Nail psoriasis - Radboud Repository

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Unraveling nail psoriasis
Karlijn Klaassen
Proefschrift
Thesis Radboud university medical center, Nijmegen, The Netherlands,
with summary in Dutch.
Financial support of this thesis was kindly provided by:
Galderma Benelux B.V., Janssen-Cilag B.V., Pfizer B.V., Leo Pharma B.V.,
Fagron B.V., Celgene Corporation B.V.
Cover design and lay-out
Promotie In Zicht, Arnhem
ter verkrijging van de graad van doctor
aan de Radboud Universiteit Nijmegen
op gezag van de rector magnificus prof. dr. Th.L.M. Engelen,
volgens besluit van het college van decanen
in het openbaar te verdedigen op donderdag 6 november 2014
om 12:30 uur precies
door
Printing
Ipskamp Drukkers BV, Enschede
ISBN
978-94-6259-343-5
Copyright © K.M.G. Klaassen 2014
All rights reserved. No parts of this book may be reproduced in any form
or by any means without permission of the author.
Gedicht Toon Hermans Vandaag is de dag,
met vriendelijke toestemming van de Stichting Toon Hermans
Karlijn Maria Geertruda Klaassen
geboren op 30 juni 1986
te Groesbeek
Promotor
Prof. dr. dr. P.C.M. van de Kerkhof
Copromotor
Dr. M.C. Pasch
Manuscriptcommissie
Prof. dr. P.L.C.M. van Riel
Prof. dr. Ph. I. Spuls (Universiteit van Amsterdam)
Prof. dr. W.M. Prokop
Vandaag
Vandaag is de dag,
hij komt maar één keer,
morgen dan is het
vandaag al niet meer.
Niet zeuren, geniet
van het leven, het màg,
maar doe het vandaag,
want vandaag is de dag.
Paranimfen
Karin Lammers
Romy Keijsers
Toon Hermans
Bron: Vandaag is de dag, Elsevier de Boekerij de Fontein 1984
Contents
List of abbreviations
9
Chapter 1
General Introduction and outline of this thesis
11
Chapter 2
Prevalence and clinical characteristics of nail psoriasis
2.1 Fingernail psoriasis reconsidered: a case-control study.
2.2 Nail psoriasis: a questionnaire-based survey.
Chapter 3
63
Quality of life in patients with nail psoriasis 3.1 The impact of fingernails psoriasis on patients’ health-related 65
and disease specific quality of life.
3.2 Nail psoriasis, the unknown burden of disease.
81
Chapter 4
Scoring systems in nail psoriasis 4.1. Scoring nail psoriasis.
97
99
Chapter 5
Nail psoriasis and onychomycosis
5.1 The prevalence of onychomycosis in patients with nail
psoriasis; a systematic review.
113
115
Chapter 6
Nail psoriasis and psoriatic arthritis
6.1 Nail psoriasis, an early indicator for destructive psoriatic
arthritis?
135
137
Chapter 7
Summary, discussion and future perspectives
153
Chapter 8
Nederlandse samenvatting
167
Chapter 9
9.1 List of publications
9.2 Curriculum Vitae
9.3Dankwoord
185
187
189
33
35
49
List of abbreviations
3DThree-dimensional
CI
Confidence interval
DIP
Distal interphalangeal
DLQI
Dermatology life quality index
HC
Healthy control
HLA
Human leukocyte antigen
HRQoL
Health-related quality of life
ICC
Intraclass correlation coefficient
ILInterleukin
NAPSI
Nail psoriasis severity index
NAS
Nail area severity
N-NAIL
Nijmegen-nail psoriasis assessment index tool
NPQ10
Nail psoriasis quality 10
PASI
Psoriasis severity area index
PGA
Physician global assessment
PNSS
Psoriasis nail severity score
PsA
Psoriatic arthritis
QoL
Quality of life
RA
Rheumatoid arthritis
SAPASI
Self-administered psoriasis area and severity index
SD
Standard deviation
SF-36
Short form-36
SppSpecies
STROBE
Strengthening the Reporting of OBservational Studies in Epidemiology
Th 1 cells
Type 1 helper T cells
Th 17 cells Type 17 helper T cells
TNF
Tumor necrosis factor
USUltrasound
VAS
Visual analogue scale
Chapter 1
General Introduction
and outline of this thesis
GENERAL INTRODUCTION AND OUTLINE OF THIS THESIS
1. The nails
Nails cover the dorsal aspects of the digits, and are an integral part of the digital tip.
The shape and opacity of the nail varies considerably among individuals, and
throughout life the appearance of the nail changes with alteration in thickness,
contour, surface and color. In daily practice, disorders of the nail are common and are
often a diagnostic and therapeutic challenge for the doctors. Nail disorders can
present as a change of color, shape or structure of the nail, and are sometimes
accompanied by changes of the surrounding tissue. Abnormalities of the growth and
development of the nail can impede with several functions of the nail which can give
varying complaints. Although nails are a skin appendage, they have their own signs
and symptoms which may relate to varies medical conditions.
1.1 Function of the nail
The nail apparatus serves various important functions. The lateral, proximal, and
distal borders of the nail protect against intrusion of the nail apparatus by bacteria
and external substances, and the nail plate protects the distal phalanx, the fingertip,
and the surrounding tissue against trauma. The nail plate also enhances the sensory
discriminatory ability of the fingertips through counter-pressure that opposes the
volar side of the terminal phalanx.1, 3 Besides above mentioned functions, nails can
also be used as a defense mechanism, a tool for scratching, a tool for the manipulation
of small objects, and as a cosmetic accessory. The latter function emphasizes the
major role nails play in social interactions. Nails can give a reflection of an individual’s
well being, as several internal and dermatological conditions can express nail features.
In fact, nail changes may occasionally provide clues to the diagnosis of underlying
disease, sometimes before the clinical presentation of the disease. 4 One of the
dermatological diseases which can be preceded or accompanied by nail features is
psoriasis.
1.2 Development of the nail
In embryos the digits can be distinguished upward of 8 weeks of gestation. From nine
weeks of gestations the first elements of the nail apparatus start to develop, as a
transverse ridge on the distal dorsal surface of the digit develops, described as the
primary nail field. In the next four weeks this ridge moves more proximal and
eventually invaginates beneath the emerging proximal nail fold.5 At 13 weeks of
gestation a wedge of matrix moves proximally, and by 14 weeks the nail plate is seen
emerging from beneath the proximal nail fold.3 At 17 weeks the nail plate covers most
of the nail bed, and from week 20 and further the nail plate and finger grow in parallel.
13
1
CHAPTER 1
1.3 Anatomy of the nail
The nail unit can be subdivided into the proximal nail fold, the cuticle, the nail matrix,
the nail plate, the hyponychium, and the nail bed (see Figure 1).6 The proximal nail fold
is a continuation of the skin, that folds underneath itself, and continues into the
cuticle (eponychium) which adheres to the dorsal aspect of the nail plate. It protects
the nail matrix from external influences.1 The nail plate is produced in the nail matrix,
which is located beneath the proximal nail fold. It is the growth center of the nail
(see Figure 2). As shown in Figure 2, the nail plate can be divided into three layers;
the dorsal layer, the intermediate (germinative matrix) layer, and the ventral layer.
As the nail grows, cells of nail matrix divide, differentiate, keratinize, and form the nail
plate.1, 3 The nail plate grows from proximal to distal by sliding over the nail bed,
whereupon the distal end detaches from the nail bed.7 The hyponychium is located
underneath this free edge of the nail plate at the distal end. It is the transition of nail
bed to normal epidermis of the fingertip.1 The nail bed is located underneath the nail
plate and is the vascularized area of the nail apparatus.1, 3 A longitudinal pattern of
ridges in the nail bed provides attachment to the ventral aspect of the nail plate which
has corresponding ridges. This enhances adhesion between these two structures
and enables the free edge of the nail plate to be used as a tool without lifting the nail
from the nail bed.5
1
Figure 2. Close-up of the nail matrix and the different layers of the nail plate.
(from Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F.1).
2. Psoriasis
2.1 Epidemiology
Psoriasis is a common, and chronic skin disease characterized by epidermal hyper
proliferation. The prevalence of psoriasis in Europe varies between 0.7% and 2.9%,
with a preference for the Caucasian population.8, 9 Although psoriasis may begin at
any age, two peak incidences have been reported; an early onset type (16-22 years of
age) and a late onset type (57-60 years of age). A previous study has shown that 37.1%
of psoriasis patients had the first signs of skin disease before the age of 20 years.10
There is no gender predilection.11 Psoriasis often presents with skin signs but may also
exhibit abnormalities in the joints and on the nails, even in patients without psoriasis
of the skin.
2.2 Clinical features
Figure 1. Anatomy of the nail apparatus.
(from Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F.1).
14
The most characteristic psoriatic lesion consists of sharply demarcated erythematosquamous plaques, typically in a symmetrical distribution, and characteristically
localized on the extensor prominences of the upper and lower extremities, scalp,
lumbosacral region and umbilicus.12 The clinical course is characterized by remissions
and exacerbations, influenced by various exacerbating factors.2 Psoriasis is heterogeneous in the clinical presentation with several clinical phenotypes. The most common
clinical variant, psoriasis vulgaris, affects approximately 85% to 90% of all patients
with psoriasis.2, 13 Other localizations of psoriasis include flexural (inverse) psoriasis,
scalp psoriasis, seborrhoeic psoriasis and palmoplantar psoriasis, and other types
of psoriasis are guttate psoriasis, eyrthroderma and pustular psoriasis. While skin
15
CHAPTER 1
manifestations are the most characteristic finding in psoriasis, lesions as a consequence
of psoriasis can also manifest in the nails of these patients, predominantly in patients
with psoriatic arthritis (PsA).
1
2.3 Pathogeneses
Psoriasis appears to be a multi-factorial disease with an interplay of many genetic and
environmental factors.2 The exact underlying mechanisms are still unclear, but genetic
susceptibility, abnormal function of keratinocytes, and immunological disturbances
of the innate and acquired immune system are postulated.2
2.3.1 Environment
Various environmental factors have been identified in the pathogenesis of psoriasis.
Streptococcal throat infections, medications, stressful life events and smoking are
known factors which can trigger psoriasis. These factors, and many others, can also
exacerbate or modify the disease in patients.2
2.3.2 Genetic factors
Population studies have shown that the incidence of psoriasis is greater among
first-degree and second-degree relatives of patients with psoriasis than among the
general population.2 Genome-wide association studies have identified nine
chromosomal loci (PSORS1 through PSORS9) which can be linked to psoriasis.2 The
major genetic determinant seems to be PSORS1, which probably accounts for 35 to
50% of the hereditary of psoriasis. Human Leukocyte Antigen (HLA)-Cw6, involved in
the antigen-presentation, seems to be the susceptible allele located on PSORS1.
However, patients with nail psoriasis and/or PsA are more frequently HLA-Cw6
negative.14 In recent years several other genome-wide association studies identified
genes related to the adaptive immunity, innate immunity and skin barrier function.15-17
2.3.3 Immunological factors
During the years various cells and mediators playing a role in the immunopathogenesis of
psoriasis have been identified or postulated, including keratinocytes, dendritic cells,
T lymphocytes, complement proteins, and varies cytokines and chemokines. A widely
accepted model for the interplay of cells and their mediators is demonstrated in
Figure 3. This Figure shows that an initial trigger (e.g., trauma, infection, stress) can
induce a cascade of events leading to the activation of dendritic cells through the
production of cytokines (tumor necrosis factor α (TNF-α), interferon-α, interferon-Ү,
interleukin (IL)-1β, and IL-6) by innate immune cells. When activated, the dendritic
cells start to present antigens and secrete mediators (e.g., IL-12, IL-23) to T cells. This
leads to the differentiation of type 1 and type 17 helper T cells (Th1, Th17). These
activated T cells subsequently secrete mediators (IL-17A, IL-17F, IL-22) which then
16
Figure 3. Schematic suggested overview of the pathogenesis of psoriasis.
(from Nestlé FO, Kaplan DH, Barker J.2).
activate keratinocytes leading to keratinocyte hyperproliferation and the secretion
of different chemokines. The hyperproliferation of the keratinocytes is responsible
for the clinical feature of scaling, while the chemokines are responsible for attraction
of more inflammatory cells to the skin. In recent years more and more pieces of the
immunological puzzle have been added or adapted in this model. This has resulted in
the production of molecules interfering in the pathogenic steps, the so-called
biologics. This is a class of pharmaceuticals that are proteins produced by recombinant
DNA technology which inhibit different actions of several above mentioned cytokines,
thereby preventing the full pathogenetic cascade, and reducing the clinical features
of psoriatic disease. However, the pathogenetic picture is still expanding and there
are still many pieces which have to be discovered as shown in recent publications.18
17
CHAPTER 1
3. Nail Psoriasis
1
3.1 Epidemiology
The prevalence of nail psoriasis documented in the literature varies between 10% and
82%, with an estimated lifetime incidence of 80% to 90%.1, 19-32 A study by de Jong et
al., among 1728 psoriasis patients, found nail involvement in 79.2%, which indicates
that the prevalence of nail psoriasis might often be underestimated.20 Nail psoriasis in
the absence of cutaneous disease is present in 5% to 10% of psoriatic patients.26, 33 The
prevalence of nail psoriasis in children seems to be much less frequent, varying from
7% to 13%.3, 25, 34
A
B
C
D
E
F
G
H
3.2 Pathogenesis
Identical to psoriasis of the skin, expression of the same psoriatic inflammation process
in the nail matrix or nail bed causes the clinical features seen in the nail. However,
because of the particular physiology and anatomy of the nail apparatus, characteristic
psoriatic features seen on the skin, like erythema and hyperkeratosis, have a different
clinical expression in the nail.
3.3 Clinical aspects of nail psoriasis
The clinical nail manifestations seen in psoriasis depend on the localization of the
inflammation in the nail unit. When psoriasis is present in the nail matrix it can give
the following manifestations: pitting, leukonychia, red spots of the lunula, Beau’s
lines and crumbling of the nail plate, whereas psoriasis of the nail bed presents as
oil-drop discoloration, splinter haemorrahages, subungual hyperkeratosis and/or
onycholysis. The different nail features seen in nail psoriasis are discussed below, and
clinical examples are displayed in Figure 4.
3.3.1 Nail matrix
Pitting. A pit indicates a defect in the uppermost layers of the nail plate. In psoriatic
inflammation clusters of parakeratotic cells disrupt the process of normal keratinization
as they accumulate on the surface of the nail plate. When the nail plate grows past
the nail fold, the clusters of cells shed from the nail plate, leaving a superficial
depression within the nail plate. Sparse pits can be seen in healthy individuals, and
can also appear in other diseases (e.g., alopecia areata, lichen planus, chronic
eczema), but are typically numerous and deeper in patients with psoriasis.1 In psoriasis
they often can be found in a linear pattern rather than involving the whole nail plate.
Red spots lunula. Red spots in the lunula is an infrequently found phenomenon in nail
psoriasis. The prevalence varies between 0.4% and 10.1% in patients with nail
psoriasis.29, 35-38 The red spots may be a consequence of inflammatory processes in the
nail matrix that likely reflect distal matrix involvement. Red spots in the lunula are
18
Figure 4. Nail manifestations seen in nail psoriasis.
Nail bed features; A. Oil-drop discoloration (arrow); B. Onycholysis; C. Subungual hyperkeratosis; D. Splinter
hemorrhages. Nail matrix features; E. Pitting of the nail plate; F. Crumbling in proximal quadrants nail plate;
G. Leukonychia; H. Red spots in the lunula (arrow).
documented in several other (dermatological) disorders (e.g., lichen planus, alopecia
areata, cardiac failure, hepatic cirrhosis).
Crumbling. In nail plate crumbling, the plate is thickened, largely deformed, and with
an irregular and scaly surface.39 The structure of the nail plate is lost, and is seen in
severe involvement of the matrix in nail psoriasis.
Leukonychia. Leukonychia is the whitish discoloration of the nail plate. Since the nail
plate is smooth, it represents psoriatic alterations in the intermediate and ventral
layers of the nail plate, and is attributable to the matrix dysfunction. The nail has
milky white spots due to the presence of parakeratotic cells within the nail plate.
Leukonychia does not fade with pressure and moves distally as the nail grows.39 This
phenomenon is also rather frequently seen in healthy nails.
Beau’s lines. Beau’s lines are transverse ridges and indentations in the nail plate
caused by a temporary cessation of cell division in the nail matrix. These indicate a
mild insult to the proximal nail matrix that interferes with matrix keratinization,
resulting in a temporary reduced nail plate formation. After recovery of the nail
matrix the nail plate formation also recovers and the nail plate regains its normal
19
CHAPTER 1
thickness. They are usually deep in the central portion of the nail plate and move
distally with nail growth. Multiple lines indicate a repetitive insult.39
3.3.2 Nail bed
Onycholysis. Onycholysis describes the whitish discoloration seen at the distal end of
the nail, caused by detachment of the nail plate from the nail bed. Because a
parakeratotic psoriatic area of the nail bed detaches from the nail plate and a space
between the nail plate and nail is created, air can enter this space between the two
structures, causing the whitish discoloration. It generally starts distally due to disruption
of the onychocorneal band and moves proximally.
Oil-drop discoloration. Psoriatic lesions in the nail bed can give oil-drop colored
patches which can be seen through the nail plate.1 Both oil-drop discoloration and
onycholysis are the results of the same pathogenic process, namely parakeratotic
changes in the nail bed. Desquamation of these parakeratotic cells at the hyponychium
leads to onycholysis. 40, 41
Subungual hyperkeratosis. Nail bed hyperproliferation with accumulation of keratinocytes under the nail plate which do not desquamate, results in subungual hyper
keratosis. 41 The extent to which the nail plate is elevated depends on the degree of
psoriatic activity and resulting accumulation of nail bed-derived cells.
Splinter hemorrhages. These linear, “splinter” shaped hemorrhages are the result of
dehiscence of fragile capillaries found in the nail bed of psoriatic patients.1, 42 Because
of the nail plate changes and capillary fragility, psoriatic nail units are predisposed to
develop splinter hemorrhages, most commonly precipitated by traumas. 41 Most of
them can be seen at the distal third of the nail plate. Proximal splinter hemorrhages
can be seen in various cardiovascular, renal and pulmonary diseases. 43
3.4 Treatment of nail psoriasis
Treatment of nail psoriasis is challenging and hindered by the construction of the nail
apparatus. The delivery of effective drugs to the nail unit is limited because of the
impermeability of the nail plate and inaccessibility of the nail matrix by topical
treatments. The toxicity associated with many conventional systemic therapies
makes treatment even more challenging. 44 Moreover, as nails grow slowly (fingernails
3.47 mm/month, toenails 1.62 mm/month), 45 treatment has to be persevered for a
long time which is a challenge for the compliance of patients.46 The treatment options
available for the treatment of the cutaneous component are not registered for the
treatment of nail features specifically, and evidence-based studies infrequently focus
specifically on the effects on the nails. However, a study of de Jong et al.20 showed
that only 35.4% of nail psoriasis patients was treated for their nail features, while a
major part of these patients reported that they were restricted in their daily activities,
housekeeping and/or profession in 58.9%, 56.1% and 47.9% respectively. This article
20
from 1996 emphasizes that effective treatment options for nail psoriasis are highly
desirable.20 However, a Cochrane review from 2013 concluded that there is only high
quality evidence for treatment of nail psoriasis with two biologics and radiotherapy.47
Only 18 studies could be included as the quality of studies was generally poor. 47
The use of the biologics infliximab (TNF-α antagonist) and golimumab (also TNF-α
antagonist, not registered for patch psoriasis in the Netherlands), resulted in
significant improvement of nail psoriasis. Although frequently used, there is limited
evidence for the efficacy of topical therapies in nail psoriasis. Positive effects of solely
or combined therapy with topical corticosteroids and vitamin D3 analogues are most
frequently described. 48-51 It is recommended that before application of topical
therapy, the nail plate must be trimmed back as close as possible to the nail bed.19
Intralesional corticosteroid injections, injected in the proximal nail fold, have been
shown effective in the treatment of predominantly nail matrix lesions. 40 In few,
mostly uncontrolled trials, triamcinolone has been injected in varies concentrations
(10 - 40 mg/ml) and dosages schemes (weekly or monthly) showing positive effects.52-54
However, it should be taken into account that injection into the nail matrix region is
very painful due to the lack of space, and local anesthetics are sometimes necessary.
Repetition of treatment is frequently needed, however repetition frequency is limited
because of the risk of atrophy.55 When local therapies fail, systemic therapies may be
used. However, clinicians are restrained in the prescription of systemic therapies for
nail psoriasis solely, because of the potential toxicity, 41 so the advantages and
disadvantages should be taken into account. Indications for prescribing systemic
treatments are because of severe cutaneous psoriasis, coexistence of PsA, or when
nail psoriasis is interfering with patients’ quality of life and is refractory to other
therapies.47 Methotrexate seems to be a good first option,40, 56, 57 followed by fumaric
acid, ciclosporin, and acitretin.56 In the Netherlands, biologic treatment can be
prescribed for treatment of patients with moderate to severe plaque psoriasis who
had not responded to phototherapy and methotrexate and/or ciclosporin, or who
had contraindications to, or did not tolerate these therapies.58 According to the
guideline of the Dutch dermatological association there is no indication for biologic
therapy for patients with solely nail psoriasis, most likely because of the high costs of
therapy and the absence of an appropriate label. However, in literature there are
studies describing the effects of biologics on psoriasis nail features. Although all
biological therapies have demonstrated varying levels of efficacy in treating nail
psoriasis, the most robust data are available for infliximab.38, 47, 56, 59 But positive effects
from adalimumab, etanercept (both TNF-α inhibitors), and golimumab on nail features
have also been described.60, 61, 62, 63
3.5 Evaluating the severity of nail psoriasis
Scoring systems are indispensable in this era of evidence-based medicine. They are
21
1
CHAPTER 1
needed to objectify and to evaluate a treatment response. Using one and the same
scoring system for a certain disease is also prerequisite to compare results of different
studies. The most common methods to determine disease severity in psoriasis, such
as the psoriasis area and severity index (PASI), do not include specific features of nail
psoriasis. In the past years attention towards nail psoriasis and the treatment of nail
psoriasis in literature is increasing and specific nail psoriasis severity scores are
needed. In 2003 the nail psoriasis severity index (NAPSI) was developed by Rich et al.,
one of the first nail specific scores created for the measurement of nail psoriasis
severity. 44 During the course of years several other nail psoriasis scoring systems
have been developed, however the NAPSI is most widely used in clinical trials. 40 In
this NAPSI score the nail is divided into 4 equal quadrants. Each quadrant is then
evaluated for the presence or absence of nail matrix (pitting, red spots in the lunula,
crumbling, leukonychia) and nail bed (onycholysis, splinter hemorrhages, oil-drop
discoloration, subungual hyperkeratosis) features separately. Each nail is assigned a
nail bed and a nail matrix score of 0-4, and combined the score for one nail can range
from 0-8. The nail bed and nail matrix scores of all nails are summed and the maximum
score for the fingernails can range from 0-80, with higher scores indicating more
severe nail psoriasis.
psoriasis. Studies using the DLQI in these patients showed significant more impairment
in nail psoriasis patients.28, 30 However, the specific impact of nail features on QoL cannot
be abstracted from this scorings systems. Therefore, nail psoriasis specific instruments
need to be developed, validated and used.
3.6 Evaluating the impact on quality of life
4.1 Epidemiology and pathogens
It is already known that dermatological conditions can have a substantial impact on
patients’ quality of life (QoL).64 As psoriasis can be present on visible parts of an
individuals’ body, the impact can be significant.64 Scoring systems have been
developed and validated to measure the impact of diseases on QoL. Health-related
quality of life (HRQoL) scores can be generic, dermatology-specific, or disease-specific.
An often used generic HRQoL questionnaire is the Short-Form 36 (SF-36) which
measures different aspects of health applicable on every patient, and makes
comparison between the impact of different diseases possible.65, 66 A frequently used
dermatology-specific questionnaire is the Dermatology Life Quality Index (DLQI)
which have been developed to measure the impact of dermatological conditions on
QoL.67 It is an easy applicable and short questionnaire consisting of ten questions
concerning the most common limitations of QoL caused by skin conditions. Question
categories are symptoms, daily activities, work and school, leisure, feelings, treatment
and personal relationships. The higher the score, the more the QoL is impaired.
A limitation of the DLQI, when applied to nail psoriasis patients, is that it does not
specifically displays the impact of nail features on QoL. Therefore, recently Ortonne
et al.68, developed the nail psoriasis questionnaire, NPQ10, a nail psoriasis specific
QoL questionnaire. The questionnaire consists of ten questions constructed to
address the physical aspects which are associated with nail psoriasis.68 Until 2010, the
DLQI was the most disease-specific QoL instrument applicable for patients with nail
Onychomycosis is an infection of the nail apparatus by fungi that include
dermatophytes, nondermatophyte moulds and yeast.70 A recent systematic review
showed that the mean prevalence of onychomycosis is 11% in the general population,
however these numbers depend on geographical and ethnical factors.71 The main
causative pathogens of onychomycosis are dermatophytes (Trichophyton rubrum and
Trichophyton mentagrophytes) and are responsible for 80-90% of cases.72, 73 Yeast
(Candida species (spp.)) and nondermatophyte moulds (e.g., Acremonium spp.,
Alternaria spp., Aspergillus spp.) are much less frequently cultured as primarily
pathogens. Of these, Candida species are the most common and account for
approximately 1.5% to 6% of nail infections, more frequently in fingernails than in
toenails.7, 74, 75 Dermatophytes are normally transmitted through infected moist floors
areas, and are less frequently transmitted by personal contact. Tinea pedis (mycoses
of the foot) can lead to onychomycosis and has been associated with onychomycosis
in 30-59% of cases.76
22
3.7 Differential diagnosis of nail psoriasis
Differential diagnostic considerations in patients suspicious for having nail psoriasis
are onychomycosis, lichen planus, contact dermatitis, alopecia areata, bacterial
infection, idiopathic onycholysis, yellow-nail syndrome, and congenital pachyonychia.
Top of the differential diagnostic considerations in these patients is onychomycosis.
Onychomycosis can clinically mimic nail psoriasis, and is the most frequent nail
disease as it accounts for more than half of all nail abnormalities, and one-third of all
mycotic skin infections.69 Discrimination between onychomycosis and nail psoriasis
can be complicated as clinical nail features as subungual hyperkeratosis and
onycholysis are also frequently seen in onychomycosis.
4. Onychomycosis
4.2 Clinical presentation
Several types of onychomycosis have been recognized which are categorized according to
clinical presentations and route of invasion. The most prevalent type of onychomycosis
is distal and lateral subungual onychomycosis. In this type the organism invades the
nail bed and underside of the nail plate at the hyponychium and migrates towards
23
1
CHAPTER 1
proximal.7 Clinically, infection of the nail results in subungual hyperkeratosis and
onycholysis, which are both frequently seen in nail psoriasis. Therefore, it may be
impossible to distinguish clinically nail psoriasis from onychomycosis.
4.3 Risk factors
Various predisposing factors for the development of onychomycosis are known like
environmental factors (community bathing areas, moist areas), and subject characteristics (e.g., age, gender). But also several disease modalities have been associated
with a higher risk of onychomycosis like diabetes mellitus and peripheral vascular
disorders.77 In addition, patients with immunosuppressive disorders or patients using
immunosuppressive therapy are at a higher risk of developing onychomycosis.78 Also
psoriasis is named as a risk factor of onychomycosis, however, if patients with (nail)
psoriasis really have a higher risk of developing onychomycosis remains unclear. In
recent years more and more psoriasis patients are using immunosuppressive
therapies which might increase the risk of developing onychomycosis in this groups of
patients.79
nail plate is insufficient. Oral treatment with systemic antimycotics form the mainstay
of therapy of onychomycosis. However, for efficacy of therapy, compliance is needed
for a long period considering the slow growth rate of the nail. In addition, systemic
antimycotics have a realistic risk of side effects.72 Terbinafine (ergosterol synthesis
blocking ) is one of the most effective systemic therapy for onychomycosis.72, 82 It is
effective against predominantly dermatophytes and some moulds. However it has
less activity against C. albicans. Itraconazole is a more broad-spectrum antifungal
triazole, and is also effective against C. albicans.7 Most frequently seen adverse events
are gastrointestinal adverse effects (e.g., nausea, diarrhea). Hepatic site effects can
occur with both treatment modalities, so the monitoring of liver enzymes is advised.7, 72
Because of the disadvantages and long-term administration, differentiation between
nail psoriasis and onychomycosis is important in order to prevent overtreatment.
5. Psoriatic arthritis
5.1 History and epidemiology
4.4 Diagnosis
Clinical discrimination between nail psoriasis and onychomycosis is often difficult,
therefore appropriate diagnostic techniques are important to ensure correct diagnosis
and treatment. Diagnostic techniques including direct microscopy (10% potassium
hydroxide preparations), fungal culture (cultures with and without cycloheximide), and
polymerase chain reactions may identify onychomycosis and help to distinguish it from
nail psoriasis. Direct microscopy can be used to test for the presence or absence of
fungi, and based on the microscopic elements seen one can make a differentiation
between dermatophytes and yeast, however a reliable identification of the exact
pathogen can only be made by culture. When using direct microscopy false-negative
rates in 5% to 15% of patients are described.7 With culture the specific microorganism
can be identified.7 Since most dermatophytes tend to grow slowly in culture, cultures
must be continued for 3 weeks before they are pronounced negative.80 Correct
localization of sample collection is important and depends on the type of onychomycosis.
In distal and lateral subungual onychomycosis the nail should be clipped short and
should be taken from the transition zone into healthy nail and from the underside of the
nail plate.7 Coexistence of onychomycosis and nail psoriasis also occurs, as both are
frequent disorders in the general population.81
4.5 Treatment
Treatment of onychomycosis is mainly by antimycotics, and topical as well as systemic
antimycotics are registered. The advantage of topical therapy is the limited number
of side-effects, however curative response is extremely poor as penetrations into the
24
The association between psoriasis and joint disease was first recognized by Alibert,83
and has been defined as an inflammatory arthritis, usually seronegative for
rheumatoid factor, associated with psoriasis. Though PsA is known for more than two
centuries, it was initially thought to be a variant of rheumatoid arthritis (RA). The
discovery that rheumatoid factor is present in majority of patients with rheumatoid
arthritis but only in minority of patients with PsA resulted in the differentiation of two
separate disease entities.84 PsA is uncommon in the general population (0.25%
prevalence in the United States), but its prevalence in psoriasis patients varies
between 6% and 42% according to different study population.85-89 The prevalence of
nail psoriasis in patients with PsA is very high reaching nearly 50-87 percent.86,88
Typically, the cutaneous psoriasis lesions precede the development of joint
involvement by 12 years.88, 90 Psoriasis patients with nail involvement, scalp lesions,
and intergluteal lesions are associated with an increased risk of developing PsA in the
course of their disease.86
5.2 Clinical manifestations
The main symptom of PsA is arthritis which can affect any joint, but most common
the peripheral joints of the hands and feet.90 Various clinical patterns of joint
distribution can be seen; distal predominant pattern, asymmetrical oligoarticular,
symmetrical polyarticular resembling seronegative RA, spondylitis, and arthritis
mutilans. However the majority of patients has polyarthritis, followed by
oligoarthritis.88 Besides swollen en tender joints, PsA is frequently accompanied by
dactilytis (32-48%), enthesitis (25-53%), nail psoriasis (50-87%), and/or uveitis
25
1
CHAPTER 1
(4-18%).84 Dactilytis is a diffuse swelling of an entire digit caused by a combination of
enthesitis, tenosynovitis and arthritis. Entheses are sites at which tendons or
ligaments are integrated into bone.91 Longstanding inflammation of a joint can give
deformation of the joint leading to disabilities. Joint damage is seen in 27% of patients
within ten months of start symptoms, and in 47% of patients within two years of
symptom onset despite treatment.92
5.3 Pathogenesis
The pathogenesis of PsA is complex with an interplay of environmental, genetic and
immunological factors comparable to that seen in psoriasis. PsA has an important
hereditary factor as it is documented that the risk in first-degree relatives of patients
with PsA was 30-55 times higher than in the general population. In contrast to
psoriasis, PsA patients are frequently HLA-Cw6 negative. Associations have been
found between PsA and several other class I HLA genes, like HLA-B27, HLA-B38 and
HLA-B39.90, 93 Originally, it was thought that the link between arthritis and psoriasis
could be explained by an autoimmune reaction to a common autoantigen in both skin
and synovium.94 However, recent studies showed that the inflammation starts in the
entheses instead of the synovium, from which T cells, dendritic cells, mast cells,
neutrophills and macrophages infiltrate the synovium of joints in a similar manner as
described in psoriasis.90 Recently several studies have been published which speculate
on the association between nail psoriasis and PsA with the entheses as epicenter of
the disease, as there might be a direct anatomical link between inflammation of the
distal interphalangeal (DIP) joint and nail changes via the entheses of the extensor
tendon.95-98
Aims and outline of the thesis
This thesis describes studies on the different aspects of nail psoriasis in order to provide
insight into the prevalence, clinical manifestations, and the impact on patients’ QoL
of patients with nail psoriasis. In addition, studies contributing to the elucidation of
the link between nail psoriasis and psoriatic arthritis, and the coexistence of (nail)
psoriasis and onychomycosis are described.
To improve care for patients with nail psoriasis, it is essential to acquire knowledge
concerning this disease. The documented data on the prevalence and clinical
characteristics are incomplete and divergent, and prevalence numbers vary considerably
in literature. Therefore, the aim of chapter 2 was to give insight into the prevalence
of nail psoriasis, and to obtain quantitative information on the clinical characteristics
of patients with nail psoriasis. A secondary aim of this chapter was to give insight into
self-reported treatment experiences of patients with nail psoriasis.
26
Psoriasis can be found at several different localizations which may be of various
impact on patients‘ QoL. In particular psoriasis on highly visible areas of the skin, such
as the face and hands, can have a significant impact. The aim of chapter 3 was to
achieve more insight into the quality of life of psoriatic patients with nail psoriasis,
and to characterize the patients with nail involvement which are more prone to the
impact of the nail alterations caused by psoriasis.
Fortunately, attention towards nail psoriasis is increasing, and more and more
studies are attempting to evaluate therapeutic options for nail psoriasis. Scoring
systems are indispensable for the evaluation of the severity of disease and to monitor
treatment response, but also to compare results from different studies. Several
scoring systems have been proposed to assess nail psoriasis severity. Despite the
importance, there is lack of consensus on the most appropriate of these measures. In
chapter 4 we compared these different nail psoriasis scoring systems in patients with
nail psoriasis, and evaluated the competence of these different assessment tools.
Furthermore, it was attempted to formulate a better scoring system.
Clinical manifestations associated with nail psoriasis are heterogeneous in their
representation and many psoriatic nail features may morphologically resemble
onychomycosis. It is hypothesized that morphological abnormalities in psoriatic nails
are predisposing factors for onychomycosis and vice versa. Consequently, the goal of
chapter 5 was to systematically review all available literature concerning the
prevalence of onychomycosis in psoriasis patients to give insight into the coincidence.
Based upon the high prevalence of nail psoriasis in PsA patients, and the increased
percentage of PsA patients with nail psoriasis, it was already concluded that there is
an association between nail psoriasis and PsA. It was thought that the link between
arthritis and psoriasis could be explained by an autoimmune reaction to a common
autoantigen in both skin and synovium. However, this hypothesis is challenged by
recent studies which emphasize on the association between PsA and nail psoriasis
with the entheses as the epicenter of both manifestations. It is suggested that they
play a key role, as the entheses of the DIP joint are suggested as the anatomical link
between the nails and the joints and therefore as starting point of a generalized
disease. Therefore, the aim of chapter 6 was to contribute to the elucidation and
exploration of the hypothesis concerning the anatomical link between nail psoriasis
and PsA with the extensor entheses as the epicenter.
The results of the subsequent chapters, together with the possible implications for
future clinical research and care are summarized and discussed in chapter 7.
27
1
CHAPTER 1
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24.
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31
1
Chapter 2
Prevalence and clinical characteristics
of nail psoriasis
Chapter 2.1
Fingernail psoriasis reconsidered:
a case-control study
H.M.J. van der Velden
K.M.G. Klaassen
P.C.M. van de Kerkhof
M.C. Pasch
Journal of the American Academy of Dermatology 2013;69:245-252
CHAPTER 2
PREVALENCE AND CLINICAL CHARACTERISTICS OF NAIL PSORIASIS
Abstract
Introduction
Background: Literature concerning clinical signs and frequency of nail psoriasis is
incomplete. Recent studies focus only on signs included in the Nail Psoriasis Severity
Index (NAPSI).
The prevalence of nail psoriasis varies between 10% and 79%.1-6 It is reported that
80% to 90% of psoriatic patients develop nail psoriasis some time during their
disease.1-4,6 However, psoriatic nail lesions rarely appear as the only clinical
manifestation of psoriasis, as psoriasis limited to the nails occurs in only 1% to 10% of
patients with psoriasis.1,3,4 It is mentioned that psoriatic arthritis (PsA) is associated
with higher rates of nail psoriasis, and the severity of nail disease correlates with
indicators of severity of joint disease.7 Previous research states that nail psoriasis is
associated with both longer duration and greater extent of skin disease.2
The clinical spectrum of nail psoriasis is heterogeneous, depending on the
involvement of nail bed, nail matrix, or both. Widely accepted manifestations attributed
to psoriatic inflammation of the nail matrix are pitting, red spots in the lunula, leukonychia,
and nail plate crumbling. Nail bed manifestations are oil-drop discoloration, onycholysis,
splinter hemorrhages, and subungual hyperkeratosis.5,6 Additional symptoms found
in literature include Beau’s lines, onychomadesis, nail fold involvement, and
longitudinal ridging.6 These are not included in the widely used Nail Psoriasis Severity
Index (NAPSI) scoring system, which is limited to the first eight mentioned nail
changes. Using this instrument each quadrant of each fingernail is evaluated for
presence or absence of nail bed or nail matrix disease. The sum of the scores for all
the fingernails is the NAPSI score for the patient at that time (see Figure 1 for an
example of calculation).8 In most recent studies concerning nail psoriasis only the
total NAPSI score is used. Literature concerning the frequency of each specific clinical
sign of nail psoriasis is limited.2,7,9-17
The aim of this study was to describe the epidemiological characteristics and the
frequency of clinical signs of fingernail psoriasis and compare them with healthy
controls.
Objective: We sought to describe clinical characteristics of fingernail psoriasis in
comparison with healthy controls.
Methods: We collected data on 49 patients with fingernail psoriasis who visited our
outpatient department and 49 control subjects, through questionnaires and clinical
examination. The disease severity was measured by the NAPSI.
Results: Mean NAPSI score in patients and control subjects was 26.6 and 3.6,
respectively. Most items included in the NAPSI were specific for nail psoriasis.
Onycholysis and splinter hemorrhages were most frequently observed. Leukonychia
was more frequent in control subjects. Longitudinal ridges and Beau’s lines are not
included in the NAPSI but are significantly more frequently seen in patients than in
control subjects.
Limitations: Limited sample size was a limitation.
Conclusion: The NAPSI was able to discriminate patients with fingernail psoriasis
from healthy control subjects. Onycholysis and splinter hemorrhages were the most
prevalent fingernail changes in psoriatic patients. Leukonychia was more frequently
observed in control subjects, which raises the question of whether leukonychia
should remain in the NAPSI. On the other hand, longitudinal ridges and Beau’s lines
occurred more frequently in psoriasis patients but are not included in the NAPSI.
Methods
Study population
A total of 49 patients with fingernail psoriasis were recruited consecutively in this
case-control study from the outpatient clinic at the Department of Dermatology of
the Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Patients were included from December 2009 through July 2012. Included patients
were older than 18 years with clinically diagnosed fingernail psoriasis (NAPSI score ≥
1). Patients who used artificial nails in the past six months or had presence of a skin
disease (other than psoriasis), which is associated with nail manifestations, were
excluded, as were patients with toenail involvement exclusively, because of the
increased risk of coexistence of onychomycosis. To exclude patients with concomitant
37
2
CHAPTER 2
onychomycosis, clippings and subungual scrapings of affected fingernails were collected
for direct microscopic examination (10% potassium hydroxide preparations) and fungal
culture. Cultures were carried out on two different types of Sabouraud dextrose
agar: one with chloramphenicol and cycloheximide and one without cycloheximide.
None of the patients tested positive.
In addition, a total of 49 age- and gender-matched control subjects were included.
They were healthy individuals older than 18 years without (skin) diseases or medication
associated with nail manifestations and were recruited from patients, visitors, and
employees of the above mentioned outpatient clinic.
2
Survey details
The survey of the psoriatic patients consisted of a questionnaire taken by interview
and clinical examination conducted by the same investigator. The interview included
items concerning demographic patient characteristics, general health, psoriasis-
related data, and specific nail psoriasis questions. Diagnosis of concomitant PsA
was made through physical examination by a rheumatologist. Nail manifestations in
both groups, i.e., fingernail psoriasis and healthy control, were documented and
photographed.
Severity of disease measurement
The severity of psoriasis was assessed by the Psoriasis Area and Severity Index (PASI)
(range 0-72).18 Higher scores indicate more severe psoriasis of the skin. The body
surface area represents the percentage of body surface affected and classifies the
severity of the condition. The severity of fingernail psoriasis was assessed by the
NAPSI score (Figure 1).8 Additional nail changes (e.g., Beau’s lines, onychomadesis,
longitudinal ridging, and nail fold involvement) were also assessed for each fingernail.
The fingernails of the healthy control subjects were scored for the presence of the
same manifestations of nail psoriasis and a NAPSI score was measured.
Statistical analysis
Data were entered in a Statistical Package for Social Sciences (SPSS 18.0, SPSS Inc,
Chicago, IL) database and subsequently statistical analyses were performed.
Descriptive statistics were provided using mean (SD) and median (range) for normally
and nonparametric distributed numeric values, respectively. Frequencies and
percentages were used for categorical variables. Missing values were not included to
calculate percentages. Comparison of numeric variables were analyzed with the
unpaired t tests or the Mann-Whitney U test and the χ2 or Fisher exact test was used
for differences between categorical variables. Spearman rank test was used to
explore the relationship between continuous variables. P values less than 0.05 were
considered to be statistically significant. All tests were 2-sided.
38
Figure 1. Fingernail psoriasis; grading with Nail Psoriasis Severity Index (NAPSI).8
The nail is divided into 4 quadrants. Each quadrant is evaluated for presence or absence of nail bed
psoriasis (0-4) and nail matrix psoriasis (0-4). Score is 0 if no sign of nail bed involvement is present in any
quadrant. Score is 4 if signs of nail bed involvement are present in all 4 quadrants. Score for matrix is
calculated in a similar way. In this example, pitting and nail plate crumbling are present in quadrants A, B,
and C, and therefore score for nail matrix psoriasis is 3. We see onycholysis, splinter hemorrhages, and nail
bed hyperkeratosis in quadrants C and D, and therefore score for nail bed psoriasis is 2. Sum of these
scores is total score of that nail (in this example 5), with minimum of 0 (representing no nail psoriasis) and
maximum of 8, with higher scores indicating more severe nail psoriasis. Sum of all fingernails (not in this
Figure) would be total NAPSI score, ranging from 0 to 80. Beau’s lines are also present, but they are not
included in NAPSI score.
Results
A total of 49 psoriatic patients and 49 healthy control subjects were included in the
study. The descriptive demographical patient characteristics have been summarized
in Table 1. No statistical difference was observed between psoriatic patients and
control subjects for gender and age. The mean age of the included psoriatic patients
was 48 years (±SD 13.4). The mean age at onset of psoriatic skin manifestations was
29 years (±SD 14.1) and the mean duration of skin disease was 19 years (±SD 13.6).
Median PASI score was 3.7 (range 0.0-29.5) with a mean body surface area of 6.6%
(±SD 11.2). At study enrollment 19 patients (38.8%) were actively treated with systemic
therapy.
Nail psoriasis features started predominantly after the onset of the cutaneous
lesions, with a mean delay of 9 years and appeared most frequently simultaneously
on fingernails and toenails (79.6%). Mean age of onset of fingernail psoriasis was 38
39
CHAPTER 2
Table 1 Sociodemographic and clinical characteristics.
Table 2 Frequency of fingernail changes.
Nail psoriasis
group
(n = 49)
Control
group
(n = 49)
p-value
Gender, n (%)
Female
Male
23 (46.9)
26 (53.1)
23 (46.9)
26 (53.1)
1.000 (NS)
Age (years), mean ±SD
48 ± 13.4
48 ± 13.4
0.958 (NS)
Age start psoriasis (years), mean ±SD
29 ± 14.1
Duration of psoriasis (years), mean ±SD
19 ± 13.6
Age start nail psoriasis (years), mean ±SD
38 ± 12.6
Duration of nail psoriasis (years), mean ±SD
10 ± 8.1
Localization nail psoriasis, n (%)
Fingernails
Toenails
Both
10 (20.4)
0 (0)
39 (79.6)
NAPSI score, mean ±SD
26.6 ± 14.5
Modified target NAPSI score, mean ±SD
10.4 ± 7.3
PASI score, median ( range)
3.7 (0.0 –29.5)
BSA score, mean ±SD
6.6 ± 11.2
Nail psoriasis
group
(n = 49)
Control
group
(n = 49)
p-value
Subungual hyperkeratosis
23 (46.9)
1 (2.0)
<0.001*
Oil-drop discoloration
33 (67.3)
0 (0)
<0.001*
Splinter hemorrhages
46 (93.9)
18 (36.7)
<0.001*
Onycholysis
46 (93.9)
9 (18.4)
<0.001*
Nail plate crumbling
21 (42.9)
0 (0)
<0.001*
Red spotted lunula
1 (2.0)
0 (0)
1.000 (NS)
Leukonychia
20 (40.8)
32 (65.3)
0.015*
Pitting
36 (73.5)
5 (10.2)
<0.001*
Longitudinal ridges
20 (40.8)
8 (16.3)
0.007*
Nail fold involvement
8 (16.3)
0 (0)
0.003*
Beau’s lines
5 (10.2)
0 (0)
0.027*
Onychomadesis
1 (2.0)
0 (0)
1.000 (NS)
Nail signs included in the NAPSI, n (%)
2
Nail signs not included in the NAPSI, n (%)
3.6 ± 3.3
<0.001*
NS, not significant
* p<0.05 (significant).
BSA, Body Surface Area; NAPSI, Nail Psoriasis Severity Index; NS, not significant; PASI, Psoriasis Area
and Severity Index; SD, standard deviation.
years (±SD 12.6) and mean duration of nail disease was 10 years (±SD 8.1). The mean
number of fingernails presenting with psoriasis-specific nail changes in patients with
nail psoriasis was 8.3 (±SD 2.2). The mean number of involved fingernails for the left
hand was 4.1 (±SD 1.1) and for the right hand was 4.2 (±SD 1.3).
The observed frequency of fingernail changes in the studied population is
displayed in Table 2. All eight nail manifestations included in the NAPSI were seen:
onycholysis (93.9%), splinter hemorrhages (93.9%), pitting (73.5%), oil-drop discoloration
(67.3%), subungual hyperkeratosis (46.9%), nail plate crumbling (42.9%), leukonychia
(40.8%), and red spots in the lunula (2.0%) (Figure 2). Onycholysis was predominantly
seen in the distal quadrants of the fingernail (60.0%). Median number of pits per
fingernail was 5.5 (range 1-26); 74.2% of patients had less than 10 pits. As expected,
the frequency of most nail changes was statistically significantly lower in the control
group (Table 2). However, leukonychia was significantly more frequent in healthy
control subjects (65.3% vs. 40.8%, p=0.015).
40
Nail changes not included in the NAPSI, but seen in psoriatic patients, were
longitudinal ridges (40.8%, mean 4.3 fingers affected), nail fold involvement (16.3%,
mean 4.3 fingers affected), Beau’s lines (10.2%, mean 1.8 fingers affected), and
onychomadesis (2.0%, mean 1.0 finger affected). Of these, only longitudinal ridges
were seen in the control group (16.3%).
The mean NAPSI score in patients and control subjects was 26.6 (±SD 14.5) and
3.6 (+SD 3.3), respectively (p<0.001). When separated, in both study groups nail
matrix NAPSI scores were higher than nail bed NAPSI scores, in psoriatic patients,
respectively, 14.6 (+SD 11.6) and 12.8 (+SD 8.0), and in control subjects, respectively,
2.5 (+SD 2.8) and 1.1 (+SD 1.8). Overall, 44 psoriatic patients (89.8%) showed both nail
matrix and nail bed changes; the remaining patients had matrix changes only. In the
control group 40 individuals (81.6%) showed any fingernail changes, most of them
were minor.
Of the 49 patients with psoriatic fingernail disease, nine patients (18.4%) displayed
nail changes as the exclusive manifestation of psoriasis. Also nine psoriatic patients
(18.4%) were given the diagnoses of PsA by a rheumatologist, of which five patients
41
CHAPTER 2
Discussion
*
A
B
C
D
E
F
Figure 2. Fingernail psoriasis. Nail changes in fingernail psoriasis observed in this study.
A, Nail fold involvement, nail plate crumbling, and splinter hemorrhage (arrow).B, Leukonychia (asterisk),
pitting, and onycholysis. C, Oil-drop discoloration, onycholysis, and splinter hemorrhages (arrow).D, Beau’s
lines, onycholysis, and splinter hemorrhages (arrows). E, Longitudinal ridges and splinter hemorrhages
(arrow). F, Subungual hyperkeratosis.
mentioned arthritis of the distal interphalangeal joints. NAPSI and PASI scores of
patients with and without PsA were not significantly different (p=0.079).
Correlations
No significant correlation was found between NAPSI and PASI scores (Spearman r
=0.042, p=0.784). The age of onset of fingernail psoriasis was positively correlated to
age of onset of cutaneous manifestations of psoriasis (Spearman r =0.718, p<0.001).
42
We collected data on 49 adult psoriatic patients with fingernail involvement to
describe the features of fingernail psoriasis and their prevalence. We compared these
results with data collected on 49 age- and gender-matched control subjects without
fingernail disease to determine which of the observed features are disease-specific
for fingernail psoriasis. Patients with concomitant onychomycosis were excluded
from this study, because Gupta et al.19 found a higher prevalence of onychomycosis in
psoriatic patients and discussed that fungal infection might have a role in the
maintenance or aggravation (Koebnerization) of nail psoriasis. Diagnosis of nail
psoriasis was made clinically and not confirmed histologically, which may have
influenced our study results. Furthermore, we enrolled 19 patients who were actively
treated with systemic therapy, which could affect the nail signs we have observed.
Reports of prevalence of clinical features of nail psoriasis vary considerably in the
literature, which may partly be a result of differences in descriptions and definitions
used in previous studies. Grover et al.9 reported onycholysis as the most prevalent
nail change in 76.0% of patients. Gisondi et al.15 studied nail involvement in psoriatic
patients using ultrasonography and found onycholysis to be the most common clinical
sign. Other studies reported pitting2,10-12,14,17, oil-drop discoloration,7 or subungual
hyperkeratosis13,16 to be the most prevalent nail change in psoriatic patients. The most
prevalent fingernail changes found in our fingernail psoriasis group were onycholysis
(93.9%) and splinter hemorrhages (93.9%). Three previous studies found splinter
hemorrhages to be the second (20.4%10) or third (39.3%,14 42%17) most common
manifestation in fingernail psoriasis. However, others reported it to be less common,
ranging from 1% to 28.9%.7,11,12,15,16 Onycholysis and splinter hemorrhages are
manifestations of nail bed psoriasis. However, overall nail matrix NAPSI scores were
higher than nail bed NAPSI scores in our patients. This result is in line with previous
investigations.12,20 The red spotted lunula is an infrequent nail change in psoriasis. In our
study population only one psoriatic patient (2.0%) showed red spots in the lunula. In
previous studies this nail symptom was observed in 0.4% by Aktan et al.16, in 1.3% by
Kyriakou et al.,7 and in 10.2% by Rich et al.12 In most previously published literature
concerning nail psoriasis additional nail symptoms such as Beau’s lines and longitudinal
ridging were not taken into account and scored, probably because these features are
not included in the NAPSI score8 and may be even less specific for psoriasis than the
eight above-mentioned features. Nevertheless, we found Beau’s lines in 10.2% of
patients and in none of the control subjects (Figure 1). Longitudinal ridging was even
present in 40.8% of patients with fingernail psoriasis but also in 16.3% of healthy
control subjects, making this feature rather sensitive but not specific for fingernail
psoriasis. Both longitudinal ridging and Beau’s lines can be explained by the
inflammatory process in the proximal nail matrix. Baran21 also has recognized the
43
2
CHAPTER 2
relevance of Beau’s lines for estimating disease activity in nail psoriasis and included
the number of Beau’s lines in his nail psoriasis severity scoring system.
Various nail symptoms known to occur in nail psoriasis (splinter hemorrhages,
onycholysis, pitting and subungual hyperkeratosis) were also observed in the control
group without nail disease. However, those nail changes were significantly less
frequent in the control group compared with the fingernail psoriasis group. In
contrast, leukonychia was even more frequently seen in the control group. This
finding suggests that leukonychia is not a nail psoriasis-specific symptom and raises
the question of whether leukonychia is the consequence of the inflammatory process
characterizing psoriasis or just occurring in nail psoriasis because it has a very high
prevalence in the general population. Leukonychia was present in over 65% of our
healthy control subjects. Consequently, the NAPSI score and especially the positioning
of leukonychia in this score should perhaps be reconsidered. The same applies to the
red spotted lunula, because this sign was rarely observed. However, the red spotted
lunula, oil-drop discoloration, and nail plate crumbling were only observed in patients
with fingernail psoriasis and therefore seem more specific for the diagnosis of nail
psoriasis.
The NAPSI score is an objective tool for the evaluation of nail psoriasis8 and the
interobserver reliability is established.16,22 A modification of this scoring system, the
modified (target) NAPSI score, using gradation systems for the different nail signs,
was proposed by two separate study groups.23,24 Chandran et al.25 found excellent
agreement on the modified NAPSI24 among rheumatologists and dermatologists. Our
study results made us reconsider these (modified) NAPSI scoring systems. We
question whether leukonychia should remain in nail psoriasis disease severity scores
and whether additional symptoms, such as Beau’s lines, should be added. Baran21
proposed a different scoring system, which meets these criteria. However, to our
knowledge reliability assessment of this scoring system has not yet been done and
assessing nail psoriasis severity based on only four clinical features seems
questionable. Furthermore evaluating subungual hyperkeratosis with a calliper is not
convenient. Different fingernail findings have been taken into account in the grading
system used by Cannavò et al.,26 but again additional symptoms, such as Beau’s lines,
were not taken into account and interrater reliability assessment of this scoring
system has not been performed yet. Additional studies assessing the reliability and
sensitivity of the different scoring systems and larger observational case-control
studies concerning clinical signs of nail psoriasis to decide which symptoms should be
part of an optimal nail score are needed.
We did not find a correlation between mean NAPSI scores and mean PASI scores.
This raises the question of whether nail psoriasis is a comorbidity of psoriasis or an
isolated disease expression. Rich et al.12 also did not find a correlation between
baseline NAPSI and PASI scores. However, improvement of PASI score did correlate
44
increasingly over time with the percentage improvement of NAPSI score in a group of
patients with psoriasis treated with infliximab. Of course, this only shows that this
anti-tumor necrosis factor-α treatment is effective against psoriasis of the skin and
psoriasis of the nails but does not prove direct correlation between both. The same
was found by Sánchez-Regaña et al.20; as the skin lesions improve, the nail symptoms
improve as well. On the other hand Augustin et al.27 found significantly higher PASI
scores in psoriatic patients with nail involvement compared with patients without
nail involvement. Further research with a larger sample size is needed to see whether
there is a direct relation between nail psoriasis and the cutaneous manifestations of
psoriasis.
Based on the questionnaire fingernail psoriasis started predominantly after the
onset of the skin lesions, with a mean delay of nine years. Interestingly, De Marco et
al.28 and Palmou et al.14 found a similar delay in the onset of PsA. Those delays may be
explained by shared pathogenetic principles, which differ from the pathogenesis of
psoriatic skin disease. Psoriatic disease, encompassing skin, joint and nail involvement,
has been considered as an autoimmune disorder with a major role for adaptive
immunity. However, recently the view on the pathogenesis of psoriatic joint and nail
disease has been challenged.29-31 Genetic studies fail to demonstrate a human
leukocyte antigen-Cw6 (HLA-Cw6) association in nail psoriasis and PsA.32-34 The nails
and joints share a common microanatomical basis and psoriatic nail and joint disease
may be linked to tissue-specific factors that lead to activation of innate immune
responses (autoinflammatory basis), rather than adaptive immunity (autoimmune
basis).29-31
In conclusion, the most common clinical signs of nail involvement in our fingernail
psoriasis study group were onycholysis and splinter hemorrhages. Red spots in the
lunula appear to be an infrequent sign. Various nail psoriasis symptoms, such as
splinter hemorrhages, also appeared in individuals without nail disease, however
they were significantly less frequent. Remarkably, we showed that leukonychia
appears frequently in individuals without nail disease and is a nail change found in
both healthy individuals and patients with fingernail psoriasis. Therefore, it should be
reconsidered whether leukonychia is the consequence of the inflammatory process
of psoriasis or a more common phenomenon and whether it should play a role in any
scoring system for nail psoriasis, such as the NAPSI score. On the other hand,
longitudinal ridges and Beau’s lines occurred more frequently in fingernail psoriasis
but are not included in the NAPSI. A significant correlation between NAPSI and PASI
scores could not be found, which raises the question whether nail psoriasis is a
comorbidity of psoriasis or an isolated disease expression.
45
2
CHAPTER 2
References
1
Langley RG, Dauden E. Treatment and management of psoriasis with nail involvement: a focus on
2
Dermatology 1996;193:300-3.
3
Baran R. The burden of nail psoriasis: an introduction. Dermatology 2010;221:1-5.
4
Armesto S, Esteve A, Coto-Segura P, Drake M, Galache C, Martinez-Borra J, et al. Nail psoriasis in
individuals with psoriasis vulgaris: a study of 661 patients. Actas Dermosifiliogr 2011;102:365-72.
5
Zaias N. Psoriasis of the nail. A clinical-pathologic study. Arch Dermatol 1969;99:567-79.
6 Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: anatomy,
pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol
2007;57:1-27.
7
Kyriakou A, Patsatsi A, Sotiriadis D. Detailed analysis of specific nail psoriasis features and their
correlations with clinical parameters: a cross-sectional study. Dermatology 2011;223:222-9.
8
Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad
Dermatol 2003;49:206-12.
9 Grover C, Reddy BS, Uma Chaturvedi K. Diagnosis of nail psoriasis: importance of biopsy and
histopathology. Br J Dermatol 2005;153:1153-8.
10 Brazzelli V, Carugno A, Alborghetti A, Grasso V, Cananzi R, Fornara L, et al. Prevalence, severity and
11 Kaur I, Saraswat A, Kumar B. Nail changes in psoriasis: a study of 167 patients. Int J Dermatol 2001;40:
601-3.
12 Rich P, Griffiths CE, Reich K, Nestle FO, Scher RK, Li S, et al. Baseline nail disease in patients with
moderate to severe psoriasis and response to treatment with infliximab during 1 year. J Am Acad
Dermatol 2008;58:224-31.
13 Salomon J, Szepietowski JC, Proniewicz A. Psoriatic nails: a prospective clinical study. J Cutan Med Surg
2003;7:317-21.
14 Palmou N, Marzo-Ortega H, Ash Z, Goodfield M, Coates LC, Helliwell PS, et al. Linear pitting and splinter
haemorrhages are more commonly seen in the nails of patients with established psoriasis in comparison
to psoriatic arthritis. Dermatology 2011;223:370-3.
15 Gisondi P, Idolazzi L, Girolomoni G. Ultrasonography reveals nail thickening in patients with chronic
plaque psoriasis. Arch Dermatol Res 2012;304:727-32.
16 Aktan S, Ilknur T, Akin C, Ozkan S. Interobserver reliability of the Nail Psoriasis Severity Index. Clin Exp
Dermatol 2007;32:141-4.
17 Calvert HT, Smith MA, Wells RS. Psoriasis and the nails. Br J Dermatol 1963;75:415-8.
18 Schmitt J, Wozel G. The psoriasis area and severity index is the adequate criterion to define severity in
chronic plaque-type psoriasis. Dermatology 2005;210:194-9.
19 Gupta AK, Lynde CW, Jain HC, Sibbald RG, Elewski BE, Daniel CR, et al. A higher prevalence of
onychomycosis in psoriatics compared with non-psoriatics: a multicentre study. Br J Dermatol
1997;136:786-9.
20 Sanchez-Regana M, Sola-Ortigosa J, Alsina-Gibert M, Vidal-Fernandez M, Umbert-Millet P. Nail
psoriasis: a retrospective study on the effectiveness of systemic treatments (classical and biological
therapy). J Eur Acad Dermatol Venereol 2011;25:579-86.
21 Baran RL. A nail psoriasis severity index. Br J Dermatol 2004;150:568-9.
22 Kacar N, Ergin S, Erdogan BS. The comparison of Nail Psoriasis Severity Index with a less time-consuming
qualitative system. J Eur Acad Dermatol Venereol 2008;22:219-22.
23 Parrish CA, Sobera JO, Elewski BE. Modification of the Nail Psoriasis Severity Index. J Am Acad Dermatol
2005;53:745-6.
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24 Cassell SE, Bieber JD, Rich P, Tutuncu ZN, Lee SJ, Kalunian KC, et al. The modified Nail Psoriasis Severity
Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.
J Rheumatol 2007;34:123-9.
25 Chandran V, Gottlieb A, Cook RJ, Duffin KC, Garg A, Helliwell P, et al. International multicenter psoriasis
and psoriatic arthritis reliability trial for the assessment of skin, joints, nails, and dactylitis. Arthritis
Rheum 2009;61:1235-42.
26 Cannavo SP, Guarneri F, Vaccaro M, Borgia F, Guarneri B. Treatment of psoriatic nails with topical
cyclosporin: a prospective, randomized placebo-controlled study. Dermatology 2003;206:153-6.
27 Augustin M, Reich K, Blome C, Schafer I, Laass A, Radtke MA. Nail psoriasis in Germany: epidemiology
28 De Marco G, Cattaneo A, Battafarano N, Lubrano E, Carrera CG, Marchesoni A. Not simply a matter of
psoriatic arthritis: epidemiology of rheumatic diseases in psoriatic patients. Arch Dermatol Res
2012;304:719-26.
29 McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic
disease. J Eur Acad Dermatol Venereol 2009;23:9-13.
30 McGonagle D, Benjamin M, Tan AL. The pathogenesis of psoriatic arthritis and associated nail disease:
31 McGonagle D, Palmou Fontana N, Tan AL, Benjamin M. Nailing down the genetic and immunological
basis for psoriatic disease. Dermatology 2010;221:15-22.
32 Ho PY, Barton A, Worthington J, Thomson W, Silman AJ, Bruce IN. HLA-Cw6 and HLA-DRB1*07 together
are associated with less severe joint disease in psoriatic arthritis. Ann Rheum Dis 2007;66:807-11.
33 Fan X, Yang S, Sun LD, Liang YH, Gao M, Zhang KY, et al. Comparison of clinical features of
HLA-Cw*0602-positive and -negative psoriasis patients in a Han Chinese population. Acta Derm
Venereol 2007;87:335-40.
34 Gudjonsson JE, Karason A, Runarsdottir EH, Antonsdottir AA, Hauksson VB, Jonsson HH, et al. Distinct
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47
2
Chapter 2.2
Nail psoriasis:
a questionnaire-based survey
K.M.G. Klaassen
M.C. Pasch
British Journal of Dermatology 2013;169:314-319
CHAPTER 2
Abstract
Introduction
Background: Skin manifestations are the most characteristic finding of psoriasis. However,
nail involvement is also a clinical feature of disease although it is often overlooked.
The documented prevalence of nail psoriasis varies between 10.0% and 81.1%.
While skin manifestations are the most characteristic finding in patients with psoriasis,
nail involvement is an often overlooked feature of the disease.1 The documented
prevalence of nail psoriasis is divergent and varies between 10.0% and 81.8% of
patients with psoriasis, with an estimated lifetime incidence of 80-90%.2-17 Nail
psoriasis in the absence of cutaneous disease is present in only 5-10% of patients with
psoriasis.10,18
The nail unit can be subdivided into the nail plate, nail bed and nail matrix. The
nail matrix, at the proximal end of the nail, synthesizes the nail plate.19 Clinical
manifestations associated with nail psoriasis are divergent in their representation,
and correlate with the anatomical subunit of the nail that is affected by the disease.18
Psoriatic disease of the nail matrix causes characteristic nail manifestations such
as red spots in the lunula, leukonychia, pitting and nail plate crumbling.3 Clinical
manifestations associated with nail bed involvement are oil-drop discoloration,
splinter hemorrhages, subungual hyperkeratosis and onycholysis.3 This variability of
clinical manifestations and localization makes treatment of nail psoriasis challenging.
Both the delivery of effective topical drugs to the nail unit and the toxicity associated
with many conventional systemic therapies make treatment even more difficult.11
In addition, nail disease can be refractory to treatment and different features can
respond variably to different treatments.19 However, research in the field of nail
psoriasis is sparse but certainly important, as the impact of onychopathy on the
quality of life is high, particularly if considered in terms of poor cosmetic appearance,
pain and restrictions in activity of daily living. 4, 13
To improve care for patients with nail psoriasis, it is essential to acquire knowledge
concerning this disease. Therefore, the aim of this study was to obtain quantitative
information on the characteristics of patients with psoriasis with nail involvement
compared with psoriasis patients without nail involvement in a large cohort, and to
give insight into treatment experiences of patients with nail psoriasis.
Objectives: The aim of this investigation was to gain knowledge about the prevalence
and clinical manifestations of nail psoriasis and patients’ experiences of treatment of
nail psoriasis.
Method: A structured, self-administered questionnaire was distributed to all members
(n=5400) of the Dutch Psoriasis Association. The questionnaire enquired about sociodemographic patient characteristics, disease-related data and treatment of nail
psoriasis. Patients reported their nail manifestations with photographs after instruction.
Patients with nail psoriasis were compared with patients without nail psoriasis.
Results: A response rate of 27.0% was achieved. The prevalence of nail psoriasis was
66.0%. The most frequently observed psoriatic nail manifestation was pitting (65.4%),
whereas red spots in the lunula were infrequently seen (6.5%). Patients with nail
psoriasis more frequently stated psoriasis capitis (75.8% vs. 65.7%), genital psoriasis
(32.7% vs. 20.3%) and psoriatic arthritis (46.4% vs. 30.6%) compared with patients
with psoriasis without nail involvement. Only 16.0% of patients received treatment
for nail psoriasis. Systemic therapies were most frequently stated as being effective
for nail lesions.
Conclusion: Nail manifestations seem to be more prevalent in patients with psoriasis
than previously thought. In addition, nail psoriasis is shown to be associated with
widespread and more severe forms of psoriasis, and different treatment options are
experienced as being effective for nail psoriasis. Notwithstanding, nail psoriasis is still
an often overlooked feature of the disease.
Material and methods
Setting and participants
A structured questionnaire was developed to assess the clinical characteristics of nail
psoriasis and to assess patients’ experiences of treatment of nail psoriasis. This
self-administered questionnaire was distributed to all members (n=5400) of the
Dutch Psoriasis Association together with an invitational letter explaining the purpose
of the study and reply-paid envelopes. The questionnaire was completed anonymously
and no incentives were given. The investigation was conducted from the 14 April 2011
51
2
CHAPTER 2
and responses were accepted through to 1 August 2011. Prior to the distribution of the
questionnaire a pilot study was conducted on 10 patients to improve the quality of
the questionnaire.
Table 1 Sociodemographic and clinical characteristics of patients with and
without nail involvement.
Nail
involvement
(n = 963)
No nail
involvement
(n = 496)
p- valuea
All patients
(n = 1459)
Female
464 (48.2)
272 (54.8)
0.012
736 (50.4)
Male
489 (50.8)
216 (43.5)
Questionnaire
The questionnaire enquired about the sociodemographic patient characteristics (e.g.,
age, sex, work), psoriasis medical data (e.g., age of onset, type of psoriasis, family
history, treatment history), questions concerning nail psoriasis (e.g., presence of nail
psoriasis, features of nail psoriasis, localization, age of onset) and questions concerning
treatment history of (nail) psoriasis and potential unmet medical need. Instruction
photographs showing pitting, oil-drop discoloration, leukonychia, onycholysis, red
spots in the lunula, splinter hemorrhages and subungual hyperkeratosis were
included. Based on these photographs, patients could indicate which of the nail
features were present.
Not reported
8 (1.6)
18 (1.2)
Age (years), mean ±SD
56.9 ± 12.8
58.7 ± 15.1
0.026
57.5 ± 13.7
Age start psoriasis (years),
mean ±SD
24.4 ± 14.0
28.3 ± 16.7
<0.001
25.7 ± 15.1
Duration of psoriasis (years),
mean ±SD
32.4 ± 15.3
30.3 ± 16.8
0.024
31.7 ± 15.9
0.153
918 (62.9)
Positive
621 (64.5)
297 (59.9)
Negative
188 (19.5)
117 (23.6)
305 (20.9)
154 (16.0)
82 (16.5)
236 (16.2)
Unknown
Type of psoriasis, n (%)
Plaque psoriasis
662 (68.7)
293 (59.1)
<0.001
955 (65.5)
Guttate psoriasis
546 (56.7)
277 (55.8)
0.868
823 (56.4)
49 (5.1)
17 (3.4)
0.153
66 (4.5)
729 (75.7)
324 (65.3)
116 (12.0)
38 (7.7)
Pustular psoriasis
Psoriasis capitis
Erythrodermic psoriasis
Results
a
In total, 5400 questionnaires were distributed. Within the study period 1475 were
completed and returned, resulting in a response rate of 27.3%. Of the 1475 patients
who completed the questionnaire, 16 were excluded due to missing values. After
exclusion of invalid questionnaires, 1459 datasets (27.0%) were suitable for analysis.
10 (1.0)
705 (48.3)
Family history, n (%)
Data were entered into a Statistical Package for Social Sciences 18.0 (SPSS inc.,
Chicago, IL, U.S.A.) database and subsequent statistical analyses were performed
using SPSS. Descriptive statistics were provided using mean (SD) and median (range)
for normally and nonparametrically distributed numeric values, respectively.
Frequencies and percentages were used for categorical variables. Missing values
were not included in calculation of percentages. Comparisons of numeric variables
were analysed with the unpaired t-tests or the Mann-Whitney U test and the χ2 or
Fisher exact test was used for differences between categorical variables. One-way
ANOVA was used when more than two means were compared. P-values <0.05 were
considered to be statistically significant.
Patients
2
Gender, n (%)
<0.001
1053 (72.2)
0.011
154 (10.6)
Psoriatic arthritis
446 (46.3)
151 (30.4)
<0.001
597 (40.9)
Inverse psoriasis
255 (26.5)
102 (20.6)
0.015
357 (24.5)
Genital psoriasis
315 (32.7)
100 (20.2)
<0.001
415 (28.4)
Level of significance; t-test for numerical statistics and χ2-test for categorical statistics.
25.7 ± 15.1 years with a mean duration of disease of 31.7 ± 15.9 years. The mean age at
diagnosis of psoriasis was 27.6 ± 15.3 years.
In total, 62.9% (n = 918) of the respondents had a positive family history of psoriasis.
Patient characteristics
The distribution of patient characteristics is reported in Table 1. The mean age ± SD of
the respondents was 57.5 ± 13.7 years. Among the respondents, 736 were female (51.1
%) and 705 were male (48.9%). The self-reported mean age at onset of psoriasis was
52
Nail Psoriasis
Of the 1459 respondents, 963 patients (66.0%) stated that their nails had been
affected by psoriasis at some time during the course of their disease. This corresponds
53
CHAPTER 2
40
Table 2 Self-reported characteristics of patients with nail psoriasis.
35
Nail involvement ( n = 963)
36.4 ± 14.7
Duration of nail psoriasis (years), mean ±SD
20.4 ± 13.5
Localization, n (%)
25
Toenails only
108 (11.2)
10
Both
597 (62.0)
5
Nail features, n (%)
Pitting
Onycholysis
630 (65.4)
Leukonychia
309 (32.1)
130 (13.5)
63 (6.5)
Treatment for nail psoriasis, n (%)
Yes
158 (16.4)
No
781 (81.1)
Unknown
9
0-
-19
10
9
-2
20
24 (2.5)
to 17.8% of the entire study population (n=5400). The most frequently observed
psoriatic nail manifestation was pitting (65.4 %) followed by onycholysis (57.7%)
(Table 2). Splinter hemorrhages and red spots in the lunula were infrequently seen
(13.5% and 6.5%, respectively). Nail psoriasis involved predominantly the nail matrix
and nail bed simultaneously (59.0%). Most frequently, both the fingernails and
toenails were affected simultaneously (62.0%, n= 597). The mean number of affected
fingernails was 5.9 ± 3.3 and the mean number of affected toenails was 5.3 ± 3.3.
The mean age at onset of nail psoriasis was 36.4 ± 14.7 years. Figure 1 shows that
nail features started predominantly after the onset of the cutaneous lesions, with a
mean delay of 11.5 ± 13.0 years. However, psoriatic involvement of the nail may begin
at almost any age, given the broad range reported by the patients (age range 1-90
years). Of the patients with nail psoriasis, 3.7% had nail psoriasis as an initial
presentation of their psoriasis, and 16.8% of the patients developed psoriatic skin
and nail lesion simultaneously. The remaining patients (79.5%) developed nail lesions
after the start of cutaneous psoriasis manifestations.
9
-3
30
9
-4
40
9
-5
50
9
-6
60
9
-7
70
9
-8
80
9
-9
90
Age group
399 (41.4)
324 (33.6)
Red spots
0
556 (57.7)
2
15
244 (25.3)
14 (1.5)
Age at onset
psoriasis
20
Fingernails only
Unknown
54
Percentage
Age at onset of nail psoriasis (years), mean ±SD
Age at onset
of nail psoriasis
30
Figure 1. Distribution of ages at onset of nail psoriasis vs. onset of psoriasis.
The mean age at the onset of skin manifestations of psoriasis in the group of
patients with nail involvement (24.4 ± 14.0 years) was significantly lower than in the
group without nail features (28.3 ± 16.7 years, p=<0.001). Thirteen patients aged 18
years or younger returned the questionnaire, of whom four (30.8%) stated that they
had nail psoriasis. When comparing those with onset of psoriasis under the age of 18
years with those with onset above the age of 18 years, no statistical difference was
found for the prevalence of nail psoriasis (p=0.163, χ2-test).
Type of psoriasis
As shown in Table 1, psoriatic arthritis (PsA) was present in 446 patients (46.3%)
with nail psoriasis, compared with 151 patients (30.4%) without nail involvement
( p= <0.001, χ2-test). The prevalence of nail psoriasis in patients with PsA was 74.7%.
Regarding the possible localizations of psoriasis, genital psoriasis, inverse psoriasis
and psoriasis capitis were also seen significantly more frequently in patients with
nail involvement.
Treatment nail psoriasis
Of the 963 patients with nail psoriasis, 158 (16.4%) indicated that they had received
treatment specific for their nail psoriasis (Table 2). Figure 2 shows which therapies
patients found to be effective for their nail psoriasis, whether or not started initially
for their nail lesions. The three therapies most frequently mentioned as being
effective for treatment of nail lesions were all systemic therapies (biologics, n=20;
55
CHAPTER 2
Number of patients
25
20
20
20
16
15
15
10
8
7
6
4
5
3
3
3
3
he
r
Ot
Na
il p
ol
ish
ia
ln
ai
l
on
ﬁc
cti
Ar
ti
tin
re
ca
l in
je
Ac
it
Lo
di
cu
re
Pe
xa
t
rti To e
co p
i
st ca
er l
oi
ds
UV
th
er
a
Ci
clo py
sp
or
in
e
re
co
ho
t
M
et
ar
ic
Fu
m
Bi
ol
og
ics
ac
id
0
Treatment modality
Figure 2. Effective therapies against nail psoraisis based on patients’ experiences.
UV, ultraviolet.
fumaric acid, n=20; and methotrexate, n=16). In total, 108 respondents reported that
they had experienced some form of treatment that was effective for their nail
psoriasis. Of all the patients with nail psoriasis, 46.7%, stated that they would like to
receive treatment for their nail disorder.
Discussion
Few large studies on the epidemiology of nail psoriasis and patients’ experiences of
treatment of nail psoriasis have been conducted. The present study illustrates that
66% of the patients with psoriasis reported nail involvement at some time during the
course of their skin disease, starting predominantly several years after the onset of
cutaneous psoriasis lesions. Furthermore, very few patients received treatment for
their nail psoriasis, while nail lesions can have a substantial impact on patients’ quality
of life. 4 However, some patients certainly experienced the positive effect of several
psoriasis treatment options.
The large number of patients responding to our questionnaire provides valuable
insight into the epidemiology of nail psoriasis, which is a presentation of psoriasis
that has received limited attention from medical professionals until now. Two-thirds
of the patients reported nail psoriasis, which indicates a high prevalence. It may be
assumed that patients with nail psoriasis preferentially returned the questionnaire,
which might have caused a response bias. Therefore, the value of 66.0% might be an
56
overestimation and likely must be revised downwards. Nevertheless, even assuming
that all of the non-responders do not have nail involvement, still 17.8% of the patients
with psoriasis in the Dutch Psoriasis Association stated that they have nail involvement.
The true percentage of nail involvement in patients with psoriasis will therefore lie
between 17.8% and 66.0%. In the literature, percentages of patients with psoriasis
with nail involvement vary between 10.0% and 81.8%. 4, 9, 20, 8, 10, 12, 14, 15, 21, 22, 7 Comparison
of the different prevalence numbers of nail psoriasis found in different studies is
difficult as a consequence of the different methodological designs. A design comparable
with the present study was used in two studies. 4, 15 Both studies sent a questionnaire
to members of their national psoriasis association and found higher prevalence rates
of 79.2% and 72.8%. Most prevalence studies were secondary-based studies including
consecutive patients with psoriasis from outpatient clinics. Diagnosis was made by
clinical examination. These studies found prevalence rates varying between 47.4%
and 78.3%. Two studies7, 14 included consecutive patients with psoriasis from their
outpatient clinical and excluded patients using systemic therapies. The nail psoriasis
prevalence rates were 66.7% and 47.4%, the mean Psoriasis Area and Severity Index
(PASI) was 12.8. One study 10 included consecutive patients with an exacerbation of
their psoriasis and found a prevalence of 78.3%. Augustin et al.13 examined the nails of
patients from both primary and secondary care and found a prevalence of 40.9%. A
phase III study of 378 patients with psoriasis with PASI >12 found a prevalence of nail
psoriasis of 81.8%.21 More severe psoriasis seems to be related to a higher prevalence
of nail psoriasis.13, 15, 21 It might be expected that our prevalence number is an
overestimation, as patients who are members of a patients’ association might have
more severe psoriasis, but the a prevalence rate of 66.0% seems in line with the
discussed cohort studies. Only two studies found prevalence rates below 40.0%.12,22
The prevalences found in the remaining studies varied between 40% and 80%, and
are in line with the result of the present study.
Few previous studies investigated the prevalence of nail psoriasis in children.
These studies showed a lower prevalence of nail psoriasis compared with adults,
varying from 7.0% to 39.4%.23-26 In our study only 13 children aged 18 years or younger
responded, of whom 30.8% stated that they had nail psoriasis. Most likely, few
children are members of the Dutch Psoriasis Association. Larger studies must be
conducted to estimate the prevalence of nail psoriasis among children. We did not
find a significant difference of the prevalence of nail psoriasis between patients with
childhood onset of psoriasis vs. adult onset, but lower prevalence rates of nail
psoriasis in paediatrics are expected as we found that nail psoriasis seems to express
several years after the onset of the cutaneous psoriasis lesion.
It is evident from this study that there are few patients who received therapy for
their nail psoriasis, as only 16.0% stated that they received some form of treatment.
A 1996 study by de Jong et al. 4 on the same patient group revealed that 35.4% had
57
2
CHAPTER 2
used treatment for psoriatic nail lesions. This percentage more than halved in a time
frame of 16 years, while the therapeutic options for psoriasis have increased.
Studies concerning the quality of life in patients with psoriasis with nail
involvement showed that the impairments and restrictions experienced because of
the nail disease are significant. 4, 13, 15, 27 Despite data showing that nail disease can be
an important determinant of functional impairment in psoriasis, management of nail
psoriasis is still often, or even more, overlooked compared to 16 years ago. One
possible explanation for this undertreatment is that therapies for psoriatic nail
disease are perceived to be ineffective by dermatologists, and results are seen only
after a long period of treatment, as nails grow and recover slowly. The principal
motivation to seek treatment is most often the cutaneous component, and the focus
of psoriasis treatment therefore goes to the cutaneous component. Langley and
Dauden18 concluded that the clinical evidence for nail psoriasis treatments are sparse,
and the effect of most treatment modalities is not proven in clinical trials, but recent
investigations concerning systemic therapies in nail psoriasis have shown promising
results.18, 28, 29 In addition, our results on patients’ experience support such findings.
Patients stated that they have experienced positive effects of treatments on their nail
psoriasis, in particular with systemic therapies. Our data support the findings that nail
psoriasis can be treated effectively, but studies and publications must focus more on
the effects of therapies on nail psoriasis because evidence is missing.
The prevalence of the different manifestations seen in nail psoriasis varies
considerably in the literature. Our result, showing that pitting, onycholysis and
oil-drop discoloration were the most frequently seen nail changes, is in agreement
with most previous studies.14, 21, 30, 31 The study design, using photographs in self-administered questionnaires, made it possible to collect data on the clinical
manifestations of nail psoriasis in a large number of patients. A limitation of this
design is that patients self-assessed the presence of nail features, which might give an
over- or underestimation of nail features. Nevertheless, the results are in line with
previous cohort studies, so we could confirm that onycholysis, pitting and oil-drop
discoloration are frequently seen in nail psoriasis.14, 21, 30 We found that red spots in
the lunula and splinter hemorrhages were infrequently found in nail psoriasis (6.5%
and 13.5%, respectively). This is in line with the findings of Kyriakou et al.,14 who found
a prevalence of red spots in the lunula of 1.3%, and with the results of Aktan et al.,32
who found a prevalence of 0.4%. Prevalence numbers of splinter hemorrhages in the
literature vary between 1.0% and 42.0%,14, 16, 21, 31, 32 only one study found splinter
hemorrhages in the top three most frequently seen nail manifestation in nail
psoriasis.8
Previous studies have already focused on the correlation between nail psoriasis
and skin involvement patterns (e.g., plaque-type psoriasis, psoriasis punctuate,
psoriasis pustulosa).12, 14 In accordance with these studies we found that nail psoriasis
58
had no relationship with punctuate and pustulate psoriasis. On the other hand we did
find a relation between the different localizations of psoriasis (genital, joints, capitis
and inverse) and nail involvement. The association between nail psoriasis and these
localizations of psoriasis (genital, capitis and inversa) has not been described
previously to our knowledge. The presence of nail psoriasis was already correlated
with more severe clinical manifestations of psoriasis in terms of higher PASI.7, 13, 16
Moreover, nail psoriasis is significantly more frequently seen in PsA, even reaching a
prevalence of 70-80%.33 Our data confirmed that PsA occurs more frequently in
patients with nail psoriasis. The pathophysiology of nail dystrophy has been
postulated to be more closely associated with joint symptoms than with skin
symptoms.1 It has been hypothesized that there is a direct link between inflammation
of the distal interphalangeal joint and psoriatic nail changes via the enthesis, which
forms the connection between those structures. 1, 34-36 Taken all these findings into
account, it might be hypothesized that patients with nail psoriasis are more likely to
have more extensive and severe forms of psoriasis with widespread localization and
involvement of joints. All of these findings should be taken into account when
considering the therapeutic options for patients with psoriasis with nail involvement.
As our questionnaire-based study asked retrospectively for information, a recall bias
might be present, which can cause either an over- or underestimation of the results.
Also, a selection bias might be created by questioning the members of the Dutch
Psoriasis Association, as members of a patient-support association may possibly not
represent a random sample of patients with psoriasis. It may be speculated that these
patients are perhaps more interested or worried about their disease or they might
suffer from more severe psoriasis. On the other hand the influence of social desirability
in answering the questions was minimized. Bearing in mind the multiple differential
diagnosis for nail psoriasis, we deliberately asked if diagnosis was made by a general
practitioner or a medical specialist. The main advantage of the study design was that
a large number of patients could be included.
Conclusion
In summary, nail manifestations seem to be more prevalent in patients with psoriasis
than previously thought, and nail psoriasis seems to be associated with more
extensive forms of psoriasis. However, only a minority of patients with nail psoriasis
receive treatment, but patients have experienced positive effects on nail symptoms
with different types of therapies. When considering therapy for patients with nail
psoriasis these results might influence the choice of therapy. Nail psoriasis still seems
to be an overlooked feature of the disease and further research must focus on the
effect of psoriasis treatment on the nails.
59
2
CHAPTER 2
References
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17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
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Armesto S, Esteve A, Coto-Segura P, et al. Nail psoriasis in individuals with psoriasis vulgaris: a study of
661 patients. Actas Dermosifiliogr 2011;102:365-72.
Calvert HT, Smith MA, Wells RS. Psoriasis and the nails. Br J Dermatol 1963;75:415-8.
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Radtke. Nail psoriasis as a severity indicator: results from the PsoReal study. 2011;2:1-6.
Brazzelli V, Carugno A, Alborghetti A, et al. Prevalence, severity and clinical features of psoriasis in
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Hallaji Z, Babaeijandaghi F, Akbarzadeh M, et al. A significant association exists between the severity of
nail and skin involvement in psoriasis. J Am Acad Dermatol 2012;66:12-3.
Cassell S, Kavanaugh AF. Therapies for psoriatic nail disease. A systematic review. J Rheumatol 2006;33:
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Augustin M, Kruger K, Radtke MA, Schwippl I, Reich K. Disease severity, quality of life and health care in
plaque-type psoriasis: a multicenter cross-sectional study in Germany. Dermatology 2008;216:366-72.
Rich P, Griffiths CE, Reich K, et al. Baseline nail disease in patients with moderate to severe psoriasis and
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Heller J. Die Krankheiten der Nägel. Berlin; 1900.
Nanda A, Kaur S, Kaur I, Kumar B. Childhood psoriasis: an epidemiologic survey of 112 patients. Pediatr
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Al-Mutairi N, Manchanda Y, Nour-Eldin O. Nail changes in childhood psoriasis: a study from Kuwait.
Pediatr Dermatol 2007;24:7-10.
Chiam LY, de Jager ME, Giam YC, de Jong EM, van de Kerkhof PC, Seyger MM. Juvenile psoriasis in
European and Asian children: similarities and differences. Br J Dermatol 2011;164:1101-3.
Farber EM, Nall L. Nail psoriasis. Cutis 1992;50:174-8.
Ortonne JP, Baran R, Corvest M, Schmitt C, Voisard JJ, Taieb C. Development and validation of nail
Kyriakou A, Patsatsi A, Sotiriadis D. Anti-TNF agents and nail psoriasis: a single-center, retrospective,
comparative study. J Dermatolog Treat 2013;24:162-8.
29. Ortonne JP, Paul C, Berardesca E, et al. A 24-week randomized clinical trial investigating the efficacy and
safety of two doses of etanercept in nail psoriasis. Br J Dermatol 2013;168:1080-7.
30. Grover C, Reddy BS, Uma Chaturvedi K. Diagnosis of nail psoriasis: importance of biopsy and
31. Kaur I, Saraswat A, Kumar B. Nail changes in psoriasis: a study of 167 patients. Int J Dermatol 2001;40:
601-3.
32. Aktan S, Ilknur T, Akin C, Ozkan S. Interobserver reliability of the Nail Psoriasis Severity Index. Clin Exp
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33. Scarpa R, Oriente P, Pucino A, et al. Psoriatic arthritis in psoriatic patients. Br J Rheumatol 1984;23:246-50.
34. McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic
35. Ash ZR, Tinazzi I, Gallego CC, et al. Psoriasis patients with nail disease have a greater magnitude of underlying
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61
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Chapter 3
Quality of life in
patients with nail psoriasis
Chapter 3.1
The impact of fingernail psoriasis
on patients’ health-related and diseasespecific quality of life
K.M.G. Klaassen*
H.M.J. van der Velden*
M.C. Pasch
Dermatology 2014 (accepted)
*These authors attributed equally
CHAPTER 3
QUALITY OF LIFE IN PATIENTS WITH NAIL PSORIASIS
Abstract
Introduction
Background: The impact of various dermatological conditions on quality of life has
been extensively studied, however the impact of nail psoriasis on quality of life is an
underexplored area.
Psoriasis vulgaris is a chronic inflammatory skin disorder which is frequently
accompanied by nail changes and/or joint disease (i.e. psoriatic arthritis, PsA). The
prevalence of nail disease among psoriasis patients varies between 10% and 81%, and
the reported lifetime incidence in psoriatic patients is 80% to 90%.1 The characteristics of nail psoriasis are pitting, onycholysis, splinter hemorrhages, subungual
hyperkeratosis, red spots in the lunula, oil-drop discoloration, leukonychia and nail
plate crumbling, which can be divided into nail matrix and nail bed symptoms.2,3
Psoriatic nail lesions rarely appear as the only clinical manifestation of psoriasis, as
psoriasis limited to the nails occurs in only 1% to 18% of patients with psoriasis.2,4,5
It is known that psoriasis on visible areas of the skin, such as the face and hands,
may have a substantial negative impact on physical, psychological and social
dimensions of quality of life (QoL).6-10 Fingernail psoriasis is also highly visible and
therefore it is likely to influence QoL, but the impact of this disease on QoL is an
underexplored area. As a result, little information is available concerning this topic.
Besides the cosmetic aspect, intact nails play a critical role in protecting the distal
phalanges of the digits from mechanical and chemical trauma. The nails contribute to
the tactile discrimination and fine motor capacities of the fingertips, and consequently
partly or total loss of nail quality means that those functions may be compromised.11
De Jong et al.12 were the first to describe the consequences of nail psoriasis on
patients’ daily life, and they reported that the condition can be associated with
varying degrees of physical impairment and loss of dexterity, including the ability to
retrieve small objects. The objective of our study was to investigate the impact of
fingernail psoriasis on patients’ QoL using validated questionnaires concerning
health-related quality of life (HRQoL) and a modified disease-specific questionnaire.
Objective: To investigate the impact of fingernail psoriasis on patients’ quality of life.
Methods: A cross-sectional observational study using validated questionnaires
concerning quality of life (Short Form-36, and a modified onychomycosis questionnaire)
was performed in 49 patients with fingernail psoriasis.
Results: The mean Short Form-36 scores for fingernail psoriasis patients were
comparable to the mean scores of the Dutch reference population. However, mean
scores on the modified onychomycosis quality of life questionnaire for all domains
were reduced. Localisation, gender and duration of nail psoriasis influenced the
impact of nail psoriasis on patients’ quality of life.
Conclusion: Fingernail psoriasis can interfere with patient’s social, mental, and
physical well-being. Assessing patients’ quality of life in daily practice offers the
opportunity of a patient-centred approach to treatment.
Material and Methods
Study design and participants
A cross-sectional observational study was performed among patients with clinically
diagnosed fingernail psoriasis (Nail Psoriasis Severity Index, NAPSI >5) who visited the
outpatient clinic of the Department of Dermatology of the Radboud university
medical center, Nijmegen, The Netherlands. After informed consent had been given,
49 patients (≥18 years) were included between December 2009 and July 2012.
Patients who had used artificial nails in the past 6 months or had presence of a skin
disease (other than psoriasis) associated with nail manifestations were excluded. To
exclude patients with concomitant onychomycosis, clippings and subungual scrapings
of affected fingernails were collected for direct microscopic examination (10%
67
3
CHAPTER 3
potassium hydroxide preparations) and fungal culture. Cultures were carried out on
two different types of Sabouraud dextrose agar: one agar contained chloramphenicol
and cycloheximide, and one agar contained chloramphenicol without cycloheximide.
None of the patients tested positive for fungus on nail clippings or scrapings. Patients
who were unable to fill in the questionnaire because of illiteracy or mental impairment
or who had suffered a recent serious life event that could affect their present
experienced QoL were also excluded. We have previously studied the clinical features
of fingernail psoriasis in the above-mentioned patient group.3
Survey details
The survey consisted of a questionnaire taken by interview (H.M.J. van der Velden)
and self-administered questionnaires. The interview included items concerning
demographic patient characteristics and psoriasis-related data. The severity of
fingernail psoriasis was measured by the NAPSI (range 0-80).13 Severity of psoriasis of
the skin was assessed by the Psoriasis Area and Severity Index (PASI) (range 0-72).14
The following self-administered questionnaires were included:
SF-36. The SF-36 is a generic multidimensional instrument used for patients’ self-
assessment of HRQoL, consisting of the following 9 dimensions: (1) limitations in physical
activities because of health problems (physical functioning); (2) limitations in usual
activities because of physical health problems (role physical functioning, RP); (3)
bodily pain; (4) general health perceptions; (5) vitality; energy and fatigue; (6) social
functioning; (7) limitations in usual role activities because of emotional health problems
(role emotional functioning); (8) mental health; (9) expected health change. The subscale
scores were transformed to a 0-100 scale with higher scores indicating better HRQoL
in the domain being measured. We used the validated Dutch version of the SF-36.
Normative data have been estimated for the Dutch population by Aaronson et al.15
Modified fingernail onychomycosis QoL questionnaire. At the start of this study an
adequate and validated questionnaire assessing the disease-specific QoL of nail
psoriasis had not been developed yet. Drake et al.,11 developed a validated onychomycosis-specific questionnaire designed to quantify the impact of onychomycosis on
patients’ QoL. Considering our patient population, we used the fingernail-specific
questionnaire. The questionnaire consisted of 24 questions concerning social
dimension (9 questions), emotional dimension (10 questions) and nail-related
symptoms (5 questions). To develop a Dutch version of the questionnaire, the original
questionnaire was translated ‘back’ and ‘forward’. The questionnaire was linguistically
modified without any relevant change to the original questionnaire. We replaced the
question ‘others are afraid of catching mycosis from me’ by ‘others are afraid of
catching nail psoriasis from me’. Scale scores were calculated according to the
68
instructions from Drake et al.,11 with 0 representing the worst and 100 representing
the best QoL. The scale was compared to the Dermatology Life Quality Index (DLQI)
by bivariate correlation (convergent validation).16 We found a good correlation
between both scores (r=-0.712, p<0.01).
Visual Analogue Scales (VAS) for pain and Patients’ Global Assessment (PGA) of disease
severity. To measure pain, two VAS of 100 mm each were included. The first VAS
assessed the pain sensation experienced from nail lesions, and the second VAS
measured the pain sensation of the cutaneous psoriasis lesions. Other requirements
included the PGA of disease severity on a scale of 0 to 4 (complete control of nail
psoriasis to no control).
Data were entered in a Statistical Package for Social Sciences (SPSS 18.0, SPSS Inc.,
Chicago, Ill, USA) database and subsequently statistical analyses were performed.
Descriptive statistics were provided using mean (± standard deviation, SD) and
median (range) for normally and non-parametric distributed numeric values,
respectively. Missing values were not included to calculate percentages. We analysed
the influence of possible relevant variables (e.g., gender, age, disease severity) on the
QoL scores. Comparison of numeric variables were analysed with the unpaired t-tests
or the Mann-Whitney U test. The χ2 or Fisher exact test was used for differences
between categorical variables. ANOVA and Gabriel’s post hoc tests were used to
determine the (significant) differences between more than two groups in a univariative
analysis of variance setting. P-values <0.05 were considered to be statistically
significant. All tests were two-sided.
Results
We enrolled 23 women (46.9%) and 26 men (53.1%) with a mean age of 48 years (±SD
13.4). Further descriptive demographic patient characteristics are summarized in
Table 1 and have been extensively analysed in a previous article by van der Velden et al.3
SF-36
Table 2 shows the mean scores for the 9 dimensions of the SF-36. When compared to
the mean values of the healthy Dutch reference group,15 no significant differences
were found except for the role emotional functioning dimension. Patients with nail
psoriasis scored a mean value of 94.6 (±SD 20.8) compared to a score of 82.3 (±SD
32.9) (p<0.001) in the reference group. The mean values in all domains were higher
for males compared to females, except for the domain of expected health change.
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CHAPTER 3
Table 1 Sociodemographic and clinical patient characteristics.
Table 2 M
ean SF-36 scores in our study compared to a healthy Dutch reference
group 15.
Feature
Patients
(n = 49)
Study patients
(n = 49)
Reference groupa
(n = 1742)a
Gender, n (%)
Male
Female
26 (53.1)
23 (46.9)
mean (± SD)
mean (± SD)
Physical functioning
86.7 (22.5)
83.0 (22.8)
Age (years) mean ±SD
48 ± 13.4
Role physical functioning
78.6 (36.5)
76.4 (36.3)
Age at psoriasis onset (years), mean ±SD
29 ± 14.1
Role emotional functioning
94.6 (20.8)*
82.3 (32.9)*
Duration of psoriasis, (years), mean ±SD
19 ± 13.6
Vitality, energy and fatigue
66.7 (20.2)
68.6 (19.3)
Age at nail psoriasis onset, (years), mean ±SD
38 ± 12.6
Mental health
75.5 (15.9)
76.8 (17.4)
Duration of nail psoriasis, (years), mean ±SD
10 ± 8.1
Social functioning
84.5 (19.7)
84.0 (22.4)
Bodily pain
78.1 (20.5)
74.9 (23.4)
General health perceptions
68.2 (20.0)
70.7 (20.7)
Expected health change
55.1 (24.5)
NA
Localization of nail psoriasis, n (%)
Fingernails only
Toenails only
Both, finger- and toenails
10 (20.4)
NA
39 (79.6)
NAPSI, mean ±SD
26.6 ± 14.5
PASI, median (range)
3.7 (0.0 – 29.5)
BSA, %, mean ±SD
6.6 ± 11.2
3
a
Aaronson et al. [15].
*Significant (p=<0.001).
Scores range from 0 (worst quality of life) to 100 (best quality of life). SD, standard deviation, NA, not
available.
BSA, Body Surface Area; NA, Not applicable; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area
and Severity Index; SD, standard deviation.
None of these differences were significant (data not shown). A decrease in the mean
values in each domain was observed with increasing age, especially for the physical
functioning, social functioning and expected health change dimensions, where
statistical significance was reached (97.9 vs. 75.0 p=0.016, 92.1 vs. 75.0 p=0.017, 67.9
vs. 53.0 p=0.027, respectively). Patients with PsA documented decreased HRQoL in all
domains except for expected health change. Significant lower scores were found in
the domains of physical functioning, role physical functioning and bodily pain (63.1 vs.
91.7 p=0.002, 56.3 vs. 83.1 p=0.045, 65.3 vs. 81.0 p=0.049, respectively).
Modified fingernail onychomycosis QoL questionnaire
Table 3 shows the results of the modified fingernail onychomycosis QoL questionnaire,
and Table 4 shows the mean scores in relation to relevant variables. The calculated
mean score for the social scale was 75.1 (±SD 22.0), for the emotional scale 78.8 (±SD
16.6), and for the symptom scale 74.4 (±SD 21.0). The most important aspects
influencing patients’ QoL were the feeling that other people noticed their nail problem
and that their nails look neglected, which are both part of the social dimension. It is
noteworthy that 49% of patients experienced some degree of pain caused by their
70
nail manifestations. Females recorded more impaired QoL in all three scales compared
to men, however no statistical significance was reached. Increasing age seems to give
a decreased impact of fingernail psoriasis on patients’ QoL, as a trend of increasing
scores was seen with increasing age. Patients with both fingernails and toenails
involved recorded lower scores in all three scales compared to patients with nail
psoriasis limited to the fingernails. Statistical significance was reached in the symptom
scale (p=0.023). We could not show a clear correlation between disease severity, as
measured by the NAPSI, and the disease-specific QoL score. The mean scores for the
three dimensions (social problems, emotional problems, symptoms) increased when
the duration of fingernail psoriasis was prolonged, indicating that the negative impact
of fingernail psoriasis decreased when duration of fingernail psoriasis increased.
Patients diagnosed with PsA and fingernail psoriasis scored higher QoL scores when
compared to fingernail psoriasis patients without PsA; statistical significance was not
reached. Fingernail psoriasis influenced emotional well-being, social dimension and
symptoms more negatively in patients with a higher educational level.
VAS for pain and PGA of disease severity
Patients assessed their disease severity with a mean PGA of three, which indicates
limited control of fingernail psoriasis. The majority of patients (69.4%) stated limited
71
72
3 (6.1)
20 (40.8)
0 (0.0)
27 (55.1)
18 (36.7)
44 (89.8)
10 (20.4)
25 (51.0)
17 (34.7)
42 (85.8)
3. I feel uncomfortable shaking hands because of
my nail problem.
4. I tend to hide my nails.
5. I feel my family and friends do not take my nail
problem seriously.
6. My nails look neglected.
7. I am embarrassed when going out to eat or to a
party.
8. I have to explain to others what is wrong with
my nails.
9. Others are afraid of catching nail psoriasis
from me.
38 (77.5)
46 (93.9)
30 (61.2)
33 (67.3)
15 (30.6)
10 (20.4)
20 (40.8)
12 (24.5)
12 (24.5)
11. It costs a lot of money to look after my nails.
12.I worry that my nail problem is contagious.
13.I feel self-conscious because of my nail problem.
14.I am upset by the appearance of my nails.
15.I worry about having this nail problem for the
rest of my life.
16.I feel I have to keep my nails cut short.
17. I cannot forget that I have this nail problem.
18.My nail problem is a nuisance.
19.I worry this might spread.
21 (42.9)
27 (55.1)
25 (51.0)
21 (42.9)
27 (55.1)
20.My nails are thick and discoloured.
21.I have difficulty cutting my nails.
22.I have pain in my fingers and nails.
23.The nails seem to be being eaten away.
24.I find it difficult to work with my hands.
Symptoms
28 (57.1)
10.I feel disheartened because of my nail problem.
Emotional problems
17 (34.7)
14 (28.6)
8 (16.3)
11 (22.4)
9 (18.4)
7 (14.3)
9 (18.4)
17 (34.7)
16 (32.7)
15 (30.6)
29 (59.2)
15 (30.6)
11 (22.4)
13 (26.5)
2 (4.1)
7 (14.3)
11 (22.4)
13 (26.5)
9 (18.4)
13 (26.5)
15 (30.6)
14 (28.6)
2. I think that other people notice my nail problem.
17 (34.7)
n (%)
n (%)
1. People find it unpleasant to look at my nails.
Social problems
Questions
Yes,
a little
Not at all
8 (16.3)
10 (20.4)
10 (20.4)
9 (18.4)
7 (14.3)
11 (22.4)
12 (24.5)
10 (20.4)
6 (12.2)
8 (16.3)
2 (4.1)
3 (6.1)
1 (2.0)
4 (8.2)
8 (16.3)
3 (6.1)
6 (12.2)
6 (12.2)
13 (26.5)
1 (2.0)
5 (10.2)
4 (8.2)
11 (22.4)
11 (22.4)
n (%)
Yes,
moderately
3 (6.1)
3 (6.1)
3 (6.1)
3 (6.1)
10 (20.4)
6 (12.2)
6 (12.2)
2 (4.1)
3 (6.1)
8 (16.3)
3 (6.1)
2 (4.1)
0 (0.0)
0 (0.0)
1 (2.0)
2 (4.1)
4 (8.2)
3 (6.1)
12 (24.5)
1 (2.0)
5 (10.2)
4 (8.2)
4 (8.2)
4 (8.2)
n (%)
Yes,
very much
Table 3 The results of the modified fingernail onychomycosis quality of life questionnaire.
No data
n (%)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
1 (2.0)
0 (0.0)
Yes,
extremely
n (%)
3 (6.1)
5 (10.2)
1 (2.0)
4 (8.2)
0 (0.0)
5 (10.2)
2 (4.1)
2 (4.1)
2 (4.1)
1 (2.0)
0 (0.0)
0 (0.0)
1 (2.0)
0 (0)
3 (6.1)
1 (2.0)
2 (4.1)
3 (6.1)
3 (6.1)
2 (4.1)
3 (6.1)
2 (4.1)
3 (6.1)
3 (6.1)
CHAPTER 3
3
73
CHAPTER 3
Table 4 Mean scale scores of the modified onychomycosis score in relation to
relevant variables.
Social
Emotional Symptoms
problems problems
N
m
mean
mean
mean
All
49
0
75.1
78.8
74.4
Gender
Male
Female
26
23
76.7
73.2
82.6
74.6
79.2
68.6
Age, years
< 40
40 - 55
> 55
14
18
17
74.0
70.7
80.6
77.0
78.5
80.7
75.8
71.4
76.5
3
16
2
91.7
78.0
100.0
84.2
82.0
97.5
78.3
73.1
100.0
9
15
4
80.0
65.2
64.6
80.8
73.7
67.5
80.6
70.0
65.0
81.4
73.4
87.3
76.7
88.3*
70.2*
61.8*
78.8
81.2*
70.9
79.4
82.8
64.7
82.5
74.1
84.9
72.8
85.0
77.4
82.2
72.6
Highest educational level
Primary education
Junior general secondary education
Senior general secondary education/
pre-university education
Community college
University of professional education
University of science
0
0
0
0
Localization of nail psoriasis
Fingernails
Finger- and toenails
10
39
Duration of nail psoriasis, years
<6
6 - 10
> 10
16
13
17
Psoriatic arthritis
Yes
No
9
40
3
0
*Significant (p<0.05). 0 to 100 scale: 0 is worst quality of life, 100 is best quality of life.
N, number of patients; m, missing.
to no control of nail psoriasis. Mean scores on the VAS were 15.4 mm (±SD 3.0) for
the pain sensation caused by fingernail psoriasis and 22.0 mm (±SD 4.0) for the pain
sensation caused by the skin lesions. Correlation between the VAS for pain caused
by fingernail psoriasis and the total modified onychomycosis QoL score was -0.298
(p=0.05), indicating that pain of the nail apparatus negatively influences the QoL.
Significant correlations were also found between this VAS for pain and the following
74
SF-36 domains; vitality, energy and fatigue (r=-0.390, p<0.01); role emotional
functioning (r=-0.390, p=0.05); social functioning (r=-0.405, p<0.01); bodily pain
(r=-0.546, p<0.01).
Discussion
It is well known that patients with chronic medical conditions, such as psoriasis,
report diminished QoL.8,9 There is evidence that psoriasis located on visible body
parts has a greater impact on QoL, compared to lesions located on less visible body
areas.7,10 Fingernail disease is highly visible and therefore it is likely to influence QoL.
Previous studies have shown that onychomycosis impairs various aspects of QoL,11,17
and only a few studies investigated the effect of nail psoriasis on patients’ QoL.12,18,19
Our results indicate that fingernail psoriasis can interfere with important aspects of
patients’ QoL and that nail-specific questionnaires may contribute to more
individualised and problem-specific treatment of these patients.
Our SF-36 data confirmed that age and gender influences patients’ well-being.
The impact on HRQoL was lower for males and gained with increasing age, as generally
observed.15,20,21 It is assumed that increasing impairment of physical functioning is the
result of an increase in comorbidities and the diminishing vitality associated with
increasing age.
Our observations showed comparable SF-36 scores in both patients with
fingernail psoriasis and the healthy Dutch reference population.15 These data indicate
that fingernail psoriasis does not determine patients’ perceptions of their general
health. Heydendael et al.,6 studied the impact of psoriasis of the skin on HRQoL, also
using the SF-36. They compared a group of 85 patients with moderate to severe
psoriasis (mean PASI 13.7) with a Dutch reference group of 1742 persons without
chronic illness, and found impairment of HRQoL in patients with psoriasis compared
to healthy controls. This study shows that the outcome of the SF-36 scores can be
influenced by cutaneous psoriasis lesions. In the present study patients were treated
for their cutaneous lesions, resulting in a median PASI of only 3.7, which indicates low
activity of skin disease. Consequently the impact of additional cutaneous psoriasis
lesions on patients’ HRQoL is considered to be limited in this study. An explanation for
the small impairment in physical and mental domains of the SF-36 in fingernail
psoriasis is that the SF-36 is not a particularly sensitive measure for nail disorders; it
was designed to estimate HRQoL and does not specifically assess the burden of
fingernail disease on patients’ QoL. To compensate for this limitation, we used a
modified onychomycosis questionnaire designed by Drake et al.,11 which focuses on
QoL issues in patients with a nail disease, and applied the questionnaire to patients
with fingernail psoriasis. The results indicated that fingernail psoriasis has a relevant
impact on patients’ QoL on either social, emotional or symptom dimensions.
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CHAPTER 3
Drake et al.,11 used their questionnaire for onychomycosis patients and compared
the results from four different countries (Germany, Italy, France and the United
States). These results are in line with our data concerning fingernail psoriasis patients,
showing comparable impact of both nail diseases on patients’ QoL. On the other
hand, the Polish onychomycosis patients investigated by Szepietowski et al.17 scored
much lower mean scores on all dimensions than our fingernail psoriasis patients. This
could be explained by significant cultural differences in notions of health and illness
perceptions between different countries.11
Using the modified onychomycosis QoL questionnaire showed that patients with
nail psoriasis seem to experience the greatest burden on the social dimension.
Patients are most frequently worried about the judgement of others concerning their
nails. In addition, pain experienced by nail psoriasis also seems to be an important
aspect of the burden of this disease. Half of the patients stated that they experienced
pain in their fingers and nails as scored by the modified questionnaire. Ortonne et al.18
reported a similar percentage of 59%. The results we found on the VAS scores on pain
caused by nail lesions are in line with these results. The VAS score correlated with the
total modified onychomycosis QoL score and various dimensions of the SF-36,
indicating that increasing pain caused by nail psoriasis negatively influences the QoL.
As a consequence, we emphasize that clinicians should take the social burden and
pain caused by nail psoriasis into account when treating patients with nail psoriasis.
The QoL scores resulting from the disease-specific QoL questionnaire were
influenced by different variables. Interestingly, we found a trend in women and patients
with higher educational levels to show more impaired QoL in all three investigated
dimensions. Szepietowski et al.17 found similar results according to gender and
educational level in patients with onychomycosis. However, no gender differences
according to the symptom dimension were found. They registered more severe
symptoms in patients with lower educational levels. Ortonne et al.18 also found
statistically significant greater impairment in women with nail psoriasis as measured
by their disease-specific questionnaire, NPQ10, which was published after the start of
this study and therefore could not be used in this study. Furthermore, Augustin et al.19
measured QoL in 1430 nail psoriasis patients using the DLQI and found also higher
scores, i.e. greater impairment, in women. The gender differences were also seen in
the SF-36 questionnaire and are therefore probably not disease-specific. The
influence of the educational level may be explained by the fact that patients with
higher educational levels are generally more socially active. Therefore, they have
more opportunities to have their nail disease noticed by other people.17
Increasing age seems to decrease the impact of fingernail psoriasis on disease-
specific QoL. However, previously we stated that older patients with fingernail
psoriasis documented more impaired HRQoL on the SF-36. This might be explained by
the fact that the factor ‘general health’ or in other words the impact of comorbidities
76
on QoL is eliminated in a disease-specific questionnaire. Patients seem to accept their
nail disease better with increasing age. Earlier studies also noted a decreased impact
of disease with increasing age in patients with psoriasis.9
Patients with nail psoriasis of both finger- and toenails reported reduced disease-
specific QoL in all three dimensions compared to patients with exclusive fingernail
psoriasis, but this was only significant for the symptom dimension. Previous studies in
nail psoriasis and onychomycosis patients found fairly similar results.17,18 This leads to
the conclusion that more extended nail disease causes not only more severe
symptoms, but also more psychosocial impairment, both in patients with nail psoriasis
and with onychomycosis. Disease-specific QoL is also influenced by the duration of
fingernail psoriasis; recent diagnosis is associated with greater impairment. It seems
that the impact of fingernail abnormalities fades over time because of acceptance.
These results confirm those of Ortonne et al.18 We could not show a clear correlation
between disease severity, as measured by the NAPSI, and the disease-specific QoL score.
Most previous studies concerning QoL in nail psoriasis were conducted with
self-administered questionnaires, the authors having to rely on the patient’s judgment
concerning diagnosis and disease severity. In this study all patients were interviewed
and clinically examined by the same trained medical doctor to reach the highest
validity. Furthermore, patients with concomitant onychomycosis were excluded from
the study. The disadvantage of this approach is that a limited number of patients
could be included. Therefore, trends can be seen according to the mean scores of the
questionnaires, but statistical significance was not always reached. A larger number
of patients is needed to confirm these findings. Another limitation of this study might
be a selection bias, because we included patients who visited the outpatient clinic of
a tertiary referral hospital and therefore sought attention for their psoriasis. They
may not represent a random sample of fingernail psoriasis patients, because these
patients might suffer from more severe (nail) psoriasis or may experience a greater
disease burden.
In summary, fingernail psoriasis seems to reduce patient’s physical, mental and social
well-being and should not be overlooked by dermatologists. Given the burden of
disease in individual patients, an instrument which accurately and precisely measures
the burden of nail psoriasis would be valuable for both clinical care and research
purposes. Assessing patients’ QoL offers the opportunity to address these issues in a
patient-centred approach to treatment.
77
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CHAPTER 3
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health survey collected by mail versus telephone interview: Results from a national survey. Medical
care 1994;32:551-67.
3
79
Chapter 3.2
Nail psoriasis, the unknown burden
of disease
K.M.G. Klaassen
M.C. Pasch
Journal of the European Academy of Dermatology and Venereology
2014 Epub ahead of print
CHAPTER 3
Abstract
Introduction
Background: Psoriasis can be found at several different localizations which may be of
various impact on patients‘ quality of life (QoL). One of the easy visible, and difficult
to conceal localizations are the nails.
Psoriasis is a chronic, inflammatory skin disease characterized by notable lesions that
may appear on variable parts of the body.1 It can be experienced as extremely
distressing, and is known to affect patients’ quality of life (QoL) comparable to that of
other chronic diseases.2,3 Psoriasis can be found at several different localizations
which may be of various impact on patients‘ QoL. In particular psoriasis on highly
visible areas of the skin, such as the face and hands, can have a significant impact. 4
One of the easy visible, and difficult to conceal localizations are the nails. A substantial
number of psoriatic patients have nail involvement, varying from 10% to 80%, with an
estimated lifetime incidence of 80-90%.2, 4-19 This prevalence is even higher in patients
with psoriatic arthritis (PsA).19 The most prevalent features seen in nail psoriasis are
pitting and onycholysis.16, 18, 20-22 Despite the high prevalence of nail psoriasis, the
specific impact of nail psoriasis on patients’ functioning and well being has not gained
much attention in the past. Nails enhance fine touching, tactile sensitivity, retrieving
small objects and play a role in an individual’s body image perception. It is already
known that nail abnormalities in general are considered a significant problem, and
can influence a person’s self-esteem.23, 24 Previous literature showed that patients
suffering from nail psoriasis can also experience alterations in QoL.7 The burden of
nail psoriasis can be determined by physical symptoms, psychological burden and
restrictions in profession and activities.7 Moreover, nail psoriasis always has been a
therapeutic challenge for patients and dermatologists because the nail apparatus
limits the absorption of most of the topical treatments.25 Treatment tends to focus on
clearing the cutaneous component, and the nails are often overlooked by the
clinicians, so nail features are frequently a longstanding problem.7
The aim of this study was to achieve more insight into the QoL of psoriatic
patients with nail psoriasis by means of validated questionnaires, and to characterize
the patients with nail involvement which are more prone to the impact of the nail
alterations caused by psoriasis.
Objective: To achieve more insight into the QoL of psoriatic patients with nail
psoriasis, and to characterize the patients with nail involvement which are more
prone to the impact of the nail alterations caused by psoriasis.
Method: A self-administered questionnaire was distributed to all members (n=5400)
of the Dutch Psoriasis Association. The Dermatology Life Quality Index (DLQI) and the
Nail Psoriasis Quality of life (NPQ10) score were included as QoL measures. Severity
of cutaneous lesions was determined using the Self-Administered Psoriasis Area and
Severity Index (SAPASI).
Results: Patients with nail psoriasis scored significantly higher mean scores on the
DLQI (4.9 vs. 3.7, p=<0.001) and showed more severe psoriasis (SAPASI, 6.6 vs. 5.3,
p=<0.001). Patients with coexistence of nail bed and nail matrix features showed
higher DLQI scores compared with patients with involvement of one of the two
localizations exclusively (5.3 vs. 4.2 vs. 4.3, p=0.003). Patients with only nail bed
alterations scored significant higher NPQ10 scores when compared with patients with
only nail matrix features. Patients with psoriatic arthritis (PsA) and nail psoriasis
experiences more impairments compared with nail psoriasis patients without PsA
(DLQI 5.5 vs. 4.3, NPQ10 13.3 vs. 7.0). Females scored higher mean scores on all QoL
scores.
Conclusion: Greater attention should be paid to the possible impact nail abnormalities
have on patients with nail psoriasis, which can be identified by nail psoriasis specific
questionnaires such as the NPQ10. As improving the severity of disease may have a
positive influence on QoL, the outcome of QoL measurements should be taken into
account when deciding on treatment strategies.
Material and methods
Patients
A self-administered questionnaire was distributed to all members (n=5400) of the
Dutch Psoriasis Association together with an invitational letter explaining the purpose
of the study. The same patients were involved in a previous study on the epidemiology
of nail psoriasis.18 The questionnaire was completed anonymously and no incentives
were given. The investigation was conducted from 14 April 2011 and responses were
accepted through to 1 August 2011. The questionnaire involved the following validated
questionnaires.
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CHAPTER 3
Dermatology Life Quality Index (DLQI)
Patients’ QoL was measured using the DLQI. The DLQI consists of ten questions on
several aspects of patients’ life that may be affected by a skin disease.26 This
international validated questionnaire comprises ten questions concerning six areas;
symptoms and feeling, daily activities, leisure, work and school, personal relationship
and treatment. Each question is scored on a four or five-point Likert scale. The scores
are summed, giving a range from 0 (no impairment of life quality) to 30 (maximum
impairment).26 The Dutch version of the DLQI is a back- and forward translation of the
questionnaire by a native speaker, and has been approved by the original group of
Finlay et al. in 1998. No substantial modifications have been made during the
translation of the DLQI, only linguistically.
Nail Psoriasis Quality of life (NPQ10)
The NPQ10 is a 10-item quality of life questionnaire specific for nail psoriasis. The
questionnaire was designed and validated by Ortonne et al.27 Each question is scored
on a three-point scale; ranging from 0 to 2. Summing the scores gives a range from 0
(no impairment on QoL) to 20 (maximum impairment).27 No validated Dutch version
existed. Therefore, the questionnaire was backward and forward translated. One
item was excluded. This question concerning the interference of nail psoriasis with
the ability to drive a car, was removed because of the wide age range of the target
population and the chance on lots of missing data. Consequently, the score can range
from 0 to 18. Eventually, scores were converted to percentages.
Self-Administered Psoriasis Area and Severity Index (SAPASI)
This instrument allows patients to assess the severity of their psoriasis. Patients rate
redness, induration and scaliness of an average psoriasis lesion using three visual
analogue scales, and shade the involved area of their skin on a silhouette of the
human body. Based on silhouette shading, an investigator assigns a numeric value of
0 to 6 using the same cut points of the Psoriasis Area and Severity Index (PASI).28 The
SAPASI weights the involved area as the original PASI score.29 The range of the SAPASI
is 0-72, with increasing SAPASI scores indicating increasing severity of psoriasis.
Data were entered in a database and subsequently statistical analysis was performed
using Statistical package for Social Sciences (SPSS 20.0, IBM Corp, Armonk, NY).
Descriptive statistics were provided using mean (±SD) and median (range) for normally
and non-parametric distributed numeric values respectively. Frequencies and
percentages were used for categorical variables. Missing values were not included to
calculate percentages. Comparison of numeric variables were analysed with the
unpaired t-tests or the Mann-Whitney U test and the chi square or Fisher exact test
84
was used for differences between categorical variables. One way ANOVA was used
when more than two means were compared. P-values of ≤0.05 were considered to
be statistically significant.
Results
Patients
The patient characteristics and clinical details are presented, and extensively analysed
before by Klaassen et al.18 A total of 5400 questionnaires were sent out, and 1459
questionnaires were returned and suitable for analysis. The mean age of the
respondents was 57.5 years (±SD 13.6 years). Among the respondents, 736 were
female (51.1%) and 703 were male (48.9%). Of the total group of respondents 963
patients (66.0%) reported nail involvement.
SAPASI
Table 1 shows the mean rates of the scores (DLQI, SAPASI and NPQ10), subdivided for
patients with and without nail psoriasis. Psoriasis severity, as measured by the SAPASI,
was for respondents with nail psoriasis significantly higher when compared with
psoriatic patients without nail involvement, 6.6 (±SD 4.9) and 5.3 (±SD 4.3)(p =<0.001)
respectively. When distinguishing between exclusively nail matrix involvement,
exclusively nail bed involvement or coexistence of both, SAPASI scores were
significantly higher in patients with coexisting symptoms from both localizations (5.6
vs. 5.8 vs. 7.2 respectively, p=<0.001). Mean SAPASI was significant higher in nail
psoriasis patients with PsA compared with nail psoriasis patients without arthritic
involvement (7.0 vs. 6.2 respectively, p=0.010). The correlation between having nail
psoriasis and the SAPASI was small, but significant 0.133 (p=<0.001).
DLQI
Patients with nail involvement experienced significant more impaired QoL compared
with patients without nail psoriasis, mean scores were 4.9 (±SD 5.0) and 3.7 (±SD 4.4)
respectively (p=<0.001). The presence of nail symptoms is associated with greater
impairment in all DLQI domains (see Table 2). There was a significant correlation
between DLQI scores and having nail psoriasis of 0.115 (p=< 0.001), even when
correcting for SAPASI scores. QoL was also significantly more impaired in patients
with coexistence of nail bed and nail matrix features compared with patients with
involvement of one of the two localizations exclusively (5.3 vs. 4.2 vs. 4.3 respectively,
p=0.003). The mean DLQI scores for nail psoriasis patients with PsA were significantly
higher when compared with nail psoriasis patients without PsA (5.5 vs. 4.3, p=<0.001).
In addition, the DLQI scores for psoriasis patients with PsA (without nail manifestations)
was equal to the score of nail psoriasis patients with involvement of both nail matrix
85
3
86
5.6 (3.9)
5.8 (3.8)
7.2 (5.4)
7.0 (5.5)
6.2 (4.2)
6.4 (4.9)
6.8 (4.9)
PsA
Yes
No
Sex
Men
Women
4.3 (4.5)
4.2 (5.0)
5.3 (5.2)
5.5 (5.5)
4.3 (4.5)
4.5 (4.7)
5.2 (5.4)
PsA
Yes
No
Sex
Men
Women
3.8 (9.3)
10.5 (13.9)
11.4 (14.7)
13.3 (16.6)
7.0 (10.5)
7.5 (12.2)
12.6 (15.5)
PsA
Yes
No
Sex
Men
Women
<0.001
<0.001
<0.001**
0.032
<0.001
0.003*
-
0.226
0.010
<0.001*
-
p-value
-
-
-
-
3.4 (4.0)
4.0 (4.7)
4.1 (4.9)
3.5 (4.1)
-
3.7 (4.4)
5.2 (3.8)
5.3 (4.7)
5.8 (5.4)
5.1 (3.7)
-
5.3 (4.3)
No nail
involvement
(n = 496)
*
Significances were found between patients with coexistence of nail bed and nail matrix features
compared with patients with involvement of one of the two localizations.
** Significance was found between patients with nail bed features solely or in combination with nail matrix
features compared with patients with nail matrix manifestations solely.
DLQI, Dermatology Life Quality Index; n, number; NPQ10, Nail Psoriasis Quality 10; PsA, Psoriatic arthritis;
SAPASI, Self-administered Psoriasis Area and Severity Index.
9.9 (14.0)
NPQ10 score, mean (±SD)
Localisation Nail matrix
Nail bed
Nail matrix and nail bed
NPQ10 scores
4.9 (5.0)
DLQI score, mean (±SD)
Localisation
Nail matrix
Nail bed
DLQI scores
6.6 (4.9)
SAPASI score, mean (±SD)
Localistion
Nail Matrix
Nail Bed
SAPASI scores
Nail involvement
(n = 963)
Table 1 Mean scores questionnaires (SAPASI, DLQI, NPQ10).
-
-
-
-
0.113
0.185
-
<0.001
0.903
0.168
-
<0.001
p- value
-
<0.001
0.458
-
<0.001
0.024
-
-
-
6.7 (5.5)
5.7 (4.1)
6.0 (4.6)
6.2 (4.9)
4.5 (4.9)
-
5.1 (5.4)
4.0 (4.3)
4.2 (4.5)
4.8 (5.2)
-
-
-
-
6.1 (4.7)
-
p-value
All patients
(n = 1459)
CHAPTER 3
3
87
CHAPTER 3
3
58
735 (81.2)
11 (1.2)
9. Because of my nail psoriasis, I am more irritable than usual,
and bad-tempered with people
159 (17.6)
58
762 (84.2)
7 (0.8)
8. Because of my nail psoriasis, I avoid doing big jobs around the house
136 (15.0)
58
889 (98.2)
5 (0.6)
7. Because of my nail psoriasis, someone helps me to get dressed
11 (1.2)
57
826 (91.2)
9 (1.0)
6. Because of my nail psoriasis, I have trouble turning on my door key
71 (7.8)
60
676 (74.9)
31 (3.4)
5. Because of my nail psoriasis, I have trouble putting on my socks
196 (21.7)
57
804 (88.8)
13 (1.4)
89 (9.8)
56
677 (74.6)
217 (24.0)
4. Because of my nail psoriasis, I get dressed more slowly than usual
and nail bed (without arthritic involvement) ( 4.1 vs. 5.0 respectively, p=0.078).
Correlation between the DLQI and SAPASI was 0.487 (p=<0.001).
13 (1.4)
Answer options
n, number; SD, standard deviation.
3. Because of my nail psoriasis, I don’t do any of the jobs I usually do
around the house
<0.001
59
0.017
0.4 (0.7)
712 (78.8)
0.3 (0.8)
0.5 (0.8)
178 (19.7)
0.4 (1.0)
14 (1.5)
Relationships
Treatment
2. Because of my nail psoriasis, I have difficulty putting my shoes on
<0.001
<0.001
Missing
n
0.5 (1.1)
0.2 (0.6)
Never
n (%)
0.8 (1.3)
0.4 (0.7)
Sometimes
n (%)
Leisure
Work or school
Always
n (%)
<0.001
59
<0.001
0.8 (1.2)
580 (64.2)
1.5 (1.4)
1.1 (1.4)
285 (31.5)
1.7 (1.5)
39 (4.3)
Symptoms and feelings
Daily activities
Missing
n
p - value
Not very painful
n (%)
No nail
involvement
n = 496
mean (±SD)
Very painful
n (%)
Nail involvement
n = 963
mean (±SD)
Not painful
n (%)
Table 2 Dimensions Dermatology Life Quality Index (DLQI).
88
n, number.
This study shows that nail psoriasis can have detrimental effects on QoL. Distress are
particularly prominent in nail psoriasis patients with PsA, female gender, and more
extensive nail psoriasis. Using the NPQ10 gives insight into the daily restrictions
patients with nail psoriasis experience. Combining data concerning individual restrictions
1. Would you say that your psoriasis of the nails is mostly
Discussion
Question
The results of the NPQ10 are shown in Table 1 and 3. The mean QoL score for all nail
psoriasis patients was 9.9 (±SD 14.0). Men with nail psoriasis scored significantly
lower on the NPQ10 compared with women (7.5 and 12.6 respectively, p=<0.001)
which indicates less impairment of QoL caused by nail psoriasis in men. Mean NPQ10
scores were significantly higher for PsA patients with nail involvement when compared
with patients with nail involvement without PsA, 13.3 and 7.0 respectively (p=<0.001).
When comparing scores between the different localizations of nail psoriasis, QoL was
more affected in patients with solely nail bed features compared with patients with
nail matrix features only. The correlation between NPQ10 scores and the DLQI scores
was r=0.389 (p=<0.001). Correlation between NPQ10 and SAPASI scores was 0.209
(p=<0.001). When looking at the questions separately, patients were most restricted
in putting on shoes or socks and activities around the house (see also Table 3).
Table 3 Results Nail Psoriasis Quality of Life 10 (NPQ10).
NPQ10
89
CHAPTER 3
with data concerning QoL will allow us to individualize treatment for patients with
nail psoriasis.
Previous literature showed that psoriasis can have substantial effects on patients
QoL, and the impact has been shown to be similar to that of major chronic diseases
including cardiovascular diseases, diabetes mellitus and depression.3,30,31 However,
the specific impact of nail lesions on patients’ QoL gained little attention in the past. 4,15
QoL questionnaires in dermatology can be generic, dermatology-specific or disease-specific.32 Studies focusing on the impact of nail features on QoL predominantly
used the DLQI, a non-disease-specific questionnaire, measuring the impact of
cutaneous disorders in general.33 Our results on the DLQI are in agreement with
previous studies. Radtke et al. (questionnaires-based survey, n= 2449) found higher
impairment of QoL, using the DLQI, in patients with psoriasis and nail involvement
when compared with patients without nail involvement (mean scores 7.2 vs. 5.3
respectively, p=<0.001).15 They also found higher cutaneous psoriasis severity in
patients with nail involvement. A study by Augustin et al. (outpatient clinic, n=3531)
also assessed QoL using the DLQI on patients with psoriasis. Again, significant higher
mean scores were stated by patients with nail features (men 8.6 vs. 6.9, and women
9.5 vs. 7.6). However, patients with nail psoriasis generally also had more severe
psoriasis (PASI score), more frequently PsA and longer duration of psoriasis. 4 Nail
involvement seems to decrease patients QoL additionally to the cutaneous lesions.
However, QoL differences might be suggested to be attributed to the fact that
psoriasis patients with nail involvement have a higher prevalence of PsA or more
severe psoriasis. Previous literature showed that in psoriasis patients, joint
involvement places an additional burden on the already diminished QoL caused by
the cutaneous lesions.34, 35 This could also contribute to the differences of QoL scores
found between psoriasis patients with and without nail features, as patients with nail
psoriasis have significantly more frequently PsA.18 However, our data showed that the
impact of having nail psoriasis on the QoL is comparable to impact of PsA (in psoriasis
patients without nail involvement) provided that nail psoriasis is present in both nail
matrix and nail bed. In addition, a study of Rosen et al. showed decreased QoL scores
in patients with PsA compared with psoriasis patients without joint involvement on
different QoL scores, except for the DLQI. This could be explained by the fact that the
DLQI reflects the impact of the cutaneous lesions, not of the restrictions caused by
the joint problems.34 Moreover, QoL differences might be suggested to be caused by
differences in severity of cutaneous psoriasis lesions. As nail manifestations
predominantly precede the presentation of PsA, it would be interesting to determine
the impact of nail manifestations in the course of their disease.36 We found significant
higher SAPASI scores in patients with nails psoriasis (6.6 vs. 5.3, p=<0.001). Previous
studies also confirmed higher disease severity in patients with nail psoriasis.9,15,16,32
Therefore we conducted a secondary analyses controlling for severity of psoriasis
90
(SAPASI) and these results still showed that patients with nail psoriasis had worse QoL
independent of the severity of their cutaneous lesions. Our data show that the
presence of extended nail disease of both nail matrix and nail bed psoriasis
simultaneously can have a negative influence on QoL independent from the influence
of PsA or psoriasis severity. However, when using the DLQI it stays unclear if the
differences found on the DLQI might be explained by solely the presence of nail
lesions, higher prevalence of PsA, more severe psoriasis in this group of patients or
a combination of factors.
So, when using the DLQI in patients with both skin lesions and nail features, it is
difficult to separate the influence of nail features on QoL from the cutaneous lesions.24
To overcome this problem, Ortonne et al.27 developed a QoL scale measuring solely
the impact of nail psoriasis on patients’ quality of life (NPQ10). The NPQ10 showed
good internal consistency (cronbachs’ α 0.88) and reproducibility and the results
correlated with the DLQI scoring (R=0.48).27 The NPQ10 is the first and only scale,
until now, focusing on nail psoriasis specifically, however, few studies used this
questionnaire. The present study shows that nail psoriasis restricted patients most
frequently in putting on shoes or socks (21.2% and 25.1%) and activities around the
house (25.3%). Nail psoriasis patients were rarely limited in getting dressed or turning
around keys (1.8% and 8.8%). Of all nail psoriasis patients 35.8% experienced pain to
a greater or lesser extent. The localization of psoriasis in the nail apparatus seems to
be associated with the degree of impairment of QoL. Patients with nail bed
involvement solely stated significant higher mean scores on the NPQ10 compared to
patients with solely nail matrix involvement. This finding emphasizes that nail bed
features, such as subungual hyperkeratosis and onycholysis, might restrict patients
more than matrix lesions (e.g., pitting). This is in contrast with the finding that patients
with both nail matrix and nail bed involvement simultaneously scored significant
higher scores on the DLQI when compared with patients with features of one of the
two localizations solely. However, patients with simultaneous involvement of nail bed
and nail matrix seem to have significant more severe psoriasis which results in higher
DLQI scores as the DLQI reflects the impact of the cutaneous lesions and not
specifically the nail features. In addition, the DLQI takes the impact of cosmetic
effects of disease into account as the focus of the NPQ10 is centered around the
restrictions nail features entail. Patients with both nail bed and nail matrix features
might score higher on the DLQI as a combination of features may have a higher
esthetical impact. In contrast, nail bed features might interfere more with functioning
which may lead to higher NPQ10 scores compared with patients with solely nail
matrix manifestations.
Patients with PsA and nail involvement scored significantly higher mean NPQ10
scores compared with nail psoriasis patients without PsA. This could either indicate
that patients with PsA have more severe nail psoriasis and consequently more
91
3
CHAPTER 3
restrictions in daily live or that having arthritis negatively affects the items questioned
in the NPQ10. Further research, correlating nail psoriasis severity scores of these
groups with NPQ10 scores have to confirm or renounce this hypothesis.
Gender seems to influence QoL scores as women score higher on both QoL
scores. Zachariae et al. reported comparable results using the DLQI.37 Both found that
women scored higher on items concerning experiences of embarrassment or self
consciousness and influence of disease on the choice of clothing. This might be
explained by the fact that women and men respond different to disfiguring disease.37, 38
Limitations
A selection bias might be created by questioning the members of a psoriasis
association, as members of a patient support association may possible not represent
a random sample of patients with psoriasis. It may be speculated that these patients
are perhaps more worried about their disease or they might suffer from more severe
psoriasis than psoriasis patients who did not join a patient support group. Interview
by a medical doctor might be more accurate, however, the study design made it
possible to include a large number of patients. Modifying the NPQ10 is also a limitation
of the study. However, as the questionnaire is sparsely used, this study gained insight
into the experienced restrictions of nail disease despite of using a modified version.
Conclusion
In clinical practice, there is a great challenge for dermatologists to improve QoL of
patients with nail psoriasis. To do so, greater attention should be paid to the possible
limitations that these patients experience which can be identified by nail psoriasis
specific questionnaires such as the NPQ10. As improving the severity of disease may
have a positive influence on QoL, the outcome of QoL measurements should be taken
into account when deciding on treatment strategies. In addition, patients’ gender,
presence of PsA and localization of nail features can have a role in individualized
treatment of nail psoriasis.
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37. Zachariae R, Zachariae C, Ibsen HH, Mortensen JT, Wulf HC. Psychological symptoms and quality of life
of dermatology outpatients and hospitalized dermatology patients. Acta Derm Venereol 2004;84:205-12.
38. Roenigk RK, Roenigk HH, Jr. Sex differences in the psychological effects of psoriasis. Cutis 1978;21:529-33.
94
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95
Chapter 4
Scoring systems in nail psoriasis
Chapter 4.1
Scoring nail psoriasis
K.M.G. Klaassen
M.T. Bastiaens
L.G.J.M. Plusjé
R.L. Baran
M.C. Pasch
Journal of the American Academy of Dermatology 2014 Epub ahead of print
CHAPTER 4
SCORING SYSTEMS IN NAIL PSORIASIS
Abstract
Introduction
Background: Scoring systems are indispensable in evaluating the severity of disease
and monitoring treatment response.
Nail involvement is seen in 10% to 80% of psoriatic patients and manifests as features
resulting from nail matrix or nail plate alterations.1,2,3,4 The variability of clinical
manifestations makes treatment challenging, and the efficacy of therapies in nail disease
seems limited because of the impermeability of the nail plate and inaccessibility of
the nail matrix.1 However, research into the field of nail psoriasis is important, as
the impact of onychopathy on quality of life is high.3,5 Fortunately, attention to nail
psoriasis is increasing, and more and more studies are attempting to evaluate
therapeutic options for nail psoriasis.
The use of validated severity scores is important, particularly in this era of
evidence-based medicine. Scoring systems are not only required to evaluate the
severity of disease and to monitor treatment response, but also to compare results
from different studies. The Psoriasis Area and Severity Index (PASI) is widely accepted
as the criterion for assessment of psoriasis severity.6 However, it does not specifically
consider the severity of nail involvement and is therefore of no use in evaluating
treatments for nail psoriasis. Several scoring systems have been proposed to assess
nail psoriasis severity. Despite the importance, there is lack of consensus on the most
appropriate of these measures.7,8 The Nail Psoriasis Severity Index (NAPSI) is the most
frequently used scoring system; however, a number of other scoring systems for nail
psoriasis can be identified in the literature.9-15 Each of these tools scores the absence or
presence of nail psoriasis manifestations, but they differ in the selection and type of
scoring of features included, and all have their advantages and disadvantages. The aim of
this study was to compare the different nail psoriasis scoring systems in patients with
fingernail psoriasis, and to evaluate the competence of these different assessment
tools in relation to the severity of nail psoriasis in terms of Physician Global Assessment
(PGA). Furthermore, the authors attempted to formulate a better scoring system,
taking into account the advantages and disadvantages of all evaluated tools.
Objective: We sought to evaluate the competence of various nail psoriasis severity
scoring systems and to develop a new scoring system.
Method: The authors conducted a prospective, observational, single-point study of
36 patients given the diagnosis of fingernail psoriasis. Seven scoring systems were
evaluated: Nail Psoriasis Severity Index (NAPSI), modified NAPSI, target NAPSI,
Psoriasis Nail Severity Score , Nail Area Severity, Baran and Cannavò et al. All tools
were correlated with the Physician Global Assessment. Obtained information was
integrated into the Nijmegen–Nail psoriasis Activity Index tooL (N-NAIL), and
interrater and intrarater reliability will be assessed.
Results: Physician Global Assessment showed an acceptable correlation with the
scoring system designed by Baran (r=0.735, p=< 0.01) and the Psoriasis Nail Severity
Score (r=0.734, p=<0.01). Target NAPSI showed low correlation (r=0.203, p=>0.05).
The correlation between Physician Global Assessment and the N-NAIL was 0.861
(p=<0.01). Excellent agreement was found for the intrarater and interrater reliability
of the N-NAIL.
Limitations: Sample size was limited.
Conclusion: An adequate nail psoriasis scoring system is needed, as studies of
treatments for nail psoriasis are on the horizon. Clinical severity of nail psoriasis was
best reflected by the N-NAIL, followed by the Baran system and the Psoriasis Nail
Severity Score.
Patients
In all, 36 patients with fingernail psoriasis (nail PGA ≥1) were included in this
prospective, observational, single-point study performed at the outpatient clinic at
the Department of Dermatology, Radboud university medical center, Nijmegen, The
Netherlands. All patients in the study, conducted between March 2011 and December
2012, were older than 18 years. Patients who used artificial nails during the preceding
six months or exhibited a (skin) disease associated with nail manifestations (e.g.,
lichen planus, alopecia areata, eczema) were excluded. To exclude patients who
101
4
CHAPTER 4
Modified
NAPSI
Target
NAPSI
Baran
Cannavò
et al
PNSS
NAS
Table 1 Outline of the various systems that score nail psoriasis severity.
NAPSI
had (concomitant) onychomycosis, clippings and subungual scrapings of affected
fingernails were collected for direct microscopic examination (10% potassium hydroxide
preparations) and fungal culture. All patients were stabile on systemic and/or topical
antipsoriatic therapy for at least three months.
Pitting
+*
+†
+‡
+†
+‡
+*
+§
Leukonychia
+*
+*
+‡
-
-
-
-
Red spots lunula
+*
+*
+‡
-
-
-
-
Crumbling
+*
+§
+‡
-
+‡
+*
-
Onycholysis
+*
+§
+‡
+§
+‡
+*
+§
+*
+*
+‡
-
-
-
-
Oil drop
+*
+§
+‡
-
+‡
-
+§
+*
+*
+‡
+≠
+‡
+*
+≠
Beau’s lines
-
-
-
+¶
-
-
-
Survey details
A medical history was taken by interview. Subsequently, a trained investigator
(KMGK), assessed seven nail psoriasis scoring systems: NAPSI11, modified NAPSI10,
target NAPSI14, the Nail Area Severity (NAS)15, the Psoriasis Nail Severity Score (PNSS)13,
a system developed by Baran,12 and a tool developed by Cannavò et al.9 Scores were
assigned to patients’ fingernails. Explanatory notes and an outline of the differences
among the seven assessment tools are displayed in Table 1. Patients had digital
photographs taken of each of their fingernails. The photographs were then rated by
four independent clinicians trained in nail psoriasis scoring, who assigned an overall
fingernail PGA to each patient. The PGA chosen for this study was a five-point ordinal
static scale (ranging from clear to very severe) used to assess the global severity of
disease. Interrater agreement was assessed for the PGA. In addition, the severity of
psoriasis was assessed by the PASI (PASI, range 0-72).16
Based on the results, a new nail psoriasis scoring system-the Nijmegen-Nail
psoriasis Assessment Index tooL (N-NAIL)-was developed. To assess the interrater
intrarater reliability of the new system, two dermatologists not involved in the design
of the study received brief instruction. Subsequently, a computer displayed a series
of photographs of the fingernails of 25 patients randomly selected from the group of
36. To asses intrarater reliability, these photographs were randomly repeated with an
interval of at least one week.
Questionnaires
4
Feature is scored (+) or not scored (-) in the tool.
NAPSI, Nail Psoriasis Scoring Index; NAS, Nail Area and Severity; PNSS, Psoriasis Nail Severity Score.
*Feature is scored for absence or present as 0 or 1 point, respectively.
‡Feature is scored qualitatively for severity (1= mild, 2=moderate, 3=severe).
§Feature is scored quantitatively for percent area of involvement .
†Feature is scored quantitatively (numeric) for number of pits (1=1-10, 2=11-49, 3=>50 in modified
NAPSI and 1=<10, 2=10-20, 3=>20 in Baran)
≠Feature is scored quantitatively in thickness (mm).
¶Feature is scored quantitatively for number of Beau’s lines (1=1, 2= 2-3, 3= > 3)
Two quality-of-life scores, the Dermatology Life Quality Index (DLQI), and the Nail
Psoriasis Quality of life 10 (NPQ10), were included in the study.17, 18
Data were entered in a Statistical Package for Social Sciences (SPSS 20.0, IBM Corp.,
Armonk, NY) database and subsequently statistical analyses were performed.
Descriptive statistics were provided using mean (±SD) and median (range) for normally
distributed and nonparametric distributed numeric values, respectively. The
correlations between the measures were evaluated by the Spearman correlation
coefficients or Pearson correlation coefficients for parametric and nonparametric
distributed variables, respectively. Concordance of the PGA scores by the four
clinicians was determined by intraclass correlation coefficient (ICC). The interrater
and intrarater reliability of the N-NAIL was determined using the ICC (two-way mixed
102
model, average agreement). Agreement can be qualified as excellent, substantial, or
moderate for ICC values in the 0.81 to 1.00, 0.61 to 0.80, and 0.40 to 0.60 ranges,
respectively.
Results
Patients
A total of 36 psoriatic patients with fingernail psoriasis were enrolled. Descriptive
patient characteristics are summarized in Table 2. The mean age of the included patients
was 51.5 (±SD 15.0) years. Eleven women (30.6%) and 25 men (69.4%) were included.
103
CHAPTER 4
Table 2 Patients characteristics (n=36).
Table 3 M
ean scores of the various nail psoriasis scoring systems and their
correlation with the Physician Global Assessment (PGA).
Feature
Gender, n (%)
Female
Male
11 (30.6)
25 (69.4)
Score
Mean (overall)
SD
Correlation
with PGA
PGA
2.03
0.97
1
Age (years), mean (±SD)
51.5 (15.0)
Baran
20.08
15.54
0.735*
Age start psoriasis (years), mean (±SD)
29.2 (15.3)
PNSS
12.64
7.39
0.734*
Age start nail psoriasis (years), mean (±SD)
36.5 (16.6)
NAPSI
27.25
15.43
0.669*
Duration of psoriasis (years), mean (±SD) 22.6 (14.5)
Modified NAPSI
23.58
15.05
0.665*
Mean delay (years), mean (±SD)
7.22 (11.4)
Cannavò et al.
20.06
14.42
0.653*
NAS
27.64
22.41
0.472*
Target NAPSI
10.22
4.60
0.203
NPQ10
3.07
3.63
0.202
DLQI
7.17
6.46
0.160
PASI
4.67
3.10
0.149
Family history, n (%)
Positive
Negative
Unknown
18 (50.0)
15 (41.7)
3 (8.3)
Nail psoriasis localization, n (%)
Fingernails
Fingernails and toenails
Unknown
10 (27.7)
23 (63.9)
3 (8.4)
Nail feature, n (%)
Pitting
Leukonychia
Red spots lunula
Crumbling
Onycholysis
Beau’s lines
29 (80.6)
15 (41.7)
6 (16.7)
18 (50.0)
35 (97.2)
33 (91.7)
22 (61.1)
18 (50.0)
11 (30.6)
Correlation
The ICC for interrater consistency of the PGA was 0.920, indicating excellent agreement
between raters. Therefore, the principal investigator’s PGA scores could be used to
correlate with the nail psoriasis scoring systems. The mean scores of the scorings
systems and the correlation coefficients with the PGA are shown in Table 3. The PGA
showed an acceptable correlation with the Baran12 assessment tool (r=0.735, p=<0.01)
and the PNSS (r=0.734, p=<0.01). Of the nail psoriasis scoring systems, only the target
NAPSI showed low correlation with the PGA (r=0.203, p=>0.05). The remaining tools
showed moderate correlation with the PGA. Of the quality-of-life scores, only the
target-NAPSI and the NAS showed a significant correlation with the NPQ10 (r=0.490,
p=<0.01 and r=0.387 p=0.05, respectively).
104
4
* Correlation is significant at the 0.01 level.
DLQI, Dermatology Life Quality Index; NAPSI, Nail Psoriasis Severity Index; NAS, Nail Area Severity;
NPQ10, Nail Psoriasis Quality of life 10; PASI, Psoriasis Area and Severity Index; PGA; Physician Global
Assessment; PNSS, Psoriasis Nail Severity Score.
The N-NAIL
Based on detailed analysis of the correlation of the current nail psoriasis scoring
systems with the PGA, the N-NAIL was developed (Appendix) and used for the same
36 patients as the other scoring systems. The correlation between the PGA and the
N-NAIL was 0.861 (r=0.861, p=<0.01) indicating a higher correlation than any of the
current scoring systems. The N-NAIL was stable for multiple ratings of the same
patient by a single observer (ICC rater 1: 0.989, 95% confidence interval 0.975-0.995;
rater 2: 0.967, 95% confidence interval 0.919-0.986), and the interrater reproducibility
was excellent with an ICC of 0.899.
Discussion
Scoring systems are indispensable for the evaluation and comparison of medical
treatments. Over the past few years, promising treatment options for nail psoriasis
have become available. This has increased the need for an optimal scoring system for
this disease. Several tools have been suggested and used in many publications. For
this study, seven nail psoriasis scoring systems were evaluated, compared, and
105
CHAPTER 4
correlated with the clinical severity in terms of PGA to find out in which the clinical
severity is optimal mirrored. The authors were able to show that the nail psoriasis
score developed by Baran12 and the PNSS showed an acceptable correlation with the
PGA. However, integrating the obtained information from these evaluations resulted
in the development of the N-NAIL, which clearly reflected clinical severity better than
existing scoring systems, accompanied by excellent agreement on reliability.
Because no gold standard for nail psoriasis severity scoring exists, it was decided
to use clinical severity, expressed as PGA, as the reference in this study. The
established interobserver consistency between PGA scores of the four independent
clinicians turned out to be very high (0.920), proving the value of the PGA as a mean
to express disease severity in these patients. A limitation of the study was the use of
photographs in the assessment of the agreement of PGA and N-Nail between
observers. The predominant limitation experienced was the assessment of subungual
hyperkeratosis based on photographs. However, when analyzing the interobserver
agreement for the PGA, the ICC was 0.920 and for the N-NAIL it was 0.899, indicating
excellent agreement between clinical observations and observations based on
photographs. A study of Farhi et al.19 also showed that the PGA for psoriasis severity,
based on photographs, is an accurate and consistent method.19
A major drawback of all current nail psoriasis scoring systems is the lack of
validation. Spuls et al. already demonstrated that none of the severity scores for
plaque psoriasis are adequately validated.20 The NAPSI and the modified NAPSI are
the only systems that have been validated to some extent.10, 14, 21, 22 Cassell et al.
showed good interrater reliability (0.98 Cronbachs’ alpha) and construct reliability of
the modified NAPSI. However, they found significant interobserver variability when
using the NAPSI score. Aktan et al. assessed the interobserver reliability of the NAPSI
and found moderate to good interobserver consistency.21 However, it was suggested
by Parrish et al. that the NAPSI score, regularly used in clinical trials, lacks sensitivity
to reflect meaningful clinical improvement.14 They illustrated that significant clinical
improvement of severity of nail psoriasis is sometimes not reflected in the NAPSI
score.14 This is in line with our results, as both scores showed only moderate
correlation with clinical severity in terms of PGA. When looking at the N-NAIL scoring
system, intraobserver and interobserver reliability showed excellent agreement.
Based on these surveys, it was decided to exclude red spots in the lunula from the
scoring system, as they have little influence on the clinical picture. Leukonychia was
also omitted from the N-NAIL, because it is as least as frequently seen in the healthy
population.23 Therefore, leukonychia seems to be nonspecific for nail psoriasis. In addition,
the two scoring systems best correlating with the PGA both included only four nail
psoriasis features, of which three are scored by both (onycholysis, pitting, and
subungual hyperkeratosis). The authors chose to include these three nail features in
the N-NAIL because they are frequently seen in nail psoriasis and, more importantly,
largely determine the clinical picture of disease.3,26-29 In addition, both oil-drop
discolorations and onycholysis are the results of the same pathogenic process,
namely, parakeratotic changes in the nail bed. Desquamation of these parakeratotic
cells at the hyponychium leads to onycholysis.30,31 As onycholysis is related to oil-drop
discoloration, the authors chose to integrate those two features into one single
feature. In the N-NAIL, they are scored by percentage of involved area to give an
impression of the severity. Finally, it was decided to include Beau’s lines in this new
assessment tool. The scoring developed by Baran was the only system to include
Beau’s lines.12 Even though Beau’s lines are far from specific for nail psoriasis, a recent
study has shown that the prevalence in nail psoriasis is much higher than in the
general population,23 and they define a large extent of the clinical picture.
As a result of the evaluation of the existing scoring systems, the authors chose to
score all ten fingernails in the N-NAIL as a consequence of the low correlation between
the PGA and the target-NAPSI. Scoring one single nail does not seem to illustrates the
clinical severity of nail psoriasis; the evaluation of more nails seems relevant. Recently
a new nail psoriasis scoring systems, the Nail Assessment in Psoriasis and Psoriatic
Arthritis, was published, and demonstrated that at least four fingernails need to be
scored by the NAPSI for a representative reflection of nail psoriasis severity when
compared with the total NAPSI scores.32 Nail Assessment in Psoriasis and Psoriatic
Arthritis focuses on quality of life and patient need. This can be complementary, as
previous studies have shown that nail psoriasis can have a substantial impact on
patients’ quality of life.3, 33 However, as presented in our results, clinical severity is
better represented by using a more qualitative scoring system like the N-NAIL. In
addition, as already shown by Parrish et al.,14 the NAPSI might lack sensitivity to reflect
responsiveness because it scores only presence or absence of manifestations.
23-25
The N-NAIL
Following the extensive analyses of the existing nail psoriasis scoring systems, the
authors found that the newly constructed N-NAIL better reflects clinical severity than
all other tested nail psoriasis scoring systems. In the N-NAIL, red spots in the lunula
and leukonychia were not included. Red spots in the lunula are documented in several
other disorders (e.g., lichen planus, alopecia areata), and are an infrequently seen
feature with a prevalence between 0.4% and 10.1% in patients with nail psoriasis.2, 21,
106
Conclusion
To our knowledge, this study is the first to compare seven different nail psoriasis
severity scores in correlation with clinical severity. An adequate nail psoriasis scoring
system is needed, as studies on treatments for nail psoriasis are upcoming. Clinical
severity of nail psoriasis was best reflected by the N-NAIL, followed by the Baran12
system and the PNSS. The N-NAIL showed excellent agreement among raters.
107
4
CHAPTER 4
References
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de Vries AC, Bogaards NA, Hooft L, Velema M, Pasch M, Lebwohl M, et al. Interventions for nail psoriasis.
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Augustin M, Ogilvie A. Methods of outcomes measurement in nail psoriasis. Dermatology 2010;221:23-8.
Cannavo SP, Guarneri F, Vaccaro M, Borgia F, Guarneri B. Treatment of psoriatic nails with topical
cyclosporin: a prospective, randomized placebo-controlled study. Dermatology 2003;206:153-6.
Cassell SE, Bieber JD, Rich P, Tutuncu ZN, Lee SJ, Kalunian KC, et al. The modified Nail Psoriasis Severity
Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.
J Rheumatol 2007;34:123-9.
Dermatol 2003;49:206-12.
Baran RL. A nail psoriasis severity index. Br J Dermatol 2004;150:568-9.
Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G, McHugh NJ. Psoriatic arthritis: outcome of disease
subsets and relationship of joint disease to nail and skin disease. Br J Rheumatol 1994;33:834-9.
Parrish CA, Sobera JO, Elewski BE. Modification of the Nail Psoriasis Severity Index. J Am Acad Dermatol
2005;53:745-6.
de Jong EM, Menke HE, van Praag MC, van De Kerkhof PC. Dystrophic psoriatic fingernails treated with 1%
5-fluorouracil in a nail penetration-enhancing vehicle: a double-blind study. Dermatology 1999;199:313-8.
Schmitt J, Wozel G. The psoriasis area and severity index is the adequate criterion to define severity in
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a comprehensive review of validation data and clinical results. Br J Dermatol 2008;159:997-1035.
Farhi D, Falissard B, Dupuy A. Global assessment of psoriasis severity and change from photographs:
a valid and consistent method. J Invest Dermatol 2008;128:2198-203.
Spuls PI, Lecluse LL, Poulsen ML, Bos JD, Stern RS, Nijsten T. How good are clinical severity and outcome
measures for psoriasis?: quantitative evaluation in a systematic review. J Invest Dermatol 2010;130:933-43.
Aktan S, Ilknur T, Akin C, Ozkan S. Interobserver reliability of the Nail Psoriasis Severity Index. Clin Exp
Dermatol 2007;32:141-4.
Chandran V, Gottlieb A, Cook RJ, Duffin KC, Garg A, Helliwell P, et al. International multicenter psoriasis
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van der Velden HM KK, van de Kerkhof PC, Pasch MC. Fingernail psoriasis reconsidered: A case-control
study. J Am Acad Dermatol 2013;69:245-52
25. Rich P, Griffiths CE, Reich K, Nestle FO, Scher RK, Li S, et al. Baseline nail disease in patients with moderate
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2008;58:224-31.
26. Palmou N, Marzo-Ortega H, Ash Z, Goodfield M, Coates LC, Helliwell PS, et al. Linear pitting and splinter
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to psoriatic arthritis. Dermatology 2011;223:370-3.
27. Brazzelli V, Carugno A, Alborghetti A, Grasso V, Cananzi R, Fornara L, et al. Prevalence, severity and
28. Kaur I, Saraswat A, Kumar B. Nail changes in psoriasis: a study of 167 patients. Int J Dermatol 2001;40:
601-3.
29. Calvert HT, Smith MA, Wells RS. Psoriasis and the nails. Br J Dermatol 1963;75:415-8.
30. Radtke MA, Beikert FC, Augustin M. Nail psoriasis - a treatment challenge. J Dtsch Dermatol Ges
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32. Augustin M, Blome C, Costanzo A, Dauden E, Ferrandiz C, Girolomoni G, et al. Nail Assessment in
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Psoriasis Outcomes. Br J Dermatol 2014;170:591-8.
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109
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CHAPTER 4
Appendix The Nijmegen-Nail psoriasis Activity Index tooL.
110
Feature
Manner of scoring
Onycholysis/oil-drop discoloration
0= absent
1= 0-25%
2= 25-50%
3=> 50%
Pitting
0 = absent
1= mild
2= moderate
3= severe
Crumbling
0= absent
1= mild
2= moderate
3= severe
Beau’s lines
0= absent
1= 1 Beau Line
2= 2 Beau Lines
3= ≥ 3 Beau Lines
0= absent
1= 1 mm
2= 2mm
3= ≥ 3mm
4
111
Chapter 5
Nail psoriasis and onychomycosis
Chapter 5.1
The prevalence of onychomycosis
in patients with psoriasis;
a systematic review
K.M.G. Klaassen
M.G. Dulak
M.C. Pasch
Journal of the European Academy of Dermatology and Venereology 2013;28:533-541
CHAPTER 5
NAIL PSORIASIS AND ONYCHOMYCOSIS
Abstract
Introduction
We systematically reviewed all available literature concerning the prevalence of
onychomycosis in patients with nail psoriasis and the distribution of pathogens
causing onychomycosis in this specific group of patients. Databases searched were
Pubmed, EMBASE and the Cochrane Controlled Clinical Trial Register. All studies
reporting on the prevalence of onychomycosis in nail psoriasis were obtained, and
quality assessment was determined by the STrengthening the Reporting of
OBservational studies in Epidemiology checklist. Literature search revealed 720
studies, of which 10 studies met the inclusion criteria. The major limitation of the
review was the heterogeneity of the included studies, which prevented the possibility
to conduct a meta-analysis. However, the average prevalence of 18.0% of onychomycosis in psoriatic patients seems to be increased when compared with control
groups and literature on healthy population, even though the ultimate evidence
remains lacking. An in the literature hypothesized shift in causative agents from
dermatophytes to yeasts and/or moulds could not be confirmed. The clinical
consequence of the relatively high prevalence of onychomycosis in psoriasis may be
a general advise to rule out onychomycosis or concomitant onychomycosis in these
patients with (suspected) nail psoriasis. This advise is stressed by the relative
simplicity of treating the contribution of onychomycosis in the nail dystrophy but also
the fact that nail psoriasis mostly is treated by immunosuppressive drugs, like
steroids, methotrexate or biologics which may aggravate mycotic nail infections.
Although the most characteristic findings of psoriasis are skin manifestations, another
commonly recognized feature is nail involvement. The documented prevalence of
nail involvement in psoriasis patients varies between 15% and 79%, with an estimated
lifetime incidence of 80-90%.1-7
Clinical manifestations associated with nail psoriasis are heterogeneous in their
representation and many psoriatic nail features may morphologically resemble
onychomycosis. Onychomycosis is the most common nail disease and constitutes
about half of all nail abnormalities.8 Clinical discrimination between nail psoriasis and
onychomycosis often is difficult. Diagnostic techniques including direct microscopy,
fungal culture and polymerase chain reactions may identify onychomycosis and help
to distinguish it from nail psoriasis. However, coexistence of onychomycosis and nail
psoriasis also occurs, as both are frequent disorders in the general population.9 It is
hypothesized that morphological abnormalities in psoriatic nails are predisposing
factors for onychomycosis and vice versa. In healthy nails, the compact orthokeratotic
nail plate acts as a natural barrier preventing the development of fungal infections,
which may be disturbed in abnormal nail plates in diseases such as nail psoriasis.
Therefore, it is hypothesized that the prevalence of onychomycosis in patients with
nail psoriasis might be higher than in the general population.9, 10 However, the immune
response against microbial skin infections appears to be remarkably strong in
psoriasis, and the fast turnover of the nails in psoriasis patients may constitute an
effective defense against dermatophytes.11 Therefore, a decreased prevalence of onychomycosis might be possible as well. The documented prevalence of onychomycosis
in patients with nail psoriasis varies considerably in the literature and conclusions
concerning the prevalence and vulnerability of psoriatic nails for onychomycosis are
ambiguous. Consequently, our primary goal was to systematically review all available
literature concerning the prevalence of onychomycosis.
The secondary aim was to review the literature concerning the pathogens of
onychomycosis in psoriatic patients. Onychomycosis can be a fungal infection with a
mould or a yeast. Dermatophytes are the most frequently causative pathogens found
in onychomycosis and are responsible for up to 90% of toenail infections and at least
50% of fingernail infections.12 Several publications suggest that onychomycosis in
psoriatic patients is more commonly caused by a yeast than in non-psoriatic patients.11,
13, 14
Other publications cannot confirm these data.15, 16 Knowing if there do exist
differences in the spectrum of pathogens responsible for onychomycosis in normal
patients and in psoriatic patients is not only important for the individual patient, who
may need other drugs to treat the onychomycosis but also might help to understand
the assumed immunological differences between psoriatic and non-psoriatic individuals.
117
5
CHAPTER 5
Methods
We performed a systematic review of all studies investigating the prevalence of
onychomycosis in psoriatic patients. Search strategies were developed in consultation
with a research librarian with systematic review expertise. Three bibliographic
databases were searched for articles published from January 1980 to April 2012.
Involved databases were PubMed, EMBASE and the Cochrane Controlled Trial Register.
Medical Subject Heading and free text searches embracing the following terms were
used: ‘psoriasis’, ‘nail’ and ‘onychomycosis’, including all possible synonyms and nail
features (see also Figure 1). The literature search was limited to articles written in
English, French, German and Polish language.
#1 Nails (MesH)
#2 Nail*
#3 Toenail*
#4 Fingernail*
#5 Leuconychia
#6 Leukonychia
#7 Pitting
#8 Subungual hyperkeratosis
#9 Onycholysis
#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9
#11 Psoriasis (MesH)
#12 Psoria*
#13 #11 or #12
#14 Onychomycosis (MesH)
#15 Fungal
#16 Yeast
#17 Dermatophyte
#18 #14 or #15 or #16 or #17
#19 #10 AND #13 AND #18
Figure 1. Search strategy.
After the initial search was performed, titles and abstracts identified from the
searches were reviewed for relevance by two independent reviewers (KMGK and
MCP), taking into account the inclusion and exclusion criteria. Inclusion criteria were
full text papers which included prevalence studies of onychomycosis in psoriatic
patients and confirmed diagnosis of onychomycosis by direct microscopy and culture
118
or by a histomycological diagnostic test with periodic acid Schiff staining. Excluded
were review articles and articles published only in abstract form. Also articles without
a control group were excluded. When results from the same study were published
more than once, data from interim publications were excluded. Articles without data
on the prevalence of onychomycosis in nail psoriasis were excluded during the first
selection step. Differences in selection between the reviewers were discussed with a
third investigator when necessary.
Once the relevant studies were identified, full publications were retrieved
and reviewed for final inclusion. The two reviewers (KMGK and MCP) determined
independently which studies indeed fulfilled the inclusion criteria. The bibliographies
of the included articles were retraced for additional articles. Reviewers were not
blind to the names of authors, institutions or journals.
The same reviewers independently extracted data using a predefined data
extraction form, which included: study design, author, source of data, number and
origin of the psoriatic patients, number and origin of the controls, method for
selecting cases, population characteristics, localization of nail clipping, prevalence
number and specification of species. Methodological quality of the reviewed studies
was assessed independently by use of the STrengthening the Reporting of OBservational
studies in Epidemiology (STROBE) criteria, which involved an assessment of both
internal and external validity.17 Disagreements were resolved by consensus, and when
consensus could not be reached, by a third investigator. Three categories for quality
assessment were established arbitrary. When the study fulfilled more than 80% of
the criteria stated in STROBE it was categorized as A, B when 50-80 % of the criteria
were met and C when less than 50% of the criteria could be achieved.
Results
Study selection
A total of 723 eligible articles were identified using the described search terms in
Pubmed, EMBASE and Cochrane search databases, from which 152 duplicate records
were removed. From the remaining, 542 articles were excluded because abstracts
showed that the studies were not eligible for inclusion because they did not directly
deal with the subject. Finally, 29 articles seemed to be relevant for detailed evaluation.
After full text screening, 10 articles were considered appropriate for inclusion (see
Figure 2).11, 13, 15, 16, 18-23 The clinical and study characteristics of the included articles are
summarized in Table 1. Of the ten studies included, six were published between 2000
and 2012, two studies were published in the 1990s 15, 24 and two studies were published
in the 1980s.16, 22 The total number of patients assessed in these studies was 2176, with
a range of 70-561 patients per study. The studies were predominantly conducted in
119
5
120
Articles included after
screening references
N= 1
N = 10
Excluded after full text
examination ( N = 20)
Unavailable: 2
Review article: 1
Duplicate study group: 1
Subject: 2
Language restrictions: 4
No control group: 10
Figure 2. Flow chart.
Prevalence
The prevalence figures for onychomycosis in psoriatic patients for each of the studies
are summarized in Table 2. As shown in this Table, the sources of data were heterogeneous (e.g., recruitment of patients, localization of clipping) as well as patient
inclusion and exclusion criteria. This heterogeneity made reliable comparison between
studies impossible. However, the combined prevalence of 18.0% of onychomycosis
in the studies (392 out of 2176 psoriasis patients) compared to 9.1% in the control
group (159 out of 1748, studies with onychomycosis control group excluded) may give
some indication.
1983
2001
1986
Denmark
Germany
Hungary
Leibovici et al.19
Kacar et al.20
Pawlaczyck et al.21
Staberg et al.22
13
Stander et al.
16
Szepes et al.
Zawirska et al.23
B
C
C
C
C
C
C
2006
2007
2006
1998
922
245
142
102
164
3986
41
102
341
30
561
239
79
113
168
481
78
250
137
70
Inpatients
Outpatients
Outpatients
Outpatients
Outpatients
Outpatients
In and Out
patients
Inpatients
Outpatients
Outpatients
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Psoriasis
Selected
patients
* Sample taken from clinical affected nails
† Sample taken from both clinical affected and unaffected nails,
‡ Samples in the control group were taken when nails were clinically abnormal, in the patient group samples were taken of all patients
(clinically) abnormal and normal).
STROBE, Strengthening the Reporting of OBservational studies in Epidemiology,
A: more than 80%, B: 50-80%, C:<50%
Poland
Poland
Turkey
Israel
2003
Denmark
Larsen et al.11
B
2004
Sweden
Hamnerius et al.18
B
1997
Source
N = 723
Canada/
America
Gupta et al.15
N = 29
A
Excluded after screening
titles and abstracts
N = 542
Controls, n
N = 571
Patients, n
Duplicate articles excluded
N = 152
Publication
date
Toenails†
Both†
Both†
Both†
Both*
Both*
Toenail*
Both*
Toenail†
Toenail ‡
Location nail
clipping
Cochrane
N=6
Country
EMBASE
N = 473
Study
various European countries (n= 7), two studies were conducted in Asia, and one
combined Canadian/American study was included.
STROBE
classification
PubMed
N = 244
Table 1 Characteristics of Individual studies included in this review.
CHAPTER 5
5
121
CHAPTER 5
Table 2 P revalence numbers of the included studies.
Study
Percentage
Percentage
onychomycosis onychomycosis,
clinically affected
patients, %
(patients),%
Direct
Percentage
Percentage
onychomycosis onychomycosis, microscopy
clinically affected
control, %
(controls),%
Culture
12.7
6.9
+
Medium
Conclusion
Toenails
Gupta et al. 15
27.0
43.8
+
KOH
1.
2.
3.
Hamnerius et al.18 4.6
U
2.4
U
+
KOH 10%
Parkers ink
+
Leibovici et al.19
47.8
U
28.4
U
+
KOH
+
Zawirska et al.23
11.4
U
3.3
U
+
KOH 20%
DMSO 40%
+
1.
2.
Sabouraud glucose agar + cycloheximide
+chloramphenicol + CCG
Casamino acids erythriol albumin agar + CCG
Littman oxgall agar + streptomycin
Significant higher prevalence in
psoriasis patients
Sabouraud agar + CCG
Dermatophyte medium + cycloheximide +
gentamycine
No significant difference.
No altered susceptibility.
Sabouraud glucose agar
1. + Cycloheximide
2. – Cycloheximide
1.
2.
Sabourauds dextrose agar
Sabourauds dextrose agar + cycloheximide +
chloramphenicol
Significant higher prevalence in
psoriasis patients
(p=0.0054)
Higher prevalence (significance
unknown)
5
Toenails and fingernails
Larsen et al.11
21.5
26.2
12.7
34.0
+
Calcofluor
white
+
Kacar et al. 20
13.1
28.6
7.9
40.6
+
KOH
20%
+
1.
2.
3.
Sabourauds dextrose agar on potato agar
Lactophenol cotton blue
Fermentation test Wickerham
No significant difference
Pawlaczyck et al.21 6.0
18.8
-
39.5
+
KOH
20%
+
1.
2.
Sabourauds agar
Sabourauds agar + chloramphenicol +
cycloheximide
Staberg et al.22
26.9
30.8
19.5
U
+
KOH
30%
+
1.
+ Chloramphenicol + cycloheximide
Higher prevalence but nonsignificant
Stander et al.13
30.4
U
19.6
U
+
+
Malzagar + antibiotics
Szepes et al.
63.1
U
-
66.0
+
1.+penicillin
2.
+streptomycine
16
Sabouraud glucose agar
1. +Chloramphenicol + cycloheximide
2.+Chloramphenicol
No significant difference (p 0.13)
CCG, gentamicin; KOH, potassium hydroxide; U, unknown,
122
123
CHAPTER 5
Table 3 Differentiation of pathogens found in psoriatic patients with onychomycosis.
Study
Patients
Controls
Conclusion
Dermatophyte,
n (%)
Yeast,
n (%)
Mould,
n (%)
Dermatophyte,
n (%)
Yeast,
n (%)
Mould,
n (%)
Gupta et al.15
45 (84.9)
3 (5.7)
5 (9.4)
41 (87.2)
3 (6.4)
3 (6.4)
No significant difference (p=0.58).
Dermatophytes most prevalent in both groups
Hamnerius et al.18
No differentiation
No differentiation
No differentiation
No differentiation
No differentiation
No differentiation
No specification of pathogens
Leibovici et al.19
42 (77.8)
6 (11.1)
6 (11.1)
27 (93.1)
2 (6.9)
0 (0)
Same profile but moulds were more prevalent in psoriatic
patients
Zawirska et al.23
No differentiation
No differentiation
No differentiation
No differentiation
No differentiation
No differentiation
No specification of pathogens
Toenails only
Toenails and fingernails
Kacar et al. 20
8 (61.5)
3 (23.1)
2 (15.4)
1 (25.0)
0 (0)
3 (75.0)
Nail psoriasis risk factor for dermatophyte onychomycosis
(p=0.02)
Larsen et al.11
8 (36.4)
10 (45.5)
4 (18.2)
12 (50.0)
7 (29.2)
5 (20.8)
More prevalent yeast in psoriasis patients
Pawlaczyck et al.21
19 (65.5)
8 (27.6)
2 (6.9)
1013 (64.2)
347 (22.0)
148 (9.4)
Dermatophytes frequently seen in nail psoriasis
Staberg et al.22
10 (47.6)
10 (47.6)
1 (4.8)
4 (50.0)
4 (50.0)
0 (0.0)
Higher prevalence yeast in psoriasis patients with nail
involvement
Stander et al.13
22 (28.9)
48 (62.2)
6 (7.9)
11 (55.0)
7 (35.0)
2 (10.0)
Higher probability of yeast in psoriatic nails
Szepes et al.
9 (12.9)
26 (37.1)
35 (50.0)
45 (20.0)
65 (28.9)
115 (51.1)
Rate of dermatophytes is lower while the frequency of yeast
was higher
16
When considering all studies individually, the prevalence of onychomycosis in
psoriatic patients varied from 4.6% to 63.1% compared to 2.4% to 66.0% in controls.
Three studies concluded that the prevalence of onychomycosis was significantly
higher in patients with psoriasis compared with healthy controls. The remaining seven
studies reported no significant differences between the prevalence of onychomycosis
in psoriatic patients compared to controls, although all except one found higher
prevalence numbers in psoriatic patients.
Pathogens
Various studies distinguished between the different pathogens and documented the
percentages of dermatophytes, non-dermatophyte moulds, and yeast. Table 3 gives an
overview of these results. Five studies concluded that yeast and/or non-dermatophyte
124
5
moulds were more frequently found in psoriatic nails compared with the pathogens
found in nails of non-psoriatic patients, although differences were significant in only
the study of Stander et al.11, 13, 16, 19, 22 Three studies concluded that the distribution of
the different species was comparable with the control population, dermatophytes
were most frequently found.15, 20 Kacar et al. even found a higher prevalence of
dermatophytes in psoriatic patients than in controls, but the absolute number of
positive cultures in this study was remarkably low.20 In the two remaining studies no
pathogen differentiation was available. Of the included studies four studies focused
only on the toenails, the other studies took nail samples from both toe- and fingernails.
However only three studies made a specification between finger- and toenails in the
analysis of the pathogen distribution (see Table 4).
125
CHAPTER 5
126
U
9.4
51.1
60.6
42.1
341
137
Controls*
Patients
*
Control group existed of patients with clinical onychomycosis.
No., number; U, unknown.
9.6
79
Patients
Szepes
et al.16
142
Larsen
et al.11
Controls
0
10.9
31.4
5.9
83
U
U
66.0
66.0
51.0
U
20.0
U
29.0
U
225
0
7.6
24.1
31.7
16.1
31.9
4.1
19.8
28.1
0
25
0
2.1
14.8
16.9
16.6
8.3
50.3
0
20.7
4.1
24
U
12.8
14.1
26.9
4.6
47.7
78
Patients
0
47.7
0
0
21
U
7.3
12.2
19.5
0
37.4
41
Controls
Staberg
et al.22
0
50.3
12.3
0
8
%
Toenails
%
Toe
Finger
Toe
Finger
No.
Total
Mould (%)
Yeast (%)
No. of Dermatophyte (%)
patients
Finger
Toe
Patients
group
Study
No. of patients with fungal infections
Table 4 Studies with differentiation between localization of onychomycosis and pathogen distribution.
%
Fingernails
%
Both
Discussion
During the past decades several studies were conducted in order to gain knowledge
on the prevalence of onychomycosis in psoriatic patients. In some studies an increased
prevalence was shown, while this could not be confirmed in others. The same lack of
uniformity was found in reports on the involved pathogens in onychomycosis in
psoriatic patients. This systematic review is an attempt to give an overview of the
available literature and acquire more certain knowledge on these clinical relevant
topics.
We systematically reviewed all available literature on the prevalence of onychomycosis in psoriatic patients. After thorough inspection of all literature, ten
studies specific focusing on the prevalence of onychomycosis in psoriatic patients
could be included. However, because of heterogeneity between studies, a metaanalysis could not be made. These major differences also indicate differences in their
methodological quality. Tools of quality assessment are well established in systematic
reviews of randomized controlled trials but the use of quality assessment tools to
appraise observational studies is less well established and no gold standard exists. In
the absence of these quality assessment tools, we used the STROBE checklist to
compare the included studies for methodological quality. We have taken into account
that the STROBE was developed for authors of reports and not for assessing the
quality of a study, 17, 25 but because no validated tool existed the STROBE was used.
The absence of accepted quality assessment tools implies that studies included in the
review were given equal weight in the analyses regardless of methodological quality.26
Therefore, the results from the STROBE are displayed in Table 1, but were not used to
strengthen or weaken the interpretation of the results from individual studies.
Overall, more than 50% of the included studies was classified in the lowest category
(c) which gives some kind of insight into the rather low quality of most studies. Only
one study fulfilled the criteria for the highest STROBE classification.15
Prevalence
As mentioned above, a meta-analysis could not be made because of the considerable
differences in the protocols of the ten studies. Factors limiting comparability include
methods of case/control identification, differences in sample size, different age
distributions of the study populations, as well as localization of nail clippings,
techniques and criteria used for detecting onychomycosis and the focus on fingernails
and/or toenails. Another confounding factor may be the known heterogeneity in
prevalence between different ethnic groups and continents. However, even studies
conducted in the same country can document impressive differences.21, 23, 27, 28 As a
consequence of these differences an overview of the results shows a wide variation
of the onychomycosis prevalence in psoriatic patients, ranging from 4.6% to 63.1%,
127
5
CHAPTER 5
while the prevalence in the control groups ranged from 2.4% to 66.0%. Combining all
ten studies, 392 of the 2176 psoriasis patients were diagnosed with onychomycosis, a
prevalence of 18.0% compared to a combined prevalence of 9.1% in the control
groups (excluding the studies with onychomycosis patients as controls). In the
literature several studies investigated the prevalence of onychomycosis in the general
population. One Canadian study investigated the prevalence of onychomycosis in
15 000 patients and found a prevalence of 6.5% in the Canadian general population.29
A prevalence of 8.4% was found in Finland (n=800) and an Indonesian study
documented a prevalence of 4.7%.30, 31 The ACHILLES project, a survey of diseases of
the foot in 11 European countries (19 588 patients) found onychomycosis to be the
most frequent fungal foot infection and estimated an extraordinary high prevalence,
based on mycological examination, of 20.9%.32 These studies suggest that the
prevalence of onychomycosis varies considerably between different parts of the
world. The pooled prevalence of 18.0% among psoriatic patients which has been
estimated in this systematic review seems to be elevated when compared to the
prevalence of the control groups and the percentages found in the general population
except when compared to the results of the ACHILLES project. However, the combined
prevalence is not fully comparable with these published prevalences in the general
population as the study populations were not matched for other predisposing factors
such as age, comorbidities (e.g., diabetes) and geographical region.
Looking in more detail to the studies, three studies showed a significant higher
prevalence of onychomycosis in psoriasis patients than among controls. Furthermore,
the prevalence of onychomycosis was higher in the psoriasis group compared with
the control group in six out of seven remaining studies, although no statistical
differences were found. So, in only one out of ten studies the prevalence of
onychomycosis in psoriasis patients was not higher than in controls. Therefore, and
because of the difference between the prevalence in the general population, it seems
reasonable to conclude that the prevalence of onychomycosis indeed seems to be
higher among patients suffering from psoriasis, even though the ultimate evidence
remains lacking. The main reason of not finding significant differences between the
prevalence of onychomycosis in psoriasis patients and healthy controls therefore
may not be the absence of differences but rather the small sizes of the groups that
were investigated and weaker methodological quality of some studies. Based on an
overview of studies it cannot be proven that the prevalence of onychomycosis in nail
psoriasis is higher although a tendency towards higher prevalence numbers can be
seen when all studies are pooled.
Various arguments concerning the vulnerability of psoriatic nails for fungal microorganisms are discussed. Some authors defend the hypothesis that morphological
abnormalities in these nails (e.g., hyperkeratosis and onycholysis) are predisposing
factors for invasion of the nail by microorganisms,9, 10, 15 as this can be seen as
128
secondary invasion in an already abnormal nail.33 The fact that psoriasis patients may
use systemic and topical immunosuppressive drugs which may facilitate the
development of fungal infections of the nail is rarely mentioned but certainly may be
of importance.34 In addition, it is mentioned that abnormal capillary units in nail
psoriasis impairs the defense normally supplied by healthy hyponychium and weakens
the defense system of the nail against invading microorganisms.19 On the other hand,
Dorschner et al.35 demonstrated that presence of antimicrobial peptides in the nail
with activity against nail pathogens may account for the ability of the nail unit to
resist infection in the absence of direct access to cellular immune system. Arguments
contradicting mentioned arguments favouring mycotic infections are the fact that
the immune response against microbial skin infections is remarkably strong in
psoriasis, giving a possible explanation why the prevalence of onychomycosis in
psoriatic patient might have been lower than in healthy controls.36 Furthermore, it
has been shown that psoriatic nails have a higher turnover and desquamation rate,
and thereby decreasing the opportunity for fungal organism to invade the nail keratin
compared to healthy nails.37
Pathogens
Dermatophytes are most frequently the causative pathogens found in onychomycosis
in the non-psoriatic population and are responsible for up to 90% of toenail infections
and at least 50% of fingernail infections. The main causative dermatophytes are
Trichophyton rubrum and Trichophyton mentagrophytes, found in 80-90%.38 Yeast
and non-dermatophyte moulds are much less frequently cultured as primarily
pathogens. Of these, Candida species are the most common and account for
approximately 1.5% to 6.0% of nail infections, more frequently in fingernails than in
toenails.8, 10, 39 However, the prevalence of nail disease caused by dermatophytes,
yeasts and non-dermatophyte moulds depends on localization and geographic
region. A relative high incidence of Candida infections is generally found in more
tropical climates. 40 For example, an incidence of 38.4% was found in a large number
of onychomycosis patients in Brazil.41 According to a Canadian study, the pathogen
distribution in toenail onychomycosis in the general population showed predominantly
dermatophytes (92.9%) followed by non-dermatophyte moulds (4.3%) and yeast
(2.8%). 42 In the above mentioned European ACHILLES project the cultured pathogens
in fungal foot infection were also predominantly dermatophytes (Trichophyton
species 75.1%), followed by Candida species (11.8%) and Aspergillus species (5.9%).32 In
the German study by Mügge et al. among almost 1000 onychomycosis patients, yeast
infections were found the causative agent in even higher percentages, namely in 20%
of pedal onychomycosis and in 56% of finger nail onychomycosis. 43
When looking at the included studies, non-dermatophyte moulds and yeast were
frequently cultured, but in majority of studies no significant differences were found.
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5
CHAPTER 5
It was hypothesized by Larsen et al. that the altered subungual tissue and onycholysis
may facilitate the invasion of yeast. Furthermore, the fast turnover of the nails in
psoriasis patients theoretically may constitute an effective defense against
dermatophytes.11 In addition it was suggested that glycoprotein material, present in
the nail, might be inhibitory to dermatophytes. 44 However, localization of
onychomycosis must be taken into account as dermatophytes are the most common
causative pathogens of onychomycosis in toenails, while yeasts are more frequently
isolated from fingernails.33 Many of included studies took nail clippings from clinical
affected nails of both finger- and toenails. Onychomycosis in healthy controls is most
likely localized on toenails while psoriasis patients more frequently also have
dystrophic fingernails.7 In the analysis of data (and comparison of healthy controls
and psoriasis patients), the pathogen distribution has to be specified for toenails and
fingernails separately. Unfortunately, only three studies made a specification
between finger- and toenails concerning the pathogens. It seems that in both patients
and controls dermatophytes and moulds are predominantly seen in toenails, and
yeast in fingernails. However, we were not able to draw conclusion based on these
three studies. All three studies show different pathogen distribution patterns when
controls were compared with psoriatic patients. Because of heterogeneity (e.g., nail
clipping localization, clinical affected and unaffected nails) and quality differences
between studies no final conclusion on the microorganisms found in onychomycosis
in psoriatic patients could be made.
Conclusion
This systematic review gives an overview of all available literature on the coexistence
of onychomycosis and nail psoriasis. Because of heterogeneity between studies, and
low methodological quality no ultimate conclusion can be drawn as no meta analysis
could be conducted. However, when giving an overview of included studies, the
prevalence of onychomycosis in psoriatic patients seems to be increased when
compared to control groups and literature on healthy population, even though the
ultimate evidence remains lacking. A hypothesized shift in causative agents from
dermatophytes to yeasts and/or moulds could not be confirmed. Future research
concerning this topic is important. The clinical consequence of the relatively high
prevalence of onychomycosis in psoriasis may be a general advise to rule out
onychomycosis in these patients with nail abnormalities before concluding the
patient is suffering from nail psoriasis. This advise is stressed by the fact that nail
psoriasis mostly is treated by immunosuppressive drugs, like steroids, methotrexate
or biologics which may aggravate mycotic nail infections.
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Kacar N, Ergin S, Ergin C, Erdogan BS, Kaleli I. The prevalence, aetiological agents and therapy of
onychomycosis in patients with psoriasis: a prospective controlled trial. Clin Exp Dermatol 2007;32:1-5.
Pawlaczyk M, Rokowska A, Chmielewska I, et al. Does onychomycosis more frequently affect patients
suffering from psoriasis? Mikologia Lekarska 2007;14:52-5.
Staberg B, Gammeltoft M, Onsberg P. Onychomycosis in patients with psoriasis. Acta Derm Venereol
1983;63:436-8.
Zawirska A, Adamski Z, Kurek L. Dermatophyte infections in psoriatic patients. Mikologia Lekarska;13:287-90.
Malka N, Contet-Audonneau N, Reichert-Penetrat S, Truchetet F, Barbaud A, Schmutz JL. Onychomycosis
and nail psoriasis. Journal de Mycologie Medicale 1998;8:192-5.
Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality and susceptibility to bias in observational
studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007;36:666-76.
Mallen C, Peat G, Croft P. Quality assessment of observational studies is not commonplace in systematic
reviews. J Clin Epidemiol 2006;59:765-9.
Salomon J, Szepietowski JC, Proniewicz A. Are psoriatic nails predisposed to fungal infection? Korean
Journal of Medical Mycology 2003;8:43-7.
Czarnecka A, Hryncewicz-Gwozdz A, Plomer-Niezgoda E, Kolodziej T. Analysis of risk of onychomycosis
in psoriatic patients. Mikologia Lekarska 2008;15:213-15.
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29. Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA, Summerbell RC. Prevalence and epidemiology
of onychomycosis in patients visiting physicians’ offices: a multicenter canadian survey of 15,000
patients. J Am Acad Dermatol 2000;43:244-8.
30. Heikkila H, Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol 1995;133:699-703.
31. Bramono K, Budimulja U. Epidemiology of onychomycosis in Indonesia: data obtained from three
individual studies. Nihon Ishinkin Gakkai Zasshi 2005;46:171-6.
32. Burzykowski T, Molenberghs G, Abeck D, et al. High prevalence of foot diseases in Europe: results of the
Achilles Project. Mycoses 2003;46:496-505.
33. Tchernev G, Penev PK, Nenoff P, et al. Onychomycosis: modern diagnostic and treatment approaches.
Wien Med Wochenschr 2013;163:1-12.
34. Sanchez-Regana ML, Videla S, Villoria J, et al. Prevalence of fungal involvement in a series of patients
with nail psoriasis. Clin Exp Dermatol 2008;33:194-5.
35. Dorschner RA, Lopez-Garcia B, Massie J, Kim C, Gallo RL. Innate immune defense of the nail unit by
antimicrobial peptides. J Am Acad Dermatol 2004;50:343-8.
36. Palatsi R, Hagg P. The immune response against microbial infections in the skin--weak in atopic
dermatitis and strong in psoriasis. Duodecim 2011;127:127-34.
37. Dawber RP, Samman PD, Bottoms E. Fingernail growth in idiopathic and psoriatic onycholysis. Br J
Dermatol 1971;85:558-60.
38. Baran R. The burden of nail psoriasis: an introduction. Dermatology 2010;221:1-5.
39. Roberts DT. Prevalence of dermatophyte onychomycosis in the United Kingdom: results of an omnibus
survey. Br J Dermatol 1992;126:23-7.
40. Hay R. Literature review. Onychomycosis. J Eur Acad Dermatol Venereol 2005;19:1-7.
41. Souza LK, Fernandes OF, Passos XS, Costa CR, Lemos JA, Silva MR. Epidemiological and mycological data
of onychomycosis in Goiania, Brazil. Mycoses 2010;53:68-71.
42. Gupta AK, Jain HC, Lynde CW, Watteel GN, Summerbell RC. Prevalence and epidemiology of unsuspected
onychomycosis in patients visiting dermatologists’ offices in Ontario, Canada--a multicenter survey of
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43. Mugge C, Haustein UF, Nenoff P. Causative agents of onychomycosis--a retrospective study. J Dtsch
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44. Zaias N. Psoriasis of the nail. A clinical-pathologic study. Arch Dermatol 1969;99:567-79.
132
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Chapter 6
Nail psoriasis and psoriatic arthritis
Chapter 6.1
Nail psoriasis, an early indicator of
destructive psoriatic arthritis?
K.M.G. Klaassen
M.J.M. Ploegmakers
P.C.M. van de kerkhof
W.M. Klein
M.C. Pasch
Submitted
CHAPTER 6
NAIL PSORIASIS AND PSORIATIC ARTHRITIS
Abstract
Introduction
Background. Patients with nail psoriasis have a higher prevalence of psoriatic arthritis
(PsA), however the pathogenetical relationship between these is unclear. Entheses
are suggested as the epicenter of disease, which might explain the pathogenesis in an
anatomical way.
The relationship between psoriasis and arthritis was first described in 1818.1
The prevalence of psoriatic arthritis (PsA) in patients with psoriasis varies from
approximately 7% to 40% in literature.2-6 This percentage is even higher in psoriasis
patients with nail involvement, reaching nearly 70%.7
Why psoriasis patients with nail psoriasis have a notable higher prevalence of
PsA, and specifically arthritis of the distal interphalangeal (DIP) joint, is not fully
elucidated.8,9 Originally, it was thought that the link between arthritis and psoriasis
could be explained by an autoimmune reaction to a common autoantigen in both skin
and synovium.10 However, this hypothesis is challenged by recent studies which
emphasize on the association between PsA and nail psoriasis. McGonagle et al.
proposed a hypothesis concerning the pathogenesis in which entheses play a central
role.11-13 Entheses are sites at which tendons or ligaments are integrated into bone.14
They are suggested as the epicenter of both nail psoriasis and PsA, as there might be
a direct anatomical link between inflammation of the DIP joint and nail changes in
psoriasis via the entheses of the extensor tendon.12,13 Imaging studies showed that the
fibers of the entheses of the extensor tendon extent to, and fuse with the area of the
nail matrix.12,15,16 They seem to be integrated into a synovio-entheseal complex
connecting nail and joint. This finding led to the suggestion that nail manifestations in
PsA are an extension of entheseal changes or vice versa.15,17 Recent publications
explored this hypotheses, and documented that enthesopathy can already be found
in the entheses of the lower extremities in clinically asymptomatic patients with nail
psoriasis. As the entheses of the DIP joint are suggested as the anatomical link and
starting point of a generalized disease, standardized visualization and comparison of
these structures in symptomatic and asymptomatic nails of nail psoriasis patients
without clinical evidence of PsA would be interesting. Therefore, the aim of this study
was to contribute to the elucidation and exploration of the hypothesis concerning the
anatomical link between nail psoriasis and PsA with the extensor entheses as the
epicenter, using three dimensional (3D) ultrasound (US).
Objective. To contribute to the elucidation and exploration of the hypothesis
concerning the anatomical link between nail psoriasis and PsA with the extensor
entheses of the distal interphalangeal joint as the epicenter.
Methods. To explore the pathogenesis of nail psoriasis and PsA, we conducted a
cross-sectional cohort study, visualizing the entheses of the distal interphalangeal joint
of patients with fingernail psoriasis (n=54), psoriasis patients without nail involvement
(n=32) and healthy controls (HC, n=32) using three dimensional ultrasound.
Results. The results showed that patients with nail psoriasis have significant thicker
radial entheses compared to psoriasis patients without nail involvement (1.285 mm
vs. 1.216 mm, p=0.009) and HCs (1.285 mm vs. 1.223 mm, p=0.008). No significant
differences in entheseal thickness were found between entheses of adjacent involved,
and adjacent uninvolved nails (1.297 mm vs. 1.253 mm, p=0.13). No differences were
found for the ulnar entheses.
Conclusion. The present study could not confirm an anatomical relation between nail
psoriasis and PsA as the underlying, and triggering pathogenic mechanism, as
entheseal thickening is also present in entheses of uninvolved nails. An explanation
for the link between nail psoriasis and PsA might be sought at the genetic level.
Patients
A cross-sectional cohort study was conducted at the Departments of Dermatology
and Radiology of the Radboud university medical center, Nijmegen, The Netherlands.
Patients were included from September 2012 to March 2013. A total of 56 psoriatic
patients with fingernail psoriasis (NAPSI >5), 32 psoriasis patients without nail
involvement (NAPSI ≤5) and 32 HCs were included. Referred patients diagnosed with
psoriasis, and psoriasis patients from the psoriasis database of the Department of
139
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CHAPTER 6
Dermatology were approached, and asked to participate in the study. All psoriatic
patients have been diagnosed with psoriasis before, and participants were excluded
if they had a current or previous history of (psoriatic) arthritis. Patients using systemic
antipsoriatic therapy at the moment of inclusion or in the previous three months
were excluded. Patients and controls with presence of a disease other than psoriasis
which is associated with nail manifestations (e.g., alopecia areata, lichen planus) were
also excluded.
Clinical data collection
Clinical data was collected by a trained physician (KMGK). Psoriatic fingernail features
and nail psoriasis severity were assessed by clinical examination, using the Nail
Psoriasis Severity Index (NAPSI).38 The severity of psoriasis was assessed using the
Psoriasis Area and Severity Index (range 0-72).39 Clippings and subungual scrapings
of all patients were collected for direct microscopic examination (10% potassium
hydroxide preparations) in order to rule out the presence of a concomitant onychomycosis. When present, the clipping was taken from a clinical affected fingernail,
otherwise from digit one of the right hand. Patients with concomitant onychomycosis
were excluded from the study.
Wakefield et al. (1= no flow, 2= single vessel signal, 3=confluent vessel signal in less
than half of the area, 4=vessel signal in more than half of the area). 40
Statistics
The number of included patients was determined in consultation with the statistic
department of the Radboud university medical center. Data were entered in a
Statistical Package for Social Sciences (SPSS 20.0, IBM Corp., Armonk, NY) database
and subsequently statistical analyses were performed. Descriptive statistics were
provided using mean (±95%CI) or median (range) for normally and nonparametric
distributed numeric values, respectively. To assess reliability of entheseal thickness
assessment, the images of 220 randomly chosen fingernails were evaluated
independently by both investigators. Intraclass correlation coefficient (ICC) values
were calculated between the two investigators. ANOVA was used to estimate the
differences between the groups, and multiple linear regression was used to determine
the independent association between entheseal thickness and groups adjusted for
age and sex. A p-value <0.05 was considered statistically significant.
Ultrasound
The clinical examination (clinical physician: KMGK), ultrasound imaging (four trained
radiographers) and ultrasound interpretation (two radiologists: WMK and MJMP)
were performed separately by different investigators who were unaware of each
other’s results. Both radiographers and radiologist were blinded for the diagnosis of
the patients. Patients were asked not to communicate with the radiographers
concerning their skin and/or nail condition. The ultrasound images were performed
using the SomoVu automated 3D breast volume scanner (ABVS) developed by
U-systems, Inc (Sunnyvale, CA). For all acquisitions, a linear 8-MHz/10-MHz transducer
with a width of 14.5 cm was used. During imaging, patients placed both pronated
hands on the bottom of a bin filled with ultrasound transmission gel. The 3D ultrasound
was conducted on all ten fingernails in two stages (stage one digit 2 till 5 of both
hands, stage 2 digit 1 of both hands). Axial 3D scans ran from the distal end of the
fingers to the middle of the most cranial midphalanx. Each 3D volume was generated
with an in-plane resolution of 0.285 mm x 0.285 mm and a slice thickness of 0.6 mm.
Power Doppler of the ABVS was equipped with a two-dimensional handheld linear
18MHz transducer for all ten fingernails in the axial plane of the nail plate. The
radiologist evaluated the images and conducted measurements. Subsequently the
thickness of the extensor tendon was measured just distal of the DIP joint at the
division of the tendon in an ulnar and a radial section, proximal to the insertion (see
Figure 1). Severity of the Doppler signal was graded into four stages according to
140
6
Figure 1. Axial ultrasonographic appearance (using the automated 3D breast ultrasound
system) of the entheses of the extensor tendon of the distal interphalangeal (DIP) joint.
Entheses are indicated by the asterisks. The image is located just distal of the DIP joint of digit 4 of the left
hand, and shows the division of the tendon in an ulnar and radial section. DP, distal phalange, s, skin.
141
CHAPTER 6
Results
Table 1 The patient characteristics of all three groups.
Patients
We included 54 patients (with 540 entheses) diagnosed with fingernail psoriasis
without PsA, 32 (320 entheses) psoriasis patients without nail involvement, and 32
(320 entheses) healthy controls (HC). Two patients were excluded because of the
diagnosis of PsA. Descriptive patient characteristics are reported in Table 1. The HCs
were significantly younger when compared to both psoriasis groups. PASI and
duration of disease were comparable in both psoriasis groups (3.9 (0-24.1) vs. 3.0
(0-9.9), p=0.061 and 23.9 95%CI 19.6-28.2 vs. 26.3 95%CI 20.3-32.3, p=0.757). After
studying the images, 421/540 entheseal images in the nail psoriasis group were
available for analyses. In the psoriasis group 186/320 fingernails were available for
analysis, and 278/320 in the control group.
142
No nail
involvement ‡
(n = 32)
Healthy
controls
(n = 32)
Female
27 (50.0)
16 (50.0)
12 (37.5)
Male
27 (50.0)
16 (50.0)
20 (62.5)
p-value
Gender, n (percentage)
Ultrasonography entheses
All entheses were separately analyzed, and the results for radial and ulnar entheseal
thickness are shown in Table 2. On ultrasound examination mean radial entheseal
thickness in the nail psoriasis group was with 1.285 millimeter (mm) (95% CI
1.261-1.316), significantly thicker when compared to the psoriasis group without nail
involvement (1.216 mm 95%CI 1.181-1.251 , p=0.009) or compared to the HCs (1.223
mm 95%CI 1.194-1.252, p=0.008). After correcting for age and sex, entheseal thickness
was still higher in patients with nail psoriasis (see Table 3 for regression analysis).
Mean entheseal thickness did not differ between psoriasis patients without nail
involvement, and HCs (1.216 mm vs. 1.223 mm, p=0.956). When excluding the entheses
of adjacent uninvolved nails (n=148) in the nail psoriasis group, differences were
comparable (see Table 2). When analyzing the ulnar entheseal data, no differences
between the three groups were found. Only when excluding the measures conducted
on the entheses with a adjacent NAPSI equal to zero, significant thicker entheses
were found in the nail psoriasis group when compared to the psoriasis group without
nail features (see Table 2). When comparing entheseal thickness between involved
(NAPSI >0) and uninvolved (NAPSI =0) nails within individuals diagnosed with nail
psoriasis, no significant differences were found (radial: 1.297 mm vs. 1.253 mm,
p=0.13, ulnar: 1.234 vs. 1.199 p=0.223). When distinguishing between the different
localizations of nail psoriasis (e.g., nail bed, nail matrix), patients with both nail bed
and nail matrix features simultaneously showed the thickest radial entheses. This was
significantly higher when compared to nails with solely nail matrix lesions. The ulnar
entheses were significantly thicker in nails with solely nail bed features compared to
solely nail matrix features. Power Doppler of the nail bed did not show a difference in
blood flow between the groups.
Nail
involvement †
(n = 54)
Age yr, mean (95%CI)
52.9 (49.2-56.7) 55.7 (50.3-61.0)
39.9 (34.7-45.1)** <0.001
Age start psoriasis yr,
mean (95%CI)
28.7 (24.5-33.0) 29.9 (23.7-36.1)
NA
0.801
Duration of psoriasis yr,
mean (95%CI)
23.9 (19.6-28.2)
26.3 (20.3-32.3) NA
0.757
NAPSI, mean (95%CI)
23.4 (19.1-27.7)*
1.8 (1.2-2.4)
2.3 (1.7-3.0)
<0.001
PASI, median (range)
3.9 (0-24.1)
3.0 (0-9.9)
NA
0.061
Nail features, n (%)
Pitting
Leukonychia
Red spots lunula
Crumbling
Onycholysis
41 (75.9)*
16 (29.6)
5 (9.3)
13 (24.1)*
44 (81.5)*
37 (68.5)*
30 (55.6)*
12 (22.2)*
8 (25.0)
8 (25.0)
0 (0)
0 (0)
5 (15.6)
11 (34.4)
2 (6.3)
0 (0)
4 (12.5)
20 (62.5)**
0 (0)
0 (0)
3 (9.4)
7 (21.9)
0 (0)
0 (0)
<0.001
0.004
NS
0.001
<0.001
0.003
<0.001
0.001
Type of psoriasis, n (%)
Plaque psoriasis
Guttate psoriasis
Pustular psoriasis
Psoriasis capitis
Inverse psoriasis
Genital psoriasis
Erythodermic psoriasis
31 (60.8)
29 (56.9)
2 (3.9)
39 (76.5)
12 (24.5)
15 (31.3)
0 (0)
18 (60.0)
10 (33.3)
3 (9.4)
15 (50.0)
3 (10.3)
4 (13.8)
2 (6.7)
NA
NA
NA
NA
NA
NA
NA
0.945
0.042
0.275
0.015
0.128
0.087
0.067
NAPSI ≤ 5.
NAPSI >5.
*
Significances were found between patients with nail psoriasis compared to healthy controls
and psoriasis patients without nail involvement.
**
Significances were found between healthy controls and both psoriatic groups.
N, number; NA, not applicable;NAPSI, Nail Psoriasis Severity Index; NS, non significant;
PASI, Psoriasis Area and Severity Index; yr, year.
†
‡
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CHAPTER 6
Table 2 T he radial and ulnar entheseal thickness compared between the three
groups.
Mean
entheseal
thickness
(mm)*
p-value
Mean
entheseal
thickness
(mm)**
p-value
1.285 vs. 1.216
0.009
1.297 vs. 1.216
0.003
Nail psoriasis vs. Healthy controls 1.285 vs. 1.223
0.008
1.297 vs. 1.223
0.002
Psoriasis vs. Healthy controls
1.216 vs. 1.223
0.956
1.216 vs. 1.223
0.956
Radial
Nail psoriasis vs. Psoriasis
Ulnar
Nail psoriasis vs. Psoriasis
1.225 vs. 1.175
0.090
1.234 vs. 1.175
0.032
Nail psoriasis vs. Healthy controls 1.225 vs. 1.207
0.668
1.234 vs. 1.207
0.387
Psoriasis vs. Healthy controls
0.422
1.175 vs. 1.207
0.422
1.175 vs. 1.207
All entheses of the nail psoriasis group were taken into account (also entheses adjacent to nails with
a NAPSI equal to zero).
**
Entheses of fingernails in the nail psoriasis group with a NAPSI equal to zero were excluded in the
measurement.
*
Table 3 Regression parameters for radial entheseal thickness (mm) with 95%
confidence intervals (CI), an univariate and multivariate linear regression
model.
Entheseal thickness
Variable
Unadjusted (95% CI)
Adjusted (95%CI)
Sex
Women
Men
0.144 (0.169-0.212)
0.00 (reference)
0.142 (0.109-0.176)
0.00 (reference)
Age (years)
0.000 (-0.001-0.001)
-0.001 (-0.003-0.000)
Group
Nail psoriasis
Psoriasis
Healthy controls
0.062 (0.023-0.101)
-0.007 (-0.055-0.040)
0.00 (reference)
0.56 (0.016-0.096)
0.011 (-0.039 – 0.061)
0.0 0 (reference)
CI, confidence interval.
144
Inter-observer agreement
When taken all entheseal measurements together, an ICC of 0.805 (95% CI 0.722–0.861)
was found between observers, indicating a good agreement. When analyzing entheseal
thickness measurements for all ten fingernails separately, the ICC varied from 0.502
to 0.917 (digit 1 right to digit 5 left, 0.911, 0.502, 0.874, 0.660, 0.617, 0.764, 0.790,
0.905, 0.917, 0.795, respectively).
Discussion
This study is an important contribution to the understanding and exploration of the
link between nail psoriasis and PsA. Based upon the high prevalence of nail psoriasis
in PsA patients, and the increased percentage of PsA patients with nail psoriasis, it
was already concluded that there is an association between nail psoriasis and PsA.18,19
McGonagle et al. hypothesized on this association, and proposed that entheses might
play a key role in the link between nail psoriasis and PsA, as they seem to be the
anatomical connection between the nail apparatus and the DIP joint.12,13,20,21 According
to their hypothesis, psoriatic inflammation at the entheses of the extensor tendon at
the dorsal side of the distal phalange can induce arthritis through the release of
pro-inflammatory mediators. Alternatively, microtraumata caused by the forces
exerted on the entheses might induce a Koebner response resulting in an enthesitis,
and subsequently nail and joint disease.12,11 If this hypothesis is correct, the first sign of
both psoriatic nail disease and psoriatic joint disease is an inflammatory reaction at
the entheses. This inflammatory reaction would include swelling of the entheses, as
has been shown in other studies concerning enthesitis, followed by clinical signs of
nail psoriasis and by radiological and clinical signs of PsA of the DIP joint.22 It may be
expected that swelling of the entheses of the extensor tendon close to the nail matrix
is more pronounced in psoriatic nails than in healthy nails. Therefore, visualization of
the entheses of the extensor tendon of the DIP joint in psoriasis patients, with or
without nail involvement is highly informative. In order to test the above mentioned
hypothesis we decided to measure the thickness of the entheses in several groups of
(psoriasis) patients, as Gandjbakhch et al. showed in a literature review that 94% of
studies measured the thickness of the entheses for defining presence of enthesitis.22
Accurate measurements of the entheses of this tendon is prerequisite, since this tendon
is a subtle structure. It is already documented that conventional musculoskeletal US
is a reliable technique for the visualization of entheses in general.22-24 However, two
dimensional US is an operator-dependent technique associated with operational
variability predominantly caused by positioning of the probe; small deviations in the
angle in which the probe is placed can result in differences in measured diameters of
entheses. To compensate for this potential error we decided to use 3D US. Three-
dimensional US is emerging as an US modality with a number of possible advantages
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over conventional two-dimensional US.25 A major advantage of 3D US is that it reduces
dependability to sonographers’ expertise in positioning of the probe, as it scans in a
standard manner,25 and several entheses can be scanned in one session. This is the
first study using 3D US as imaging technique for the visualization of the entheses in
nail psoriasis patients, and our results confirmed that it is a reliable technique showing
a good interrater reliability in the visualization of entheses.26 Nevertheless, a
limitation of using this technique in the present study was the number of missing
data. This was caused by a certain lack of experience by the radiographers using a 3D
US transducer for the visualization of musculoskeletal structures of the hand.
Therefore, technique and protocol development for scanning nails and entheses
needs optimization.
In response to the hypotheses of McGonagle et al., several studies focused on
the entheses of PsA and (nail) psoriasis patients, and showed that enthesopathy can
be present in the absence of clinical joint symptoms.2,20,27 Our results concerning the
radial entheses of the extensor tendon, are in line with previous studies, concluding
that subclinical entheseal thickening can be found in nail psoriasis patients.20 Previous
studies concentrated on the entheses of the lower extremities and the common
extensor of the upper extremity, while the present study visualized the entheses of
the extensor tendon of the DIP joint. This different approach was chosen in order to
be able to draw conclusions concerning the above mentioned hypothesis, in which
the anatomical interrelationship between the entheses of this tendon and the nail
apparatus play a role in the development of clinical signs of nail psoriasis. Based on
our results and the literature it might be concluded that subclinical enthesopathy in
nail psoriasis patients seems to be present in localizations anatomically linked to the
nail apparatus, but also in more remote entheses which do not have a direct relation
with the nail.12 Since increased tendon thickness is a common and early feature of soft
tissue inflammation,22, 28 we decided to assess this feature of enthesopathy, and did
not focus on the whole spectrum of enthesopathy (e.g., enthesophytes, erosions).28
This approach made it possible to evaluate numerous entheses.
Our finding, that the measures of the entheses on the ulnar side were not
comparable with the measures on the radial side is remarkable. However, previous
studies also showed preference for the radial site in several rheumatologic conditions.
Tan et al., concluded that in early rheumatoid arthritis patients, a propensity for
involvement of the radial side of metacarpophalangeal joints two and three was
found for erosions and synovitis.29 They related radial and ulnar differences to local
biomechanical and anatomical factors in the joint.29 Another study in patients with
rheumatoid arthritis also showed that pannus formation and vascularization appeared
to be localized preferentially on the radial side of the proximal interphalangeal joints
and metacarpophalangeal joints.30 Considering the marked differences between the
radial and ulnar sides in the peripheral small joints of rheumatoid arthritis patients,
146
biomechanical factors might also play a role in the ulnar and radial entheses of the
DIP joint which might clarify the differences found. However, future research may
substantiate and further elucidate this finding.
The presented results, showing that there is no difference in entheseal thickness
between entheses of adjacent involved or uninvolved nails within the group of
patients with nail psoriasis, militates against an anatomical-based pathophysiological
mechanism as promoted in earlier hypotheses.12,13,15,31 In favor of the hypotheses, we
should have found a difference between the thickness of entheses of affected and
unaffected nails. Our results disputing against the anatomical link hypothesis are
strengthened by a study of Scarpa et al. which found no difference in the distribution
of DIP-joint arthritis (based on X-ray findings) between PsA patients with and without
nail involvement,32 and a study of Tan et al. showed that a patient with a high
inflammation signal at the extensor entheses on MRI had no nail abnormalities.15
These, and our findings argue against an anatomical link. An adaptation of the
anatomical link hypothesis could be that entheseal abnormalities are the initial sign
of early PsA, and inflammation evolves secondary to the nail apparatus. Future
follow-up studies might be needed to reject or confirm this. Taking the anatomical based pathogenic association between nail psoriasis and
PsA as a starting point, nail matrix features of psoriasis should be most frequently
occurring in enthesitis, because previous imaging and cadaver studies showed that
the vessels of the extensor tendon fuses with the nail matrix.15,16 When distinguishing
between the different localizations of nail psoriasis in our population, radial entheses
were thinnest in patients with nail matrix features solely, and thickest in patients with
involvement of both nail matrix and nail bed. On the ulnar side, entheses were
thickest in nails with solely nail bed involvement. Our findings are, again, not
compatible with an anatomical pathogenic link. Love et al. associated the features of
nail psoriasis with PsA, and concluded that the strongest association with arthritis
could be found for onycholysis, which is the prototype of nail bed involvement in
psoriasis.17,33 Another study concluded that the pattern of nail involvement (i.e., nail
matrix vs. nail bed involvement) between psoriasis and PsA patients was almost
similar. Only pitting, a nail matrix feature, was more frequently seen in psoriasis
patients without arthritic involvement. Based on our findings and the literature there
does not seem to be a clear pattern of, or a predilection for, certain nail features in
nail psoriasis patients with enthesopathy, making an anatomical pathogenic link not
very likely.
Taken all together, our results indicate that an anatomical based pathogenic
association between nail psoriasis and PsA is not plausible. Entheseal thickening is
present in localizations anatomically related to the nail apparatus, but also in more
remote entheses, and in entheses linked to clinical uninvolved nails of nail psoriasis
patients without PsA. However, the incidence of nail disease among PsA patients and
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joint disease among nail psoriasis patients is remarkably high. An explanation for this
could be sought at the genetic level.34, 35 It is already suggested that psoriasis and PsA
might not share a common etiology, but have underlying genetic heterogeneity, as
PsA is a clinical heterogeneous disease with various extra-articulair manifestations
(e.g., nail features, skin involvement, uveitis).36 Several authors have shown that both
psoriasis and PsA have genetic associations but also have distinct susceptibility genes.
Psoriasis (without joint involvement) has a high association with HLA-C*06, while PsA
patients are significantly more frequent HLA-C*06 negative. Three haplotypes,
containing B*27 and B*39:01, were associated with PsA but were not increased in a
psoriasis cohort.35,36 Like PsA patients, nail psoriasis patients are also more frequently
HLA-C*06 negative.34 This might be an indication that nail psoriasis and PsA might
share genetic susceptibility loci, explaining the coincidence of them, rather than an
anatomical basis for this. In the search for genetic explanations, it might be taken into
account that both nail psoriasis and PsA are associated with more widespread
disease.3,37
Conclusion
Early diagnosis and treatment of PsA is important to prevent destruction of the joints,
and to avoid disease related disabilities. If the presence of nail disease in psoriatic
patients is a risk factor for arthritic disease, then the presence of nail manifestations
might influence the choice and timing of therapy in these patients, and this may
prevent irreversible damage of the joints. Subclinical entheseal thickening of the
extensor tendon of the DIP joint is present in nail psoriasis patients. However, an
anatomical association between nail psoriasis and PsA as the underlying and triggering
pathogenic mechanism is unlikely. Future studies have to be conducted to elucidate
the link, which might be found in the field of genetics.
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McGonagle D, Tan AL, Benjamin M. The nail as a musculoskeletal appendage--implications for an
improved understanding of the link between psoriasis and arthritis. Dermatology 2009;218:97-102.
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associated with onycholysis: the Reykjavik Psoriatic Arthritis Study. Scand J Rheumatol 2010;39:299-302.
Williamson L, Dalbeth N, Dockerty JL, Gee BC, Weatherall R, Wordsworth BP. Extended report: nail
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24. Gutierrez M, Filippucci E, De Angelis R, Salaffi F, Filosa G, Ruta S, et al. Subclinical entheseal involvement
in patients with psoriasis: an ultrasound study. Semin Arthritis Rheum 2011;40:407-12.
25. Iagnocco A, Riente L, Delle Sedie A, Filippucci E, Salaffi F, Meenagh G, et al. Ultrasound imaging for the
rheumatologist. XXII. Achilles tendon involvement in spondyloarthritis. A multi-centre study using high
frequency volumetric probe. Clin Exp Rheumatol 2009;27:547-51.
26. Merot O, Guillot P, Maugars Y, Le Goff B. Three-dimensional versus two-dimensional ultrasonographic
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27. Girolomoni G, Gisondi P. Psoriasis and systemic inflammation: underdiagnosed enthesopathy. J Eur
28. Balint PV, Kane D, Wilson H, McInnes IB, Sturrock RD. Ultrasonography of entheseal insertions in the
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29. Tan AL, Tanner SF, Conaghan PG, Radjenovic A, O’Connor P, Brown AK, et al. Role of metacarpophalangeal
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30. Hau M, Schultz H, Tony HP, Keberle M, Jahns R, Haerten R, et al. Evaluation of pannus and vascularization
of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis by high-
resolution ultrasound (multidimensional linear array). Arthritis Rheum 1999;42:2303-8.
31. McGonagle D, Palmou Fontana N, Tan AL, Benjamin M. Nailing down the genetic and immunological
basis for psoriatic disease. Dermatology 2010;221:15-22.
32. Scarpa R, Manguso F, Oriente A, Peluso R, Atteno M, Oriente P. Is the involvement of the distal inter
phalangeal joint in psoriatic patients related to nail psoriasis? Clin Rheumatol 2004;23:27-30.
33. Love TJ, Gudjonsson JE, Valdimarsson H, Gudbjornsson B. Psoriatic arthritis and onycholysis -- results
from the cross-sectional Reykjavik psoriatic arthritis study. J Rheumatol 2012;39:1441-4.
34. Gudjonsson JE, Karason A, Antonsdottir AA, Runarsdottir EH, Gulcher JR, Stefansson K, et al.
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35. Winchester R, Minevich G, Steshenko V, Kirby B, Kane D, Greenberg DA, et al. HLA associations reveal
genetic heterogeneity in psoriatic arthritis and in the psoriasis phenotype. Arthritis Rheum 2012;64:1134-44.
36. Boehncke WH, Kirby B, Fitzgerald O, van de Kerkhof PC. New developments in our understanding of
psoriatic arthritis and their impact on the diagnosis and clinical management of the disease. J Eur Acad
37. Klaassen KM, van de Kerkhof PC, Pasch MC. Nail Psoriasis: a questionnaire-based survey. Br J Dermatol
2013;169:314-9.
38. Rich P, Scher RK. Nail Psoriasis Severity Index: a useful tool for evaluation of nail psoriasis. J Am Acad
Dermatol 2003;49:206-12.
39. Schmitt J, Wozel G. The psoriasis area and severity index is the adequate criterion to define severity in
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Elsevier 2010.
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Chapter 7
Summary, discussion and
future perspectives
SUMMARY, DISCUSSION AND FUTURE PERSPECTIVES
Introduction
The purpose of the studies presented in this thesis was to obtain insight into various
aspects of the spectrum of nail psoriasis. In this concluding chapter the main findings
of the current thesis will be outlined and discussed according to the aims of each
chapter as formulated in chapter 1. Subsequently, directions for future research
arising from these conclusions will be outlined.
Aim 1.1: T o obtain more insight into the prevalence and clinical characteristics
of nail psoriasis.
Although various studies focused on the prevalence of nail psoriasis, the prevalence
remained unclear, with the reported prevalence ranging from 10% to 80%. Therefore,
the prevalence in a large group of psoriasis patients was studied and described in
chapter 2.2. Our data showed a nail psoriasis prevalence of 66% in a group of 1459
psoriasis patients. Based on the study design (self-reported questionnaires among
members of a patient association), it might be possible that our prevalence is an
overestimation. However, when comparing with the literature, studies of various
methodology predominantly stated a prevalence between 47% and 81%,1-6 and only
two studies found a prevalence below 40%,7, 8 indicating that the prevalence found in
this chapter might be a good reflection of the reality. The overall conclusion is that
the prevalence rate of nail involvement in psoriasis patients is higher than often
estimated, and recognition of typical characteristics of nail psoriasis is important as it
is a frequent, and sometimes early, manifestation of the disease. Therefore,
knowledge of the prevalence of the different manifestations seen in nail psoriasis is
essential for doctors treating patients with skin and nail diseases. In order to focus on
the features of nail psoriasis we conducted two studies which are displayed in chapter
2.1 and 2.2. In chapter 2.1 onycholysis (93.9%), splinter hemorrhages (93.9%), and
pitting (73.5%) were most frequently seen, scored by a trained clinician. In chapter
2.2 pitting (65.4%), onycholysis (57.7%) and oil-drop discolorations (41.4%) were most
frequently documented by the patients themselves. Pitting and onycholysis were
found frequently in both studies, despite the different study designs, which is in line
with previous studies. 4, 6, 9, 10 Both studies showed that the red spotted lunula is a
phenomenon sparsely seen in nail psoriasis (2.0% and 6.5%, respectively). In contrast,
Beau’s lines were frequently seen in nail psoriasis patients in study 2.1. Unfortunately,
the presence of Beau’s lines was not asked in the questionnaire which was filled in by
the patients. In literature Beau’s lines in nail psoriasis are sparsely taken into account,
only a study of Garzitto et al.11 measured this phenomenon and found a prevalence of
29.4%. It used to be generally accepted that leukonychia is a typical nail feature of
psoriasis. However, the control group included in chapter 2.1 had significantly more
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frequently leukonychia of the nails when compared to the nail psoriasis patients
(65.3% vs. 40.8%, p=0.015). Based on our result and a similar result found in response
to our article by Garzitto et al.11, we can conclude that leukonychia is not a specific
feature for nail psoriasis. The most commonly used nail psoriasis severity scoring
systems, the Nail Psoriasis Severity Index (NAPSI), uses leukonychia and red spots in
the lunula as two of the eight classical features seen in nail psoriasis, and does not
take Beau’s lines into account. Based on the results of chapter 2.1 and 2.2, the
construction of the NAPSI should be reconsidered, based on the prevalences of the
characteristic features found in the nail psoriasis and control groups. The obtained
data on clinical characteristics and prevalence is valuable for the evaluation of
diagnostic criteria for nail psoriasis and education of dermatologist and general
practitioners in recognition of nail psoriasis.
Aim 1.2: T o obtain insight into self-reported treatment experiences of patients
with nail psoriasis.
Study 2.2 showed that 16% of nail psoriasis patients received treatment for their nail
lesions, while 47% of patients stated that they would like to receive treatment for
their nail features. These data demonstrate that there is a discrepancy between the
need for treatment in nail psoriasis patients and the actual number of patients treated
for their nail psoriasis. The number of patients treated for nail psoriasis is even
considerably lower when compared to data on a similar patient group in 1996.1 A
possible explanation for the low percentage of patients receiving treatment for their
nails might be that the cutaneous component dominated the clinical picture, so the
focus of psoriasis treatment therefore goes to the cutaneous component. Another
possible explanation for this undertreatment might be that therapies for psoriatic
nail disease are perceived to be ineffective by dermatologists, and results are seen
only after a long period of treatment as nails grow and recover slowly. Finally, patients
might consider their treatment as a treatment focusing on the cutaneous psoriasis
features but be ignorant that the same treatment might combat nail psoriasis as well.
However the low percentage is remarkable knowing that treatment options are
increasing, assertiveness of patients is growing, and cosmetic aspects are increasingly
important. In chapter 2.2 patients did report that they experienced positive effects
on their nails of varies predominantly systemic treatments (e.g., biologics, fumaric
acid, methotrexate). In line with the experiences of nail psoriasis patients described
in study 2.2, several studies documented positive effects of various treatment
modalities on nail psoriasis, and research on this topic is increasing.12-22 A recent
Cochrane review showed that there is high quality evidence available for treatment
of nail psoriasis with two anti- tumor necrosis factor (TNF) biologics (infliximab and
golimumab) and radiotherapy.13 However, only 18 studies could be included as the
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quality of studies was generally poor.13 Our data and this review indicate that high
quality research on the effects of treatments on nail psoriasis is highly needed.
However, all trials should use one and the same methodology to guarantee that
comparison of the results will be possible. In conclusion, we hope that with these
data a signal is emitted for the need of high quality evidence on the efficacy of
therapies on nail features as nail psoriasis is still undertreated, and the conditions for
further research need optimization as the methodologies differ and quality is lacking.
However, treatment of nail psoriasis needs a patient-centered approach as the
systemic anti-psoriasis therapies are potential toxic, so the advantages and
disadvantages of each therapeutic option should be taken into account. Furthermore,
indications for prescribing systemic treatment in nail psoriasis, like severe cutaneous
psoriasis, coexistence of psoriatic arthritis (PsA), or when nail psoriasis is interfering
with patients’ quality of life, should be formulated so guidelines can be developed.
Aim 2: T o achieve more insight into the quality of life of
nail psoriasis patients.
In response to the low percentage of respondents who received treatment for their
nail manifestations found in chapter 2, it was decided to investigate the impact of nail
features on patients’ quality of life in chapter 3. In chapters 3.1 and 3.2 we presented
data of various generic, dermatology-specific and nail psoriasis-specific quality of life
scores in nail psoriasis patients.
In chapter 3.1 no validated specific nail psoriasis quality of life score was available
so it was chosen to use a generic quality of life score, and to modify an onychomycosis
quality of life questionnaire developed by Drake et al.23 By using a generic score (Short
Form-36) we were able to show that nail psoriasis (with minimal cutaneous activity)
has no influence on patients’ perception of their general health as expressed by this
score. Although the modified onychomycosis questionnaire of Drake et al.23 was only
partly validated, the results of this questionnaire showed that patients do experience
limitations because of their nails comparable to the impact of onychomycosis.23 The
results of the modified onychomycosis questionnaire showed that patients with nail
psoriasis experienced the greatest burden on the social dimension. Patients are
worried about the judgment of others concerning their nails, but also half of patients
experience pain because of the nail features. These results indicate that clinicians
should take the social burden and pain caused by the nails into account when treating
psoriasis patients.
In chapter 3.2, the most frequently used quality of life score in dermatology was
used, the Dermatology Life Quality Index (DLQI). Patients with nail psoriasis scored
significant higher mean scores compared to psoriasis patients without nail
involvement (mean DLQI 4.9 and 3.7, p=<0.001 respectively) indicating more impaired
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quality of life when nail features are present. However, when looking at the
interpretation of the DLQI scores of the nail psoriasis and psoriasis group, both fall
into the same effect category (category two, DLQI score 2-5), indicating a small effect
on patients’ life.24 Despite the significant difference, the clinical meaning of the
difference between the two groups is questionable, but the difference is significant
and cannot be ignored. In the interpretation of the results it should be taken into
account that the DLQI measures the impact of a dermatological condition, and not
specifically nail features. The difference between the groups might be explained by
the higher cutaneous psoriasis severity in the nail psoriasis group as seen in the
SAPASI (6.6 versus 5.3, p=<0.001 respectively) or the higher prevalence of PsA in the
group of nail psoriasis patients as discussed in the article. When using the DLQI the
specific impact of nail disease in psoriasis patients on quality of life remains unclear.
These results indicate that the DLQI is not specific enough for estimating the burden
nail features may have on patients’ life, possibly caused by the nature of the questions
which do not include specific questions on the nails.
In 2010 a nail psoriasis specific quality of life questionnaire, the Nail Psoriasis
Quality of life (NPQ10) was developed by Ortonne et al., and could be applied in
chapter 3.2.25 This questionnaire showed that patients were restricted in various
daily activities (e.g., putting on shoes or/and socks), and 36% of psoriasis patients with
nail involvement experienced pain. Localization of nail psoriasis turned out to be
important as nail bed features lead to more impairments than nail matrix features do.
In contrast to the DLQI and Short Form-36, the focus of the NPQ10 is centered around
the restrictions nail features entail. These data and the data of the modified
onychomycosis questionnaire indicate that it is valuable to use an instrument that
measures the burden of nail psoriasis for both clinical care and research purposes, as
it offers the opportunity for a patient-centered approach. It would be interesting to
apply the quality of life score into the follow-up of treatment to determine the
changes in quality of life during treatment options. However, in our opinion the
quality of life score for nail psoriasis needs further improvement and development as
the mean score of the NPQ10 was 9.9% (on a maximum score of 100%) indicating that
the score is not used in its full range, and this might reflect that most patients do not
experience most of the limitations mentioned, while other relevant questions are
missing. Certain questions (e.g., ‘because of my nail psoriasis, someone helps me to
get dressed’) might be replaced by questions concerning restrictions more specific
for nail psoriasis patients as used in the onychomycosis score. However, the NPQ10 is
sparsely used in research so future studies are needed to confirm or reject our
findings, or further modification and validation of the onychomycosis questionnaire
is needed. The value of the results found in these two studies is that it shows that
nail psoriasis can have a significant impact on specific items of patients’ quality of
life, and clinicians should pay attention to the nails in the treatment of psoriasis.
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Scoring system for quality of life in nail psoriasis might need further development
and application.
Aim 3: T o give insight into the various existing nail psoriasis
severity scoring systems and to develop a scoring system
better reflecting clinical severity.
In consequence of the results of study 2.1 and 2.2, experiences gained and the literature,
it became evident that scoring nail psoriasis severity using the NAPSI had major
limitations. Therefore, the aim of chapter 4 was to compare the existing scoring systems
including the NAPSI with a standard score for clinical severity to give insight into the
existing scoring systems, and to develop a system which is able to reflect clinical severity
more accurate. In literature seven nail psoriasis scoring systems were described and
included in this study. A scoring system developed by Baran et al.26 and the Psoriasis
Nail Severity Score (PNSS)27 showed an acceptable correlation with clinical severity in
terms of Physician Global Assessment (PGA) of 0.735 and 0.734 respectively. The
frequently used NAPSI showed moderate correlation with the PGA (r=0.669). In
addition, literature showed that the NAPSI is not always responsive in the reflection of
clinical improvement.28, 29 This might be caused by the fact that the NAPSI only scores
presence or absence of clinical nail features instead of severity of these features.
Consequently, in chapter 4 a scoring system reflecting clinical severity more accurate
was developed. In response to the results of chapter 2 and based on the evaluation of
the existing nail psoriasis severity scores, we developed the Nijmegen-Nail psoriasis
Activity Index tooL (N-NAIL). The results showed that the N-NAIL reflected clinical
severity much better than the seven existing scoring systems (r=0.861). In the N-NAIL
certain nail features were added (Beau’s lines) or removed (e.g., leukonychia, red dots
in the lunula) when compared with the classical nail psoriasis scoring system. Also the
manner of scoring was adapted, not only absence or presence of nail features were
scored but a gradation of severity was given in combination with numeric scoring of
some features (e.g., Beau’s lines). The N-NAIL was validated to some extent as the
interrater and intrarater reliability were established. The results showed an interrater
reliability varying from 0.967 to 0.989 and an intrarater reliability of 0.899 indicating
excellent reproducibility of the N-NAIL. However for further validation more clinimetric
properties should be investigated. Estimating the responsiveness (the ability of a
scoring system to detect changes over time) of the N-NAIL in the treatment of nail
psoriasis patients would be of great value. In addition, the response distribution should
be estimated, examining whether the entire range of the score is used. But also the
interpretability, the degree to which one can assign qualitative meaning to a quantitative
score, should be estimated. Eventually this should result into categorization of the
outcomes related to the clinical picture. As reported by the Cochrane report in 2013,13
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it was not possible to pool and compare the results of the different studies on treatment
of nail psoriasis. The development and the optimization of the N-NAIL is a first step into
promoting the use of one and the same scoring system which reflects clinical severity
accurately, making the comparison of treatment options in nail psoriasis possible, and
eventually give insight into the treatment possibilities for nail psoriasis patients.
However, the introduction of an adequate clinical scoring system alone will not cover
the full load of nail psoriasis. For the future, an ultimate nail psoriasis scoring system is
a system reflecting clinical severity accurately, but also takes the burden of disease and
patient-reported outcome into account as shown in chapter 3. In this era of personalized
medicine patients’ experience on the effects of treatment should be taken into account
and maybe incorporated into the N-NAIL together with a measurement for quality
of life.
Aim 4: t o systematically review all literature available concerning the
prevalence of onychomycosis in (nail) psoriasis patients.
The aim of chapter 5 was to provide insight into the susceptibility of psoriasis patients
for the development of onychomycosis. Because of the heterogeneity of studies it
was not possible to perform a meta-analysis in this systematic review. Ten articles
could be included, and therefore conclusions are based on an overview of these
systematically included articles. A wide range in prevalence of onychomycosis was
found; 4.6% to 63.1% in the psoriasis group and 2.4% to 66.0% in control groups, with
a combined prevalence of 18.0% and 9.1% respectively. Prevalences of onychomycosis
in the general population documented in the literature are 6.5%, 8.4%, 4.7%,and
20.9%, so close to the combined prevalence of the control group of the articles in this
review.30-33 However, the prevalence of onychomycosis in psoriasis patients seems to
be elevated compared to the prevalence in the general population as stated in the
literature, and the prevalence found in the control groups of the included studies, but
the ultimate evidence is lacking. In literature various arguments concerning the
assumed vulnerability of psoriatic nails for fungal microorganisms are discussed.
Arguments contradicting a favoring mycotic infection are the fact that the immune
response against microbial skin infections is remarkably strong in psoriasis, and the
fast turnover of the nails in psoriasis would protect the nail against invasion of
microorganisms.34 The morphological changes of the nails in psoriasis patients
(hyperkeratosis, onycholysis), and the use of immunosuppressive therapies for
psoriasis are arguments for an increased vulnerability of psoriasis nails. In accordance
to the latter argument a recent article was published on the development of
onychomycosis in nail psoriasis patients after starting anti-TNF therapy.35 The results
showed that nail psoriasis patients treated with infliximab developed significantly
more frequently onychomycosis (33.0%) after 24 weeks of treatment compared to
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healthy controls and nail psoriasis patients treated with adalimumab and etanercept.
These results indicate that immunosuppressive therapy increases the risk of
developing onychomycosis in (nail) psoriasis. In conclusion, the overview indicates a
higher vulnerability of nail psoriasis patients for the development of onychomycosis,
and clinicians should be aware of this vulnerability. For the future it would be
interesting to differentiate between nail psoriasis patients which are more prone to
develop a coexisting mycotic infection according to treatment type or type of nail
feature seen (nail bed or nail matrix features). Hypothetically, pathogens most likely
invade the nails of patients having onycholysis and hyperkeratosis preferably then
patients with for example only pitting (matrix features).
When looking at the specific pathogens causing onychomycosis in nail psoriasis,
no shift in causative agents from dermatophytes to yeast and/or moulds could be
seen based on the overview. Also here, the variability in methodology of the included
studies made comparison troublesome. Most studies did not differentiate between
pathogens found in the fingernails or toenails, while it is known that localization of
onychomycosis must be taken into account as dermatophytes are the most common
causative pathogens of onychomycosis in toenails, while yeast are more frequently
isolated from fingernails.36
The major limitation of chapter 5 was the heterogeneity of available studies. We used
the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology)
checklist as a quality assessment tool for the evaluation of the quality of included
studies. However, the primary goal of the STROBE is to serve as a guideline for authors of
reports of observational studies, not for grading the quality of studies in a systematic
review. For reviews of observational studies numerous tools have been proposed,
however no tool has been adopted for widespread use. Sanderson et al.37 even
showed that a candidate tool is missing. In contrast, for randomized controlled trials
quality tools are well established. In the future a consensus must be reached in the
development of quality criteria for observational studies to promote higher quality
research and making quality assessment possible, also for observational studies.
Aim 5: T o contribute to the elucidation of the link between nail psoriasis an
psoriatic arthritis.
In recent years several publications speculated on the anatomical link between nail
psoriasis and PsA. In chapter 6 we aimed to contribute to the elucidation of this
assumed link. Based on the hypothesis of McGonagle et al., suggesting that entheses
might play a key role in the link between nail psoriasis and PsA, we investigated this
anatomical-based link using three-dimensional ultrasound imaging of the extensor
tendon of the distal interphalangeal joint in nail psoriasis patients. The results showed
that patients with nail psoriasis had significant thicker radial entheses compared to
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both control groups (healthy controls and psoriasis patients without nail involvement).
However, no significant differences in entheseal thickness were found between
entheses of adjacent involved and adjacent uninvolved nails, and no association was
found between entheseal thickening and nail matrix features. The results presented in
chapter 6 make an anatomical based co-pathogenesis of nail psoriasis and PsA less
likely. As discussed and hypothesized in this chapter a possible explanation for the
coincidence of nail psoriasis and PsA might rather be sought at the genetic level. As
previously described, the major genetic determinant for development of psoriasis is the
allele HLA-cW6 located on PSORS1. However, patients with PsA and/or nail psoriasis are
more frequently HLA-cW6 negative which might point towards genetic-based but
immunological driven similarities of nail psoriasis and PsA patients.38 As PsA can lead to
deformity and invalidation, prevention and early recognition is important as it seems
that early diagnosis and treatment will reduce irreversible joint damage. It is still
questionable whether early intervention will prevent or delay the onset of PsA in
psoriasis patients without joint involvement. Presence of nail psoriasis might help to
identify patients with increased risk of development of PsA, however not all patients
with nail psoriasis will develop PsA. Therefore it would be interesting to search for
similarities in the genetic profile of both nail psoriasis and PsA patients or to identify a
marker which might be a predictor for the development of PsA. Understanding the
genetic and resulting immunological differences between the different psoriasis
phenotypes may allow the development of targeted therapies that treats nail psoriasis
patients before PsA is destructive and hereby may prevent disabling joint disease. The
predominant limitation in the search for an explanation for the link between nail
psoriasis and PsA is the time span. Most patients develop arthritic involvement years
after the first signs of psoriasis. This calls for a registry or a large longitudinal cohort
study with an follow-up of certain decades, identifying the patients who develop nail
psoriasis and eventually PsA, and taken into account that not all patients with PsA have
nail psoriasis.
Conclusion
In recent years progress has been made to increase the knowledge on nail psoriasis.
We have shown that nail psoriasis is a prevalent feature seen in psoriasis patients
with onycholysis and pitting as characteristic features. Based on these results an
improved nail psoriasis severity scoring system was developed, the N-NAIL. We have
also shown that patients with nail psoriasis experience impaired quality of life, and
seem to be more prone to a mycotic infection of the nail. Finally, we tried to elucidate
the link between nail psoriasis and PsA, and we showed that most likely this link is not
anatomically-based. As mentioned above, there are still many aspects to explore for
patients with nail psoriasis, and the presented results will hopefully contribute to
further unraveling of the spectrum of nail psoriasis.
162
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25. Ortonne JP, Baran R, Corvest M, Schmitt C, Voisard JJ , Taieb C. Development and validation of nail
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The J Invest Dermatol 2002;118:362-5.
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Chapter 8
Nederlandse samenvatting
en discussie
NEDERLANDSE SAMENVATTING
Introductie
Het doel van de onderzoeken gepresenteerd in dit proefschrift was om inzicht te
krijgen in de verschillende aspecten van nagelpsoriasis. In dit afsluitende hoofdstuk
zullen de conclusies van het proefschrift samengevat en bediscussieerd worden aan
de hand van de doelstellingen geformuleerd in hoofdstuk 1. Vervolgens zullen
richtingen voor toekomstig onderzoek beschreven worden, gebaseerd op de
geformuleerde conclusies.
Doel 1.1: Inzicht verkrijgen in de prevalentie en klinische karakteristieken van
nagelpsoriasis.
Hoewel in het verleden verschillende studies zich gericht hebben op de prevalentie
van nagelafwijkingen in psoriasis patiënten blijft de prevalentie onduidelijk; de
gerapporteerde prevalentie varieert tussen de 10% en 80% in de literatuur. Daarom
werd in hoofdstuk 2.2 de prevalentie in een grote groep psoriasis patiënten
bestudeerd en gerapporteerd. De resultaten toonden een nagelpsoriasis prevalentie
van 66% in een groep van 1459 psoriasis patiënten. Gezien de onderzoeksopzet (zelfgerapporteerde vragenlijsten onder de leden van een patiëntenvereniging) kan het
zijn dat de gevonden prevalentie een overschatting van de werkelijkheid is. Echter,
wanneer we dit percentage vergelijken met de percentages beschreven in de
literatuur, zien we dat de prevalentie varieert van 47% tot 81%1-6; slechts twee studies
vonden een prevalentie beneden de 40%. Dit geeft aan dat het percentage
gepresenteerd in dit hoofdstuk mogelijk een reële afspiegeling van de werkelijkheid
is. Op basis van de gevonden resultaten en de literatuur kunnen we concluderen dat
de prevalentie van nagelpsoriasis onder psoriasis patiënten vaak onderschat wordt
en dat herkenning van karakteristieke nagelpsoriasis manifestaties belangrijk is
omdat het een frequent voorkomend, en soms vroege manifestatie van de ziekte is.
Kennis over de prevalentie van de verschillende kenmerken die in nagelpsoriasis
gezien worden is derhalve essentieel voor artsen die patiënten met huid en nagelafwijkingen behandelen. In hoofdstuk 2.1 en 2.2 worden de resultaten gepresenteerd
van twee studies waarin de focus op de kenmerken van nagelpsoriasis ligt. In
hoofdstuk 2.1 werden onycholyse (93.9%), splinterbloedingen (93.9%) en pitting
(73.5%) het meest frequent gezien. In hoofdstuk 2.2 werden pitting (65.4%),
onycholyse (57.7%) en het olievlekfenomeen (41.4%) het frequentst gedocumenteerd.
Pitting en onycholyse werden frequent gerapporteerd in beide studies, ondanks de
verschillen in studieopzet. Deze bevindingen komen overeen met de literatuur. 4,6,9,10
Beide studies toonden aan dat red spots in de lunula een fenomeen is dat zelden
gezien wordt in nagelpsoriasis (2.0% en 6.5%, respectievelijk). Daarentegen toont
hoofdstuk 2.1 dat Beau’s lines frequent gezien worden nagelpsoriasis. Helaas werd er
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niet naar de aanwezigheid van Beau’s lines gevraagd in de vragenlijst die werd
ingevuld door de patiënten geïncludeerd in hoofdstuk 2.2. Uit de literatuur blijk dat
Beau’s lines zelden geëvalueerd worden in nagelpsoriasis studies. Alleen in een studie
van Garzitto et al.11 werd dit fenomeen gerapporteerd en zij vonden een prevalentie
van 29.4% in nagelpsoriasis patiënten. Het is algemeen aanvaard dat leukonychia een
karakteristieke nagelmanifestatie is in psoriasispatiënten. Echter, de nagels van de
controlegroep in hoofdstuk 2.1 toonden significant vaker leukonychia in vergelijking
met de nagelpsoriasis patiënten (65.3% vs. 40.8%, p=0.015). Op basis van de gevonden
resultaten en een vergelijkbaar resultaat gevonden in een studie van Garzitto et al.,
uitgevoerd naar aanleiding van het onderzoek gepresenteerd in hoofdstuk 2.1,
kunnen we concluderen dat leukonychia een niet-specifieke uiting van nagelpsoriasis
is. In het meest frequent gebruikte nagelpsoriasis scoringssysteem, de Nail Psoriasis
Severity Index (NAPSI), zijn leukonychia en red spots in de lunula geïncludeerd als
twee van de acht klassieke nagelmanifestaties gezien in psoriasis. Beau’s lines worden
niet gescoord in de NAPSI. Gezien de resultaten beschreven in hoofdstuk 2.1 en 2.2,
dient de constructie van de NAPSI heroverwogen te worden. De gepresenteerde
gegevens met betrekking tot de klinische karakteristieken en prevalentie van
nagelpsoriasis zijn tevens waardevol voor de diagnostiek en evaluatie van
nagelpsoriasis, maar ook voor het onderwijzen van dermatologen en huisartsen in
het herkennen van nagelpsoriasis.
Doel 1.2: Inzicht verkrijgen in de behandelervaringen van patiënten met
nagelpsoriasis.
Studie 2.2 toonde aan dat 16% van de nagelpsoriasis patiënten een behandeling
kreeg voor zijn nagelafwijkingen, terwijl 47% van de patiënten verklaarde dat zij graag
behandeling zouden willen krijgen voor hun nagelpsoriasis. Deze gegevens tonen aan
dat er een discrepantie bestaat tussen de behandelbehoefte van nagelpsoriasis
patiënten en het werkelijke aantal patiënten dat behandeld wordt specifiek voor hun
nagelpsoriasis. Het aantal patiënten dat voor nagelpsoriasis behandeld wordt is zelfs
aanzienlijk lager in vergelijking met een vergelijkbare groep patiënten in 1996.1 Een
mogelijke verklaring voor het lage percentage patiënten dat behandeling voor
nagelpsoriasis krijgt zou kunnen zijn dat de cutane psoriasis manifestaties het klinisch
beeld domineren waardoor de focus van de psoriasis behandeling op de cutane
component ligt. Een andere mogelijke verklaring zou kunnen zijn dat dermatologen
behandeling van nagelafwijkingen behorende bij psoriasis als ineffectief ervaren
mede omdat resultaten vaak pas gezien worden na een lange behandelperiode
omdat de nagels langzaam groeien en herstellen. Ten slotte zouden patiënten hun
psoriasis behandeling kunnen beschouwen als een behandeling gericht op de cutane
psoriasis laesies onwetende dat dezelfde behandeling ook hun nagelafwijking kan
170
behandelen. Het lage percentage is echter opmerkelijk wetende dat de behandelopties
toenemen, de assertiviteit van de patiënten groeit en cosmetische aspecten steeds
belangrijker worden. In hoofdstuk 2.2 verklaarde patiënten dat zij positieve effecten
hebben ervaren op hun nagelafwijkingen van verschillende, voornamelijk systemische
medicamenten (bv. Biologics, fumaarzuur, methotrexaat). In overeenstemming met
de ervaringen van de patiënten beschreven in hoofdstuk 2.2 laten verschillende
andere studies positieve effecten zien van verschillende behandelopties.12-22 Een
recent Cochrane review laat zien dat er gekwalificeerd bewijs is voor de effectiviteit
van infliximab en golimumab (anti-tumor necrosis factor) en radiotherapie op
nagelpsoriasis.13 Er konden echter maar 18 studies geïncludeerd worden in dit review
omdat de kwaliteit van de studies over het algemeen laag was.13 Onze resultaten,
samen met de resultaten gepresenteerd in het review, tonen aan dat hoogwaardig
onderzoek naar de effecten van behandelingen op nagelpsoriasis noodzakelijk is.
Trials naar de effectiviteit van behandelingen op nagelpsoriasis zouden echter allen
dezelfde methodologie moeten gebruiken om te garanderen dat vergelijking van de
resultaten mogelijk is en de kwaliteit van de onderzoeken goed is. De behandeling
van patiënten met nagelpsoriasis vraagt echter om een patiëntgecentreerde
benadering gezien de potentiële toxiciteit van de systemische antipsoriasismedicamenten. Daarom moeten de voor- en nadelen van ieder therapeuticum meegenomen
worden in de behandeloverweging. Bovendien moeten er indicaties geformuleerd
worden voor het voorschrijven van systemische medicatie in nagelpsoriasis patiënten
zodat richtlijnen ontwikkeld kunnen worden. Voorbeelden van indicaties voor
systemische behandeling zouden kunnen zijn de aanwezigheid van tevens artritis
psoriatica, ernstige cutane psoriasis, of wanneer de nagelmanifestaties de kwaliteit
van leven in groter mate beïnvloed. Wij hopen dat met de gepresenteerde resultaten
een signaal afgegeven wordt voor de noodzaak voor het genereren van onderzoek
van hoge kwaliteit naar de effectiviteit van behandelingen op nagelpsoriasis.
Doel 2: Meer inzicht krijgen in de kwaliteit van leven van nagelpsoriasis
patiënten.
Naar aanleiding van het lage percentage nagelpsoriasis patiënten dat behandeld
wordt voor zijn nagelmanifestaties zoals beschreven in hoofdstuk 2, werd er besloten
om de impact van nagelpsoriasis op de kwaliteit van leven van deze patiënten te
onderzoeken in hoofdstuk 3. In hoofdstuk 3.1 en 3.2 presenteren we de resultaten
van verschillende generieke, dermatologiespecifieke en nagelpsoriasisspecifieke kwaliteit
van leven vragenlijsten toegepast op nagelpsoriasis patiënten. Ten tijde van het opzetten
van studie 3.1 was er geen gevalideerde nagelpsoriasis-specifieke kwaliteit van leven
score beschikbaar en werd ervoor gekozen om een generieke kwaliteit van leven
score te gebruiken te samen met een gemodificeerde onychomycose kwaliteit van
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leven vragenlijst primair ontwikkeld door Drake et al.23 Door gebruik te maken van
een generieke score (Short Form-36, SF-36) was het mogelijk om aan te tonen dat
nagelpsoriasis (met minimale cutane psoriasis activiteit) geen invloed heeft op de
perceptie van de algemene gezondheid door deze patiënten. De resultaten van de
gemodificeerde vragenlijst van Drake et al. lieten zien dat nagelpsoriasis patiënten
weldegelijk restricties ervaren vanwege hun nagelafwijkingen. De resultaten op deze
vragenlijst lieten ook zien dat de voornaamste ziektelast ervaren wordt in de sociale
dimensie. Patiënten maken zich zorgen over het oordeel van anderen vanwege nagelafwijkingen. Daarnaast ervaart de helft van de patiënten pijnklachten veroorzaakt
door de nagelafwijkingen. De gepresenteerde resultaten geven aan dat clinici
rekening moeten houden met de (sociale) impact en pijnklachten veroorzaakt door
de nagelafwijkingen wanneer zij een nagelpsoriasis patiënt behandelen.
In hoofdstuk 3.2 werd de meest gebruikte kwaliteit van leven score in de
Dermatologie toegepast op nagelpsoriasis patiënten; de Dermatology Life Quality
Index (DLQI). Patiënten met nagelpsoriasis scoorden een significant hoger gemiddelde
score in vergelijking met psoriasispatiënten zonder nagelafwijkingen (gemiddelde
DLQI 4.9 versus 3.7, p=<0.001, respectievelijk). Deze resultaten laten zien dat psoriasis
patiënten een lagere kwaliteit van leven ervaren wanneer er nagelafwijkingen
aanwezig zijn. Wanneer we echter kijken naar de interpretatie van de DLQI score, zien
we dat beide groepen in dezelfde effect categorie vallen (categorie twee, DLQI score
2-5). Deze categorie geeft aan dat de invloed van de dermatologische afwijking op de
kwaliteit van leven laag is.24 De klinische betekenis van het verschil tussen de twee
groepen is twijfelachtig ondanks de significantie, maar het verschil is aanwezig en kan
niet genegeerd worden. Bij het interpreteren van de resultaten van de DLQI moet wel
rekening gehouden worden met het feit dat de DLQI de impact van cutane afwijkingen
in het algemeen meet en niet specifiek de impact van nagelpsoriasis. Het verschil
tussen de beide groepen zou dus mogelijk verklaard kunnen worden doordat de
psoriasis in de nagelpsoriasisgroep ernstiger is dan in groep patiënten zonder nagelafwijkingen zoals aangetoond met de SAPASI score (6.6 vs. 5.3, p=<0.001, respectievelijk).
Een andere mogelijke verklaring zou de hogere prevalentie van artritis psoriatica in
nagelpsoriasispatiënten kunnen zijn zoals bediscussieerd in het artikel. Wanneer je
de DLQI gebruikt blijft de specifieke impact van nagelpsoriasis op de kwaliteit van
leven dus onduidelijk. De resultaten tonen aan dat de DLQI niet specifiek genoeg is
om de impact van nagelpsoriasis op de kwaliteit leven te bepalen, wat mogelijk te
verklaren is door de aard van de vragen gezien deze niet specifiek betrekking hebben
op de nagels.
In 2010 werd er een nagelpsoriasis specifieke kwaliteit van leven vragenlijst
ontwikkeld en gepubliceerd door Ortonne et al., de Nail Psoriasis Quality of life 10
(NPQ10), welke vervolgens toegepast kon worden in hoofdstuk 3.2.25 De resultaten
van deze vragenlijst lieten zien dat patiënten voornamelijk beperkingen ervaren in de
172
dagelijkse activiteiten (bv. aantrekken van schoenen en/of sokken) alsmede dat 36%
van de psoriasispatiënten met nagelafwijkingen pijn ervaart. De lokalisatie van de
nagelafwijkingen bleek van belang; nagelbed afwijkingen blijken tot meer beperkingen
te leiden dan wanneer er alleen nagelmatrix afwijkingen aanwezig zijn. In tegenstelling
tot de DLQI en de SF-36 ligt de focus van de NPQ10 op specifieke restricties die nagel
afwijkingen met zich mee zouden kunnen brengen. De resultaten van de NPQ10 en de
gemodificeerde onychomycose vragenlijst geven aan dat het waardevol is om een
instrument te gebruiken dat specifiek de ziektelast meet die nagelafwijkingen met
zich meebrengen omdat dit mogelijkheden biedt voor een patiëntgerichte aanpak.
Voor de toekomst zou het interessant kunnen zijn om een specifieke score te
gebruiken in de follow-up van behandelingen voor nagelpsoriasis om zo veranderingen
in kwaliteit van leven gedurende behandelingen inzichtbaar te maken. Naar onze
mening moeten de kwaliteit van leven scores voor nagelpsoriasis patiënten echter
wel verder ontwikkeld en verbeterd worden. De gemiddelde score op de NPQ10 was
9.9% (met een maximum van 100%). Dit geeft aan dat de score niet in zijn volledige
bereik wordt gebruikt. Een mogelijke verklaring hiervoor zou kunnen zijn dat de
meeste patiënten de restricties opgenomen in deze vragenlijst niet ervaren en andere
relevante vragen missen. Bepaalde vragen (bv., ‘vanwege mijn nagelpsoriasis, heb ik
hulp nodig bij het aankleden’) zouden mogelijk vervangen moeten worden door
vragen die betrekking hebben op restricties meer specifiek voor nagelpsoriasis zoals
de vragen die in de onychomycose vragenlijst toegepast worden. De NPQ10 is echter
nog nauwelijks toegepast in onderzoeksverband en toekomstig onderzoek is nodig
om onze bevindingen te bevestigen dan wel te weerleggen. Verdere modificatie en
validatie van de onychomycose vragenlijst zou ook een mogelijke optie voor de
toekomst kunnen zijn. De waarde van de resultaten gevonden in de bovengenoemde
twee studies is dat ze laten zien dat nagelpsoriasis weldegelijk een significante impact
kan hebben op specifieke aspecten binnen de kwaliteit van leven van patiënten en
clinici zouden meer aandacht moeten hebben voor de nagels wanneer zij psoriasis
gaan behandelen. Specifieke scoringssystemen voor de kwaliteit van leven in nagel
psoriasis moeten verder ontwikkeld en toegepast worden.
Doel 3: Inzicht geven in de verschillende bestaande nagelpsoriasis
scoringssystemen voor het bepalen van de ernst van nagelpsoriasis en
het ontwikkelen van een scoringssysteem dat de klinische
ernst beter weergeeft.
Naar aanleiding van de resultaten van studie 2.1 en 2.2, onze ervaringen en de
literatuur, werd het duidelijk dat het scoren van de ernst van nagelpsoriasis middels
de NAPSI limitaties met zich meebrengt. Het doel van hoofdstuk 4 was daarom om
de verschillende bestaande nagelpsoriasis scoringssystemen voor de ernst van
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nagelpsoriasis, inclusief de NAPSI, te vergelijken met een standaard score voor de
klinische ernst, de Physician Global Assessment (PGA), om op deze manier inzicht te
krijgen in de kwaliteit van de bestaande systemen en om een scoringssysteem te
ontwikkelen die de klinische ernst beter weergeeft. In de literatuur worden zeven scorings
systemen beschreven en deze werden allen gebruikt in hoofdstuk 4. Een scorings
systeem ontwikkeld door Baran26 en de Psoriasis Nail Severity Score (PNSS)27 lieten
een acceptabele correlatie met de PGA van respectievelijk r=0.735 en r=0.734 zien.
De frequent gebruikte NAPSI score liet een matige correlatie ten aanzien van de PGA
zien (r=0.669). Daar komt bij dat eerdere studies hebben laten zien dat de NAPSI niet
altijd sensitief genoeg is voor het weergeven van klinische verbetering over tijd.28,29
Dit wordt mogelijk veroorzaakt doordat de NAPSI alleen de aanwezigheid of
afwezigheid van de verschillende klinische afwijkingen scoort in plaats van de mate
van ernst. Naar aanleiding van deze resultaten werd er in hoofdstuk 4 een scoringssysteem ontwikkeld die de klinische ernst meer accuraat weergeeft. In de ontwikkelingsfase werden de resultaten van hoofdstuk 2 meegenomen en uiteindelijke werd
de Nijmegen-Nail psoriasis Activity tooL (N-NAIL) ontwikkeld. De resultaten toonden
dat de N-NAIL een veel betere reflectie van de mate van ernst van nagelpsoriasis
weergeeft in vergelijking met de zeven bestaande scoringssystemen (r=0.861).
Verschillende nagelafwijkingen gezien in nagelpsoriasis werden toegevoegd (Beau’s
lines) of verwijderd (bv. leukonychia, red spots in de lunula) in vergelijking met de
klassieke nagelpsoriasis scoringssystemen. Daarnaast werd de N-NAIL tot op zekere
hoogte gevalideerd. De resultaten lieten een interobserver betrouwbaarheid
variërend van 0.967 tot 0.989 zien en een intraobserver betrouwbaarheid van 0.899
wat aangeeft dat de N-NAIL een excellente reproduceerbaarheid heeft. Voor de
toekomst moeten er echter nog verschillende clinimetrische aspecten van de N-NAIL
bepaald worden om de score volledig te valideren. Het bepalen van de responsiviteit
(het vermogen van een scoringssysteem om veranderingen in de tijd weer te geven)
van de N-NAIL met betrekking tot behandeling van nagelpsoriasis zou van grote
waarde zijn. Daarnaast zou de responsdistributie bepaald moeten worden waarin
duidelijk wordt of de score over zijn volledige reikwijdte gebruikt wordt. Maar ook de
interpretatie, de mate waarin je een kwalitatieve betekenis aan een kwantitatieve
score geeft, zou bepaald moeten worden. Uiteindelijk zou dit moeten resulteren in de
categorisatie van de uitkomstmaat gerelateerd aan het klinische beeld. Zoals
gepresenteerd in het Cochrane onderzoek uit 2013, is het niet mogelijk om de
resultaten van de verschillende studies met betrekking tot de behandeling van
nagelpsoriasis samen te voegen en te vergelijken omdat de methodologie en de
manier van scoren van de ernst van nagelpsoriasis verschilt. De ontwikkeling en
optimalisatie van de N-NAIL is een eerste stap richting de promotie van het gebruik
van een en hetzelfde scoringssysteem dat de klinische ernst betrouwbaar weergeeft
en op deze manier de vergelijking van uitkomsten van behandelopties mogelijk
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maakt. Uiteindelijk moet dit inzicht geven in de behandelopties voor patiënten met
nagelpsoriasis. De introductie van een adequaat klinisch scoringssysteem alleen dekt
echter niet de gehele lading. Het ultieme nagelpsoriasis scoringssysteem zou een
systeem moeten zijn dat de klinische ernst accuraat weergeeft, maar ook de kwaliteit
van leven en mening van de patiënt mee laat wegen zoals weergegeven in hoofdstuk 3.
In dit tijdperk van personalized medicine zou naast de N-NAIL ook de ervaring van
patiënt en de kwaliteit van leven meegenomen moeten.
Doel 4: Systematisch review van alle beschikbare literatuur met betrekking tot
de prevalentie van onychomycose in (nagel) psoriasis patiënten.
Het doel van hoofdstuk 5 was om inzicht te geven in de prevalentie van onychomycose
in psoriasispatiënten middels een systematisch review van de literatuur. Vanwege de
heterogeniteit van de studies was het niet mogelijk om een meta-analyse te
verrichten. Er konden tien studies geïncludeerd worden en de conclusies in dit
hoofdstuk zijn gebaseerd op een overzicht van deze systematisch verworven studies.
Een breed spectrum van prevalenties van onychomycose in psoriasis patiënten werd
gevonden; van 4.6% tot 63.1% in de psoriasis groep en van 2.4% tot 66.0% in de
controle groep. Dit resulteerde in een gecombineerde prevalentie van respectievelijk
18.0% en 9.1%. In de literatuur worden onychomycose prevalenties beschreven van
6.5%, 8.4%, 4.7% en 20.9% in de algemene populatie. Deze waardes lijken merendeels
overeen te komen met de gecombineerde prevalentie van de controle groep
gevonden in dit review.30-33 De prevalentie van onychomycose in psoriasispatiënten
lijkt verhoogd te zijn in vergelijking met de prevalentie in de algemene populatie en
de geïncludeerde controlegroepen, maar het ultieme bewijs hiervoor ontbreekt nog.
In de literatuur worden verschillende argumenten met betrekking tot de
veronderstelde verhoogde kwetsbaarheid van psoriasisnagels voor mycosen
geopperd. Argumenten die een verhoogde kwetsbaarheid voor mycosen tegenspreken
zijn het feit dat de immuunrespons tegen microbiële huidinfecties opvallend sterk is
in psoriasispatiënten. Tevens zou de verhoogde groeisnelheid van de nagels van
psoriasis patiënten de nagel theoretisch kunnen beschermen tegen invasie van microorganismen.34 De morfologische veranderingen van de nagels van psoriasispatiënten (hyperkeratose, onycholyse) en het gebruik van immunosuppressieve therapieën
zijn argumenten voor een verhoogde vatbaarheid voor het ontwikkelen van een
onychomcyose in deze patiënten groep. Een recent gepubliceerd artikel gaat in op dit
laatste argument en laat resultaten zien met betrekking tot de ontwikkeling van
onychomcycose in nagelpsoriasispatiënten na het starten van anti-TNF therapie. De
resultaten toonden dat nagelpsoriasispatiënten die behandeld werden met infliximab
significant frequenter een onychomycose ontwikkelden (33.0%) na 24 weken
behandeling in vergelijking met gezonde controles en nagelpsoriasis patiënten die
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behandeld werden met adalimumab of etanercept. Deze resultaten laten zien dat
bepaalde immunosuppressieve therapieën het risico op het ontwikkelen van een
onychomycose in nagelpsoriasis patiënten verhoogt.
Op basis van het review kan geconcludeerd worden dat nagelpsoriasispatiënten
een verhoogd risico hebben op het ontwikkelen van een onychomycose en clinici zich
bewust moeten zijn van dit verhoogde risico. Voor de toekomst zou het interessant
zijn om te differentiëren tussen nagelpsoriasispatiënten die meer vatbaar zijn voor het
ontwikkelen van een coeexistente onychomycose gebaseerd op het type behandeling en
type nagelafwijkingen (nagelbed of nagelmatrix afwijkingen). Hypothetisch gezien
zouden pathogenen een voorkeur kunnen hebben voor nagels met voornamelijk
nagelbedafwijkingen in vergelijking met nagels met bijvoorbeeld alleen nagelmatrix
afwijkingen
In het review werd geen verschuiving gezien in de soort verwekker in psoriasispatiënten ten opzichte van gezonde controles. In de literatuur wordt gesuggereerd
dat de verwekker van een onychomycose vaker een gist en/of non-dermatophyt zou
zijn wanneer er nagelpsoriasis aanwezig is. Maar ook hier werd de vergelijking van de
verschillende onderzoeksresultaten bemoeilijkt door de heterogeniteit van de
geïncludeerde studies. Het merendeel van de studies maakt geen verschil tussen de
soort pathogenen gevonden in teennagels of vingernagels. Het is echter bekend dat je
rekening moet houden met de lokalisatie van de onychomycose gezien dermatophyten de
meeste voorkomende verwekker zijn van een onychomycose van de teennagels en
gisten meer frequent voorkomen aan vingernagels.36
De voornaamste beperking van hoofdstuk 5 was de heterogeniteit van de
beschikbare studies. Wij hebben de STROBE (STrengthening the Reporting of
OBservational studies in Epidemiologie) checklist gebruikt als meetinstrument om de
kwaliteit van de geïncludeerde studies te evalueren. Het primaire doel van de STROBE
is echter om te dienen als leidraad voor auteurs van observationele studies en niet
voor het graderen van de kwaliteit van studies in een systematisch review. In de
literatuur worden er verschillende potentiële meetinstrumenten voor observationele
studies genoemd, echter geen van allen is geaccepteerd voor algemeen gebruik.
Sanderson et al.37 toonde zelfs aan dat een kandidaatsinstrument mist. Kwaliteitsinstrumenten voor gerandomiseerde gecontroleerde trials daarentegen zijn goed
ontwikkeld. In de toekomst moet consensus over de ontwikkeling van kwaliteitscriteria voor observationele bereikt worden om kwaliteitsonderzoek te bevorderen en
een kwaliteitsbeoordeling mogelijk te maken, ook voor observationele studies.
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Doel 5: O
m bij te dragen aan het ophelderen van de link tussen nagelpsoriasis
en artritis psoriatica.
In de afgelopen jaren is er in verschillende publicaties gespeculeerd over de
anatomische link tussen nagelpsoriasis en artritis psoriatica (PsA). Het doel van
hoofdstuk 6 was om bij te dragen aan de opheldering van de gesuggereerde link.
Gebaseerd op een hypothese van McGonagle et al., die suggereert dat entheses
mogelijk een sleutelrol spelen in de link tussen nagelpsoriasis en PsA, hebben wij
deze op anatomie gebaseerde link onderzocht middels drie dimensionale echografie
van de extensor pees van het distale interphalangeale gewricht in nagelpsoriasis
patiënten. De resultaten toonden dat patiënten met nagelpsoriasis significant dikkere
radiale entheses hadden in vergelijking met beide controle groepen (gezonde
controles en psoriasis patiënten zonder nagelafwijkingen). Er werden echter geen
significante verschillen gevonden tussen de dikte van entheses aangrenzend aan
aangedane nagels en entheses aangrenzend aan nagels zonder afwijkingen binnen de
groep nagelpsoriasis patiënten. Ook werd er geen associatie gevonden tussen de
dikte van de entheses en aanwezigheid van matrixafwijkingen. De resultaten
gepresenteerd in hoofdstuk 6 maken een op anatomie gebaseerde co-pathogenese
van nagelpsoriasis en PsA minder waarschijnlijk. Een mogelijke verklaring voor de
coïncidentie van nagelpsoriasis en PsA zou misschien eerder gezocht moeten worden
op het niveau van de genetica zoals bediscussieerd en gehypothetiseerd in dit
hoofdstuk. De voornaamste genetische determinant voor ontwikkeling van psoriasis
is het allel HLA-cW6 gelokaliseerd op het gen PSORS1. Patiënten met PsA en/of
nagelpsoriasis zijn frequenter HLA-cW6 negatief wat mogelijk kan wijzen op een op
genetica gebaseerde, maar immunologisch gedreven overeenkomst tussen nagel
psoriasis en PsA.38 Omdat PsA kan leiden tot deformiteit van een gewricht en de
daarop volgende invalidatie, is preventie en vroege herkenning belangrijk, vooral
omdat het vroeg stellen van de diagnose en instellen van behandeling mogelijk tot
minder irreversibele gewrichtsschade leidt. Het is nog de vraag of dat een vroege
interventie het ontstaan van PsA in psoriasis patiënten zonder gewrichtsklachten kan
verkomen of vertragen. Inzicht in de genetische (en immunologische) verschillen
tussen de verschillende fenotypes van psoriasis kan mogelijk in de toekomst richting
gevend zijn voor welke groep psoriasispatiënten behandeld moet worden om PsA
gerelateerde destructies en de daaruit voortkomende invaliderende gewrichtsziekte
te voorkomen. De voornaamste limitatie in de zoektocht naar een verklaring voor de
link tussen nagelpsoriasis en PsA is de tijdspanne. Het merendeel van de psoriasis
patiënten ontwikkeld pas gewrichtsklachten verscheidene jaren na het ontstaan van
de eerste cutane manifestaties. Dit vraagt om een registry of een grote longitudinale
cohort studie met een follow-up van een aantal decennia waarbij ook rekening moet
worden gehouden dat niet alle patiënten met PsA nagelafwijkingen hebben.
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Conclusie
De laatste jaren is er veel vooruitgang geboekt in het verbreden van onze kennis op
het gebied van nagelpsoriasis. We hebben aangetoond dat nagelpsoriasis een veel
voorkomende manifestatie is onder psoriasis patiënten waarbij onycholyse en pitting
de karakteristieke manifestaties zijn. Gebaseerd op de resultaten werd er een
verbeterd scoringssysteem voor het bepalen van de ernst van nagelpsoriasis
ontwikkeld; de N-NAIL. Wij hebben aangetoond dat patiënten met nagelpsoriasis een
verminderde kwaliteit van leven ervaren en dat nagelpsoriasis patiënten kwetsbaarder
zijn voor het ontwikkelen van een onychomycose. Ten slotte hebben wij geprobeerd
de link tussen nagelpsoriasis en PsA op te helderen en hebben wij aan kunnen tonen
dat deze link zeer waarschijnlijk niet gebaseerd is op de anatomie. Zoals hierboven
beschreven zijn er nog steeds vele aspecten van nagelpsoriasis die verkent moeten
worden en hopelijk dragen de gepresenteerde resultaten bij aan de verdere
ontrafeling van het spectrum van nagelpsoriasis.
Referenties
1. 2. 3. 4. 5.
6. 7. 8.
9. 10.
11. 12. 13. 14. 15. 16. 17. 18.
19.
20.
21. 22.
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De Jong EMGJ, Seegers BAMPA, Gulinck MK, Boezeman JBM , Van de Kerkhof PCM. Psoriasis of the nails
Meas 2011;2:1-6.
Armesto S, Esteve A, Coto-Segura P, Drake M, Galache C, Martinez-Borra J et al. Nail psoriasis in
Kyriakou A, Patsatsi A , Sotiriadis D. Detailed Analysis of Specific Nail Psoriasis Features and Their
Salomon J, Szepietowski JC , Proniewicz A. Psoriatic nails: a prospective clinical study. J Cutan Med Surg
2003;7:317-21.
Rich P, Griffiths CE, Reich K, Nestle FO, Scher RK, Li S et al. Baseline nail disease in patients with moderate
2008;58:224-31.
Soy M, Karaca N, Umit EU, Bes C , Piskin S. Joint and nail involvement in Turkish patients with psoriatic
Grover C, Reddy BS , Uma Chaturvedi K. Diagnosis of nail psoriasis: importance of biopsy and
Kaur I, Saraswat A , Kumar B. Nail changes in psoriasis: a study of 167 patients. Int J Dermatol 2001;40:601-3.
Garzitto A, Ricceri F, Tripo L, Pescitelli L , Prignano F. Possible reconsideration of the Nail Psoriasis
Severity Index (NAPSI) score. J Am Acad Dermatol 2013;69:1053-4.
Radtke MA, Beikert FC , Augustin M. Nail psoriasis - a treatment challenge. J Dtsch Dermatol Ges
2013;11:203-19; quiz 20.
de Vries AC, Bogaards NA, Hooft L, Velema M, Pasch M, Lebwohl M et al. Interventions for nail psoriasis.
Cochrane database of systematic reviews (Online) 2013;1:CD007633.
Rigopoulos D, Ioannides D, Prastitis N , Katsambas A. Nail psoriasis: a combined treatment using
Tosti A, Piraccini BM, Cameli N, Kokely F, Plozzer C, Cannata GE et al. Calcipotriol ointment in nail
J Dermatol 1998;139:655-9.
Zakeri M, Valikhani M, Mortazavi H , Barzegari M. Topical calcipotriol therapy in nail psoriasis: a study of
Tzung TY, Chen CY, Yang CY, Lo PY , Chen YH. Calcipotriol used as monotherapy or combination therapy
with betamethasone dipropionate in the treatment of nail psoriasis. Acta Derm Venereol 2008;88:279-80.
Langley RG, Saurat JH, Reich K , Nail Psoriasis Delphi Expert P. Recommendations for the treatment of
nail psoriasis in patients with moderate to severe psoriasis: a dermatology expert group consensus.
J Eur Acad Dermatol Venereol 2012;26:373-81.
Gumusel M, Ozdemir M, Mevlitoglu I , Bodur S. Evaluation of the efficacy of methotrexate and
2011;25:1080-4.
Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C et al. Infliximab induction and maintenance
therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet
2005;366:1367-74.
Van den Bosch F, Manger B, Goupille P, McHugh N, Rodevand E, Holck P et al. Effectiveness of
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for arthritis, skin and nail lesions. Ann Rheum Dis 2010;69:394-9.
Rigopoulos D, Gregoriou S, Lazaridou E, Belyayeva E, Apalla Z, Makris M et al. Treatment of nail psoriasis
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23. Drake LA, Patrick DL, Fleckman P, Andr J, Baran R, Haneke E et al. The impact of onychomycosis on
quality of life: development of an international onychomycosis-specific questionnaire to measure
patient quality of life. J Am Acad Dermatol 1999;41:189-96.
24. AY Finlay KG. Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use.
Clin Exp Dermatol 1994;19:210-6.
25. Ortonne JP, Baran R, Corvest M, Schmitt C, Voisard JJ , Taieb C. Development and validation of nail
26. Baran RL. A nail psoriasis severity index. Br J Dermatol 2004;150:568-9.
27. Jones SM, Armas JB, Cohen MG, Lovell CR, Evison G , McHugh NJ. Psoriatic arthritis: outcome of disease
subsets and relationship of joint disease to nail and skin disease. British journal of rheumatology
1994;33:834-9.
28. Parrish CA, Sobera JO , Elewski BE. Modification of the Nail Psoriasis Severity Index. J Am Acad Dermatol
2005;53:745-6.
29. de Berker D. Biologics in nail psoriasis. Br J Dermatol 2014;170:236-7.
30. Heikkila H , Stubb S. The prevalence of onychomycosis in Finland. Br J Dermatol 1995;133:699-703.
31. Gupta AK, Jain HC, Lynde CW, Macdonald P, Cooper EA , Summerbell RC. Prevalence and epidemiology
32. Bramono K , Budimulja U. Epidemiology of onychomycosis in Indonesia: data obtained from three
individual studies. Nihon Ishinkin Gakkai zasshi 2005;46:171-6.
33. Burzykowski T, Molenberghs G, Abeck D, Haneke E, Hay R, Katsambas A et al. High prevalence of foot
34. Palatsi R , Hagg P. The immune response against microbial infections in the skin--weak in atopic
dermatitis and strong in psoriasis. Duodecim; laaketieteellinen aikakauskirja 2011;127:127-34.
35. Al-Mutairi N, Nour T , Al-Rqobah D. Onychomycosis in patients of nail psoriasis on biologic therapy: a
Opin Biol Ther 2013;13:625-9.
36. Tchernev G, Penev PK, Nenoff P, Zisova LG, Cardoso JC, Taneva T et al. Onychomycosis: modern
diagnostic and treatment approaches. Wien Med Wochenschr 2013;163:1-12.
37. Sanderson S, Tatt ID , Higgins JP. Tools for assessing quality and susceptibility to bias in observational
38. Gudjonsson JE, Karason A, Antonsdottir AA, Runarsdottir EH, Gulcher JR, Stefansson K et al.
The J Invest Dermatol 2002;118:362-5.
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Chapter 9
List of Publications
Curriculum Vitae
Dankwoord
LIST OF PUBLICATIONS
List of publications
Fingernail psoriasis reconsidered: a case-control study.
Van der Velden H.M., Klaassen K.M., van de Kerkhof P.C.M, Pasch M.C.
J Am Acad Dermatol 2013; 69:245-52.
Nail psoriasis: a questionnaire-based survey.
Klaassen K.M., van de Kerkhof P.C.M., Pasch M.C.
Br J Dermatol 2013; 169:314-9.
The impact of fingernail psoriasis in patients’ health-related and disease-specific
quality of life.
Klaassen KM*, van der Velden HJM*, van de Kerkhof PCM, Pasch MC.
Dermatology 2014; Epub ahead of print.
Nail psoriasis; the unknown burden of disease.
Klaassen KM, van de Kerkhof PCM, Pasch MC.
J Eur Acad Dermatol Venereol 2013; Epub ahead of print.
Scoring Nail Psoriasis.
Klaassen KM, Baran RL, Bastiaens M, Plusjé L, van der Kerkhof PCM, Pasch MC.
J Am Acad Dermatol 2014; Epub ahead of print.
The prevalence of onychomycosis in patient with psoriasis: a systematic review.
Klaassen KM, Dulak MG, van de Kerkhof PC, Pasch MC.
J Eur Acad Dermatol Venereol 2013;28:533-541.
Nail psoriasis: an early indicator for destructive psoriatic arthritis?
Klaassen KM, Ploegmakers M, van de Kerkhof PCM, Klein W, Pasch MC.
Submitted.
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CURRICULUM VITAE
Curriculum Vitae
Karlijn Maria Geertruda Klaassen werd op 30 juni 1986 geboren in Groesbeek, alwaar
zij opgroeide. Na het behalen van het VWO diploma aan de Nijmeegse Scholen
Gemeenschap in Nijmegen in 2004 begon zij aan haar studie geneeskunde aan de
Radboud Universiteit te Nijmegen. Karlijn behaalde haar propedeuse in 2005 en
haar artsexamen in 2011. In het kader van haar opleiding deed zij in 2010 een
onderzoekstage op de afdeling dermatologie van het UMC St Radboud waarna zij
begonnen is aan haar promotieonderzoek eveneens op de afdeling dermatologie
van het UMC St Radboud onder begeleiding van prof. dr. dr. Peter C.M. van de Kerkhof
(promotor) en dr. Marcel C. Pasch (copromotor). In januari 2014 is Karlijn gestart met
de opleiding tot dermatoloog, eveneens in het Radboudumc.
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DANKWOORD
Dankwoord
Klaar! Met veel plezier heb ik de afgelopen jaren aan dit proefschrift gewerkt. Iedereen
die op enige wijze heeft bijgedragen aan de totstandkoming van dit proefschrift wil ik
op deze plaats bedanken, waarvan een aantal mensen in het bijzonder.
Marcel Pasch. Beste Marcel, een groot deel van dit boekje heb ik te danken aan jouw
ideeën, inbreng wanneer ik het even niet meer wist en concrete dinsdagmiddag
besprekingen; mede daardoor is het eindresultaat een mooi geheel geworden! Alle
stukken die ik aanleverde werden voorzien van kritisch en waardevol commentaar, ik
heb veel van je geleerd. Bedankt dat ik jouw ideeën over onderzoek op het gebied
van nagelpsoriasis uit mocht voeren. Maar vooral ook bedankt voor het vertrouwen
in mij en de vrijheid die je mij hebt gegeven voor mijn eigen inbreng. Bedankt!
Professor dr. dr. P.C.M. van de Kerkhof. Beste professor, bedankt voor de mogelijkheid
om te mogen promoveren op uw afdeling. Uw positivisme werkt aanstekelijk en zorgt
voor een fijne sfeer op de afdeling. Mede door uw inbreng en vertrouwen in mij is het
een mooi boekje geworden.
Michelle van Rossum. Beste Michelle, zonder jouw hulp en vertrouwen in mij was dit
onderzoekstraject misschien niet op mijn pad gekomen. Ik wil je bedanken voor je
luisterend oor, vertrouwen in mij en de hulp in de afgelopen jaren, dat heeft mij erg
goed gedaan.
Alle patiënten. Zonder de ruim 1700 vrijwilligers en patiënten was dit boekje nooit tot
stand gekomen. Jullie bereidwilligheid en inzet waren voor mij zeer motiverend en
enthousiasmerend.
Willemijn Klein en Marieke Ploegmakers (afdeling Radiologie Radboudumc). Beste
Willemijn en Marieke, bedankt voor het beoordelen van de vele, vele echo’s en de
samenwerking. Het was niet de leukste radiologische klus maar mede dankzij jullie is
hoofdstuk 6 een mooi slothoofdstuk geworden!
Elise, Lia, Monique en Ria (Mammateam Radiologie Radboudumc). Bedankt voor het
maken van de vele, vele echo’s in de weekenden en in de avonduren. Zonder jullie
hulp was hoofdstuk 6 er niet gekomen en was de inclusie een stuk minder gezellig
geweest. Dank!
Anke, Annet, Juul, Romy en Margit. In de afgelopen drie jaar heb ik er niet alleen vijf
collega’s bij gekregen maar ook vijf vriendinnen! Bedankt voor de gezelligheid in de
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bieb en de vele leuke herinneringen; we hebben samen veel meegemaakt in die drie
jaar! Vrijdagmiddagborrels, meetings, bieb-medleys (Dry ice, why tell me why…), vrijgezellenfeesten en onvergetelijke bruiloften! Mede dankzij jullie heb ik drie geweldige
jaren in de bieb gehad die ik voor geen goud had willen missen! One down … five to
go! Op naar het volgende promotiefeestje!
Biebgenootjes: Anne, Renée en Lisa; bedankt voor de vele theedrink-momenten,
Boedha-momenten, het luisteren naar elkaars frustraties en het vieren van de
behaalde successen! Zonder jullie waren de afgelopen jaren een stuk saaier! Succes
met het afronden van jullie promotie trajecten!
Klinisch onderzoekers: Jorre, Maartje, Malou, Jeffrey, Sabine, Denise en Marisol: het is
een fijne onderzoeksgroep om deel van te mogen zijn. Heel veel succes met al jullie
promotie-trajecten.
Lab collega’s; ondanks dat de lab-technische LOTTO’s en Journal clubs meestal mijn
pet te boven gingen was het altijd leerzaam en gezellig. Veel succes met alle mooie
onderzoeken!
Alle arts-assistenten: bedankt voor jullie gezelligheid en collegialiteit! Haike, bedankt
voor de samenwerking, succes met het afronden van jouw nagelboekje!
Anita Theloosen en Richard Praster (afdeling vaatfunctie onderzoek). Jullie keken mij
verbaasd aan toen ik drie jaar geleden met de vraag kwam of jullie een nagel met
behulp van echografie in beeld konden brengen, maar waren direct bereid dit voor
mij uit te zoeken. Zie hier het resultaat. Dank!
Maarten Bastiaens en Leon Plusjé (dermatoloog). Bedankt voor het scoren van de vele
nagels! Ik denk dat de N-NAIL een mooie score is geworden waarin de ernst van
nagelpsoriasis goed weergegeven wordt. Bedankt voor jullie bijdrage hieraan.
Lieke van Vught (student-assistent). Bedankt voor je hulp met de echo’s op de
zaterdagen. Ik wens je heel veel succes met het laatste stukje van je opleiding en de
verdere weg die je in zal slaan!
Alle stafleden, mensen van het secretariaat, administratie en verpleging: bedankt
voor de prettige sfeer op de afdeling, ik voel me erg welkom hier.
Dear Maria, my Polish is not very well, so thank you for translating every single word
of the Polish articles of the review!
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DANKWOORD
Lieve Eefje en Andrea, ook al zien we elkaar door de drukke agenda’s minder dan ik
zou willen, mijn dank voor jullie twee kan ik niet in woorden omschrijven. Dankjewel
dat jullie er voor mij waren en zijn.
Teamgenootjes: Nikki, Dianne, Meike, Mijke, Margo, Robin, Marlou, Melissa, Karin en
Isa; bedankt voor de afleiding op de dinsdag- en donderdagavonden en zondagen!
Van jullie heb ik geleerd tot wat voor een prestaties je in staat bent zolang je maar
samenwerkt als een team. Op naar Eindhoven!
Annelies, Daan, Karin, Tineke, Ineke en Saskia. Lieve vriendinnen, ook al zie ik jullie
niet meer zo vaak als ik zou willen; door jullie kan ik terug kijken op een geweldige
studententijd! Ook nu ieder zijn eigen weg aan het gaan is voelt het altijd weer
vertrouwd wanneer we samen zijn!
Romy (paranimf). Lieve roomster, bedankt dat je vandaag naast mij wilt staan! We
kennen elkaar vanaf de eerste dag dat we op de dermatologie binnenkwamen als
afsluitende/senior coassistenten en meteen bleken we vaak op een lijn te zitten.
Bedankt voor je luisterend oor de afgelopen jaren en je altijd oprechte interesse in
mij en al de anderen. Ik ben er trots op hoe jij in drie jaar zo’n klasse boekje hebt
kunnen schrijven!
Karin (paranimf). Lieve Karin, bedankt voor je luisterend (outlook) oor en de
onvergetelijke onverwachtse vrijdagavonden! Jij weet als geen ander wat je wilt en
ben trots op wat jij tot nu toe al bereikt hebt! Maar zeker ook bedankt voor je steun
en knuffels de afgelopen vijf jaar, zonder jouw hulp en afleiding zouden de afgelopen
jaren een stuk moeilijker zijn geweest. Ik ben er trost op dat jij vandaag naast mij
staat! Nel is ons hopelijk ook vandaag goed gezind!
Lieve Kim en Jeroen, Dagmar en Bart, Loes en Joris. Bedankt voor jullie gezelligheid,
steun en interesse de afgelopen jaren. Ik kan me geen fijnere en leukere familie
wensen! We hebben het goed gedaan de afgelopen jaren! Jules, Pepijn, Sophie, Linn,
Niene en Casper bedankt voor jullie gezelligheid, knuffels en afleiding!
Lieve Henk en Diny, jullie zijn altijd erg geïnteresseerd in al mijn bezigheden!. Ik wil
jullie dan ook bedanken voor jullie betrokkenheid in alles wat Sander en ik weer
bedenken; van een huisje op de Husenhoff tot Ollie, jullie staan altijd voor ons klaar!
Maar dit is denk ik ook een mooie gelegenheid om jullie vooral ook te bedanken voor
jullie steun de afgelopen jaren, het is fijn om zo’n lieve en zorgzame schoonouders te
hebben!
191
9
CHAPTER 9
Lieve papa en mama, mijn doorzettingsvermogen en positieve instelling heb ik zeker
van jullie! Jullie leerden mij op een ongedwongen manier door te zetten maar vooral
ook van het leven te genieten. Lieve mama, ik bewonder hoe jij je door de laatste
jaren heen hebt gevochten en er toch altijd voor ons was en bent. Ik ben trots op je.
Lieve papa, vandaag is de dag, ik weet dat je trots bent op ons allemaal!
Tonnie, ook jou wil ik bedanken voor je interesse en gezelligheid de afgelopen jaren.
Ik vind het gezellig met je erbij in de familie!
Lieve Sander, het is af! Zonder jouw steun, gezelligheid, afleiding, luisterend oor, Ollie-
wandelingen, kookkunsten en geloof in mij van begin tot eind had ik dit niet voor
elkaar gekregen! Maar vooral ook voor de arm om mij heen wanneer het even wat
lastiger was en is! Jij voelt perfect aan wanneer ik die knuffel kan gebruiken!. Samen
met jou loop ik nooit alleen; You’ll never walk alone. Ik heb zin in de rest van ons leven
samen! Ps….you know what.
Liefs,
Karlijn
192

Nail psoriasis - Radboud Repository

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