starting dose of 5 mg/kg/day is
recommended, followed by a gradual dose decreasing after remission.13,14,17
Long-term therapy
Long-term continuous therapy with CsA is a less
common approach for severe psoriasis and is prescribed to obtain a significant clinical improvement
with the lowest effective dose rather than a complete
control.15, 44-47 Its duration is limited to 2 years in Europe 9, 20, 21 with the possibility of a further prolongation
in selected cases, and to 1 year in the United States.48
The typical maintenance dose is 3-3.5 mg/kg/day.49
Combination therapy
The effects of systemic CsA associated with
various topical treatments, as corticosteroids,50-52
anthralin,53 vitamin D3 analogues,54 or systemic
treatments, as methotrexate,55 fumaric acid esters,56
acitretin,57 or mycophenolate mofetil 58 have been
evaluated only in small case series and single casereports.4 The main advantage of combination therapy
610
is the possibility to minimize toxicity due to the dose
reduction,4 even if the possibility of adverse effects
arising from pharmacological interactions has to be
taken into account.6
A recent Italian study reported a clinical response
(therapeutic success or complete clinical remission)
in 80% of patients with moderate-severe plaque psoriasis who received CsA plus systemic methotrexate
or retinoids, or plus topical treatment and/or phototherapy.59
Rotational therapy
CsA treatment of psoriasis is not associated with
tachyphylaxis,4, 20, 51, 60, 61 allowing rotational therapy, whose rational is similar to that of combination
therapy, characterized by the sequential use of the
above mentioned systemic agents.20, 61, 62
An Italian study has proven, in patients with severe psoriasis, the superiority of the sequential therapy with CsA (3 mg/kg/day for 4 weeks) and narrowband UVB phototherapy compared to narrow-band
UVB phototherapy alone.63
Week-end therapy and pulse therapy
An additional therapeutic maintenance schedule
was proposed and evaluated by PREWENT (Psoriasis Relapse Evaluation with Week-End Neoral®
Treatment) study, a 24-week, double-blind placebocontrolled trial, carried out in 22 Italian hospitals or
university Dermatology units. CsA microemulsion
was used in patients with chronic plaque psoriasis
who had achieved clinical remission after continuous CsA therapy, and then randomized to receive
oral CsA 5 mg/kg/day or placebo for two consecutive
days/week for 24 weeks. Time to first relapse (adopting PASI as diagnostic criterion) was significantly
longer with CsA and PASI was significantly lower
at weeks 4-16 in CsA recipients. The incidence of
adverse events was similar in both groups.37
Similar results have been reported by another
Italian study, in which patients with severe chronic plaque psoriasis were assigned to a continuous
schedule or 4-day therapy per week, administered
for 6 months. PASI score and severity of itching
were efficiently controlled in both groups. Moreover,
the safety profile was shown more favourable in the
group with intermittent 4 days per week administration.64
October 2014
Consensus Conference Statements
—— There is consensus on the indications reported by literature for the treatment of psoriasis
variants, in particular for the doses and the duration of therapy
—— However, in clinical practice, indications
to start CsA treatment are less strict. It may be
used in the following cases with PASI<10:
−− resistance to topical drugs (experience
suggests that resistance may occur even
with PASI≥5);
−− certain clinical characteristics, e.g. the
site of the disease (palmoplantar psoriasis, genital psoriasis);
−− characteristics of the patients, including
sex, age, personal or social relationship
and employment. In fact, the impact of
psoriasis on a patient’s quality of life
(QoL) may be disproportionate to the
clinical severity, due to his/her selfperception and his/her expectations
about the treatment. Due to the young
average age of psoriatic patients, the
consequences of the psychological and
emotional stress are particular relevant
in terms of their impact on social and
sexual life leading to low self-esteem,
high anxiety, and sexual dysfunction
—— In limited extent psoriasis, e.g. nail psoriasis where PASI and NAPSI (NAil Psoriasis
Severity Index) may result quite low: CsA may
be considered even if it is not the first-line treatment. The indication has to be established on the
basis of the patient’s characteristics (e.g. personal relationship and employment). In clinical
experience,65,66 CsA has proven effective when
the ungueal variant was associated to generalized involvement
—— A weight-per-weight dose, based on the
ideal body weight is recommended. Adopting as
a reference the actual body weight, overweight
or obese patients may be exposed to high doses,
even double that those of normal weight patients,
with an increased risk of toxicity (see below for
further details). In order to obtain a better compliance with the therapy, a fixed dose (200 mg/
day) may be used in such patients
Vol. 149 - No. 5
ALTOMARE
—— To establish the optimal dose, the clinical
severity has to be taken into account: for PASI
higher than 20 and especially in cases with a
relevant inflammatory component, an induction
dose of 5 mg/kg may be appropriate; a dose of
2.5 mg/kg/day, although reported in clinical trials, has to be considered suboptimal in severe
psoriasis
—— Based on our experience, a satisfactory
control of itching is generally obtained in few
weeks, generally earlier than the control of skin
lesions
—— The clinical response has to be assessed
after the first month, when both the profiles of efficacy and safety (see the section Management of
patients) should be assessed. The treatment has
to be carried out for at least 3 months, evaluating
side effects
—— After clinical remission is achieved, multiple possibilities can be evaluated about which
the Consensus doesn’t express a unanimous recommendation, rather the advice to make a choice
according the individual patient’s characteristics,
clinical history, and needs:
−− tapering after 3 months of treatment or
−− tapering once PASI 0 has been reached
or
−− once PASI 0 has been reached, maintenance therapy for 1 month/for at least
1 month due to the high risk of relapse
—— When a relapse occurs:
−− during the tapering, then the full dose
regimen is recommended followed by
continuous therapy for 6 months
−− immediately after/close to the treatment completion (unlikely possibility),
the rotational therapy may be an option
(see below)
−− few months after the treatment completion, the treatment can be repeated, according to the disease extension and the
severity of the relapse
—— CsA high doses (5 mg/kg/day) may be
used also to control severe flares
—— The recommended dose for induction is
≥3 mg/kg/day
—— The recommended dose for long-term
therapy is 3 mg/kg/day
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—— The aim of long-term therapy is to
achieve more prolonged clearance and improve
the balance between effectiveness and safety.
Our large experience of a good safety profile
supports a prolonged duration of treatment at the
minimal effective doses in selected cases
—— Lifestyle modifications, including an appropriate diet, have a role in achieving a good
control of the disease, as indicated by a recent
Italian study where weight loss has been able to
improve the response to low-dose CsA in obese
patients with moderate-severe chronic plaque
psoriasis 67
—— Clinical experience suggests the use of
combination regimens in selected cases (“difficult cases” in terms of poor responsiveness or
clinical complexity). Combination therapy provides the opportunity to facilitate decreases in
the dose of each single drug and reduction of potential adverse effects
—— In Italian clinical practice, the association
of CsA with:
−− fumaric acid esters is not registered in
Italy
−− acitretin or methotrexate is uncommon
−− narrow band UVB is not infrequent
−− topical corticosteroids or vitamin D/vitamin D analogues is very common
—— The rational basis of rotational therapy
is reducing the exposure to a single agent in a
chronic (incurable) disease, improving both efficacy and safety profile
—— Clinical experience suggests CsA use in
cases of inadequate/incomplete responsiveness
(not cured patients who need a continuous therapy). Notably, individual clinical history has to be
taken into account
—— Italian clinical research was relevant in the
development of week-end therapy, a schedule
related to CsA effectiveness in a “real-life” clinical setting. Week-end therapy is able to provide a
longer maintenance of the remission and/or to reduce relapses in patients with moderate psoriasis.
The PREWENT Study schedule consists in the administration of systemic CsA 2 days/week, but a
schedule of 3 days/week provides a better clinical response. The choice should be based on the
characteristics of the patient or of the disease 37
—— It is noteworthy that the administration of 5
612
mg/kg/day for 3 doses per week is equivalent to the
administration of 3 mg/kg/day for 5 doses per week.
However, it is largely safer in terms of potential nephrotoxicity, since the more prolonged discontinuation decreases vasoconstriction, a well described
functional adverse effect
Atopic dermatitis
Atopic dermatitis is one of the most common
chronic relapsing childhood dermatoses which affects up to 30% of children in most cases before the
age of 5 years, but persists into adulthood in more
cases than reported by the literature (up to 3%).
Moreover, its onset may be observed in adult age,
even in elderly patients. Overall, clinical experience
suggests that atopic dermatitis is by far more frequent
than expected according to diagnostic criteria.68, 69
In the diagnosis of atopic dermatitis several criteria have been established,68-71 but there is no laboratory biomarker.
Current management of atopic dermatitis has not
curative targets, while it is focused on symptoms relief.
CsA is the only immunosuppressant agent approved in Europe for the short-term treatment of
severe atopic dermatitis that cannot be controlled
with topical therapy.4 It has not been formally approved by FDA for this indication, but it has been
recommended by American Academy of Dermatology (AAD).68, 72 There is no statement indicating the
recommended dose in atopic dermatitis, although the
therapeutic dosage used in psoriasis is conventionally administered.
The data of a systematic review clearly demonstrated the efficacy of CsA in atopic dermatitis. Body
surface area, erythema, sleep loss and corticosteroid
use were reduced in the CsA group.73
A 47% improvement in itching has been described
within 2 weeks in patients treated with high dose of
CsA.74
Short-term therapy
According to the European guidelines, an initial
dose of 5 mg/kg/day for 2 weeks has to be gradually
tapered to a dose of 1.5 mg/kg/day over 3 months,
based on the individual clinical response.9,75-78
October 2014
A meta-analysis by Schmitt 47 demonstrated the
effectiveness of short-term continuous CsA treatment (50% reduction in severity after 6-8 weeks of
therapy). Patients treated with an initial dose of 4-5
mg/kg/day showed a more rapid response at 2 weeks
(40% decrease in severity) in comparison to patients
treated with a lower initial dose of 2.5-3 mg/kg/day
(22% decrease in severity). Nevertheless, after a 6-8
week follow-up, no difference was observed between
the two doses in terms of responses.
According to results of a recent double-blind randomized, multicentre trial, CsA is superior to prednisolone in inducing a stable remission of severe eczema.79
Long-term therapy
On the basis of the above mentioned results, the
lowest effective dose is recommended if a maintenance therapy is needed.6, 78
Two randomized controlled studies reported the
effect of CsA long-term therapy to control severe
atopic dermatitis.80, 81 In a pediatric population (216 years), intermittent short-term therapy (5 mg/kg/
day) for 12 weeks was compared to a continuous
1-year course (5 mg/kg/day), the latter being associated to better outcomes in terms of short-term and
sustained clinical response and patients’ QoL.80
The second study,81 which was performed in patients with severe atopic dermatitis, compared two
long-term CsA regimens: an initial dose of 5 mg/kg/
day tapered to 3 mg/kg/day as tolerated vs 3 mg/kg/
day increased to 5 mg/kg/day as needed, both maintained the optimal dose for the following 10 months.
After 1 year, patients in the treatment group who
started with 5 mg/kg/day showed slightly better results in terms of disease control (59.8% vs. 51.7%),
and similar adverse events.
Considering relapse and worsening after CsA,
data reported is highly variable, in terms of rates and
time of occurrence.4 However, there is no evidence
of a rebound phenomenon on this drug withdrawal.47
(recommendations for adult
patients with atopic dermatitis)
—— When treating atopic dermatitis, a crucial
point is the relevant impact of the disease on QoL.
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QoL scores should be used in conjunction with objective measures of severity as an assessment tool.
Because of the rapid onset of action and marked efficacy, CsA is particularly useful in the treatment of
atopic dermatitis
—— Atopic dermatitis is often associated to severe
itching, whose significant improvement is generally
obtained in 1-2 weeks with CsA
—— In the management of atopic dermatitis skin
care, cleansing and bathing, lifestyle, diet restriction with avoidance strategies are important factors.
Patients have to be informed and instructed in order
to actively and effectively collaborate
—— With short-term therapy, a high initial dose
(4-5 mg/kg/day) is recommended to obtain a more
rapid and sustained improvement
—— With long-term therapy, the minimum effective dose of CsA to achieve substantial improvement in disease severity is appropriate
—— The duration of treatment able to obtain a
satisfactory clinical response (4-6 months) is longer than that indicated in clinical guidelines (2-3
months)
Impact of CsA on QoL
Dermatoses cause as much disability as that of
other major medical conditions. For instance, disability from psoriasis is comparable to that from arthritis, hypertension and diabetes;82 while QoL from
atopic dermatitis is impaired to a similar extent as is
seen in other common childhood diseases, such as
asthma and diabetes.83
The impact on patient’s QoL of dermatoses such
as psoriasis and atopic dermatitis is relevant 82-85
and has been shown able to affect the adherence to
medication.84 Consequently, QoL assessment tools
have been specifically developed for dermatologic
conditions (e.g. the Dermatology Life Quality Index,
DLQI, the Psoriasis Disability Index, PDI, the Eczema Disability Index, EDI, and the Psoriasis Index of
Quality of Life, PSORIQoL). In addition, the updated “rule of tens” used to select patients with severe
psoriasis who could benefit from systemic treatment
includes QoL parameters.9
The impact of a dermatological condition on QoL
doesn’t show a clear relationship with the clinical severity of the disease, as assessed with PASI and depends more on patient’s self-reported morbidity.85, 86
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In patients with dermatoses, CsA has been shown
able to improve QoL. Considering psoriasis, data of
a 1-year substudy from PISCES (Psoriasis Intermittent Short Course of Efficacy of Sandimmun Neoral)
has demonstrated an improvement in QoL (P<0.001)
and a reduction in itching and disease extent ⁄severity (P<0.001 for both).87 Similar results have been
observed for atopic dermatitis both in adults 74, 88 and
in children.80
Considering the common experience of psychological distress in patients with psoriasis, generally with
a higher burden in female patients, the PSYCHAE
study, a large observational study performed in 39
Italian dermatology centers on more than 1500 patients, has shown that, differently to methotrexate
and topical corticosteroids treatment, CsA treatment
is able to control the risk of psychological distress
assesses using the General Health Questionnaire
(GHQ) and the Brief Symptoms Inventory (BSI).29,
30 It is interesting to note that only 16% of physicians
in the PSYCHAE trial declared that they considered
a patient’s psychological status when choosing a systemic therapy for psoriasis.30
Management of patients treated with systemic CsA
CsA is the most commonly used drug by Italian dermatologists for the treatment of moderate-severe psoriasis and atopic dermatitis unresponsive to conventional therapy.7 However, due to its narrow therapeutic
window, clinicians have to take into account the multiple pharmacological interactions, and the relevant influence of comorbidities on therapeutic strategy.89
Clinical evaluation
Before starting CsA treatment, a careful clinical
evaluation has to be carried out (history, examination, baseline laboratory examinations).5, 61
Among comorbidities, previous or concurrent malignancies, hypertension, renal impairment, current
infections, or a history of previous PUVA phototherapy have to be investigated.5, 61 Skin surface should
be inspected in order to identify the presence of cancerous or actinic lesions. In case of active herpes
simplex infection or viral warts the treatment should
be postponed after healing.5, 61
Hepatitis profiles including anti-HAV, HBsAg,
anti-HBs, anti-HBc, anti-HCV and also anti-HIV
should be checked in patients treated with CsA.61
614
The adherence to dental hygiene has to be recommended and checked at 6-months periodic examinations.5, 6
Laboratory tests have to be performed both at
baseline and during the treatment. They include serum creatinine, potassium, magnesium, bilirubin,
liver enzymes, uric acid, fasting lipids, urea nitrogen,
blood cell count, and urine analysis.21, 61 According
to the international guidelines, the tests have to be
repeated during CsA treatment at definite intervals
(every 2 weeks during the first 2 months of treatment).6, 20-22
The physical examination should include blood
pressure measurement, at least in two separate occasions basally, and continuous monthly monitoring
during the treatment.5
Due to a variety of pharmacological interactions
(Tables II-IV), it is crucial to investigate the use of
any systemic drug (over-the-counter drugs included)
before initiating a treatment with CsA, and to reiterate the investigation at each visit, eventually mentioning the specific class of medication.
Notably, evidence suggests that CsA is able to
inhibit in vitro HCV replication. Some data confirm this property in vivo, in patients who underwent liver transplantation or with chronic active
hepatitis.90, 91 The Italian experience on patients
with concomitant rheumatologic disorders and
HCV infection indicates that CsA is effective and
safe, and may contribute to better outcomes.92, 93
Moreover, the short-term therapeutic association
of CsA and anti-TNF shows a satisfactory safety
profile (Table VI).91-93
—— CsA is endowed with a relevant manageability, with the possibility to dose changes (tapering or increasing according to either clinical
response or adverse effect onset)
—— There is a general consensus with the
guidelines about baseline assessment and monitoring, with some differences, already discussed
—— In contrast to guidelines recommendations, the screening for malignancies is exclusively based on clinical history
—— The screening of infectious diseases is
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Table VI.—Laboratory examinations during cyclosporine treatment.
Diagnostics
Full blood count
(erythoracytes,
leukocytes, platelets)
Liver function tests
(transaminases, alkaline
phosphatase, gammaglutamyl transferase,
bilirubin)
Electrolytes (sodium,
potassium)
Serum creatinine
Urine analysis and
sediment
Uric acid
Cholesterol, triglycerides
Magnesium
Period in weeks
Pretreatment
Week 4
Week 8
Week 12
Week 24
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Further specific test may be required according to clinical signs, risks and exposure
based on the patient’s individual history. The
measurement of blood infective markers is not
mandatory, unless a high clinical suspicion is
present
—— The first time point for laboratory test is
scheduled at the first month, later than what stated
by guidelines (2 weeks)
Contraindications
CsA is contraindicated in uncontrolled hypertension, renal disease, serious infections, and in patients
with a previous history of malignancy (excluding basal cell carcinoma).5, 20-23, 78
Moreover, the drug should be avoided in patients
previously treated with a high cumulative dose
of psoralen and ultraviolet A light phototherapy
(PUVA), due to the risk of carcinogenicity.5, 46
Skin infections superimposed to atopic eczema
do not represent an absolute contraindication, but an
adequate antibiotic therapy is needed before CsA.78
A careful evaluation of the benefit/harm balance
is requested in patients with epilepsy, severe hepatic
dysfunction, immunodeficiency disorders, diabetes,
obesity, premalignant conditions. Elderly patients
(≥65 years), patients with a history of drug or alcohol abuse, poor compliant patients are at higher risk
to develop adverse events.
For CsA use in pregnancy and lactation, see below.
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—— There is consensus on the following absolute contraindications:
−− poorly controlled hypertension,
−− severe infections,
−− malignancies (ongoing disease or previous history; particular caution with
haematological malignancies and dermatological malignancies, with the exception of basal cell carcinomas)
—— There is consensus on the following relative contraindications:
−− liver impairment,
−− concomitant administration of drugs
able to pharmacologically interact with
CsA (see above),
−− concomitant PUVA (also previous
PUVA treatment at dose >1000 J/cm²,
−− pregnancy and lactation (for more details, see below),
−− antihypertensive treatment with a combination regimen of two or more agents
Management of adverse effects
The concern about adverse effects of CsA has limited its use also in dermatology, although the doses
used to treat skin diseases are largely beneath those
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considered at risk. To reduce the risk of side effects
whose dose-dependency is definitely proven,5, 18, 20,
21 recommendations of current guidelines in terms
of dosage and monitoring have to be strictly followed.20-23
The risk of gingival hyperplasia is generally controlled by an adequate hygiene or antiseptic therapy. More severe cases may be cured by a CsA dose
reduction or azithromycin administration for 3-5
days.20
Major concerns are related to renal impairment,
hypertension, and hyperlipidemia, which are the
most relevant even if not the most common adverse
effects associated to CsA treatment. They may represent the reason why dermatologists show a certain
resistance to embrace CsA use in their clinical practices.5
—— Patients must be adequately informed
about the possibility of adverse effects and instructed on their management, thus reducing
their anxiety or distress and, indirectly, their
negative perception
—— Side effects are dose-dependent in terms
of incidence and severity, related to the duration of the therapy and reversible on discontinuation
—— In clinical practice, mild neurological/neuromuscular side effects are reported (probably
underreported and/or underdiagnosed): peripheral paraesthesias, limbs burning sensation. They
do not usually result in treatment discontinuation, since they tend to improve or disappear in
the first week(s) of treatment. However, if they
are severe and/or persistent, treatment discontinuation is suggested
—— Fatigue and gastrointestinal side effects
(nausea, diarrhoea, discomfort, pain) are rather
common, particularly in female patients. Gastrointestinal effects may be controlled with administration after the meals
—— Oral hygiene is likely to reduce the risk of
gingival hyperplasia, actually becoming an uncommon adverse event. It has to be treated with
azithromycin, 500 mg/day for 3-5 days
—— Hypertrichosis is underreported by pa-
616
tients, with the exception of female and pediatric
patients, and is reversible
— Serious adverse effects are reported with
limited frequency, but need careful and appropriate management
Renal impairment
Renal dysfunction associated to CsA therapy may
be functional or structural. Its occurrence and characteristics are largely dose-dependent, damage being
more frequent and more likely to become structural
with prolonged therapy (over 2 years) or doses (higher than 5 mg/kg/day which is considered the highest
recommended dermatological dose, i.e. up to 8-8.5
mg/kg/day which were used in the past in transplant
recipients).5, 94-96
Kidney impairment, based on either vascular or
tubular alterations, may lead to a decrease in renal
glomerular filtration rate (GFR) and in renal blood
flow (as reflected by a decreased creatinine clearance)
leading to hypomagnesaemia, decreased bicarbonate
concentration, hyperuricemia, and hyperkalemia.97
At lower doses, as those administered with intermittent short-term therapy, nephrotoxicity causes
functional changes and is reversible on drug withdrawal.5, 95, 96
Long-term and/or high dose CsA therapy is a risk
factor for tubular interstitial fibrosis 95, 96, 98 which is
mediated by an in increase in Transforming Growth
Factor-beta (TGF-β) 99 and is facilitated by older
age, concurrent hypertension or obesity.
Recommendations about prevention, monitoring
and management of renal nephrotoxicity following
the S3-European guidelines 20 and an international
statement consensus 34 are reported in Figure 1. The
best predictive factor of nephrotoxicity is the percentage of serum creatinine increase over baseline
values.96, 100
Factors likely to increase the risk of nephrotoxicity (e.g., advanced age, diabetes, nephrotoxic drugs,
obesity) should also be evaluated, and medication
charts should be carefully reviewed for potential
drug interactions.
A difference is apparent between US and European guidelines with respect to the duration of continuous treatment to prevent chronic nephrotoxicity:
a maximum of 1 year is recommended by the Ameri-
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Figure 1.—Management of nephrotoxicity.22
can Academy of Dermatology, while the British
Association of Dermatology and the European Association of Dermatology and Venereology recommend 2 years.5, 18, 20-22, 96 These strict limitations are
somewhat inconsistent with the long-term experience gathered with transplanted patients who have
undergone lifelong treatment with CsA.
—— There is consensus on the flow chart proposed by the international guidelines (Figure 3).
—— Serum creatinine and blood urea nitrogen
Vol. 149 - No. 5
are the laboratory tests of reference. Following
this flow chart, i.e. decreasing the CsA dose by
25% if creatinine rises 30% over baseline and
by 50% if the rise is ≥50%, the incidence of CsA
nephrotoxicity is rather low and reversible. Estimated glomerular filtration rate (eGFR, to be
estimated using Cockroft Gault) is not a routine
laboratory measure and may be evaluated when
serum creatinine is increased
—— Among agents able to increase nephrotoxicity, aminoglycosides, amphotericin B, ciprofloxacin, vancomycin, lovastatin, cimetidine,
acyclovir, and NSAIDs have to be mentioned
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Hypertension
Table VII.—Magnesium-rich foods.101
Food
Mg (mg/hg)
Dried almonds
Dried beans
Dried nuts
Whole wheat flour
Spinach
Potatoes
Chicken breast
264
170
160
120
60
38
32
—— The onset of hypomagnesaemia, which
occurs earlier than that of hyperkalaemia, is
a good even if poor predictor of renal impairment. Several conditions (e.g. administration
of diuretics and aminoglycosides or alcohol
consumption) are able to induce hypomagnesaemia, which favours nephrotoxicity. The
daily recommended intake of magnesium is
400-420 mg. A list of magnesium rich foods is
presented in Table VII
The incidence of new-onset hypertension with CsA
treatment ranges from 0% to 57%, being higher with a
long-term treatment and lower with short-course therapies and reversible after dose reduction and/or withdrawal or with the use of antihypertensive drugs.5, 20, 41, 61, 76
However, some studies show the lack of a clear relationship between CsA dose and frequency of hypertension
occurrence,5, 61, 100 thus suggesting a role for an individual
variability in the sensitivity to CsA hypertensive effect.5,
100 This hypothesis supports the use of antihypertensive
drugs rather than a reduction of the dose to manage the
onset of hypertension.100
The differences observed between patients with atopic
dermatitis (lower incidence) and with psoriasis (higher
incidence) may be explained by their younger age and
the increased association of obesity, respectively.5, 102, 103
A regular monitoring of blood pressure is crucial in patients with psoriasis, as they are known to be at increased
risk of cardiovascular morbidity and mortality.104
A flow-chart reporting the recommendations from current guidelines about the management of hypertension
Figure 2.—Management of hypertension.22, 61
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associated to CsA treatment is reported in Figure 2. The
choice of the antihypertensive drug is of particular interest
and somewhat controversial both in literature and in clinical practice. Calcium channel blockers are the first choice
thanks to their vasodilating effect, conferring some protection against nephropathy, although nifedipine should
be avoided because of an increased risk of gingival hyperplasia. The calcium channel blockers of the dihydropyridine class, i.e. isradipine and amlodipine represent a good
choice, since they do not modify CsA levels and exert a
vasodilating effect on the afferent arteriole, which confers
protection against nephropathy.104-106 Beta-blockers may
also be used, taking into account the possibility of the
disease worsening, while thiazide diuretics are contraindicated because of a potential increase in nephrotoxicity.
Angiotensin-converting enzyme inhibitors and potassiumsparing diuretics should be avoided as they may cause hyperkalemia and a decrease in GFR.5, 22, 61
The monitoring and control of hypertension, as
well as of hyperlipidemia (see below) is crucial in
patients with psoriasis because of their increased risk
of cardiovascular morbidity and mortality.103
—— There is consensus on the flow chart proposed by the international guidelines,20, 22 although a closer monitoring is considered more
appropriate, particularly at the beginning of the
treatment (daily monitoring during the first week
or with blood pressure levels ≥140/90 mmHg)
—— To manage hypertension, there is consensus on calcium channel blockers as the first
choice (excluding nifedipine for the increased
risk of gingival hyperplasia; preferring isradipine and amlodipine because they don’t alter
CsA levels). In clinical practice thiazide diuretics
(even if contraindicated in renal impairment) are
prescribed for short courses. Angiotensin-converting enzyme inhibitors (risk of hyperkalemia
although associated to a protective vasodilating
effect) and potassium-sparing diuretics (risk of
hyperkalemia) are contraindicated
If blood pressure levels are under control with
a previously defined antihypertensive schedule, there is controversy about the need of any
therapeutical change. In particular, angiotensinconverting enzyme inhibitors are not absolutely
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contraindicated if already included in the schedule. Considering the broad range of positions on
this clinical question, it is highly recommended
to seek the advice of a specialist consultant for a
decision on any individual case
Hyperlipidemia
Hyperlipidemia has to be carefully monitored and
controlled with diet or medications (Figure 3).20, 61
However, caution is needed with the co-administration of CsA and statins to detect myopathy (rhabdomyolysis) at an early stage. Cases of muscle toxicity have been reported with pravastatin, atorvastatin
and lovastatin. Fluvastatin is the most studied and
recommended lipid-lowering drug.20, 61
—— The absolute increase in lipid levels is
moderate, generally higher in cholesterol levels
than in triglycerides levels
—— Dietary intervention is mandatory
—— There is consensus about fluvastatin as first
choice therapy, due to its peculiar mechanism of
action, different to that of other statins.107, 108
Moreover, pravastatin has a somewhat peculiar
metabolism, being only partially catalyzed by
cytochrome P-450 isoenzymes and, differently
from other statins, competing less with CsA for
uptake by hepatocytes 109
Malignancy
An increased risk of malignancy after long-term
CsA treatment has been described in patients who
underwent organ transplantation.111, 112 A large review, investigating the incidence of malignancy in
patients treated with CsA for up to 5 years for severe
psoriasis, showed that the incidence of extracutaneous malignancy was not higher than that reported in
the general population.112
CsA enhances the induction of skin tumours by
UVA exposure.113
Actually, the risk of cutaneous squamous cell
carcinoma (SCC) increases with longer duration
of therapy, only in patients with a previous history
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Figure 3.—Management of hyperlipidemia.20, 61
of PUVA or immunosuppressant agents.112, 114-116
In fact, duration of exposure to CsA, psoralen and
UVA, exposure to methotrexate, and to immunosuppressants has a significant impact on the incidence of
non-melanoma skin cancers.112
As a consequences current guidelines suggest to
avoid association of CsA and PUVA or immunosuppressants and/or to be cautious in case of an individual history of a high cumulative dose of PUVA
or a previous history of SCC or melanoma.20, 22, 23
Again, it has to be pointed out that this association is
routinely prescribed in transplant recipients.
An increased risk of lymphoma has been shown in
transplant recipients, while in patients with autoimmune dermatoses data are controversial and confined
to isolated cases reports.5 As far as solid tumours
are concerned, comprehensive studies and single
620
cases 117 failed to show an increase in their incidence
in patients treated for psoriasis.112, 115
Infections
CsA administration may increase the general risk
of bacterial, parasitic, viral, and fungal infections, as
well as the risk of infection with opportunistic pathogens, but the actual incidence of infective complications when treating psoriasis is low.5, 20, 117 Management of infection depends on appropriate and prompt
antibiotic therapy (for the choice of drugs, see drug
interactions). In case of herpes simplex infections,
CsA therapy should be deferred until resolutions.5,
20, 22
Vaccinations given concomitantly with CsA may
be less effective. Studies in patients with transplan-
October 2014
tation taking CsA have shown inconsistent effectiveness of the influenza vaccine. Live vaccines are contraindicated and should be avoided.20, 61
Pregnancy and lactation
Because of the state of immunologic tolerance of
pregnancy, several patients with autoimmune dermatoses report an improvement during gestation.
The need for contraception should be discussed
with women of child-bearing age taking into account
that CsA can reduce the efficacy of oral contraceptives.20
CsA has been classified in category C drug by the
FDA Pregnancy Labeling Task Force 118 (studies on
animals have shown an adverse effect on the foetus,
and there are no adequate and well controlled studies
in humans, but potential benefits may warrant use of
the drug in pregnant women despite potential risks).
CsA passively crosses the placental blood barrier to
achieve 10-50% of the maternal plasma concentration.119 Its levels decrease with pregnancy due to the
increased volume distribution and metabolism.120
CsA is excreted in breast milk and its levels show a
broad variability in terms of milk-to maternal serum
concentration ratio, depending on the time of sampling and maternal dose.121
Most safety data on humans are derived from analyses of pregnancy outcomes in transplant recipients
and suggest that there is no evidence of teratogenicity.20, 61, 122, 123 A limited number of observations up to
an age of approximately 7 years in children exposed
to CsA in utero show preserved renal function and
normal blood pressure levels.10, 11
Among the oral medications approved for psoriasis, CsA is considered the safest and it has been
suggested as the best choice for pregnant women.61
A certain number of cases of prematurity and/or developmental delay is reported in children born to
mothers with solid-organ transplantations.5 Pregnant
women receiving immunosuppressive therapies after transplantation, including CsA or CsA containing regimens, are at risk of premature delivery (<37
weeks).10, 11
Breastfeeding is contraindicated in mothers taking CsA, mainly because of concerns about immunosuppression in the neonate.20-22, 36, 124 There
is evidence, even from small studies, of no adverse
events associated to breastfeeding during CsA treatment.121, 125, 126
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—— When starting CsA, a baseline pregnancy
test is not mandatory
—— CsA is contraindicated during pregnancy
Drug discontinuation is recommended when
planning an intended gestation or when an unplanned gestation is ascertained
—— Clinical experience demonstrates a good
safety profile for CsA:5
−− cases of administration in neonatal or
pediatric age without the evidence of
adverse events
−− approximately 700 pregnancies without
negative adverse events in women who
previously underwent organ transplantation 123, 127
−− there is no evidence of adverse events
in pregnant women who did not discontinue CsA treatment during pregnancy
−− there is no evidence of teratogenicity
—— Since no teratogenicity has been proven,
CsA is of choice when a systemic drug is needed
—— Cases of premature delivery have been reported
—— CsA safety profile is better than that of alternative agents (e.g. etretinate administration has
to be avoided for 2 years prior the conception)
—— At present there are no adequate and well
controlled studies in pregnant women and, therefore, CsA should not be used during pregnancy
unless the potential benefit to the mother justifies
the potential risk to the fetus
Therapeutic abortion is not an absolute indication in case of exposure to CsA of a pregnant
patient. The choice has to be made on the basis
of an acceptable risk-to-benefit balance, providing the patient with the opportunity to make an
informed decision and taking into account her
individual needs and preferences
Pediatric use
Children are less susceptible to CsA toxicity because of a reduction in drug bioavailability and a lower
predisposition to nephrotoxicity.5 CsA has been used
at high doses in pediatric transplant recipients and in
children with atopic dermatitis or psoriasis with no serious adverse effects.5, 40, 81, 128, 129 Theoretically, pedi-
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atric patients better tolerate higher CsA doses, due to
a different pharmakocinetics with clearance rates up to
four times those of adults, this meaning lower blood
concentrations for the same dose.130-132
—— CsA has been used starting from the first
year of life and cases of high dose treatment in
pediatric patients who underwent organ transplantation are described. However, caution is
needed, when changes in standard schedules or
guidelines are adopted
—— CsA management in pediatric patients
(usually to treat atopic dermatitis) needs specific
considerations and caution, even if better tolerance is proven
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128. Zaki L, Emerson R, Allen BR. Treatment of severe atopic dermatitis in childhood with cyclosporine. Br J Dermatol 1996;135(Suppl
48):21-4.
129. Dadlani C, Orlow SJ. Treatment of children and adolescents with
methotrexate, cyclosporine, and etanercept: review of the dermatologic and rheumatologic literature. J Am Acad Dermatol
2005;52:316-50.
130. Yee GC, Lennon TP, Gmur DJ, Kennedy MS, Deeg HJ. Age dependent cylcosporine pharmacokinetics in marrow transplant recipients. Clin Pharmacol Ther 1986;40:438-43.
131. Hoyer PF, Offner G, Wonigeit K, Brodehl J, Pichlmayr R. Dosage
of cyclosporine A in children with renal transplants. Clin Nephrol
1984;22:68-71.
132. Mochon M, Cooney G, Lum B, Caputo GC, Dunn S, Goldsmith
B et al. Pharmacokinetics of cyclosporine after renal transplant in
children. J Clin Pharmacol 1996;36:580-6.
Conflicts of interest.—G. Altomare has received advisory/speaker
honoraria and/or research funding from Abbvie, Novartis and Leo Pharma; F. Ayala has received advisory/speaker honoraria and/or research
funding from Abbvie, Janssen, MSD, Novartis and Pfizer; F. Bardazzi
has received advisory/speaker honoraria and/or research funding from
Abbvie, Janssen, Novartis, Schering-Plough and Pfizer; G. Bella is
an employee of Novartis Farma Italy; D Colombo is a part-time employee of Novartis Farma Italy and received grants from Allergan and
Aventis; S. Chimenti has received advisory/speaker honoraria and/or
research funding from Abbvie, MSD, Novartis and Pfizer; M. L. Flori
has received advisory/speaker honoraria and/or research funding from
Novartis; G. Girolomoni has received advisory/speaker honoraria and/
or research funding from Abbott, Almirall, Boehringer Ingelheim, Celgene, Dompè, Eli-Lilly, Galderma, GSK, Janssen, Leo Pharma, Otsuka,
Merck-Serono, Maruho, MSD, Novartis and Pfizer; G. Micali has received advisory/speaker honoraria and/or research funding from Abbvie,
Almirall, Leo Pharma, Novartis and Pfizer; A. Parodi has received advisory/speaker honoraria and/or research funding from Abbvie, Almirall,
Galderma, Leo Pharma, MSD, Novartis, Pfizer and Shire; K. Peris has
received advisory/speaker honoraria and/or research funding from Abbott, Galderma, GlaxoSmithKline, Hofmann La Roche, Janssen, Leo
Pharma, Meda, MSD and Novartis; G. A. Vena has received advisory/
speaker honoraria from Abbvie, Almirall, Astellas, Galderma, Leo Pharma, Merck-Serono, MSD, Novartis, Pfizer and UCB.
Received on December 6, 2013.
Accepted for publication on January 3, 2014.
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Scabies acquired in Chinese massage centers
TO THE EDITOR: In the last few months, we have observed three patients who contracted scabies at Chinese
massage centers. The case list is made up of three Caucasian males, aged 29, 46 and 56 years, respectively, in
good general health, heterosexuals. All three patients
were regular customers of Chinese massage centers (two
of them used to attend the same center). A clinical diagnosis of allergic contact dermatitis and unsuccessful
treatment with topical corticosteroids and oral antihistamines were made at other dermatological centers to all
three patients.
Clinical history of the three was negative for previous
scabies. History also allowed to exclude with certainty
other possible sources of infestation (no intercourses, no
direct contacts with patients affected by scabies, no direct
contacts with fomites belonging to patients with scabies in
the last six months before our examination). Latency time
ranged from 3 to 4 weeks.
Clinical picture was typical: widespread, severe pruritus, and burrows and vesicular-papular lesions at interdigital folds, wrists, axillae, chest, abdomen, pubis, penis and
buttocks.
Parasitological examinations were positive for mites,
eggs and feces in all patients.
All patients were successfully treated with 5% permethrin cream (one single application followed by
a second single application one week later). Topical
methylprednisolone aceponate (2 applications/day for
10 days) and oral hydroxyzine (25 mg/day for 10 days)
were necessary in two patients in order to control residual pruritus.
Follow-up (at 8, 7 and 4 months, respectively) was negative.
Sarcoptes scabiei var. hominis does not fly or jump: it
crawls at the rate of 2.5 cm per minute on warm skin.1
Scabies is usually transmitted by direct skin-to-skin
contacts or intercourses.1-4 A direct skin-to-skin contact
lasting between 15 and 20 minutes is needed to transfer
the mites from one person to another.3 The more parasites
on a person, the greater the likelihood and speed of transmission, either direct or indirect.1 According to some authors, intercourses are a common transmission modality
Vol. 149 - No. 5
of the infestation among adults. In a study of risk factors
for scabies in a sexually transmitted diseases unit, highrisk persons included men who have sex with men and
men with sporadic sexual contacts.5 Scabies can be therefore considered as a true sexually transmitted disease.1, 4,
6 Scabies is less commonly transmitted by clothes, sheets
and towels.1, 4 Furthermore, living mites have been found
on floors and furniture.2, 7 In a study by Arlian et al.,7
44% of dust samples of infested patients’ homes contained mites, and 64% of these mites were living. Fomite
transmission of the infestation is therefore considered to
be possible. This modality of transmission is more frequent in crusted scabies.1 Some studies have documented
survival of mites, at room temperature (21 °C) and 4080% relative humidity, for more than three days.7-10 In
particular, Arlian et al.9 demonstrated that high relative
humidity values and low temperatures favored survival,
whereas high temperatures and low relative humidity led
to early death.
Transmission among family members and in institutional settings is common.1, 3
Predisposing factors are overcrowded places, poor environmental and personal hygiene, poor nutritional status,
homelessness, severe psychiatric diseases.3
Transmission occurs by means of the gravid female,
more rarely by means of larvae and nymphs.4 Latency
time depends on mite burden and host immunity. It ranges between 3 weeks and 3 months: in most of the patients
it ranges between 3 to 6 weeks.2, 4 This is the latency
time in patients infected for the first time: in reinfestations, signs and symptoms arise after 1 to 5 days.2, 4, 11
This would mean that, although scabies does not induce
a true definitive immunity, a certain degree of cell immunity occurs, possibly towards proteolytic and hydrolytic enzymes produced by females for the construction
of the burrows and/or as a sensitization towards metabolic products released by mites during their growth or at
their death and/or as a sensitization towards saliva and/
or faeces.4
The genetic predisposition for susceptibility or resistance to Sarcoptes scabiei var. hominis infestation has been
hypothesized to be correlated with the dominance of an
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IgE-driven Th2 response in crusted (Norwegian) scabies
or an interferon-g-dominated Th1 response that induces a
mite control.12
In spite of a careful review of the international literature, we were not able to find reports of scabies acquired
through massages. Therefore, we do think that this report is the first one about this topic. It is possible that
in these patients scabies was transmitted by the sheets
that covered the futon or by the towels used by the patients after the shower. It is unlikely that scabies has been
transmitted by the oil used for the massage. As Chinese
massage centers are proliferating (at least in Milan and
its outskirts), we believe that cases of scabies caused by
massages will be observed more frequently in the next
future.
S. VERALDI
Department of Pathophysiology and Transplantation,
University of Milan, IRCCS Foundation, Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
[email protected]
E. ÇUKA
C. FRANCIA
M. C. PERSICO
References
1. Chosidow O. Clinical practices. Scabies. N Engl J Med
2006;354:1718-27.
2. Leone PA. Scabies and pediculosis pubis: an update of treatment regimens and general review. Clin Infect Dis 2007;44(Suppl
3):S153-9.
3. Hicks MI, Elston DM. Scabies. Dermatol Ther 2009;22:279-92.
4. Veraldi S, Cambiaghi S, Gianotti R. La scabbia. Milano: Edizioni
del centro dermatologico milanese; 2010. p. 13-4.
5. Otero L, Varela JA, Espinosa E, Sánchez C, Junquera ML, del Valle
A, Vázquez F. Sarcoptes scabiei in a sexually transmitted infections
unit: a 15-year study. Sex Transm Dis 2004;31:761-5.
6. Currier RW, Walton SF, Currie BJ. Scabies in animals and humans:
history, evolutionary perspectives, and modern clinical management. Ann N Y Acad Sci 2011;1230:E50-60.
7. Arlian LG, Estes SA, Vyszenski-Moher DL. Prevalence of Sarcoptes scabiei in the homes and nursing homes of scabietic patients.
J Am Acad Dermatol 1988;19:806-11.
8. Estes SA, Arlian L. Survival of Sarcoptes scabiei. J Am Acad Dermatol 1981;5:343.
9. Arlian LG, Runyan RA, Achar S, Estes SA. Survival and infectivity
of Sarcoptes scabiei var. canis and var. hominis. J Am Acad Dermatol 1984;11:210-5.
10. Ong GP, Bhatia SG. Survival of Sarcoptes scabiei. J Am Acad Dermatol 1982;6:115-6.
11. Chosidow O. Scabies and pediculosis. Lancet 2000;355:819-26.
12. Walton SF. The immunology of susceptibility and resistance to scabies. Parasite Immunol 2010;32:532-40.
Lymphedema and immunocompromised districts
TO THE EDITOR: Recent articles on angiosarcoma on
the lower abdominal wall associated with chronic lymphedema 1 and post-filarial cutaneous aspergillosis,2 as well as
Stewart-Treves syndrome 3 and giant angiofibromas in tuberous sclerosis complex,4 taken together, bear out the concept that some of us (E.R. and R.A.S.) expressed in 2007 5
of a possible role of localized lymphedema in favoring the
local onset of neoplasia and infection. In particular, we have
always considered lymph stasis equivalent to immune stasis,
thus explaining the propensity of lymphedematous sites to
harboring opportunistic tumors or infection.
Interestingly, one of the above mentioned articles,4 while
quoting a previous paper by Lu et al.6 correlates lymphedema with other clinical conditions such as trauma, surgery,
chronic inflammation, that also can render the involved cutaneous districts vulnerable and prone to developing subsequent disorders. This represents the very scenery of the
immunocompromised district (ICD).7
628
The ICD is a unifying pathogenic concept lately introduced for explaining the occurrence of tumors, opportunistic infections, and immune disorders at sites of prior
clinical events (as exemplified by chronic lymphedema in
the first place, but also herpetic infection, vaccination, and
heterogeneous physical injuries such as ionizing and ultraviolet radiation, thermal burns, and trauma), which selectively damage and immunologically alter the cutaneous
site. In this light, Kacerovska et al.’s 4 shrewd comment on
the pendulous nature of the giant angiofibroma specimens,
as indicative of localized lymphedema, directly points to
considering the sites of onset of the giant lesions as immunocompromised mini-districts due to foci of microlymphedema. This view is supported by Paul and Carlson,8
who found that lymphangiectasias are common underlying warts and in normal peritumoral skin. In this regard,
what is more demonstrative than the article by Shelley and
Wood 9 dealing with the transformation of the common
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wart into squamous cell carcinoma because of an underlying lymph stasis?
We are firmly convinced that a localized defect in immune surveillance as a result of chronic lymph stasis can
lead to a series of pathologic events in lymphedematous
districts or even micro-districts, ranging from trivial angiectasias, through benign neoplasms such as verruciform
xanthoma,10 to malignant ones such as Kaposi’s sarcoma,
basal cell carcinoma, squamous cell carcinoma, melanoma
and often invariably deadly angiosarcoma (Stewart-Treves
syndrome).3, 5
E. RUOCCO
Department of Dermatology,
Second University of Naples, Naples, Italy
V. PICCOLO
Department of Dermatology, Second University of
Naples, Naples, Italy
[email protected]
T. RUSSO
Department of Dermatology, Second University of
Naples, Naples, Italy
R. A. SCHWARTZ
Dermatology, Pathology, and Preventive Medicine
and Community Health, New Jersey Medical School,
Newark, NJ, USA
References
1. Homma E, Aoyagi S, Baba K, Iitani MM, Hata H, Shimizu H
et al. Angiosarcoma on the lower abdominal wall associated
with chronic lymphedema in an obese woman. Int J Dermatol
2012;51:1520-2.
2. Dhotre SV, Hiremath SL. Post-filarial cutaneous aspergillosis. Int J
Dermatol 2012;51:1485-6.
3. Sharma A, Schwartz RA. Stewart-Treves syndrome: pathogenesis
and management. J Am Acad Dermatol 2012;67:1342-8.
4. Kacerovska D, Kerl K, Michal M, Filipova H, Vrtel R, Vanecek T et
al. Giant angiofibromas in tuberous sclerosis complex: A possible
role for localized lymphedema in their pathogenesis. J Am Acad
Dermatol 2012;67:1319-26.
5. Ruocco E, Puca RV, Brunetti G, Schwartz RA, Ruocco V. Lymphedematous areas: privileged sites for tumors, infections, and immune
disorders. Int J Dermatol 2007;46:662.
6. Lu S, Tran TA, Jones DM, Meyer DR, Ross JS, Fisher HA et al.
Localized lymphedema (elephantiasis): a case series and review of
the literature. J Cutan Pathol 2009;36:1-20.
7. Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol
2009;23:1364-73.
8. Paul J, Carlson JA. Lymphangiectases are common underlying
warts and in normal peritumoral skin: histologic evidence of decreased immune surveillance. Am J Dermatopathol 2011;33:15260.
9. Shelley WB, Wood MG. Transformation of the common wart into
squamous cell carcinoma in a patient with primary lymphedema.
Cancer 1981;48:820-4.
10. Lu S, Rohwedder A, Murphy M, Carlson JA. Verruciform xanthoma: localized lymphedema (elephantiasis) is an essential pathogenic factor. J Cutan Pathol 2012;39:391-4.
Occupational argyria
TO THE EDITOR: A 35 year-old sales assistant in a
jewelry store was responsible for selling silver articles.
Her medical history did not include any relevant diseases
or altered blood or urine values. Two years previously,
a bluish pigment began to appear on the lunules of her
fingernails (Figure 1). More recently, bilateral gray-blue
blotches appeared on the gabella and in the naso-labial region (Figures 2, 3). Pigmented lesions of the conjunctiva
and cornea were absent. An ultrasound scan of the liver
did not reveal hyper-reflectivity. No other photo-exposed
areas presented the bluish pigmentation, neither did the
skin where covered by clothing or the mucosa. The patient
had not taken any drugs, even topical, containing Ag+,
had not undergone any unconventional therapies, and did
not have tattoos. Her exposure to silver was solely occupational: she polished silver trays and frames every day.
A skin biopsy confirmed the diagnosis by demonstrating
brownish granules in the connective tissue surrounding
sebaceous glands. Electron microscopy showed that the
Vol. 149 - No. 5
Figure 1.—A bluish pigment on the lunule of fingernail.
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CORRESPONDENCE
patient was exposed through her occupation to both soluble Ag+ and metallic silver. She cleaned the silverware in a
room behind the shop without gloves and only washed and
dried her hands quickly when clients entered the shop; thus
soluble Ag+ ions were released from the metallic silverware and absorbed by the skin through water or natural water/oil film. While the incidence of argyria is declining, its
recognition remains important; pigmentation is permanent
but benign. A few cases of occupational argyria have been
publshed in Russia,3 while occupational corneal argyrosis
most frequently affects silver solderers.4 Occupational silver intoxication is rare.2 Some cases have been reported in
relation to wearing earrings, while iatrogenic cases due to
silver sulfadiazine cream use, acupuncture and hemodialysis are increasing.5
Figure 2.—Gray-blue blotches appeared in the naso-labial region.
F. MURDACA
Dermatology Section, Department of Clinical Medicine
and Immunology, Siena University, Siena, Italy
[email protected]
L. FECI
[email protected]
S. ACCIAI
M. BIAGIOLI
M. FIMIANI
Figure 3.—Gray-blue blotches appeared on the gabella.
granules were electron dense, irregular and present in the
epidermal basal lamina but mainly in the papillary dermis,
immediately below the epithelium, in the vessel walls and
along the elastic fibres.1
The main adverse effect of chronic exposure to silver
is a permanent bluish-gray discoloration of the skin (argyria) and/or eyes (argyrosis). Most studies discuss cases
of argyria and argyrosis resulting primarily from exposure
to soluble forms of silver. The chemical reaction of silver
particles upon exposure to light results in irreversible tissue discoloration.2
The case is of particular interest because of the way the
630
References
1. Bleehen SS, Gould DJ, Harrington CI, Durrant TE, Slater DN,
Underwood JC. Occupational argyria; light and electron microscopic studies and X-ray microanalysis. Br J Dermatol
1981;104:19-26.
2. Flogel W, Widmaier S, Hotz P, Scharer L, Barthelmes D, Landau
K, Thiel MA. Corneal and conjunctival findings in systemic silver
intoxication (abstract). Klin Monatsabl Angenheilkd 2006;223:3902.
3. Chistiakov ND. Argyrosis in dermatologic practice. Med Tr Prom
Ekol 2004;12:32-6.
4. Sanchez Huerta V, De Wit-Carter G, Hernandez-Quinela E, Naranjo-Tackman R Occupational corneal argyrosis in art silver solders.
Cornea 2003;22:604-11.
5. Fisher NM, Marsh E, Lazover R. Scar-localized argyria secondary
to silver sulfadiazine cream. J Am Acad Dermatol 2003;49:730-2.
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A controversial pigmented lesion located
in the left subscapular region:
a case of “collision” tumor
TO THE EDITOR: The association of contiguous or “collision” tumors in the same biopsy specimen is not uncommon
although it is often reported in the literature.1 Most collision
tumors occur by chance, and are not derived from similar
cell lines and do not share pathogenic mechanisms.2 Some
authors support the theory that there is a pathogenetic relationship between collision tumors themselves (especially
seborrheic keratosis and melanocytic lesions); some others
postulate that contiguous tumor represents only the presence
of 2 or more common lesions juxtaposed by coincidence.3
Melanocytic nevus can occasionally be associated with several different tumor types. The most common association is
with the basal cell carcinoma (BCC) and in some cases, it
is very difficult to diagnose it clinically. Frequently, they are
also reported the association with epidermoid cyst, trichilemmal cyst, steatocystoma, hidrocystoma and dermoid
cyst, syringoma, trichoepitelioma and trichoadenoma.3 The
association of a melanocytic nevus which arises countiguously with or adjacent to seborrhoeic keratosis is however
uncommon 4 and sometimes diagnosis can be a clinical challage. We report an interesting case of composed pigmented
melanocytic nevus associated with seborrhoeic keratosis.
A.G., 25 year-old, came to our attention because she noticed a change in color and size of a nevus located in the
left subscapular region. This was present for some years
and its image had been previously acquired through epiluminescence (Figure 1).
Figure 1.—Dermoscopic features 2 years ago.
Vol. 149 - No. 5
At the time of the visit, however, it was possible to appreciate a pigmented lesion that had the clinical demoscopic features of a seborrheic keratosis (Figure 2). After
acquiring objective data conflicting with the anamnesis
Figure 2.—Dermoscopic features at the time of the second visit.
Figure 3.—Intradermal and junctional melanocytic proliferation
composed of nests of melanocytes without atypia; proliferation
of pigmented small basaloid cells with uniform appearance with
hyperkeratosis, acantosis and pseudohorn cysts (Haematoxylin &
Eosin x50).
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and the previous pictures, we decided to perform an excisional biopsy. The histological examination showed a
pigmented compound melanocytic nevus associated with
seborrheic keratoses (Figure 3). A simmetrical intradermal and junctional melanocytic proliferation composed of
nests of melanocytes without atypia was reported. Above
them there were a proliferation of pigmented small basaloid cells with uniform appearance with hyperkeratosis,
acantosis and pseudohorn cysts. These features led us to
diagnosis of composed pigmented melanocytic nevus associated with seborrheic keratosis.
This case is particular because a seborrheic keratosis in
collision with a melanocytic nevus clinically appeared as
one single lesion - the former one as an atypical spread of
the latter one - that had rapidly developed. In such cases
dermoscopy does not improve the diagnostic accuracy versus clinical examination.
In fact, even if the lesion presented the benign dermoscopic characteristics, according to the previous patient’s
pictures (which deposed for a major change of the melanocytic lesion), to the anamnesis and the possibility that
melanoma may mimic a seborrheic keratosis,5 we have decided to perform the complete excision of the lesion. The
histological examination clarified so that at the base of the
change there was the formation of a pigmented seborrheic
keratosis above the previously photographed melanocityc
nevus.
The case confirms that preoperative diagnosis of cutaneous collision tumors remains extremely difficult, even
with dermoscopy, especially when one of the lesions is
melanocytic one. By performing a large incisional or an
excissional biopsy, it will also be maximized the chance of
identifying multiple lesions.2
L. FECI
Dermatology Section, Department of Clinical Medicine and
Immunology, Siena University, Siena, Italy
[email protected]
632
E. TROVATO
M. PELLEGRINO
C. MIRACCO
Department of Human Pathology and Oncology; Pathological
Anatomy Section, University of Siena, Siena, Italy
P. TADDEUCCI
M. FIMIANI
References
1. Boyd AS, Rapini RP. Cutaneous collision tumors. An analysis of 69 cases and review of the literature. Am J Dermatopathol
1994;16:253-7.
2. PN Shams and JM Olver. A case of cutaneous collision tumour:
the importance of photographic documentation and large incisional
biopsy. Eye 2006;20:1324-5.
3. González-Vela MC, Val-Bernal JF, González-López MA, Novell M,
Fernández-Llaca H. Collision of pigmented benign tumours: a possible simulator of melanoma. Acta Derm Venereol 2008;88:92-3.
4. De Giorgi V, Massi D, Sestini S, Alfaioli B, Carelli G, Carli P. Cutaneous collision tumour (melanocytic naevus, basal cell carcinoma,
seborrhoeic keratosis): a clinical, dermoscopic and pathological
case report. Br J Dermatol 2005;152:787-90.
5. Izikson L, Sober AJ, Mihm MC, Jr, Zembowicz A. Prevalence of
melanoma clinically resembling seborrheic keratoses: analysis of
9204 cases. Arch Dermatology 2002;138:1562-6.
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