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EDITORIALS
G ITAL DERMATOL VENEREOL 2006;141:177-8
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Dermatologic radiotherapy: when, why and how?
F
or a long time, papers on dermatologic radiotherapy were practically inexistent. It is with great
pleasure that we realize a renaissance of communications about this treatment, not only for lentigo maligna
and lentigo maligna melanoma, for lymphomas but
also for skin carcinomas as mentioned in the paper
published in the February issue of the journal. The
paper worked out by Percivalle et al.1 is a very good
example to describe and to remind to the readers, especially the dermatologists, the excellence of this treatment modality.
Department of Dermatology
University Hospital CHUV, Lausanne, Switzerland
indication, the functional and cosmetic results being
excellent, especially as mentioned by the authors on
the eyelids. Therefore, it is not surprising that the
authors are able to demonstrate a cure-rate of 96.72%.
In addition, we have to stress that the department, in
Milan, has a long time experience in this field, another important factor for this success rate.
When?
Why?
The paper by Percivalle et al.1 shows that there are
especially elderly people who profit from radiotherapy. We realize that we practically have no negative
answers from all these elderly irradiated patients. They
confirm that they would repeat this treatment without
hesitation.
There are medium sized tumours especially basal
cell carcinomas, but also squamous cell carcinomas
which represent an excellent indication since they show
a good radiosensitivity and radioresponsiveness. Then
the localization of the tumors in the face are a good
Why do elderly patients especially appreciate radiotherapy ? Because this treatment modality has the following advantages:
1) provokes no pain;
2) the patient may sit or lay down only for a couple
of minutes;
3) it is done on an outpatient basis;
4) the functional and also cosmetic results are excellent;
5) important organs can be protected;
6) there is nearly no scarring.
SEE PAGE 29, VOLUME 141, ISSUE No. 1, FEBRUARY 2006
Address reprint requests to: R.G. Panizzon, Department of Dermatology,
University Hospital CHUV, Lausanne, Switwerland. E-mail [email protected]
Vol. 141 - N. 3
R. G. PANIZZON
How?
How is the treatment performed?2-6 One thing must
clearly be communicated to the patients: radiotherapy
can only be given in fractionated doses, this means in
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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PANIZZON
DERMATOLOGIC RADIOTHERAPY
the eyelashes is nearly not realized by other persons.
An important advantage with irradiation of the eye
structures is that there is never an obliteration of the
lacrymal duct and there is nearly no leucoplakia as a
consequence. Therefore, it is not astonishing that the
cosmetic result reported by Percivalle et al.1 is acceptable or good in 98.9%.
Can you offer a better treatment result especially
after a mean follow-up of 5 years for your patients ?
Therefore: there is a renaissance of Dermatologic
Radiotherapy!
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several sessions. A single session therapy is practically abandoned. On the other hand, it is not always
necessary to irradiate on a daily basis, but there is the
possibility of 2 or 3 sessions per week . We see no difficulty either by members of the family or of some
organizations (e.g. Red Cross) helping for the transportation of these patients. It must also be said that
the first session needs a little bit more time for the
treatment planning and documentation (around 45
min), but the following irradiation sessions as mentioned above are lasting only for a couple of minutes.
Radiation reactions also will appear but only at the
end of the treatment and even if these reactions sometimes are oozing, they are not painful for the patient.
Another possibility and advantage is that the radiotherapist has not to calculate with 1, 2 or 3 mm, but
mostly can include a security margin of 5 mm or more,
and still preserve the healthy tissue, this margin being
an important advantage of this treatment. Moreover,
after incomplete surgical removal which occurs in a
good part of the patients, radiotherapy might be followed. We also want to stress that the rest of the body
doesn’t irradiate and has no consequences for the
patients. In addition, there will be no general hair loss
and no intestinal (general) symptoms, and important
organs such as the eyes can be protected. After a cancericidal dose there might be hair loss in the radiation
field or loss of the eyelashes (if eyelids are irradiated)
as described in this paper. In elderly patients a loss of
178
References
1. Percivalle S, Piccinno R, Gnecchi L, Caccialanza M. Radiotherapy of
cutaneous carcinomas of the eyelids: results in 88 lesions. G Ital Dermatol Venereol 2006;141:11-5.
2. Caccialanza M. Treatment of skin carcinomas and kerato-acanthoma.
In: Panizzon RG, Cooper JS eds. Radiation treatment and radiation
reactions in dermatology. Frankfurt: Springer, 2006.p.69–82.
3. Olschewski T, Bajor K, Lang B, Lang E, Seegenschmiedt MH. [Radiotherapy of basal cell carcinoma of the face and head: Importance of
low dose per fraction on long-term outcome]. J Dtsch Dermatol Ges
2006;4:124-30.
4. Panizzon RG. Basal cell and squamous cell carcinoma – radiotherapeutic approaches. In: Sternemann M ed. Controversies in the treatment of skin neoplasias. Frankfurt: Karger, 2006. p. 38–49.
5. Schulte KW, Lippold A, Auras C, Bramkamp G, Breitkopf C, Elsmann
HJ et al. Soft X-ray therapy for cutaneous basal and squamous cell carcinomas. J Am Acad Dermatol 2005;53:993-1001.
6. Zagrodnik B, Kempf W, Seifert B, Muller B, Burg G, Urosevic M et
al. Superficial radiotherapy for patients with basal cell carcinoma.
Cancer 2003;98:2708-14.
Giugno 2006
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Clinical advances in metastatic melanoma
K. MUNTE, H.A.M. NEUMANN
E
arly knowledge of pote”ntial metastasis is a long
existing wish of many physicians. Malignant
melanoma is a frequent dermatological malignant
tumor with a high potential of metastasis. A strong
correlation exists between the metastatic potential and
the tumor depth in the dermis, as measured by the
Breslow method. However, even thin tumors (Breslow < 0.75 mm) will sometimes metastasize.
Knowledge of early metastasis is only of value if
the impact of such a finding is of help for the patient.
In the past, it has been proven that blind lymph node
dissection will not lead to higher survival rates for
melanoma patients. More recently the sentinel node
technique is widely used for melanoma patients. Until
now there is no clear evidence for the benefits of such
a procedure. Medalie and Ackerman 1 concludes in
short, no surgeon, pathologist, or oncologist is a seer,
diviner, or prophet when it comes to predicting accurately the outcome for a patient with metastasis of
melanoma; the end could come in weeks, months, or
decades. There is no justification, whatsoever, for the
procedure, scientifically or practically, and for that
reason it should be abandoned, without delay, now.
However, there also seems to be some new data supporting some effectiveness from the sentinel node
biopsy in melanoma patients.2
SEE PAGE 99, VOLUME 141, ISSUE No. 2, APRIL 2006
Address reprint requests to: K. Munte, Erasmus M.C., Dept. Dermatology and Venereology, P.O.Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: [email protected]
Vol. 141 - N. 3
Department of Dermatology and Venereology
Erasmus Medical Center, Rotterdam, The Netherlands
Rörsman was able to detect small amounts of melanin
metabolites in urine as possible result of metastasing.3
This test has never entered the clinic. Of course, nowadays there is also the 18 F-fluorodeoxyglucose (FDG)
PET scan to screen patients for metastasis, which are not
found by conventional screening methods.4, 5 Only in the
case of small long nodules and brain metastasis conventional computer tomography (CT) and magnetic
resonance imaging (MRI) are better evaluated.6 Nonetheless, FDG-PET is the modality of choice in patients
with high risk for distant metastases, suspicious for distant metastases, known with distant metastases which
can benefit from customized therapies if new lesions
are discovered or treated lesions regress and at last
patients at high risk for systemic relapse after aggressive
medical therapy.6
In the April issue of this journal, Ferrari et al. present their results about nm23 expression in primary
melanoma and the prognosis for a 10 year diseasefree interval.7 Their study population is very small for
making strong evidence. They found that expression of
nm23 protein was correlated with a disease-free interval of 5 years and even with 10 years. Consequence of
this, they also found the same positive correlation with
the survival.
What about the already in 1988 by Steeg et al. discovered nm23 gene?8
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CLINICAL ADVANCES IN METASTATIC MELANOMA
tumor progression by micro array technique in such a
way as to provide a molecular map of each tumor.
Tumor suppressor genes encode for proteins whose
normal function is to inhibit cell transformation and
whose inactivation is advantageous for tumor cell
growth and survival.
Tumor suppressor genes participate in a variety of
critical and highly conserved cell functions, including regulation of the cell cycle and apoptosis, differentiation, surveillance of genomic integrity and repair
of DNA errors, signal transduction, and cell adhesion.
Tumor suppression functions can be separated into 2
major categories: gatekeepers and caretakers.24 Gatekeepers inhibit directly tumor growth. Inactivation of
these genes contributes directly to tumor progression.
In melanoma the nm23 protein could play a caretaker role. Functionally, this molecular finding can be of
great importance for the patient. However, when a
special marker will be of use in daily practice, it should
be proven to add something new to the already known
and easy to obtain prognostic parameters, like the
Breslow thickness. It is more or less the same discussion as indicated above for the patient value, e.g. to
increase lifespan as well as quality of life for the
remaining lifespan, sentinel node biopsy and PET
scan.
The major question will be if the positive expression
of nm23 is also correlated to the Breslow thickness. If
this is the case, there is no extra value of this on it selfinteresting finding. In case, especially in thin
melanomas the Breslow thickness and nm23 expression are not correlated together regarding disease-free
interval. A large trial should be done to put this nm23
expression test on the map.
Pacifico et al. Found a significant correlation as
well between Clark levels as Breslow depth in a group
of 200 melanoma patients.25 Nevertheless, the question
is still open if nm23 negative patients with low Breslow depth are those patients who have a bad prognosis.
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Nucleoside diphosphate kinases (NDP kinases) are
a family of highly conserved proteins in eukaryotes 9 of
which 8 different genes (nm23-H1 to nm23-H8) have
been identified in humans. NDP kinases play a major
role in cell metabolism since they transfer the terminal
phosphate of a nucleoside tiphosphate to a nucleoside
diphosphate, thus equilibrating the NDP and NTP cellular pools independently of the nature of the purine or
pyrimidine bases.10, 11 The nm23 tumor metastasis suppressor gene was found to encode a protein identical to
NDP kinase.8 Nm23-H1 and nm 23-H2 tumor suppressor activities have been identified in a number of
human cancers.12-14 Studies supported the hypothesis
that the nm23 protein may act as a metastasis suppressor gene. In cancer cell lines, in vitro, expression
of nm23 reduces metastatic potential and cell motility.1517Although this effect has been extensively described,
the molecular mechanism underlying the role of nm23
in cancer is poorly understood. A number of data indicate that nm23 is a multifunctional protein reportedly
involved in a variety of cellular functions including
differentiation, proliferation, and apoptosis.18-22 Nm23
expression in melanoma is supposed to be associated
with a relative better prognosis.
Melanoma prognosis is based on histological criteria such as tumor thickness (measured by Breslow
index), level of invasion (Clark’s level), presence of
ulceration and number of mitoses per mm2. However,
these parameters do not provide a precise prognosis in
all cases: thin melanomas may develop metastases
and thick melanomas may remain focalized for many
years. For these reasons, the search for other prognostic factors is still ongoing. Many molecules playing a part in the invasiveness and metastatic dissemination of melanoma have now been identified. Expression of these molecules has been investigated in primary melanoma and correlated with prognosis. An
increase in the number of cells positive for Ki67
(detected by Mib1), cycline A, cycline D, p35, MMp2, beta l and beta 3 integrins, osteonectin, the presence of an intense inflammatory infiltrate and capillary
invasion are considered as factors of poor prognosis as
well as a decrease in P16, p27, Melan A and nm23. The
significance of CD44 modifications is still controversial. Only a small number of these different proteins
have a prognostic value independent of tumor thickness.23 These results need to be confirmed on larger
series of patients. Additional hope is given to new
techniques such as the analysis of the genes implied in
180
References
1. Medalie N, Ackerman AB. Sentinel node biopsy has no benefit for
patients whose primary cutaneous melanoma has metastasized to a
lymph node and therefore should be abandoned now. Br J Dermatol
2004;151:298-307.
2. Wong SL, Morton DL, Thompson JF, Gershenwald JE, Leong SP,
Reintgen DS et al. Melanoma patients with positive sentinel nodes who
did not undergo completion lymphadenectomy: a multi-institutional
study. Ann Surg Oncol 2006;13:809-16.
Giugno 2006
CLINICAL ADVANCES IN METASTATIC MELANOMA
16.
7.
nm23-M1 and nm23-M2, are involved in metastatic suppression of a
murine melanoma line. Cancer Res 1995;55:1977-81.
Kantor JD, McCormick B, Steeg PS, Zetter BR. Inhibition of cell
motility after nm23 transfection of human and murine tumor cells. Cancer Res 1993;53:1971-3.
Leone A, Flatow U, King CR, Sandeen MA, Margulies IM, Liotta
LA et al. Reduced tumor incidence, metastatic potential, and cytokine
responsiveness of nm23-transfected melanoma cells. Cell 1991;65:2535.
Amendola R, Martinez R, Negroni A, Venturelli D, Tanno B, Calabretta B et al. DR-nm23 expression affects neuroblastoma cell differentiation, integrin expression, and adhesion characteristics. Med
Pediatr Oncol 2001;36:93-6.
Gervasi F, D’Agnano I, Vossio S, Zupi G, Sacchi A, Lombardi D.
Nm23 influences proliferation and differentiation of PC12 cells in
response to nerve growth factor. Cell Growth Differ 1996;7:168995.
Lombardi D, Lacombe ML, Paggi MG. Nm23: unraveling its biological function in cell differentiation. J Cell Physiol 2000;182:1449.
Negroni A, Venturelli D, Tanno B, Amendola R, Ransac S, Cesi V et
al. Neuroblastoma specific effects of DR-nm23 and its mutant forms
on differentiation and apoptosis. Cell Death Differ 2000;7:843-50.
Otero AS. NM23/nucleoside diphosphate kinase and signal transduction. J Bioenerg Biomembr 2000;32:269-75.
Heenen M, Laporte M. Molecular markers associated to prognosis of
melanoma. Ann Dermatol Venerolol 2003;130:1025-31.
Oliveira AM, Ross JS, Fletcher JA. Tumor suppressor genes in breast
cancer: the gatekeepers and the caretakers. Am J Clin Pathol 2005;124
Suppl:S16-28.
Pacifico MD, Grover R, Richman PI, Buffa F, Daley FM, Wilson GD.
Nm23 as a prognostic marker in primary cutaneous melanoma: evaluation using tissue microarray in a patient group with long-term follow-up. Melanoma Res 2005;15:435-40.
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3. Rörsman H. The pigmented life of a redhead. Pigment Cell Res
2004;17:191-202.
4. Frija J, Bourrier P, Zagdanski AM, De Kerviler E. Diagnosis of a
alignant lymph node. J Radiol 2005;86(2 Pt 1):113-25.
5. Horn J, Lock-Andersen J, Sjostrand H, Loft A. Routine use of FDGPET scans in melanoma patients with positive sentinel node biopsy.
Eur J Nucl Med Mol Imaging 2006 Apr 4; (Epub ahead of print).
6. Friedman KP, Wahl RL. Clinical use of positron emission tomography
in the management of cutaneous melanoma. Semin Nucl Med
2004;34:242-53.
7. Ferrari D, Lombardi M, Ricci R, Michiara M, Pedrazzi G, Santini M
et al. Nm23 protein expression in primary melanoma correlates with
disease free interval and with survival: a 10-year follow-up study. G
Ital Dermatol Venereol 2006;141:99-106.
8. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE,
Liotta LA et al. Evidence for a novel gene associated with low tumor
metastatic potential. J Natl Cancer Inst 1988;80:200-4.
9. Lacombe ML, Milon L, Munier A, Mehus JG, Lambeth DO. The
human Nm23/nucleoside diphosphate kinases. J Bioenerg Biomembr 2000;32:247-58.
10. Lascu I, Gonin P. The catalytic mechanism of nucleoside diphosphate
kinases. J Bioenerg Biomembr 2000;32:237-46.
11. Brown PR, Agarwal RP, Gell J, Parks RE Jr. Nucleotide metabolism
in the whole blood of various vertebrates: enzyme levels and the use
of high pressure liquid chromatography for the determination of
nucleotide patterns. Comp Biochem Physiol B 1972;43:891-904.
12. Hartsough MT, Steeg PS. Nm23/nucleoside diphosphate kinase in
human cancers. J Bioenerg Biomembr 2000;32:301-8.
13. Martin KK, Pilkington GJ. Nm23: an invasion suppressor gene in
CNS tumours? Anticancer Res 1998;18:919-26.
14. Rusciano D. Differentiation and metastasis in melanoma. Crit Rev
Oncog 2000;11:147-63.
15. Baba H, Urano T, Okada K, Furukawa K, Nakayama E, Tanaka H et
al. Two isotypes of murine nm23/nucleoside diphosphate kinase,
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18.
19.
20.
21.
22.
23.
24.
25.
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Clinical relevance of antibiotic resistance in acne
I
n the April issue of the journal, Bettoli et al. report
the prevalence of P. acnes’antibiotic resistance in Ferrara over a time period of more than 5 years.1 More than
half of the P. acnes strains (55.9%) cultured from the
skin of 1 579 acne patients were resistant to at least one
antibiotic (erythromycin, clindamycin, tetracyclines or
minocyclin). Possible methodological problems in the
context with studies like this, such as unknown prior or
present therapies of patients, method of surface sampling (in this study the whole face was sampled correctly), cultivation methods, focus on P. acnes and not as
well P. granulosum or P. avidum, or the way of reporting the data have been nicely addressed elsewhere 2 and
will not be discussed here. Given the findings of a large
number of resistant P. acnes to different antibiotics, this
report poses several questions to the clinician: are the findings relevant 1) to other areas than Ferrara, 2) to the individual acne-patient, 3) the general population and 4)
should these results influence actual treatment recommendations for acne?
Local or general problems
One could argue that the problem of resistance might
only affect certain areas. Unfortunately, this is not the
Address reprint requests to: F. R. Ochsendorf, Zentrum der Dermatologie
und Venerologie, Klinikum d. J.W. Goethe-Universität, Theodor-SternKai 7, 60590 Frankfurt/M, Germany.
E-mail: [email protected]
Vol. 141 - N. 3
F. R. OCHSENDORF
Dermatology and Venereology Center
Klinikum d. J.W. Goethe-Universität, Frankfort, Germany
case. Though there are methodological discrepancies
between different studies it is evident that resistant P.
acnes strains can be found all over Europe and even
worldwide since decades. The prevalence of erythromycin-resistance ranged from 41.5% in Northern
Europe to 91% in Spain. Resistant P. acnes strains
were also reported in other continents, such as Australia, Japan or the United States. Interestingly, the
last study on propionibacterial resistance from the
USA was published in 1983.2
The regional differences can be attributed, at least
partly, to prescribing habits of antibiotics. Although in
acne patients prospective studies of this association
are still lacking, this link can be deduced from the
published reports. The lowest rates of erythromycin
resistance were found in Australia where topical antibiotics were made available only recently. In Europe
topical erythromycin and clindamycin were introduced
in the mid-1970’s. The first resistant strains were
reported in 1979. Later, the highest rate of antibiotic
resistance was found in Spain where 84% of patients
had been treated with antibiotics before in contrast to
a rate of 51% in Hungary with only 18% prior antibiotic therapy. Furthermore, direct associations between
prevalence of resistant bacteria and the use of certain
antibiotics are well known from other species: asso-
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could have other causes. Bacterial resistance is certainly not the only reason for therapeutic failures in
acne. For example, non-compliance has to be taken
into account in 31-53% of acne patients (Kupfer J,
personal communication). This, however, also drives
the emergence of resistant strains during antibiotic
therapy. Other factors, such as increased sebum-excretion rates diluting the concentration of the antibiotic,
inadequate dose, follicular pH or route of administration (among several others) might impair the therapeutic outcome of antibacterials in the absence of any
bacterial resistance.2
The following factors bear an increased risk for the
emergence of resistant P. acnes in individual patients:
poor compliance, a history of multiple courses of
antibiotics, especially sequential use of related compounds, antibiotic treatment times longer than 12
weeks, living with an antibiotic-treated patient with
acne and treatment by an acne specialist. The latter
dermatologists were more likely to be colonized with
resistant strains than other dermatologists or primary
care physicians.2
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ciations of Staph. aureus resistance rates and use of
oxacillin or an increase of streptococci-resistance with
increasing use of erythromycin were reported.3 So the
rate of resistance can be very much influenced by the
use of antibiotics. Therefore the report of Bettoli et
al.1 exemplarily highlights again a European and even
worldwide problem: the high incidence of P. acnes
strains resistant to different antibiotics. In Europe,
every second patient with acne seems to be colonized
by strains resistant to erythromycin and clindamycin.
Relevance for the individual patient
Although not generally investigated or monitored,
a high incidence of antibiotic resistance of P. acnes
must be expected everywhere. The question arises
whether these findings are just “laboratory findings”
or whether they are clinically relevant to the patient.
Already in 1989 Eady et al. reported an association
of therapeutic failures during oral erythromycin therapy and the identification of resistant P. acnes.2 Recently, a connection of tetracycline resistance and impaired
clinical efficacy to oral oxytetracycline and minocycline
was reported.4 In 2002, Mills et al.5 saw no clinical
effect of topical erythromycin 2% gel compared to its
vehicle on acne lesions. Simonart and Draimax just
reviewed the effects of topical antibiotic therapies
since 1970.6 The authors found a linear decrease of
the clinical effects over time in the studies using erythromycin. The effects of clindamycin were stable
over time. The authors attributed the association of
diminishing efficacy with time to the emergence of
resistant strains of P. acnes. So, for the individual
patient, resistance of P. acnes apparently is associated
with therapeutic failure or at least reduced efficacy.
It has to be kept in mind that the role of P. acnes in
acne can be looked at as “multiple isolated infections
of the sebaceous follicles”.2 As not every follicle of
the patient will harbour resistant P. acnes, the clinical
response depends, among other factors, on the number
of follicles which are colonized by resistant strains. As
resistant organisms are not residing in all follicles,
patients will not fail to respond completely but rather
will show a reduced response in comparison with individuals with fully susceptible propionibacterial floras.
However, a differentiation is necessary here. Acne
not responding to antibiotics should be named “antibiotic recalcitrant acne”.2 A therapeutic failure thus could
either be due to antibiotic resistance of P. acnes or
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Relevance for the community
Fortunately the resistance-mechanisms of P. acnes are
different from those of other bacteria. If acne had been
due to, for example, staphylococci, in which resistance
emerges so rapidly via plasmids, acne could have never been treated with antibiotics. But P. acnes is a bacterium of low genetic adaptability. Resistance develops
by mutational change which is transferred vertically.
Therefore, antibiotics could be used for so long.
There is no evidence that P. acnes or P. granulosum
cause acute infections. So, neither the patient nor the
community are at risk of resistant propionibacterial
infections. However, acne lesions are dominantly colonized by P. acnes and S. epidermidis. Both bacteria
could be isolated simultaneously in about 50% of
acne lesions. In Japan, more than 30% of S. epidermidis strains were resistant to erythromycin, clindamycin and roxithromycin. S. epidermidis can, in
contrast to P. acnes, transfer resistance via plasmids
to S. aureus. This has been demonstrated for gentamycin-resistance.7 Mills et al. reported a higher carriage rate and dissemination of erythromycin-resistant
S. aureus from the nares during a 12 week course of
topical erythromycin.5 So, the nares have to be regarded as a reservoir for both P. acnes and S. aureus. It is
Giugno 2006
prescribing practices: antibiotics should not be used
for mild acne. Topical retinoids should be the first
line agents in acne therapy.2, 10 Unfortunately topical retinoids are still underused in the treatment of
acne.
If indicated, antibiotics should not be used as
monotherapy. A recent prospective controlled study
of Ozolins et al. demonstrated the superiority of topical antibiotic/benzoylperoxide (BPO) combinations.4 The authors investigated the effects of oxytetracycline (2×500 mg/d p.o.), minocycline (100 mg/d
p.o.), BPO (5% topically twice daily), combination
of erythromycin (3% topically once daily) and BPO
(5% topically once daily) or a fixed combination of
erythromycin 2%/BPO 5% (topically once daily) in
649 patients with mild to moderate inflammatory
acne vulgaris of the face. They found that topical
antimicrobial therapies performed at least as well
as oral antibiotics in terms of clinical efficacy. BPO
was the most cost-effective and minocycline the least
cost-effective therapy for facial acne. The efficacy of
all three topical regimens was not compromised by
pre-existing propionibacterial resistance. The topical therapies, however, were associated with a
stronger irritation of the skin, especially in BPO
monotherapy.
Topical antibacterial therapies effectively reduce P.
acnes, but only at the treated sites. Systemic agents,
such as oral antibiotics, reduce the density of the propionibacterial population on all areas of the skin and
even in the nares. BPO and isotretinoin reduce the
propionibacterial population density by >99%. Periodic short wash-outs (effectiveness proven after only
2 days, recommended 3-5 days) with BPO during
any antibiotic therapy reduces antibiotic resistant
propionibacterial populations. However, this happens only at the treated areas and not the nares. All
approaches do not completely eliminate the organisms. One can only hope that resistant strains are
slower in re-colonizing the skin than the resistant
ones.
So localized inflammatory acne can be treated topically. For widespread inflammatory acne systemic
antibiotics are still indicated. As the identification of
resistance patterns is, in practice, almost impossible,
the treating physician has to think before prescribing
multiple courses of antibiotics for acne. He should be
aware of the resistance problem and combine any
antibiotic treatment with BPO (continuous or peri-
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very difficult to eradicate the organisms from this
location.
In the latter study 5 the rate of erythromycin-resistant coagulase-negative staphylococci increased from
37% to 88% during the treatment. This rate did not
decrease after the end of antibiotic therapy. So antibiotic resistance can persist for a considerable time.
The authors found that resistant strains were transferred to untreated areas.5 Furthermore, it was shown
that a sequential antibiotic therapy promoted the carriage rate of resistant staphylococci on the skin of contacts.7 Although not definitely proven, a direct transfer of resistant organisms to persons with close contact
is therefore very probable.
Other studies showed a 3-fold increase in the prevalence of Strept. pyogenes in acne-patients using antibiotics. This rate is as high as in patients with symptomatic pharyngitis. The carriage rate did not differ
between topical or systemic therapy.8 The carriage of
resistant bacteria on the skin of acne-patients treated
with antibiotics was not associated with an increased
rate of cutaneous infections.2 However, a recent study
showed that patients, who had received antibiotic treatment for their acne, were more likely to develop an
upper respiratory tract infection, but not a urinary tract
infection, than those with acne who were not receiving such treatment.9
A mere change of the antibiotic in cases of antibiotic-refractory acne is no solution. The lower incidence
of tetracyclince resistance in the actual 1 and reported
studies 2 indicates that selectivity of oral tetracyclines
is less than topical erythromycin or clindamycin as far
as propionibacterial resistance is concerned. The history
of antibiotic therapy shows, however, that the use of new
antibiotics just postpones the problem to the future as
any antibiotic use drives the emergence of resistant
strains. Therefore, it appears more important to ensure
that future patients can be offered antibiotic treatment,
rather than focussing on the patient presenting today.
Antibiotic acne therapy thus poses selective pressure
on different bacteria. Whether and to what extent
antibiotic therapy for acne has contributed to the prevalence of resistant bacteria and resistant bacterial infections in the community is unknown.
OCHSENDORF
Consequences for acne therapy in daily practice
The emergence and spread of resistant P. acnes
can be limited and perhaps even reduced by wiser
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References
1. Bettoli V, Borghib A, Rossic R, Ferronib M, Rigolinc F, Virgilib A. Personal experience on antibiotic resistance of propionibacteria in Ferrara. G Ital Dermatol Venereol 2006;141:117-22.
2. Eady AE, Cove JH, Layton AM. Is antibiotic resistance in cutaneous
propionibacteria clinically relevant? Implications of resistance for
acne patients and prescribers. Am J Clin Dermatol 2003;4:813-31.
3. Ochsendorf FR, Richter T, Niemczyk UM, Schäfer V, Brade V, Milbradt R. Prospective detection of important bacterial pathogens in
pyoderma and their in vitro antibiotic susceptibility. Hautarzt
2000;51:319-26.
4. Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB
et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 2005;9:iii-212.
5. Mills O, Thornsberry C, Cardin CW, Smiles KA, Leyden JJ. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta
Derm Venereol 2002;82:260-5.
6. Simonart T, Dramaix M. Treatment of acne with topical antibiotics:
lessons from clinical studies. Br J Dermatol 2005;153:395-403.
7. Jappe U. Pathological mechanisms of acne with special emphasis on
Propionibacterium acnes and related therapy. Acta Derm Venereol
2003;83:241-8.
8. Levy RM, Huang EY, Roling D, Leyden JJ, Margolis DJ. Effect of
antibiotics on the oropharyngeal flora in patients with acne. Arch
Dermatol 2003;139:467-71.
9. Margolis DJ, Bowe WP, Hoffstad O, Berlin JA. Antibiotic treatment
of acne may be associated with upper respiratory tract infections.
Arch Dermatol 2005;141:1132-6.
10. Gollnick H, Cunfliffe W, Berson D, Dreno B, Finlay A, Leyden JJ et
al. Management of acne: a report form a global alliance to improve outcomes in acne. J Am Acad Dermatol 2003;49(Suppl 1):S1-37.
11. Zouboulis CC, Piquero-Martin J. Update and future of systemic acne
treatment. Dermatology 2003;206:37-53.
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dodical wash-outs). In case of rapid recurrences, he has
to consider alternative therapies, such as isotretinoin
or antiandrogens.
Besides a correct indication of antibiotics, another
possible approach could be to limit the spread of resistant organisms. The person-to-person transfer of preexisting resistant strains appears to be the main route
of transmission. So the acne-specialist has to become
aware that he himself may transfer resistant strains
between patients! Dermatologists have to recognize
this and take appropriate methods of hygiene to avoid
it.
If antibiotics are indicated, the patient should be
informed that a good compliance is required in order
to reduce the emergence of resistance. The patient
should be clinically monitored every 6 weeks. Antibiotic therapy should be stopped as soon as doctor and
patient agree that there is no further improvement.
Finally antibiotics should not be used for maintenance
therapy. Here alternatives, such a retinoids, BPO or
azelaic acid, could be used. If these measures will be
taken an effective further use of antibiotics for acne will
still be possible. In the future other local approaches,
such as blue-light or PDT, or systemic treatments,
such as hormones or lipoxygenase-inhibitors,11 may
overcome the resistance problems during acne therapy.
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Adverse cutaneous drug reactions to cardiovascular drugs
S. BRENNER, J. MASHIAH
A
tzori et al. present the frequency, clinical pattern
and course of cutaneous adverse reaction to cardiovascular drugs recorded from October 1999 to
November 2004 in hospitalized patients and outpatients of the Dermatology Department of Cagliari University. Out of 409 cases of adverse cutaneous drug
reactions (ADR), 35 (8.5%) were associated with the
exclusive use of cardiovascular drugs. The algorithm
adopted by the Collaborating Centre for International
Drug Monitoring of the World Health Organization
(WHO) was used to determine the level of probability
of the association between the drug administration and
the adverse reaction. Cases of multiple drug use were
excluded when cardiovascular drugs were not the principle cause of the ADR, probably resulting in an underestimation of the true incidence of ADRs. The culprit
drugs were primarily ACE inhibitors, followed by
hydrochlorothiazide + ACE inhibitors or angiotensin II
antagonists, diuretics, beta-blockers, calcium channel
blockers, antiarrhythmics, aggregation inhibitors,
vasodilatators, and hypolipidemic agents. The clinical
spectrum of the ADR included exanthemic reactions,
urticaria, photosensitivity, pityriasis rosea-like eruptions, Stevens-Johnson syndrome, lichenoid dermatitis, TEN, vasculitis, erythroderma, and psoriasis.
The WHO defined ADR in 1972 as a “Response to
Address reprint requests to: S. Brenner, MD, Department of Dermatology, Tel Aviv Sourasky Medical Centre, 6 Weizmann Street, Tel Aviv
64239 Israel. E-mail: [email protected]
Vol. 141 - N. 3
Department of Dermatology, Tel Aviv-Sourasky Medical
Center and Sackler Faculty of Medicine,
Tel Aviv University, Israel
a drug that is noxious and unintended and occurs at
doses normally used in man for the prophylaxix, diagnosis or therapy of disease, or for modification of physiological function”.1 Edwards and Aronson 1 proposed
a modified definition: “An appreciably harmful or
unpleasant reaction, resulting from an intervention
related to the use of a medicinal product, which predicts
hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage
regimen, or withdrawal of the product”. These authors
classified ADRs into 6 categories: a) dose related,
including reactions related to dosage and formulation,
toxic effects; b) non-dose-related or bizarre, including
immunological and idiosyncratic reactions; c) doserelated and time-related reactions, related to the cumulative dose; d) time-related, delayed reactions such as
teratogenesis and carcinogenesis; e) withdrawal reactions; f) unexpected failure of therapy.1
ADRs are common but estimating their true incidence is nearly impossible due to inadequate reporting.
In the United States the estimated rate of medicationrelated visits to office based physicians is 7.7 per 1.000
persons, but only 7% of them initiated the visit due
to ADR.2 Recognizing ADRs requires several steps.
One of the main problems is to clarify whether the
patient is taking medication: people tend to forget tak-
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ADVERSE CUTANEOUS DRUG REACTIONS TO CARDIOVASCULAR DRUGS
incubation with the suspected drug. The specificity
and sensitivity of the test have not been defined.
Lymphocyte transformation test
After incubating lymphocytes with and without the
suspected drug for a few days, 3H-thymidine is added
for a few hours. The ratio between thymidine uptake
with and without the drug represents the lymphocyte
proliferation. However, only minor proliferation is
measured, yielding inaccurate results.
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ing occasional drugs, overlook over the counter and traditional drugs, and don’t consider long-term treatments
such as oral contraceptives as treatment. Once drug
intake has been established, it remains to decide whether
the reaction can be attributed to drug intake, and if so,
which drug is the culprit. This causality assessment of
reported ADRs is usually performed according to the
global introspection (GI) based on the World Health
Organization scale, as well as to other decisional algorithms purported to be less subjective and imprecise
than the GI.3 The causality levels used by most algorithms are certain, probable, possible, unlikely, conditional/unclassified, unassessable/unclassifable.
Among the useful causality assessment tools are
the temporal relation between the adverse reaction
and the drug intake, including the introduction or cessation of the drug, and dosage changes. The time
elapsed between the introduction of the culprit drug and
the ADR varies from seconds, minutes, hours, days,
weeks, months, to 11 years.4 Another tool is the known
ADR pattern previously related to the culprit drug, a
reaction which is in some way specific. Challenge test
can be informative but is potentially hazardous and
therefore of limited applicability. Other in vivo skin
tests include the prick test, patch test, and delayed
(tuberculin-type) test.
Several in vitro tests can help determine the offending drug but are limited by false negative results due
to an antigenic determinant that may include a binding
protein in addition to the drug, and/or an immunologic reaction arising from a metabolite of the drug rather
than the drug itself. Several in vitro tests are available
and are described below.5
RAST (radioallergosorbent test)
This test measures specific immunoglobulin E antibodies in the serum. Immunosorbent composed of
allergen extract is reacted with serum, washed, reacted with radiolabeled anti-human IgE antibody, and
washed again. The labeled antibody is proportional
to the level of specific serum IgE antibodies to the
allergen. The test is limited to IgE antibody-mediated
reactions and to drugs in which the epitope has been
defined.
Mast cell degranulation test
This type I hypersensitivity reaction-related test
measures the histamine release from mast cells after
188
Diagnosis of reactions that involve immune
complexes
Based on the fact that immune complexes cause elevated levels of lysosomal enzymes such as b-glucuronidase, the suspected drug and the patient’s leukocytes are incubated and the levels of b-glucuronidase
levels are measured.
Lymphocyte toxicity assay
This assay attempts to identify defects in the detoxification of toxic metabolites in drugs and is therefore
useful in hypersensitivity syndrome. Lymphocytes of
the patient and the drug are incubated in the presence
of human-like microsome, which includes cytochrome
p450.
Macrophage migratory inhibition factor test
This test measures the lymphokines released from
sensitized T lymphocytes by the specific antigen. Its
expression of activity correlates with delayed hypersensitivity and cellular immunity. The migration index
is the ratio between macrophage migration with and
without the suspected drug. A MIF test is considered
to be positive when the migration index is 0.80 or less.
Interferon-gamma release test
One of the most accurate and useful tests is the interferon-gamma release test, demonstrated in a number
of studies to identify the offending drug.6 Several studies have demonstrated its potential to identify the
offending drug based on the release of IFNγ from lymphocytes after exposure to one or more suspected
drugs.6 It is based on the ability of Th1 lymphocytes to
produce interleukin-2 and IFNγ when they are activated in delayed-type hypersensitivity reactions. In
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TABLE I.—Cutaneous adverse drug reactions caused by cardiovascular drugs.
Drug Reaction
Acneiform
Drug Group
Antiarrhythmic agents
Class I
Phenytoin, Quinidine
Class II
Atenolol, Oxprenolol, Propranolol
Class IV
Diltiazem, Nimodipine
Isosorbide mononutrate
Atorvastatin
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Vasodilators
Lipid lowering
Drug
Alopecia
Angioedema
ACE Inhibitors
Angiotensin II receptors Bloc.
Diuretics
Vasodilators
Anticoagulants antiplatelets
Lipid lowering
Class I
Antiarrhythmic
ACE Inhibitors
Sympathomimetics
Diuretics
Vasodilators
Anticoagulants Antiplatelets
Drug-induced lupus
erythematosus
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Lipid lowering
Eczematous
Tocainide
Acebutolol, Labetalol, Nadolol, Pindolol, Propranolol,
Sotalol
Amiodarone
Diltiazem, Nifedipine, Verapamil
Class III
Class IV
Digoxin
Enalapril, Lisinopril
Losartan
Hydrochlorothiazide
Guanethidine, Prazosin,
Anagrelide, Aspirin, Heparin, Warfarin
Clofibrate, Fenofibrate, Lovastatin,
ACE Inhibitors
Vasodilators
Thrombolytic
Lipid lowering
Bullous\Vesicular
Class I
Class II
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Encainide, Flecainide, Phenytoin, Procainamide, Quinidine,
Labetalol, Metoprolol, Sotalol,
Nifedipine, Verapamil
Class II
Class VI
Digoxin
Captopril, Enalapril, Lisinopril
Losartan,
Clonidine, Hdralazine
Aspirin, Heparin, Warfarin
Streptokinase
Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
Class I
Phenytoin, quinidine
Class II
Labetalol, Propranolol
Class III
Amiodarone
Class IV
Nifedipine
Digoxin
Captopril, Enalapril
Dobutamine
Furosemide, Hydrochlorothiazide
Clonidine, Minoxidil
Abciximab, Ardeparin, Aspirin, Clopidogrel, Dalteparin, Enoxaparin,
Heparin, Warfarin
Class I
Acecainide, Phenytoin, Quinidine, Disopyramide,
Encainide, Procainamide, Propafenone
Acebutalol, Labetalol, Pindolol, Practolol, Propranolol
Diltiazem, Nifedipine, Verapamil
Class II
Class VI
Captopril
Chlorthalidone, Furosemide, Hydrochlorothiazide, Triamterene
Clonidine, Hydralazine, Methyldopa, Reserpine
Atorvastatin, Cerivastatin, Clofibrate, Fenofibrate, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
Class I
Quinidine
Class II
Metoprolol, Practolol, Propranolol,
Digoxin
Captopril
Furosemide, Hydrochlorothiazide, Spironolactone
Clonidine, Doxazosin, Hydralazine, Methyldopa, Nitroglycerin
Aspirin, Heparin, Warfarin
Table I continued
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Continued Table I.
Drug Reaction
Erythema
Drug Group
Antiarrhythmic
Class I
Acecainide, Quinidine
Class II
Acebutalol, Carvedilol, Labetalol, Metoprolol, Nadolol
Class III
Bretylium
Class IV
Amlodipine, Diltiazem, Isradipine
Losartan
Dobutamine
Ardeparin, Clopidogrel, Enoxaparin, Ticlopidine
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ACE Inhibitors
Sympatho-mimetics
Drug
Erythema multiforme
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Lipid lowering
Exanthematous
Antiarrhythmic
Exfoliative dermatitis
Antiarrhythmic
Diuretics
ACE Inhibitors
Diuretics
Vasodilators
Fixed drug eruption
Antiarrhythmic
Sympatho-mimetics
Vasodilators
Flushing
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Thrombolytics
Lipid lowering
Hidrosis
Antiarrhythmic
ACE Inhibitors
Class I
Phenytoin, Quinidine, Tocainide
Class II
Propranolol
Class IV
Amlodipine, Diltiazem
Methyldopa
Aspirin, Dipiridamole
Atorvastatin, Cerivastatin, Clofibrate, Fenofibrate, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
Class I
Phenytoin
Class IV
Verapamil
Digoxin
Spironolacton
Class I
Phenytoin, Flecainide, Mexiletine, Quinidine, Tocainide
Class II
Practolol, Propranolol
Class III
Amiodarone
Class IV
Diltiazem, Nifedipine
Furosemide
Clonidine, Hydralazine, Sildenafil
Aspirin
Class I
Class IV
Nifedipine
Digoxin
Epinephrine
Hydralazine
Aspirin, Nicotinic acid
Class I
Flecainide, Procainamide, Quinidine, Tocainide
Class II
Atenolol, Propranolol
Class III
Bretylium
Class IV
Diltiazem, Verapamil
Adenosine
Losartan
Hydrochlorothiazide
Doxazosin, Epoprostenol, Fenoldopam, Hydralazine, Isosorbide dinitrate, Isoxsuprine, Nitroglycerin, Reserpin, Sildenafil
Aspirin, Dipiridamole, Tirofiban
Streptokinase
Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Niacin/Nicotinic acid,
Pravastatin, Simvastatin
Class I
Class II
Class III
Class IV
Adenosine
Lisinopril
Flecainide, Tocainide
Acebutolol, Metoprolol, Nadolol, Pindolol, Timolol
Amiodarone
Diltiazem, Nicardipine, Nifedipine, Nimodipine, Verapamil
Table I continued
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Continued Table I.
Drug Reaction
Hidrosis
Drug Group
Drug
Vasodilators
Losartan
Doxazosin, Epoprostenol, Fenoldopam, Isosorbide mononitrate, Nitroglycerin, Sildenafil, Terazosin
Abciximab, Tirofiban
Anistreplase
Atorvastatin
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Thrombolytics
Lipid lowering
Hypertrichosis/Hirsutism
Antiarrhythmic
Diuretics
Vasodilators
Lichenoid
Antiarrhythmic
Vasodilators
Lipid lowering
Class I
Class II
Acebutolol, Labetalol, Practolol, Propranolol, Sotalol
Class IV
Furosemide, Hydrochlorothiazide, Spironolactone, Torsemide, Triamterene
Diazoxide, Methyldopa, Prazosin
Aspirin
Simvastatin
Antiarrhythmic
Class I
ACE Inhibitors
Diuretics
Vasodilators
Class II
Class III
Class IV
Digoxin,
Hydrochlorothiazide, Spironolactone, Triamterene
Clonidine, Diazoxide, Hydralazine, Methyldopa, Minoxidil, Prazosin
Ardeparin, Aspirin, Clopidogrel, Ticlopidine, Warfarin
ACE Inhibitors
Diuretics
Macular/Maculopapular
Nail Abnormalities
Antiarrhythmic
Photosensitivity
Antiarrhythmic
Diuretics
ACE Inhibitors
Diuretics
Vasodilators
Lipid lowering
Hyper/Hypo Pigmentation
Pityriasis Rosea like
Class I
Phenytoin
Class IV
Verapamil
Spironolactone
Diazoxide, Minoxidil
Antiarrhythmic
Acecainide, Phenytoin, Procainamide, Quinidine, Tocainide
Carvedilol, Metoprolol, Propranolol
Amiodarone
Amlodipine, Diltiazem, Nifedipine, Verapamil
Class I
Quinidine,
Class II
Digoxin,
Hydrochlorothiazide,
Class I
Class II
Atenolol, Propranolol, Sotalol
Class III
Amiodarone
Class IV
Chlorthalidone, Furosemide, Hydrochlorothiazide, Hydroflumethiazide, Metolazone, Polythiazide, Torsemide, Triamterene
Methyldopa, Sildenafil
Warfarin
Atorvastatin, Cerivastatin, Fenofibrate, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
Diuretics
Vasodilators
Class I
Class II
Oxprenolol, Practolol, Timolol
Class III
Amiodarone
Class IV
Nifedipine
Hydrochlorothiazide
Clonidin, Methyldopa, Minoxidil
Antiarrhythmic
ACE Inhibitors
Vasodilators
Class II
Captopril
Clonidin
Aspirin
Labetalol
Table I continued
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Continued Table I.
Drug Reaction
Pruritus
Drug Group
Antiarrhythmic
Drug
Class I
Class II
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Class III
Class IV
Acecainide, Flecainide, Moricizine, Procainamide, Quinidine, Tocainide
Acebutolol, Carvedilil, Labetalol, Nadolol, Pindolol, Propranolol, Sotalol, Timolol
Amiodarone
Diltiazem, Isradipine, Nicardipine, Nifedipine, Nimodipine, Verapamil
ACE Inhibitors
Sympatho-mimethics
Diuretics
Vasodilators
Thrombolytics
Lipid lowering
Pseudolymphoma
Antiarrhythmic
Psoriasis
Antiarrhythmic
ACE Inhibitors
Vasodilators
Purpura
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Thrombolitics
Lipid lowering
Stevens-Johnson syndrome
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Lipid lowering
Toxic Epidermal Necrolysis
Antiarrhythmic
Diuretics
Lipid lowering
Digoxin
Captopril
Losartan
Dobutamine
Bunetanise, Dichlorophenamide, Furosemide, Hydrochlorothiazide
Clonidine, Diazoxide, Doxazocin, Epoprostenol, Guanabenez, Isosorbide mononitrate, Methyldopa, Prazosin,Sildenafil, Terazosin, Trimethaphan
camsylate
Abciximab, Anagrelide, Ardeparin, Aspirin, Clopidogrel, Dalteparin,
Dipiridamole, Enoxaparin, Heparin, Ticlopidine, Tirofiban
Streptokinase
Atorvastatin, Clofibrate, Fenofibrate, Lovastatin, Nicotinic acid
Class I
Class IV
Losartan
Phenytoin
Diltiazem
Class I
Class II
Flecainide, Quinidine
Carvedilil, Labetalol, Metoprolol, Oxprenolol, Pindolol,
Amiodarone
Class III
Digoxin
Clonidine, Mecamylamine
Aspirin
Class I
Phenytoin, Disopyramide, Quinidine
Class II
Acebutolol, Atenolol Propranolol
Class IV
Amlodipine, Diltiazem, Nifedipine
Digoxin
Enalapril
Losartan
Chlortalidone, Furosemide, Hydrochlorothiazide, Hydroflumethiazide,
Polythiazide, Spironolacton
Doxazosin, Hydralazine, Methyldopa
Aspirin, Enoxaparin, Heparin, Warfarin
Anistreplase, Streptokinase
Cerivastatin, Lovastatin, Pravastatin, Simvastatin
Class I
Phenytoin, Tocainide
Class II
Propranolol
Class IV
Diltiazem, Verapamil
Enalapril
Furosemide
Minoxidil
Atorvastatin, Cerivastatin, Clofibrate, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
Class I
Phenytoin
Class II
Propranolol
Class III
Amiodarone
Class IV
Diltiazem
Chlorthalidone
Atorvastatin, Cerivastatin, Clofibrate, Lovastatin, Pravastatin,
Simvastatin
Table I continued
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Continued Table I.
Drug Reaction
Antiarrhythmic
Drug
Class I
Acecainide, Flecainide, Lidocaine, Moricizine, Phenytoin, Procainamide, Quinidine, Tocainide
Acebutolol, Labetalol, Metoprolol, Propranolol, Sotalol,
Amiodarone
Diltiazem, Isradipine, Nifedipine, Verapamil
Class II
Class III
Class IV
Digoxin,
Losartan
Bumetanide, Furosemide, Hydroflumethiazide, Polythiazide, Spironolacton, Triamterene
Cilostazol, Clonidine, Hydralazine, Methyldopa, Sildenafil, Trimethaphancamsylate
Anagrelide, Ardeparin, Aspirin, Clopidogrel, Enoxaparin, Heparin, Ticlopidine, Warfarin
Alteplase, Streptokinase
Atorvastatin, Cerivastatin, Colestipol, Fenofibrate, Fluvastatin, Lovastatin, Nicotinic acid, Pravastatin, Simvastatin
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Urticaria
Drug Group
ACE Inhibitors
Diuretics
Vasodilators
Thrombolytics
Lipid lowering
Vasculitis
Antiarrhythmic
ACE Inhibitors
Diuretics
Vasodilators
Lipid lowering
cases of immediate-type hypersensitivity, Th2 lymphocytes are activated and produce IL-4, IL-5 and IL10. The test is performed by incubating the patient’s
lymphocytes with and without the suspected drugs.
IFNγ is collected from the supernatant and its level is
measured by enzyme-linked immunosorbent assay.
The test has a sensitivity of 54% and specificity of
92%.5
Cardiovascular diseases are one of the major medical concerns in the world today, especially in developed countries, accounting for the prevalence of cardiovascular drug usage. ADRs to these drugs were
found to account for 9.3% of medication-related officebased physician visits in the United States. The cutaneous reactions were the most commonly reported
primary symptom;2 while they may occur at any time
during the course of the treatment, some require a specific duration of drug administration before they appear.
Most cutaneous reactions are mild; indeed, some are
undistinguishable with no clinical importance, but can
become serious and potentially life threatening. It is
therefore crucial to recognize and treat adverse drug
Vol. 141 - N. 3
Class I
Phenytoin, Procainamide, Quinidine
Class II
Acebutolol, Propranolol
Class III
Amiodarone
Class IV
Captopril
Chlorthalidone, Furosemide, Ethacrynic acid, Hydrochlorothiazide,
Hydroflumethiazide, Polythiazide
Hydralazine
Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin, Simvastatin
reactions, either by reducing the dose or by replacing
the offending drug, while monitoring the cardiovascular
disease.
Treating, and even anticipating drug reactions,
requires knowledge of the mechanisms underlying the
ADR. ADRs are like any other malady. In most cases
they are multifactorial, with several mechanisms
involved in their pathogenesis. Pemphigus is an illustrative case in point. Pemphigus is a severe, chronic,
bullous, antibody-mediated disease of the skin and
mucous membranes, characterized by acute flare-ups
and remissions, and is generally considered to stem
from a genetic predisposition to the disease triggered
and/or exacerbated by one or more exogenous factors.
The acronym PEMPHIGUS was proposed to denote
the many causes of the disease: Pesticides Malignancy Pharmaceuticals Hormones Infectious agents, Gastronomy, Ultraviolet radiation, and Stress.4 Numerous factors are involved in the propagation and behavior of ADRs in pemphigus.7 The genetic factor: there
are genes that determine drug behavior, sensitivity,
metabolism, and disposition, in addition to other genes
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TABLE II.—Pemphigus caused by cardiovascular drugs.
Drug group
Thiol
Phenols
Class I
Class II
Class II
Nonthiol Nonphenol
Phenytoin
Labetalol
Amiodarone
Digoxin
Captopril
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Diuretics
Vasodilators
Clopidogrel
responsible for the enzymes propagating oxidation,
hydroxylation, and the like. The gender factor: a higher ADR rate is observed in women than in men, due in
part to hormonal influences, pharmacodynamic factors,
and reporting bias. Pharmacological factors: ADRs
can be provoked by drug dose, formulation, pharmacokinetics, pharmacodynamics, and drug interactions.
Immunologic factor: immune-mediated ADRs can be
caused by the formation of hapten, or a stimuli exerted by a drug or its metabolites that acts as a signal to
the immune system. Predisposing illnesses: immunosuppressed patients or patients with a neoplastic disease are at increased risk to develop ADR.
The range of dermatologic adverse reactions attributed to cardiovascular drugs is extensive and versatile.8 These ADRs are generally classified by the type
of reaction or by drugs and the reactions they can cause
(Table I). Classification of adverse drug reactions that
take into account the mechanisms triggering and exacerbating the ADR can ameliorate the adverse outcome
of drug treatment. Such a classification has been
applied to the drugs triggering and exacerbating pemphigus.4 They are divided into 3 main groups according to their chemical structure: drugs containing a
sulfhydryl (SH) radical (thiol drugs or SH drugs), phenols, and nonthiol nonphenol drugs. Both classifications concerning cardiovascular drugs are merged into
one table (Table II).
Adverse drug reactions are a common problem capa-
194
Enalapril
Dobutamine
Minoxidil
Aspirin, Heparin, Enoxaparin, Warfarin
ble of interfering with the treatment of every malady,
especially a life-threatening one such as a cardiovascular disease. Knowledge of the possible ADRs of
each medication, and the mechanisms involved in the
triggering and exacerbating the adverse reaction could
hasten the recognition and treatment of the reaction,
and even avoid it.
References
1. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255-9.
2. Aparasu RR. Visits to office-based physicians in the United States
for medication-related morbidity. J Am Pharm Assoc (Wash)
1999;39:332-7.
3. Macedo AF, Marques FB, Ribeiro CF, Teixeira F. Causality assessment
of adverse drug reactions: comparison of the results obtained from published decisional algorithms and from the evaluations of an expert
panel. Pharmacoepidemiol Drug Saf 2005;14:885-90.
4. Brenner S, Mashiah J, Tamir E, Goldberg I, Wohl Y. PEMPHIGUS:
an acronym for a disease with multiple etiologies. Skinmed
2003;2:163-7.
5. Goldberg I, Gilburd B, Shovman O, Brenner S. Clinical and laboratory assays in the diagnosis of cutaneous adverse drug reactions. Isr
Med Assoc J 2004;6:50-1.
6. Goldberg I, Gilburd B, Kravitz MS, Kivity S, Chaim BB, Klein T et
al. A novel system to diagnose cutaneous adverse drug reactions
employing the cellscan--comparison with histamine releasing test
and Inf-gamma Releasing Test. Clin Dev Immunol 2005;12:85-90.
7. Torpet LA, Kragelund C, Reibel J, Nauntofte B. Oral adverse drug reactions to cardiovascular drugs. Crit Rev Oral Biol Med 2s004;15:
28-46.
8. Brosnan BD, Frishman WH, Sun DK, Grossman M. Adverse dermatologic effects of cardiovascular drug therapy. Heart Dis. 2000;2:
220-47.
Giugno 2006
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Chronic urticaria: recent advances in diagnosis and treatment
U
rticaria affects 15-30% of the population and in
1.0-1.5% it persists daily or almost daily for more
than 6 weeks and is therefore conventionally deemed
to be chronic. In this form it causes severe impairment
of quality of life, comparable with that experienced
by patients with triple coronary arterial disease.1
Patients with chronic urticaria (CU) are too often
poorly served by dermatologists and allergists alike,
especially with regard to accurate diagnosis and optimum
treatment. Significant progress has recently been made
on understanding of the immunopathology of CU, and
the efficacy of H1 antihistamines, still the cornerstone
of drug treatment, continues to improve. However, for
the majority of CU patients the etiology remains enigmatic, and although H1 antihistamines are usually effective in controlling itch of CU, they are often less impressive in preventing or reducing the visible hive (wheal)
- especially in chronic idiopathic urticaria (CIU). Presumably this is because, as a late-phase immunological
reaction 2 the wheal in CIU results from actions of a
range of mediators including eicosanoids, TH2 cytokines
and proteases as well as histamine.
2St
M. W. GREAVES 1, 2
1National Skin Center, Singapore
Johns Institute of Dermatology, Guy's, Kings and St
Thomas’ Schools of Medicine and Dentistry
University of London, London, UK
times be made. Pitfalls include urticarial dermatitis 3
the rash of pre-pemphigoid, maculopapular drug eruptions, acute contact dermatitis and insect bite reactions.
A practical approach to the diagnosis of CU requires
that the 3 main subtypes, physical urticaria, urticarial
vasculitis and CIU be considered. Although accurate
information is often very hard to elicit, the duration of
individual wheals can be a useful diagnostic pointer.
Short lived wheals (less than 1 h in duration) suggest
a physical urticaria. An exception is delayed pressure
urticaria in which wheals frequently last over 24 h.
Wheals lasting more than 4-6 h but less than 24 h are
characteristic of CIU, whereas wheals persisting over
24 h should prompt consideration of urticarial vasculitis.
Diagnosis: sub-types of chronic urticaria
Does the patient have urticaria? Most of us would
have little difficulty in diagnosis, but errors can someIN THIS ISSUE SEE PAGE 207
Conflicts of interest : None declared.
Address reprint requests to: M.W. Greaves, MD, National Skin Centre, 1
Mandalay Rd, Singapore 308205, Singapore. E-mail [email protected]
Vol. 141 - N. 3
Physical urticaria
Physical urticarias represent about 45% of CU. Characteristically individual wheals last less than 1 h except
for delayed pressure urticaria. The commonest physical urticarias are symptomatic dermographism and
cholinergic urticaria. Delayed pressure urticaria frequently co-exists with CIU. If a physical urticaria turns
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CHRONIC URTICARIA: RECENT ADVANCES IN DIAGNOSIS AND TREATMENT
some of these patients have an autoimmune disease
manifesting itself as CU. This type of chronic urticaria
is conventionally designated as chronic autoimmune
urticaria (CAU).
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out to be the patient`s sole or at least predominant
problem then, apart from confirming the diagnosis by
appropriate physical urticaria challenge-testing, no
further investigations are warranted, and symptomatic
control using H1 antihistamines should be sought. The
physical urticarias have recently been reviewed.4
Immunopathology
of chronic autoimmune urticaria
Urticarial vasculitis
Urticarial vasculitis represents about 5% of all cases of CU, but is probably underdiagnosed. Individual
wheals last more than 24 h and may stain the skin due
to purpura. Itching is variable and pain or tenderness
may predominate, and unlike CIU systemic symptoms (arthralgia, fatigue, fever) may occur. This diagnosis, which needs to be confirmed by histological
examination of a skin biopsy, is important to make as
a detailed search will need to be made for underlying
causes including autoimmune connective tissue diseases, inflammatory bowel disease, viral hepatitis and
paraproteinemia, as well as for evidence of involvement
of other organs, especially the lungs and kidneys.
Schnitzler`s syndrome (IgM kappa paraproteinemia,
fever, bone pain and urticaria) may or may not show
vasculitis on skin biopsy.
Chronic idiopathic urticaria
The late-phase reaction which characterizes the
wheals of CIU is due to activation of dermal mast
cells. Although a large number of naturally occurring
immunological and non-immunological agents are
known to be capable of activating dermal mast cells,
only allergen-specific IgE reactions, anti-IgE and antiFcεR1 autoantibodies and complement C5a are of
established importance in urticaria. Dermal mast cells
secrete preformed mediators including histamine
(mainly the cause of pruritus), proteases, interleukin 1 and tumor necrosis factor-α. The cytokines cause
increased expression of adhesion molecules by
endothelium of post capillary venules. De novo synthesized mediators include leukotrienes, prostaglandins,
cytokines and chemokines resulting in leukocyte
recruitment including eosinophils which characterise
the late-phase reaction. An MHC class11- dependent
signaling pathway enables mast cells to behave as antigen presenting cells which by activating T cells are
able to maintain the longevity of the wheals.5
Until recently CIU was truly "idiopathic", but during the past decade evidence has emerged that at least
196
IgG autoantibodies in chronic autoimmune urticaria
This topic has recently been reviewed.6, 7 Isolation
of IgG high affinity IgE receptor autoantibody subclasses using protein G affinity chromatography in
patients' sera has shown that the majority of the histamine releasing activity co-localises predominantly
with IgG subclasses IgG1 and IgG3 and similar results
were also reported using immunoblotting. Significant
amounts of non-functional (non-histamine releasing)
IgG anti-FcεR1 immunoreactivity were found concurrently with histamine releasing IgG in all subclasses
studied.
The precise binding sites for anti-FcεR1 autoantibodies have yet to be elucidated. The high affinity IgE
receptor, FcεR1, consists of 4 peptide chains: intracellular γ1, γ2 and β chains and an α-chain with an
extracellular portion which bears the binding site for
IgE. Competitive inhibition studies using human
recombinant α-chain of FcεR1 have established that the
binding sites for IgG anti-FcεR1 autoantibodies are
located on the external portion of the α-chain. Binding can occur on at least 2 domains in this region of the
α-chain since inhibition experiments utilizing myeloma IgE have demonstrated blockade of some but not
all of these autoantibodies, an effect which could be
reversed by lactic acid stripping to remove basophil or
mast cell-bound IgE . These autoantibodies cross-link
and dimerise FcεR1 leading to mast cell or basophil
activation and release of histamine and other mediators.
Up to 5-10% of patients with CAU have autoantibodies with a specificity for IgE itself. These combine
with and cross-link receptor-bound IgE and, by
dimerising mast cell-bound IgE, evoke release of histamine. Removal of IgE from mast cells or basophils
by lactic acid stripping renders these autoantibodies
inactive.
Anti-FcεR1 and anti-IgE autoantibodies are functional, leading to mast cell and basophil activation and
release of histamine and other pro-inflammatory mediators.
Giugno 2006
Role of complement
study 8 we found that of 78 patients with CIU, 35% had
a positive ASST. However, histamine-releasing activity against donor basophils was found in sera of only
25% . Presumably the "false" positive ASST's were
due to the presence in serum of other wheal-inducing
factors. The ASST is at best a crude screening test and
should not be used as a specific test for circulating
autoantibodies.
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Complement depletion or inactivation diminishes
histamine release evoked by anti-FcεR1 autoantibodies in vitro. Subsequent studies established the involvement of C5a and the classical complement activation
pathway. This finding may also explain the otherwise
puzzling observation that symptoms and signs consequent upon interaction between anti-FcεR1 autoantibodies and their antigenic targets on mast cell membranes are limited to the skin since pulmonary mast
cells are devoid of C5a receptors. Activation of the
classical complement pathway and formation of C5a
is important not only to bring about dermal mast cell
activation but also because C5a is a neutrophil and
eosinophil chemoattractant contributing to the observed
accumulation of these cells in lesional skin.
GREAVES
Diagnosis of chronic autoimmune urticaria
Clinical and histological features
Although there are minor clinical differences
between CAU and CIU, none of these is sufficiently
distinctive to be clinically useful. Patients with CAU
have a significantly lower serum IgE than those with
no autoantibodies. The significance of this finding is
unclear. Histological examination of skin biopsies
shows that although the infiltrate in patients with CAU
is characterized by a more prominent granulocyte infiltrate than that of non-autoimmune patients, the frequency of other infiltrating cells was similar in both
groups, although there was a slight increase in serum
tryptase and cytokines in the CAU patients. These
small differences are insufficient to assist in diagnosis.
Autologous serum skin test
In vitro histamine release tests
Demonstration that the patient's serum will release
histamine (or other mediator) from donor basophils
or dermal mast cells remains the benchmark confirmatory test for autoimmune urticaria. Although human
basophils are widely used, human mast cells (utilizing
thin slices of foreskin or suspensions of partially purified dermal mast cells) are effective alternatives. A rat
basophil cell line in which the basophils have been
transfected with genes encoding for the α-, γ1- and
γ2-chains of FcεR1 has also been used successfully.
Utilising human donor basophils, sera from 78 CIU
patients, 27 (35%) were positive indicative of the presence of functional anti-FcεR1 or anti-IgE autoantibodies, the corresponding figures using dermal mast
cells in this study being 31 (40%).8 This test is now
commercially available.*
In addition, recent studies in 52 children have shown
that approximately 45% of children with CIU had
autoimmune urticaria as judged by basophil histamine
release evoked by these patients' sera.
Initially it was hoped that the diagnosis of autoimmune urticaria could be confirmed using a simple and
convenient immunoassay. However, numerous attempts
to develop immunoassays which will measure serum
levels of IgG anti-FcεR1 or anti-IgE have shown low
specificity and poor correlation with in vitro serum
histamine releasing and urticarial disease activity. Positive immunoreactivity has been found in several nonurticarial autoimmune diseases.
Recently there have been reports of the presence of
innate anti-FcεR1 autoantibody activity in normal
serum. These antibodies which are primarily IgM,
show cross reactivity with tetanus toxoid and may be
functional if basophils which have had IgE removed by
lactic acid are used. It has been suggested that a state
of "conditional autoimmunity" may exist in CU, dermal mast cell activation only occurring if these autoan-
In the autologous serum skin test (ASST), serum is
obtained from the patient, preferably when the urticaria
is in relapse. This is injected intradermally into the
same patient's uninvolved skin and the injected skin
examined for wheal formation 30 min later. Necessary controls include intradermal histamine and saline
injections into adjacent skin. The test is positive if the
diameter of the serum-induced wheal is at least 1.5
mm greater than the saline wheal. The test has a sensitivity of about 70% and specificity of about 80% if
performed as described above. However, experience is
*) RefLab ApS PO Box 590, Tagensvej 20 - Dep 7512, DK - 2200
required to obtain reproducible results. In a recent Copenhagen N, Denmark. WWW.reflab.dk
Vol. 141 - N. 3
197
GREAVES
eosinophilia obviates the necessity for stool examinations for ova. There is a strong association between
presence of thyroid autoantibodies and CU and these
co-segregate with anti-FcεR1 autoantibodies.11 Most
of these patients are euthyroid, but occasionally they
are hyper- or hypothyroid. Claims have been made
that correcting thyroid dysfunction, if present, or, in
euthyroid patients with antithyroid autoantibodies,
treatment with thyroxine, ameliorated the urticaria but
the evidence is not convincing. However, the association between thyroid disease and CAU is sufficiently
strong to prompt adding measurement of the plasma
level of thyroid stimulating hormone level (as a screen
for thyroid dysfunction) and thyroid autoantibodies
to the routine workup. Search for foci of infection,
food allergy and food pseudoallergy has little or no
place in the routine investigation of CU.
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tibodies encounter mast cells devoid of IgE. However, other investigators have been unable to neutralize
anti-FcεR1α using tetanus toxoid or inhibit histamine
release by this means and little or no evidence of histamine-releasing activity has been detected in healthy
sera even though large numbers of samples have been
screened. It seems reasonable, at present, to rely on
demonstration of histamine release from donor
basophils as the benchmark diagnostic test for autoimmune urticaria.
General management of chronic urticaria
Diagnostic workup
Patients with CU are frequently overinvestigated,
and a recent study failed to show that increasing the
number of laboratory tests perfomed increased the
number of identified diagnoses.9 Guidelines for diagnosis have recently been formulated.10 The first step
requires exclusion of physical urticarias by appropriate challenge testing. This includes stroking the skin
firmly for symptomatic dermographism, exercise testing for cholinergic urticaria and ice cube challenge
testing for cold urticaria. These and other procedures
have recently been reviewed.4 Identification of physical urticarias is important as, once the diagnosis is
confirmed, no further investigations are warranted,
and response to avoidance of provoking stimuli coupled with H1 antihistamine treatment is all that is needed.
If physical urticarias can be excluded, consideration should be given to the possibility that the patient
has urticarial vasculitis. Clinical features to look for
have been described above, but the clinical picture
may be unremarkable. In all cases the diagnosis must
be confirmed by a skin biopsy, histological examination of which should reveal leucocytoclastic vasculitis. Direct immunofluorescence examination of the
skin biopsy is unhelpful. If the diagnosis is confirmed,
then underlying causes must be sought as previously
outlined and investigation should include a search for
evidence of associated systemic vasculitic disease.
Patients with urticarial vasculitis associated with
hypocomplementemia are more likely to have systemic involvement than those without.
A total white blood cell count and differential is
worth doing to exclude parasitic infestation - especially in developing countries. Absence of a blood
198
Treatment
For all forms of CU basic lifestyle ground rules
need to be observed. These include avoidance of stress,
overtiredness, alcohol, NSAIDs, and tight fitting garments. Nocturnal pruritus can be reduced by tepid
showering and keeping the ambient temperature of
the bedroom cool. Cooling lotions such as calamine
with 1% menthol are popular with patients.
H1 antihistamines: pharmacological considerations
The H1 receptor, cloned and sequenced by Yamashita
et al. in 1991,12 is a G protein-coupled receptor with a
molecular weight of 40 kDa. H1 antihistamines, now
all believed to act as inverse agonists of histamine by
down-regulating the constitutively activated form of the
H1receptor, remain the cornerstone of drug treatment
of all types of CU except urticarial vasculitis in which
they are usually ineffective alone. Their clinical pharmacology and correct usage in urticaria has recently
been comprehensively reviewed.13
First introduced for the treatment of urticaria and
other dermatoses in 1947, the first genereation of H1
antihistamines were effective in relieving the itch of
urticaria, but at significant cost due to sedation and
atropine-like side effects such as bladder dysfunction,
paralysis of accommodation and raised intraocular
pressure, especially in the elderly. These and other
unwanted effects were mainly due to the ease with
which the early H1 antihistamines penetrated the blood-
Giugno 2006
is used to measure the effect of desloratadine 5 mg daily on QOL. The response appeared to be rapid, and substantial, a reduction of 2/3 in DLQI occurring within
28 days of treatment. Although ideally it should have
been placebo-controlled, it is safe to conclude from this
study that desloratadine in licensed dosage is both effective and improves QOL in most patients with CIU.
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brain barrier. Discovery of H2 receptor antagonists in
the early 1960’s did not help much, since the H2 receptor does not mediate histamine-evoked pruritus.
GREAVES
Second generation H1 antihistamines
The advent in the 1980's of a new "second generation" of H1 antihistamines (represented initially by
terfenadine and astemizole - later withdrawn due to cardiotoxicity - and later by loratidine and cetirizine) was
a major advance. The new antihistamines caused little
or no sedation in licensed dosage due to minimal penetration of the blood brain barrier as demonstrated by
the use of 11C-doxepin in positron emission tomography studies, and their recognition by the P-glycoprotein efflux pump which is present in the endothelial cells of the cerebral vasculature. However, these
second generation compounds did cause sedation in
some patients if used in off-label dosages.
New low sedation H1 antihistamines
In an effort to fine-tune the therapeutic index of these
antihistamines, improved versions have subsequently
been licensed in the USA and Europe for the indication of urticaria - initially fexofenadine, and latterly
levocetirizine (L- cetirizine) and descarboethoxyloratidine (desloratadine). These antihistamines, which are
active metabolites (or, in the case of levocetirizine, the
active R-enantiomer) of the parent compound cause
sedation no greater than placebo even if prescribed in
twice the recommended dosages or more as demonstrated by objective measures of cognitive function.
But, theoretical considerations aside, do these antihistamines show evidence-based improved efficacy
in patients with urticaria?
There is no doubt that the new compounds are effective in CU. For example, desloratadine has demonstrated efficacy (reduced pruritus, total symptom score,
number of wheals and interference in daily activities)
in at least 2 large multi-centre double blind placebo
controlled studies. However, several recent studies 1, 14
attest to the fact that quality of life (QOL) is severely
impaired in most patients with CU and accordingly it
is reasonable to expect protagonists of a new antihistamine to demonstrate that their compound is not only
effective, but also significantly improves QOL.
In this issue, Seidenari et al.15 report results of an
open study in 255 patients with CIU in which the QOL
instrument Dermatology Quality of Life Index (DLQI)
Vol. 141 - N. 3
How to get the best response with H1 antihistamines
in CU
Pruritus is the main symptom of most types of
urticaria and its diurnal periodicity should be determined in every patient. Many patients find that itching
is less troublesome during the working day when attention is distracted, onset of itching occurring characteristically when they are relaxing at home in the
evening. This needs to be taken into account in timing
the dose schedule of the antihistamines used. However, for many patients pruritus is troublesome day
and night and for them a twice daily dosage of a low
sedation H1 antihistamine is adequate.
Off-label dosages of H1 antihistamines such as desloratadine 5 mg b.i.d. or fexofenadine 180 mg b.i.d. are useful in recalcitrant cases and, in my experience and that
of others,16 devoid of adverse effects even after prolonged dosages. For persistent night time sleep disturbance an additional nocturnal dose of a sedative antihistamine such as hydroxyzine or the tricyclic doxepin,
a highly potent H1 - and H2 receptor antagonist, can be
added. However, the patient should be warned that
impairment of cognitive function may persist throughout the following day. Doxepin should be used with
extreme caution in patients with heart disease and in
the elderly, and should never be withdrawn abruptly. It
is also important to emphasise the importance of regular dosage of H1 antihistamines to avoid the problem of
development of subsensitivity (pseudotachyphylaxis ).
For a minority of patients, especially those with CIU
rather than a physical urticaria, even off-label dosages
of H1 antihistamines are poorly effective.
H2 antagonists
Cimetidine or ranitidine may occasionally be useful
in patients with severe urticaria who experience gastric hyperacidity due to elevated histamine levels, and
in patients receiving short courses of oral steroids during relapses, but otherwise have no place in contemporary management of CU.
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Other treatments
Leukotriene antagonists
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The value of adding a leukotriene antagonist such as
montelukast 10 mg daily to H1 antihistamine treatment
is controversial. A review of the literature suggests that,
although there is no clear evidence of efficacy, addition of a leukotriene antagonist does appear to help
some patients, especially those experiencing flare-ups
due to aspirin and other NSAIDs. Adverse effects are rare
but Churg-Strauss vasculopathy has been reported.
occurring after withdrawal of oral steroids. These
patients can be offered further cyclosporine treatment.
All patients receiving cyclosporine must be regularly
monitored for renal function, serum cholesterol and
triglycerides and blood pressure. Cyclosporin has also
proved to be effective in non-autoimmune "ordinary"
CIU. Other immunomodulators that have been reported effective in selected patients with CAU include
intravenous immunoglobulin and plasmapheresis.
Systemic corticosteroids
Systemic corticosteroids are useful in patients experiencing severe sometimes predictable flare-ups which
cannot be controlled by antihistamines. Brief tapering courses (e.g. 30 mg daily for 3 days; 20 mg daily
for 3 days; 10 mg daily for 3 days; 5 mg daily for 3 days
then cease) should be prescribed . European guidelines 10 discourage the use of systemic steroids as longterm treatment. Oral cyclosporine, a calcineurin
inhibitor which inhibits T cell activation and which is
proposed for the treatment of CAU (see below), is also
effective in CIU but not in physical urticarias. I use it
in selected CIU patients with severe QOL impairment
who are poorly responsive to antihistamines.
Treatment of CAU: special considerations
Patients with proven CAU are initially treated in exactly the same way as patients with CIU. However, they
usually have severe disease and frequently prove poorly responsive to antihistamines, even in off-label dosage.
Cyclosporin
Cyclosporin was shown to be effective in selected
patients who were ASST positive in a double blind
placebo controlled study.17 The dose range used is 46 mg/kg/day in addition to antihistamines. Our practice is to offer a course of up to 3 months. Eighty per
cent of patients experience total or partial remission.
In these, withdrawal of cyclosporine is followed by
sustained remission in about 1/3 of patients. One third
of patients relapse but are responsive to regular dosages
of H1 antihistamines. Although the remaining 1/3 of
patients relapse to a severity approximating to that
suffered before initiating cyclosporine, I have rarely
experienced a rebound effect such as that frequently
200
References
1. O'Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The
impact of chronic urticaria on quality of life Br J Dermatol
1997;136:197-201.
2. Grattan CEH, Boon AP, Eady RAJ, Winkelmann RK. The pathology
of the autologous serum skin test response in chronic urticaria resembles IgE-mediated late phase reactions Int Arch Allergy Immunol
1990;93:198-204.
3. Kossard, S, HamannI, Wilkinson B. Defining urticarial dermatitis.
4. Black AK. Physical urticarias. In: Greaves MW, Kaplan AP, editors.
Urticaria and angioedema. New York: Marcel Dekker; 2004.
5. Frandji P, Mourad W, Tkaczyk C, Singer M, David B, Colle JH et al.
IL-4 mRNA transcription is induced in mouse bone marrow-derived
mast cells through an MHC class11-dependent signaling pathway.
Eur J Immunol 1998;28:844-55.
6. Hide M, Francis DM, Grattan CEH, Hakimi J, Kochan JP, Greaves
MW. Autoantibodies against the high affinity IgE receptor as a cause
for histamine release in chronic urticaria. New Eng J Med
1993;328:1599-604.
7. Sabroe R, Greaves MW. Chronic idiopathic urticaria with functional autoantibodies: 12 years on. Br J Dermatol 2006;154:813-9.
8. Sabroe RA, Fiebiger E, Francis DM, Maurer D, Seed PT, Grattan CE
et al. Classification of anti-Fc_R1 and anti-IgE autoantibodies in
chronic urticaria and correlation with disease activity J Allergy Clin
Immunol 2002;110:492-9.
9. Kozel MMA, Bossuyt PMM, Mekkes JR, Bos JD. Laboratory tests and
identified diagnoses in patients with physical and chronic urticaria and
angioedema: a systematic review. J Am Acad Dermatol 2003;48:409-16.
10. Zuberbier T, Bindslev-Jensen C, Canonica W, Grattan CE, Greaves
MW, Henz BM et al. EAACI/GA_LEN/EDF guideline: definition,
classification and diagnosis of urticaria Allergy 2006;61:316-20.
11. O'Donnell BF, Francis DM, Swana GT, Seed PT, Black AK, Greaves
MW. Thyroid autoimmunity in chronic urticaria Br J Dermatol
2005;153:331-5.
12. Yamashita M, Fukui H, Suguma K, Horio Y, Ito S, Mizuguchi H et al.
Expression cloning of a cDNA encoding the bovine histamine H1
receptor. Proc Natl Acad Sci USA 1991;88:11515-9.
13. Greaves MW. Antihistamines in dermatology. Skin Pharmacol Physiol 2005;18:220-9.
14. Poon E, Seed PT, Greaves MW. Black AK. The extent and nature of disability in different urticarial conditions Br J Dermatol 1999;140:667-71.
15. Seidenari S, Cirillo A, Amoroso S, Flori ML, Amerio P, Ricciuti E et
al. Desloratadine 5 mg once daily improves quality of life in chronic idiopathic urticaria. G Ital Dermatol Venereol 2006;141:207-15.
16. Nelson HS, Reynolds R, Mason J. Fexofenadine HCL is safe and
effective for treatment of chronic idiopathic urticaria. Ann Allergy
Asthma Immunol 2000;84:517-22.
17. Grattan CEH, O'Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed
PT et al. Randomised double blind study of cyclosporine in chronic
idiopathic urticaria. Br J Dermatol 2000;143;365-72.
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Chronic idiopathic urticaria
C
hronic idiopathic urticaria (CIU) is a skin condition defined as itchy wheals on almost a daily
basis for 6 weeks or more, were a specific cause has not
been identified after full evaluation.1 Itch is the predominant symptom of urticaria and pain and burning
sensations are more suggestive of urticaria vasculitis.
CIU is a self-limited disease with a median duration of
2-4 years.
The etiopathogenesis of CIU is considered to be
autoimmune in up to 50% of cases. These patients have
detectable anti-FcER1 or anti-IgE auto-antibodies. A
strong association with thyroid autoimmunity has been
observed and confirmed in a recent large scale study.2
CIU can cause significant disability. The quality of
life of CIU patients has been studied in 142 outpatients, who experienced an impairment similar to
patients with coronary artery disease.3 The patients
had significant sleep disturbances, diminished energy,
social isolation, and difficulties in relation to work,
home activities and social life. Another smaller scale
study of 21 patients in Italy has shown that patients with
chronic urticaria had lower quality of life scores compared to patients with respiratory allergies and both
were significantly lower than healthy subjects.4
Although the cause of CIU may remain elusive, theIN THIS ISSUE SEE PAGE 207
Address reprint requests to: G. Yosipovitch, MD, Department of Dermatology, Neurobiology & Anatomy, and Regenerative Medicine, Wake
Forest University Health Sciences, Winstom-Salem, NC 27157 USA
Vol. 141 - N. 3
G. YOSIPOVITCH
Department of Dermatology, Neurobiology and Anatomy
and Regenerative Medicine
Wake Forest University Health Sciences
Winston-Salem, NC, USA
re are number of factors that worsen and aggravate its
main symptom of itch. These include ambient heat and
sweating, drugs such as NSAIDs and aspirin, alcoholic
beverages, and food additives containing salicylates
and aromatic compounds. Emotional stress can cause
flairs of CIU. Itch intensity in CIU has been related to
stress; however, it is significantly less in comparison
with other chronic pruritic dermatoses such as atopic
eczema and psoriasis.5 The clinical presentation of itch
in chronic urticaria is unique in comparison with other
types of itch, since there are usually no excoriations or
scratch marks. Most patients rub their skin rather than
scratching. The areas where wheals occur coincide with
areas of itch and are mainly located in the arms, back,
and waistband in sites of pressure. There is a significant
diurnal variation in itch of CIU; patients report more
itch in the evening and at night and 64% of patients
reported being awaken by their itch.5
H1-antihistamines are the first-line treatment for all
patients with CIU.6 Short or long-term relief of itching
was achieved in 92% of patients with CIU.5 Low-sedation antihistamines such as loratadine, cetrizine, desloratadine, fexofandane have been shown to be effective in reducing daytime symptoms of chronic urticaria.
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CHRONIC IDIOPATHIC URTICARIA
t.i.d. seems to be the most effective sedating H1-blocker
in reducing hives and itch at night time. Doxepin is a
potent oral antihistamine, but has significant sedating
and anticholinergic effects and many patients do not
tolerate it. Combination of both sedating and nonsedating H1-blockers is commonly used and recommended both in Europe as well as in the USA. Increasing the dose of non-sedating antihistamines higher
than recommended by manufacturers to twice daily
is common practice in the USA. Alternating between
different types of antihistamines is also helpful in reducing the symptoms of CIU and itch. A significant number of patients do not respond to oral antihistamines
alone.
Other treatments for CIU include oral corticosteroids. Short courses of high-dose oral corticosteroids
are helpful for antihistamine-resistant CIU. Several
regimens have been used. In the USA, there is tendency to use higher doses tapered down gradually
from 40 mg in a 3 week taper. Other treatments that
seem effective include cyclosporine A 3-5 mg/kg, which has been shown to be effective in severe cases of
autoimmune CIU. During treatment of CIU, antihistamines should be continuously administered. Recently, oral tacrolimus has been shown to be an effective
treatment for severe cases of CIU in low doses ranging between 0.05-0.2 mg/kg/day.10
Luekotriene inhibitors have been reported in anecdotal case reports to be effective in treatment of CIU.
A recent double-blind study from Italy comparing
montelukast plus desloratdine versus desloratdine 5
mg alone for moderate CIU demonstrated that the
combined therapy of desloratadine plus montelukast
does not appear to offer any advantage over desloratadine monotherapy.11 Intravenous gammaglobulins
in severe cases of CIU have also been reported in case
series of autoimmune CIU with circulating anti-FcER1
or anti-IgE auto-antibodies. Other treatments commonly used include hydroxychloroquine 400 mg/day,
as well as colchicine and dapsone; however, there are
no controlled studies to provide evidence for the efficacy of these regimens.
In conclusion, antihistamines have an important role
in reducing CIU symptoms; however, a significant
proportion of patients do not respond to these treatments alone. Other treatments for this disabling symptom have been utilized but not subjected to controlled
studies. Therefore, these treatments should be further
evaluated through double-blind, controlled studies.
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In this issue, Seidenari et al.7 report a large multi-center study performed in Italy on the effect of desloratadine 5 mg on quality of life of 255 patients aged 1879 years with moderate to severe CIU using the dermatology life quality index (DLQI), a well-validated
tool. After 28 days of treatment, desloratadine improved the quality of life of the CIU patients and their
itch intensity. One of the limitations of this study, as
identified by the authors is its design as an open-label
study. A placebo arm would have significantly improved the scientific quality of this large scale study.
However, the large study population participating in this
multicenter study suggests that desloratadine reduces
symptoms of itch and hives and has beneficial effects
on the quality of life of CIU patients. Moreover, a
recent multicenter study in Belgium assessed the effect
of desloratadine 5 mg on quality of life in 121 patients
with CIU for 42 days in an open-label fashion.8 Similar results were reported to the Italian study and 77%
of patients had a clinically significant change. The
improvement in clinical signs of itch and hives correlated to change in DLQI scores. Monroe et al. performed the only placebo-controlled study on the effect of
desloratadine 5 mg on sleep, itch and severity of CIU
in 226 patients from several centers in the US and
demonstrated significant improvement. However, the
authors did not evaluate quality of life using validated
QOL tools.9
Desloratadine is the major orally active metabolite
of loratadine. It is metabolized by glucoronidation in
the cytochrome P450 system. Desloratadine has a halflife of 19-34 h and is excreted in the urine and feces.
It is considered a safe drug and has low risk of adverse cardiovascular effects, and no reported ECG changes, which have been noted previously with astimazole
and terfenadine. No known interactions have been
reported between desloratadine and other drugs that
affect cytochrome P450. There is no data on safety of
this drug in pregnancy, and therefore it is best to avoid
using desloratadine and most other antihistamines in
pregnancy.
The efficacy of non-sedating antihistamines in CIU
has been well-documented; however, the sedating
antihistamines still have a significant role in controlling CIU. As Seidenari et al.7 pointed out, patients
with CIU have significant sleep disturbance. The classical, sedating H1-antihistamines are frequently required to manage CIU, especially in those patients who
report sleep disturbance. Hydroxyzine at 25-50 mg
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CHRONIC IDIOPATHIC URTICARIA
YOSIPOVITCH
References
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1. Greaves MW, Kaplan AP. Urticaria and angioedema. New York: Marcel Dekker; 2004.
2. O’Donnell BF, Francis DM, Swana GT, Seed PT, Kobza Black A,
Greaves MW. Thyroid autoimmunity in chronic urticaria. Br J Dermatol
2005;153:331-5.
3. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The
impact of chronic urticaria on the quality of life. Br J Dermatol
1997;136:197-201.
4. Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C
et al. Quality of life and patients’ satisfaction in chronic urticaria and
respiratory allergy. Allergy 2003;58:621-3.
5. Yosipovitch G. Ansari N, Goon A, Chan YH, Goh CL. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol
2002;147:32-6.
6. Bleehen SS, Thomas SE, Greaves MW, Newton J, Kennedy CT, Hindley F et al. Management and diagnostic guidelines for urticaria and
angio-oedema. Br J Dermatol 1987;117:81-8.
7. Seidenari S, Cirillo A, Amoroso S, Flori ML, Amerio P, Ricciuti E et
al. Desloratadine 5 mg once daily improves quality of life in chronic
idiopathic urticaria. G Ital Dermatol Venereol 2006;141: ????
8. Lachapelle JM, Decroix J, Henrijean A, Roquet-Gravy PP, De Swerdt
A, Boonen H et al. Desloratadine 5 mg once daily improves the quality of life of patients with chronic idiopathic urticaria. J Eur Acad Dermatol Venereol 2006;20:288-92.
9. Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D et al. Efficacy and safety of desloratadine 5 mg once daily in the treatment of
chronic idiopathic urticaria: a double-blind, randomized, placebocontrolled trial. J Am Acad Dermatol 2003;48:535-41.
10. Kessel A, Bamberger E, Toubi E. Tacrolimus in the treatment of severe chronic idiopathic urticaria: an open-label prospective study. J Am
Acad Dermatol 2005;52:145-8.
11. Di Lorenzo G, Pacor ML, Mansueto P, Esposito Pellitteri M, Lo Bianco C, Ditta V et al. Randomized placebo-controlled trial comparing
desloratadine and montelukast in monotherapy and desloratadine plus
montelukast in combined therapy for chronic idiopathic urticaria. J
Allergy Clin Immunol 2004;114:619-25.
Vol. 141 - N. 3
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Sequential treatment of severe recalcitrant psoriasis
with infliximab and cyclosporine
T
he use of biologicals in the treatment of psoriasis
has changed dramatically our options particularly in patients with severe psoriasis. Many patients benefit in situations were conventional treatments have
failed, are contraindicated of have produced side
effects.
Two aspects, however, remain open at present: first,
biologicals are expensive (although the overall benefit regarding not only costs for the drug, but also lower frequency of hospital admission, days of sick leave
and even loss of working capability need to be calculated) and thus reimbursement remains a matter of
daily discussion with health insurances, and second, the
combination of biologicals with conventional systemic
drugs, UV therapies and with other biologicals.
The approach to the second question will be mainly investigator initiated, since the companies producing biologicals will at present not initiate such trials.
Thus, large and randomized clinical studies will not be
possible for each of the potential combinations, be it
parallel or sequential combinations. Rather, small pilot
studies seem feasible to allow testing hypothesis of
beneficial action of certain combinations.
One aspect that has come with the advent of biologicals and the concept of long term control of psoriasis is the distinction between induction and mainIN THIS ISSUE SEE PAGE 221
Address reprint requests to: Prof. W. Sterry, Department of Dermatology
and Allergy, Skin Cancer Centre, Charite-Universitatsmedizin Berlin,
Berlin, Germany. E-mail: [email protected]
Vol. 141 - N. 3
W. STERRY
Department of Dermatology and Allergy, Skin Cancer Centre,
Charite-Universitatsmedizin Berlin, Berlin, Germany
tenance treatments in psoriasis. Once patients with
severe psoriasis have responded to an intensive induction treatment, other therapeutic options may come
into place to maintain the response. However, induction is not always easy to achieve in patients with highly active and severe psoriasis.
Here comes the study conducted by G. A. Vena et al.1
into the field. They speculated that patients that have
shown be recalcitrant to conventional treatments including cyclosporine might become sensitive to
cyclosporine after induction treatment with just 2
courses of infliximab. In their small but highly relevant
study they found that 10 out of 10 patients responded
well to infliximab at week 2, and that this response
could be maintained in 9 of 10 patients.
What are the conclusions from this study? First,
it shows that nonresponsiveness of psoriasis to conventional systemic treatment can be overcome by
short courses of infliximab, with subsequent responsiveness to the previous treatment. Second, it demonstrates that our armentarium of antipsoriatic drugs
may become more efficient by combing different
classes of systemic drugs. Third, and possibly most
important, it shows that the dermatological community will be able to contribute independently from
pharmaceutical companies to the development of
new treatment strategies. Of course, there are many
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SEQUENTIAL TREATMENT OF SEVERE RECALCITRANT PSORIASIS WITH INFLIXIMABAND CYCLOSPORINE
reported were mollusca contagiosa of the eyebrows,
Nocardia, Cryptococcus, Listeria, and septicaemia.
Some of the infections were fatal.
In summary, after the introduction of biologics in the
treatment of psoriasis, we have started to combine
them with other treatment options. The study of the
possible combinations may bring further therapeutic
benefit to our patients, but needs to be brought forward under controlled clinical trials.
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possible combinations that are worth to be tested,
but G. A. Vena and his group have demonstrated how
to proceed to gain scientific information within this
relevant therapeutic area for those patients with psoriasis that are extremely difficult to treat. For example, in Germany, where fumarates are used for systemic treatment of psoriasis, exacerbations are managed by using etanercept for 4-8 months; formal studies are lacking so far.
However, a great deal of clinical experience and
meticulous monitoring of such patients are mandatory. Two recent publications have summarized our current knowledge, mainly based on single case reports,
in combining biologics with non-biologics.2-4 Such
case reports include the development of malignant
lymphoma in a patient with cyclosporine and infliximab; most interestingly, the lymphoma went into
complete remission 5 months after the treatment had
been stopped.3 Moreover, cases with rare or opportunistic infections have been published under a variety
of combination treatments.4 Among the infections
206
References
1. Vena GA, Cassano N, Loconsole F, Malara G, Sciarrone C, Puglisi
Guerra A. Sequential treatment of psoriasis with infliximab followed
by cyclosporin: preliminary results of an open-label prospective study.
G Ital Dermatol Venereol 2006;141:
2. Cather JC, Menter A. Combining traditional agents and biologics for
the treatment of psoriasis. Semin Cutan Med Surg 205; 24:37-45.
3. Mahe E, Descamps V, Grossin M, Fraitag S, Crickx B. CD30+ T cell
lymphoma in a patients with psoriasis treated with ciclosporin and
infliximab. Br J Dermatol 2003; 149:170-3.
4. Stebbins WG, Lebwohl MG. Biologics in combination with nonbiologics: efficacy and safety. Dermatol Ther 2004;17:432-40.
Giugno 2006
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Desloratadine 5 mg once daily improves quality
of life in chronic idiopathic urticaria
S. SEIDENARI 1, A. CIRILLO 1, S. AMOROSO 3, M. L. FLORI 4, P. AMERIO 5, E. RICCIUTI 6, G. A. VENA 7,
E. BERARDESCA 8, C. LE GRAZIE 9 and The Italian Study Group on Desloratadine (DL) in Chronic Urticaria*
Aim. Desloratadine (DL) is an effective treatment for chronic
idiopathic urticaria (CIU) symptoms, but there is little information about its impact on patients’ perceived general wellbeing. The primary objective was to measure the effect of DL
on the quality of life (QoL) of CIU patients, using the Dermatology Life Quality Index (DLQI). Secondary objectives were:
evaluation of the effects of DL on pruritus and number of hives,
sleep and daily activities, overall CIU condition, and assessment of therapeutic response. Safety and tolerability of DL
were also evaluated.
Methods. Two-hundred and fifty-five patients, aged 18-79 years
and with moderate to severe CIU, were treated with DL 5 mg
once daily for 28 days. Patients recorded signs and symptoms
scores daily, and completed the DLQI questionnaire at baseline
and on treatment days 7, 14, 21 and 28. Patients and investigators jointly evaluated overall CIU condition and therapeutic response at days 14 and 28.
1Department of Dermatology, Polyclinic, Modena, Italy
2Allergology Unit, Civic Hospital, Caserta, Italy
3Allergology Unit
Civic and Benfratelli Hospital, Palermo, Italy
4Department of Dermatology
A.O. Senese (Hospital), Siena, Italy
Gemelli Polyclinic, Rome, Italy
6Dermatology Unit, Carlo Hospital, Potenza, Italy
Policlinico Consorziale Hospital, Bari, Italy
8Dermatology Institute, IRCCS San Gallicano, Rome, Italy
9Medical Department, Schering Plough Spa, Milan, Italy
*) Participating Centres.—S. Seidenari, F. Giusti - A.O. Policlinico, Modena; P. Amerio, R. Capizzi - Policlinico Gemelli, Rome; S. Amoroso, M.A.
Marino - Ospedale Civico e Benfratelli, Palermo; C. Barbera, M. Ferraro - Ospedale Generale Provinciale degli Infermi, Biella; E. Berardesca, A. Cristaudo, E. Di Lella - IRCCS S.Gallicano, Rome; G. Borroni, M. Mosca - Policlinico S. Matteo, Pavia; S. Calvieri, A.G. Righetta - Policlinico Umberto I, Rome; S. Chimenti, R. Barbati - U.S.L. Roma “C”; A. Cirillo, A. Ciccarelli - Ospedale Civile, Caserta; C. Crosti, R. Calcaterra, E. Tolomio - Ospedale S. Paolo, Milan; O.De Pità, A. Provini - Istituto Dermopatico dell’Immacolata, Rome; A. Finzi, P. Pigatto – Ospedale Maggiore Policlinico, Milan;
M.L. Flori, M. Pellegrino, A. Molinu - A.O. Senese, Siena; A.Giomi - U.S.L. N. 3, Pistoia; V. Griseta, A.Lerario - Ospedale Generale Regionale Miulli, Acquaviva delle Fonti (BA); G. Leigheb, M. Bertero, R. Zuccoli - A.O. Maggiore della Carità, Novara; P. Lisi, L. Stingeni, K. Hansel - Università
degli Studi di Perugia; M. Lospalluti, M. L. Carriera, V. Serpenti - A.U.S.L. BA/4, Bari; L. Muratore - A.O. Vito Fazzi di Lecce; A. Offidani, O. Simonetti, C. Simonini - A.O. Umberto I, Ancona; C. Ortolani, J. W. Schroder, G. Vighi - Ospedale Niguarda, Milan; F. Pezzuto, A. Pio - ASL 2, Salerno;
F. Ricciuti, L. Viola - Ospedale S. Carlo, Potenza; P. Santoianni, G. Lembo, G. Moffa - Università degli Studi Federico II, Napoli; E. Sbano, V. Altamura - AUSL BR/1, Brindisi; C. Troise, D. Bignardi, S. Voltolini - Ospedale S. Martino, Genoa; A. Tulli, A. De Benedetto, P. Toto - Università degli
Studi G. D’Annunzio, Chieti; C. Varotti, T. Bianchi - Policlinico S. Orsola Malpighi, Bologna; G. A. Vena, N. Cassano Ospedale Policlinico Consorziale, Bari; L. Zichichi, V. Maltese - A.O. S.Antonio Abate, Erice (TP).
This study was supported by Schering-Plough Spa, Italy.
Received January 24, 2006.
Accepted for publication March 30, 2006.
Address reprint requests to: S. Seidenari, Clinica Dermatologica, A.O. Policlinico di Modena, Via del Pozzo 71, 41100 Modena, Italy.
Vol. 141 - N. 3
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SEIDENARI
DESLORATADINE 5 MG ONCE DAILY IMPROVES QUALITY OF LIFE IN CHRONIC IDIOPATHIC URTICARIA
most countries in Europe, Asia and South America.8 DL
was proven to be effective in the treatment of CIU in
2 large, multicentre, double-blind, placebo-controlled
studies. Administered at a dose of 5 mg orally once daily (o.d.),9, 10 it significantly reduced pruritus, total
symptom score, number of hives and interference with
sleep and daily activities, and improved the overall
therapeutic response and global CIU status. No QoL
questionnaires were used in these studies, hence data
regarding the effects of DL treatment on the QoL of
chronic urticaria patients are lacking.
The important implications of the psychosocial
aspects of CIU for the optimal management of patients
have prompted us to evaluate the actual impact of DL
on the QoL of CIU patients, using the Dermatology
Life Quality Index (DLQI), a dermatology-specific
questionnaire that has been used extensively for different conditions over the past decade.3, 4, 11-13 Recently, the clinical meaning of the DLQI score and of its
change have been further clarified.14, 15 This multicentre, noncontrolled clinical study was designed as an
exploratory assessment of the effect of 5 mg o.d. DL
on the QoL of patients with moderate to severe CIU,
as measured by the DLQI. Secondary objectives were
evaluation of the effects of DL on pruritus and number
of hives, and on sleep and daily activities, as well as
assessment of the improvement in overall CIU condition and the therapeutic response. Safety and tolerability were also assessed.
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Results. After 28 days of treatment, DL significantly reduced
mean overall DLQI score from 9.4 (±5.4) at baseline to 3 (±4.1)
(–66.1%; P<0.001), with no significant differences between
moderate and severe patients. Improvement in QoL was significant (P<0.001) at all time points and for all DLQI domains.
All signs and symptoms scores were significantly correlated
with DLQI score.
Conclusion. Treatment with DL 5 mg for 4 weeks significantly improves symptoms and QoL in patients with CIU, irrespective of disease severity, and with a rapid onset of action.
KEY WORDS: Antihistamines - Chronic idiopathic urticaria - Dermatology life quality index (DLQI) - Desloratadine - Quality of life.
U
rticaria is a very common disorder, with chronic
idiopathic urticaria (CIU) being the form most
frequently encountered. CIU is defined as a six-week
or longer history of widespread itchy wheals or hives
in the absence of a detectable allergic, physical or
environmental cause.1 If not adequately treated, CIU
patients report problems with daily activities, social
interactions, emotions, mobility and sleep. Symptoms
and signs of CIU can be distressing and debilitating,
and CIU has been shown to affect patients’ quality of
life (QoL) even more than other severe skin diseases,
such as acne or psoriasis.2-4 Some authors found the
impact on QoL reported by CIU patients to be comparable to that of older patients with ischaemic heart
disease,5 and greater than that of patients with respiratory allergy.6
Over the past decade, information on QoL in dermatology has become an important additional measure to assess treatment efficacy, second only to clinical symptoms evaluation, especially in chronic and
recurrent diseases in which the clinical manifestations
can lead to significant decrements in emotional wellbeing, social functioning and sleep habits. Specific
tools for QoL assessment allow the evaluation of a
patient’s subjective perception of the effects of treatment on his/her life and the identification of the items
(physical, social or psychological) that most influence
improvement.7 Thus, the more information that is collected about the degree of improvement in QoL, the
more precise can be the selection of the most effective
therapy for a specific group of patients.
As the symptoms and signs of CIU are primarily
mediated by histamine, antihistamines are the firstline therapy in CIU.2 Desloratadine (DL) is a nonsedating antihistamine with potent peripheral H1-receptor blockade. This agent is indicated for the treatment
of allergic rhinitis and CIU in the United States and in
208
Materials and methods
Patients
After giving written informed consent, male and
female patients aged ≥ 18 years, and with a history of
CIU (defined as at least 6 weeks of pruritus and hives,
with hives lasting <24 h and occurring at least 2 days
per week) in the absence of identifiable causal factors
at clinical history and physical examination, were considered for admission to the run-in phase if they presented with a pruritus score ≥ 2 and a hive score ≥ 1
within 12 h prior to the consent visit. After an adequate wash-out period from all medications that could
possibly interfere with urticaria and allergic conditions, patients entered a three-day run-in prior to the
start of treatment (at visit 2). During the run-in, patients
scored their pruritus, number of hives, and the impact
of their disease on daily activities and sleep in a daily
Giugno 2006
apeutic response. The overall condition of CIU was
also evaluated at the consent visit and at visit 2 (prior
to start of treatment).
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diary. Patients with pruritus and an overall CIU condition of at least moderate severity at the end of the runin period were assigned to DL treatment.
Patients with urticaria primarily due to physical or
other known aetiological factors, pregnant or nursing
women, and patients with concomitant asthma, drug or
food allergies, or atopic dermatitis were excluded.
SEIDENARI
Study medication
DL (Aerius®; Schering-Plough) was administered
orally at a dose of 5 mg o.d. (1 tablet) for 28 consecutive days. Patients were instructed to take the drug in
the morning, after completion of their diary, with no
regard to the timing of meals.
DLQI
The DLQI is a self-administered questionnaire measuring QoL over the previous week in adult patients
with skin diseases. It consists of 10 questions scored
from 0-3 and grouped in 6 domains, and has been validated in several languages, including Italian
(http://www.dermatology.org.uk). Patients completed the questionnaire on treatment days 1 (baseline,
before treatment initiation), 7, 14, 21 and 28. The
DLQI score was calculated by summing the score for
each question (minimum 0, maximum 30) – the higher the score, the more QoL is impaired. The primary
outcome measure was the mean change from baseline in overall DLQI score at day 28. The mean changes
from baseline at weekly intervals and in individual
DLQI domains were also measured as secondary efficacy variables.
Other outcome measures
Patients assessed disease activity during the run-in
and treatment periods by scoring in their daily diaries,
using four-point scales (0-3), the following items: pruritus and number of hives (twice daily, morning [a.m.]
and evening [p.m.]), and interference with sleep (a.m.)
and daily activities (p.m.). The daily mean score of
pruritus and number of hives was then calculated as the
mean of the a.m. and p.m. ratings. Overall CIU condition and global response to therapy were evaluated
jointly by the investigator and patient after reviewing
the diaries on days 14 and 28, using a four-point scale
(0=none, 3=severe) for CIU condition and a five-point
scale (1=complete relief, 5=treatment failure) for ther-
Vol. 141 - N. 3
Safety assessments
Vital signs were recorded at every visit. Laboratory evaluations were performed at screening and at the
end of the study. All adverse events (AEs) were recorded and graded with respect to severity and potential
relation to the study drug.
Sample size and statistical analysis
It was calculated that a sample size of 246 patients
would allow estimation of the reduction in the percentage of the DLQI score after 28 days of treatment
(two-sided, 95% confidence interval for the difference
of means) with a significance level of 5% and assuming a standard deviation of the difference of 40.
Quantitative variables were described by the number of available and missing observations, mean, median, standard deviation, range (minimum and maximum), and first and third quartiles, whereas qualitative
variables were described by frequency and percentage. Missing values were tabulated with their frequency, but were not included in the calculation of
percentages. The overall statistical analysis was conducted on an intention-to-treat (ITT) basis. An analysis of covariance (ANCOVA) model was used, with the
baseline DLQI score as the covariable and the DLQI
score change (day 28 minus baseline) as the dependent
variable. The ANCOVA model was also used to analyse
secondary efficacy variables. Paired t-test and signedrank test were used to assess whether changes produced during the study were different from zero. Categorical variables, such as the overall CIU condition
assessment and the therapeutic response, were analysed
descriptively and estimated with a 95% confidence
interval following an exact binomial method (AS System release 8.02; Cary, NC, USA).
Results
Baseline characteristics
A total of 282 patients were enrolled at 28 Italian
investigational sites (see Participating Centres): 27
were screening failures, while 255 were admitted to the
treatment phase and represent the ITT population.
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SEIDENARI
TABLE I.—Demographic and disease characteristics at baseline.
Gender, n (%)
Male
Female
Age, years
Mean (median)
Range
Duration of CIU, months
Mean (median)
Range
Pruritus, n (%)
Moderate
Severe
Hives, n (%)
1-6
7-20
>20
CIU severity, n (%)
Moderate
Severe
DLQI, Mean±SD
Moderate CIU
Severe CIU
Efficacy analysis
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87 (34.1)
168 (65.9)
significantly different between the 2 groups: 1.9±0.4
in moderate and 2.3±0.4 in severe patients (P<0.001).
43.5 (42)
18-79
20.3 (8)
1.5-360
158 (62)
97 (38)
58 (22.7)
115 (45.1)
82 (32.2)
165 (64.7)
90 (35.3)
9.4±5.4
8.4±4.6
11.3±6.4
Demographic and CIU characteristics at baseline are
summarised in Table I. Most patients had a moderate
CIU condition, with moderate pruritus and up to 20
hives. The mean overall DLQI score at baseline was 9.4
(±5.4). The mean overall DLQI score was significantly
higher (P<0.001) in patients with severe CIU
(11.3±6.4) than in patients with moderate CIU
(8.4±4.6). Baseline pruritus score (a.m./p.m.) was also
After 28 days of treatment, DL significantly reduced
the mean overall DLQI score from 9.4 (±5.4) at baseline to 3 (±4.1) (66.1%; P<0.001). The reduction was
highly significant after only the first 7 days of DL
therapy (41.8%; P<0.001). The DLQI scores for moderate and severe patients before and after treatment
are shown in Figure 1A. There were no significant
differences in the DLQI mean percentage reductions
at all time points during DL treatment between patients
with moderate and severe CIU (67% and 63%, respectively, at day 28) (Figure 1B ). Analysing the DLQI
domains separately, the mean percentage reduction
was highly significant for all DLQI domains, especially for the ‘symptoms and feelings’ domain, which
was the most affected at baseline (Table II).
The distribution of the patient population across the
DLQI domains showed that, at baseline, the impact
of CIU on QoL was moderate in 40% of patients and
very large in 29.4%. After 28 days of treatment, the
impact was none to small in 79.3% of patients (Table
III).
The mean pruritus score was significantly reduced
within 24 h of the first dose of DL (mean percentage
change of a.m. score at day 2 from baseline was 33%;
P<0.001), and was further reduced up to day 28 (mean
percentage change of a.m./p.m. score from baseline
Days
11.4
12
0
8.4 *
8
6
3.5
4
2.7
2
Mean % change vs baseline
*P<0.001 vs severe
10
Mean DLQI score
7
14
A
28
-10
-20
-30
-40
-41
-42
-50
*
-60
-62
-70
*P<0.001 vs baseline
0
21
-59
*
-59
-62
-63
-67
*
*
-80
Moderate
Before
Severe
After
B
Moderate
Severe
Figure 1.—Mean DLQI total score before and after treatment in patients with moderate and severe CIU (A). Mean percentage decrease in DLQI total
score versus baseline, in moderate and severe CIU patients (B).
210
Giugno 2006
SEIDENARI
TABLE II.—Mean percentage change in DLQI domain scores, and effect of each domain on the percentage decrease in the total score.
Mean baseline
score
Mean
final score
Mean % reduction
versus baseline*
Relative impact on
mean % decrease
9.4
3.4
1.9
1.5
1.1
1.2
0.3
3
1.2
0.6
0.4
0.3
0.4
0.1
–68,1
–67.6
–68.4
–73.3
–72.7
–66.7
–33.3
100%
35.9%
20.3%
17.2%
12.5%
12.5%
1.6%
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Overall DLQI
Symptoms and feelings
Daily activities
Leisure
Work and school
Personal relationships
Treatment
*) P<0.001 versus baseline
Days
TABLE III.—Patient distribution across DLQI bands before and after
desloratadine (DL) treatment.
DLQI score
Baseline
End of treatment
0-5 (no to small effect)
6-10 (moderate effect)
11-20 (very large effect)
21-30 (extremely large effect)
26.1%
40%
29.4%
4.5%
79.3%
13.1%
7.6%
0%
7
0
14
21
28
Vol. 141 - N. 3
-20
-30
-40
-50
-60
-45
-53
57
-66
-66
-70
-73
-80
-77
-76
-90
Interference w/sleep
Interference w/daily activites
Figure 2.—Interference with sleep and daily activities scores: mean percentage decrease over treatment period. All changes P< 0.001 versus baseline.
0
Change in mean DLQI score (%)
at day 7 was 57.4%, at day 14 62.5%, and at day 21
66.6%; P<0.001 versus baseline at all time points).
No significant difference was observed in the mean
percentage decrease of the mean pruritus score at all
time points between patients with moderate and severe
CIU. The mean final score was 0.5±0.6 in moderate and
0.7±0.9 in severe patients.
The reduction in the mean number of hives score
followed a similar pattern to that seen in the mean pruritis score over the whole treatment period (–20.4%
a.m. score day 2; –49% at day 7; –56% at day 14;
–61.2% at day 21; –69% at day 28; P<0.001 versus
baseline at all time points).
A marked improvement was observed in both interference with sleep and interference with daily activities (Figure 2); these improvements were evident from
the early treatment phase. The overall CIU condition
also improved significantly over the treatment period, with 79.7% of patients showing no to mild disease at the end of treatment. The global response to
therapy, evaluated jointly by patient and investigator,
indicated a complete or marked response in 61.9% of
patients after 14 days of DL treatment and in 73.2% of
patients by the end of the study period. Furthermore,
patients demonstrating a complete/marked response
to treatment reported a significantly greater percentage
reduction in the overall DLQI score than patients with
moderate to null response to treatment (Figure 3). The
Mean % change from baseline
-10
Completed/
marked
Completed
Moderate
Mild/treatment
failure
-20
-40
-24
-33
-60
-80
-100
-81
*
Figure 3 – DLQI change according to response to treatment (*p<0.001
vs moderate and vs mild/treatment failure).
211
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TABLE IV.—Correlation coefficients between changes in DLQI score and clinical outcomes.
Spearman Correlation
Coefficient
p value
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Variable
period. The improvement in the QoL of patients was
accompanied by a significant and rapid improvement
in the signs and symptoms of CIU, namely pruritus
and number of hives. In the case of pruritus, although
baseline severity differed markedly between patients
with moderate and severe disease, the extent of
improvement after DL treatment was comparable, with
almost complete relief being achieved in both patient
subgroups. The reduction in DLQI score paralleled
the clinical improvement of CIU in terms of symptoms (pruritus, hives), overall disease conditions and
treatment response, as assessed by both patients and
investigators, with highly significant correlation coefficients. These results are consistent with those of previous studies,12, 16 which also demonstrated a highly
significant correlation between changes in DLQI scores
and clinical outcomes in patients with CIU treated
with fexofenadine. Taken together, these data suggest
that clinical improvement in CIU associated with antihistamine treatment has a significant impact on
patients’ QoL. These findings seem to exclude, at least
in CIU, the speculation, based on the lack of correlation between QoL scores and clinical measures, that
objective assessment of severity and extension of dermatitis by means of standardised scoring systems may
not adequately reflect a patient’s state of disease or
the precise outcome of the intervention.7
Little has been published so far on the effects of
antihistamine treatment on the QoL of patients with
chronic urticaria. To our knowledge, only fexofenadine
was shown to improve DLQI in a similar CIU patient
population, with a reduction in overall DLQI score
not exceeding 50% after 4 weeks of treatment with
fexofenadine 60 mg twice daily.12, 16
In our study, the DLQI was sufficiently sensitive to
discriminate between moderate and severe CIU, the
mean DLQI score at baseline being 8.4 in moderate
CIU patients and 11.3 in severe patients. These values
are consistent with the DLQI score bands recently
proposed by Hongbo et al.,15 where a score of 6-10
reflected a moderate effect on patients’ life and one
of 11-20 a very large effect. Despite the baseline difference, in the present study the DLQI score at the
end of treatment was about 3 in subgroups of both
moderate and severe patients, indicating a small impact
on QoL in all patients. The comparable efficacy of
DL, in terms of both improvements in QoL and relief
of pruritus, in both patient subgroups suggests that
the 5 mg o.d. dosage is also efficacious in patients
Pruritus (a.m./p.m.)
Number of hives (a.m./p.m.)
Interference with sleep
Interference with daily activities
Overall CIU condition
0.69
0.66
0.59
0.67
0.71
p<0.001
p<0.001
p<0.001
p<0.001
p<0.001
correlations between the improvement in the DLQI
score and the improvement in the scores of pruritus,
number of hives, interference with sleep and daily
activities, and overall CIU condition were all highly significant (Table IV).
Safety analysis
Treatment-emergent AEs occurred in 80 patients
(31.4%). The most frequent AE was headache (n=35;
13.7%), followed by nausea (n=8; 3.1%) and somnolence (n=7; 2.7%). Severe treatment-emergent AEs
were reported in 4 patients (1.6%). No serious AEs
occurred. Three patients discontinued the study owing
to related AEs (2 headache and 1 treatment failure). No
clinically significant changes in blood pressure, heart
rate or laboratory parameters were observed during
the study.
Discussion and conclusions
This is the first study to assess the effects of DL 5 mg
o.d., administered for 4 weeks, on QoL, as measured
by DLQI, in moderate to severe CIU patients. In the
study population, the mean DLQI score at baseline
was 9.4, an intermediate value compared with those
reported in previous studies 11, 12 in analogous patient
populations. The major impact on the overall score
arose from the ‘symptoms and feelings’ domain, which
explores the impact of symptoms and of the feelings
of embarrassment and self-consciousness. Our study
results demonstrate that DL is effective in significantly
reducing the overall DLQI score, as well as each single domain score, with the most important contribution
to the overall DLQI decrease being the effect on the
‘symptoms and feelings’ domain. The reduction in
DLQI score was very rapid, being statistically significant as early as 1 week after treatment initiation, and
reaching 66% by the end of the four-week treatment
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Giugno 2006
of both the type and incidence. Moreover, the improvement not only in sleep, but also in daily activities,
associated with DL treatment seems to confirm the
absence of sedation.
In conclusion, our study shows that DL, administered
at the dose of 5 mg o.d. for 4 weeks, significantly
improves QoL, pruritus and hives in CIU patients,
irrespective of disease severity, and with a rapid onset
of action. In patients with CIU, DL seems to improve
not only clinical symptoms, but also the subjective
perception of general wellbeing.
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with more severe symptoms, and no that no higher
dose is required for any patient subgroup.
It has been suggested 14 that, in the patient’s perception, a change in DLQI score of up to ±4 corresponds to almost the same, or hardly any change, in
overall QoL, and a change of ±5 or more is needed for
patients to feel at least a little or moderately better or
worse. These indications emerged from questions
answered by patients with inflammatory skin diseases
– mainly psoriasis, atopic dermatitis and acne. In our
CIU population, the average DLQI reduction was 5.7
in the subgroup with moderate disease at baseline
and 7.8 in the subgroup with severe disease, indicating, according to the Khilji hypothesis,14 that the
reduction in DLQI score was perceived by patients
as an improvement in their general wellbeing. The
finding that a significantly greater reduction in DLQI
scores was reported by patients showing greater treatment response (symptoms absent or scarcely troublesome) provides further supporting evidence for
this theory.
The assessment of the interference of CIU with
sleep was of particular interest, as this is an important
aspect of QoL that is not specifically investigated by
DLQI domains. The correlation observed between the
improvement in sleep and the decrease in overall DLQI
score following DL administration suggests that
reduced sleep interference is one of the treatment
effects contributing to the global improvement in QoL.
Our study suffers from the limitation of its noncontrolled design. However, the present results are in close
agreement, in terms of both the extent and rapidity of
the effects observed, with the clinical efficacy data
reported in previous double-blind, placebo-controlled
studies performed in comparable CIU patients.9, 10 In
our opinion, this finding reduces the bias of the singlearm design and, in addition, supports the consistency
of DL efficacy and the reliability of the effects of treatment on QoL. It could also be argued that the transferability of our results to office practice is limited by
the selection criteria of our study, which included CIU
patients with an acute disease flare in a secondary
referral setting. In this respect, it should be noted that
the impact of skin disease on the QoL of patients treated in a primary care setting has been shown to be comparable to that of secondary referral patients.17
DL 5 mg o.d. administered for 4 weeks was safe
and well tolerated in CIU patients. The AE profile
confirms the results of previous DL trials,9, 10 in terms
SEIDENARI
Vol. 141 - N. 3
Acknowledgements.—The authors are grateful to R. Perego, MD, for
her skilful cooperation in the preparation of the manuscript.
Riassunto
Desloratadina 5 mg una volta al giorno migliora la qualità
di vita nell’orticaria cronica idiopatica
Obiettivo. Desloratadina (DL) è un farmaco efficace per
il trattamento dei sintomi dell’orticaria cronica idiopatica
(OCI), ma vi sono pochi dati circa il suo impatto sul benessere generale percepito dal paziente. L’obiettivo principale
è stato misurare l’effetto di DL sulla qualità di vita dei pazienti con OCI utilizzando l’indice dermatologico della qualità
di vita (Dermatology Life Quality Index, DLQI). Gli obiettivi secondari erano: la valutazione degli effetti di DL sul
prurito e sul numero di ponfi, sul sonno e sulle attività quotidiane, sul quadro complessivo dell’orticaria nella valutazione della risposta terapeutica. Sono anche state valutate
la sicurezza e la tollerabilità di DL.
Metodi. Sono stati trattati con 5 mg di DL una volta al giorno, per 28 giorni, 255 pazienti d’età compresa tra 18 e 75 anni
con OCI da moderata a grave. I pazienti hanno registrato quotidianamente il punteggio relativo alla severità dei segni e sintomi e hanno compilato un questionario sull’indice dermatologico della qualità di vita all’inizio del trattamento e dopo 7,
14, 21 e 28 giorni. Al 14° e 28° giorno sono state valutate le
condizioni generali della OCI e la risposta terapeutica congiuntamente dagli sperimentatori e dai pazienti.
Risultati. Dopo 28 giorni di trattamento DL ha significativamente ridotto rispetto al basale il punteggio globale medio
dell’indice dermatologico della qualità di vita da 9,4 (±5,4)
a 3 (±4,1) (-66,1%; P<0,001), senza alcuna differenza significativa tra i pazienti con OCI moderata e grave. Il miglioramento della qualità di vita è risultato significativo (P<0,001)
ad ogni valutazione (dopo 7, 14, 21 giorni) e per tutti i parametri contemplati dall’indice dermatologico della qualità di
vita. Il punteggio relativo a tutti i segni e sintomi si è ridotto
significativamente a partire dal secondo giorno di trattamento, mostrando una correlazione altamente significativa con il
punteggio dell’indice dermatologico della qualità di vita.
Conclusioni. Il trattamento con DL 5 mg una volta al giorno per 4 settimane migliora significativamente i sintomi e la
qualità di vita dei pazienti con OCI, indipendentemente dal-
213
SEIDENARI
9.
cacy in the management of allergic disorders. Drugs 2003;63:
2051-77.
Ring J, Hein R, Gauger A, Bronsky E, Miller B. Once daily desloratadine improves the signs and symptoms of chronic idiopathic
urticaria: a randomized, double-blind, placebo-controlled study. Int J
Dermatol 2001;40:72-6.
Monroe E, Finn A, Patel P, Guerrero R, Ratner P, Bernstein D et al.
Efficay and safety of desloratadine 5 mg once daily in the treatment
of chronic idiopathic urticaria: a double-blind, randomized, placebocontrolled trial. J Am Acad Dermatol 2003;48:535-41.
Poon E, Seed PT, Greaves MW, Kobza-Black A. The extent and nature
of disability in different urticarial conditions. Br J Dermatol
1999;140:667-71.
Thompson AK, Finn AF, Schoenwetter WF. Effect of 60 mg twice-daily fexofenadine HCl on quality of life, work and classroom productivity, and regular activity in patients with chronic idiopathic urticaria.
J Am Acad Dermatol 2000;43:24-30.
Lewis VL, Finlay AY. Ten years experience of the Dermatology Life
Quality Index (DLQI). J Invest Dermatol Symp Proc 2004;9:169-80.
Khilji FA, Gonzalez F, Finlay AY. Clinical meaning of change in Dermatology Life Quality Index scores. Br J Dermatol 2002;147 Suppl
62:P-60.
Hongbo Y, Thomas CL, Harrison MA, Salek MS, Finlay AY. Translating the science of quality of life into practice: what do Dermatology Life Quality Index scores mean? Br J Dermatol 2004;151 Suppl
68:P45-6.
Lennox RD, Leahy MJ. Validation of the Dermatology Life Quality
Index as an outcome measure for urticaria-related quality of life. Ann
Allergy Asthma Immunol 2004;93:142-6.
Harlow D, Poyner T, Finlay AY, Dykes PJ. Impaired quality of life of adults
with skin disease in primary care. Br J Dermatol 2000;143:979-82.
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la gravità della malattia, e il suo effetto compare entro i primi 2 giorni di trattamento.
Parole chiave: Antistaminici - Orticaria cronica - Dermatology life quality index (DLQI) - Desloratadina - Qualità di
vita.
References
1. Greaves M. Chronic urticaria. J Allergy Clin Immunol 2000;105:66472.
2. Mazzotti E, Picardi A, Sampogna F, Sera F, Pasquini P, Abeni D et al.
Sensitivity of the Dermatology Life Quality Index to clinical change
in patients with psoriasis. Br J Dermatol 2003;149:318-22.
3. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical measure for routine clinical use. Clin Exp Dermatol
1994;19:210-6.
4. Grob JJ, Revuz J, Ortonne JP, Auquier P, Lorette G. Comparative
study of the impact of chronic urticaria, psoriasis and atopic dermatitis on the quality of life. Br J Dermatol 2005;152:289-95.
5. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The
impact of chronic urticaria on quality of life. Br J Dermatol
1997;136:197-201.
6. Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C
et al. Quality of life and patients’ satisfaction in chronic urticaria and
respiratory allergy. Allergy 2003;58:621-3.
7. Anderson RT, Rajagopalan R. Effects of allergic dermatosis on healthrelated quality of life. Curr Allergy Asthma Rep 2001;1:309-15.
8. Murdoch D, Goa KL, Keam SJ. Desloratadine. An update of its effi-
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Epidemiologic data about polymorphous light eruption in Italy
E.M. PROCACCINI 1, G. FABBROCINI 2, V. AFFATICATI 3, D. ASSALVE 4, P. CALZAVARA PINTON 5,
I. CAPUTI 2, A. CIAMBELLOTTI 6, M. L. FLORI 7, M. GUARRERA 6, P. IACOVELLI 8,
G. LEONE 8, P. PIGATTO 3, D. SCHENA 9, G. MONFRECOLA 2
Aim. Polymorphous light eruption (PLE) is the most common
idiopathic photodermatosis. It describes a broad clinical spectrum with chronic recurrences. It is often characterized by
non scarring pruritic erythematous papules, vesicles or plaques.
UV exposure is the main pathogenetic factor. The aim of this
study was to evaluate the prevalence of PLE in Italy, the main
clinical features and the clinical course and recurrences in a
Mediterranean population.
Methods. The study was carried out on 4 416 subjects in 8 Dermatological Units in Italy, distributed over the whole country.
Subjects were required to fill a simple questionnaire (43 questions) exploring the following topics: phototype and phenotype, and modalities of solar exposure. In the subjects with a previous PLE another questionnaire was submitted to investigate
the clinical features of PLE, number of recurrences, familiar,
pathological and pharmacological anamnesis. The study was
carried out in healthy volunteers, not affected by any dermatological disease.
Results. Among the 4 416 apparently healthy subjects who filled
out the survey, 212 gave a history consistent with a diagnosis of
PLE. The PLE prevalence was 5.89% without significant differences among the Dermatological Units distributed at different latitudes in our Country. The coalescent papules type of
PLE was the most common clinical picture (36.4%); the body
site most frequently affected was the trunk (61.1%). On the
contrary, chronically sun exposed body site (i.e. the face) is
affected just in few cases. Also people chronically sun exposed
Received November 29, 2005.
Accepted for publication May 11, 2006.
Gruppo Italiano di Fotodermatologia (GIFDE) della Società Italiana
di Dermatologia e Malattie Sessualmente Trasmesse (SIDeMaST).
Address reprint requests to: G. Monfrecola, M.D., Dept. of Dermatology,
“Federico II” University, Via S. Pansini 5, 80131 Napoli, Italy.
Vol. 141 - N. 3
1Dermatology Unit
Azienda Sanitaria Locale, Naples, Italy
Federico II University, Naples, Italy
3Dermatology Unit
IRCCS Ospedale Maggiore, University of Milan, Milan, Italy
University of Perugia, Perugia, Italy
5Dermatology Unit, Spedali Civili, Brescia, Italy
University of Genoa, Genoa, Italy
University of Siena, Siena, Italy
8Dermatology Unit
IRCCS Dermatologico S. Gallicano, Rome, Italy
University of Verona, Verona, Italy
developed PLE less frequently than occasionally sun exposed
people. Sometimes, PLE developed after a particularly intense
sun exposure (37.7% of PLE).
Conclusion. No correlations with drug assumption or environmental chemical compound have been underlined.
KEY WORDS: Polymorphous light eruption - Photodermatosis Epidemiology.
P
olymorphous light eruption (PLE) is extremely
common. The prevalence of PLE is reported to
range between 5% and 21%. The onset of symptoms
is usually in the first 3 decades and, in most series,
females outnumber males.1-4
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EPIDEMIOLOGICAL DATA ABOUT POLYMORPHOUS LIGHT ERUPTION IN ITALY
of PLE. The questionnaire had 2 parts. The first, a
screening questionnaire, detailed age, sex, skin type,
phenotype (eye color, hair color, skin color) sun habits.
In the second part only individuals experiencing symptoms of PLEwho recognized their own erption in one
of the pictures showed (Figure 1-4). The second part
assessed the natural history of their disease, time of
onset, time of disappearance, affected skin areas, use
of sunscreens, recurrences, other contemporaneous
disorders or medications.
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It is characterized by seasonal occurrence and usually starts to appear in late spring or during holidays in
sunny regions. The time interval between the beginning
of sun exposure and the outbreak of the skin eruption
may range from one hour to a few days, with the most
common interval being 1-2 days.5
Lesions may be situated on any light exposed areas,
with a predilection for the forearms, the antero-lateral surfaces of the upper arms and the v-area of the
chest. Usually the initial episode occurs after an intense
sun exposure.
Several morphological variants of PLE have been
described. PLE is usually characterized by a particular clinical pattern: a papular type; a papulovescicular
type; a plaque-type or, less frequently, a vesiculobollous or eczematous type.
Itching is almost always present. The disease generally follows a chronic course.
In some patients the severity of PLE decreases as
summer progresses.4
It is uncommon that PLE disappears spontaneously. In most cases it follows a chronic course.
Etiology is unknown. A delayed hypersensitivity
reaction to an antigen induced by radiation would
seem possible.6, 7 The most important diagnostic tool
is phototesting with the aim of inducing an isomorphic response.
The aim of this study was to assess the PLE prevalence, clinical characteristics and course in a group
of people representatives of the Italian population.
Survey population
The study was carried out in 8 centres distributed in
northern as well as in southern Italy: Genoa, Brescia,
Milan, Verona, Perugia, Siena, Rome and Naples. A
total of 4 416 subjects ranging from 16 to 48 years of
age were interviewed. People were healthy subjects
selected at random from persons accompanying familiar or friends in the Dermatological Units above indicated.
Analysis of data
Data were collected during winter from January
2004 through May 2004. People selected had been
affected with a skin eruption similar to that showed
in the photos: 1) PLE with coalescent papules (Figure
1); 2) PLE plaque type (Figure 2); 3) with small papules
(Figure 3); 4) a vesiculo-papular type (Figure 4). People were only allowed to ask if a question was unclear.
No person refused to respond.
Statistical analysis
Data collected were analyzed by SPSS software
version 11.0.
Univariate descriptive analysis and crosstables were
performed; χ2 values were performed to test any statistical association.
Results
Our results showed that in the Italian population the
most frequent phenotype was characterized by brown
hair (72.4%), brown eyes (60.3%), no solar lentigo
(61.1%) and no freckles (68.6%); 0.9% of population
was skin type I, 29.4% skin type II, 48.0% skin type III
and 21.5% skin type IV.
A percentage of 78.2% of people interviewed were
not exposed to sun during working hours; 46.9% sun
exposed for 2-3 h each day for recreational activities.
The main data collected about sun exposure during
holidays are shown in Table I.
Cases with PLE
Questionnaire design
The questionnaire included 43 questions to determine prevalence, clinical characteristics and course
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A total of 212 subjects has been identified as affected by PLE (4.8%). The prevalence of PLE in our population determined as mean of percentage among the
Giugno 2006
PROCACCINI
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Figure 1.—PLE with multiple coalescent papules.
Figure 3.—PLE with small papules.
Figure 2.—PLE plaque-type.
Figure 4.—PLE vesiculo-papular type.
TABLE I.—Sun exposures during holidays.
Hours per day of sun exposure
8-10 h=6.7%
6-8 h=16.7%
4-6 h=41.4%
2-4 h=33.5%
null=1.3%
Unknown=0.4%
of people
Period of the day of suntunning Morning=35.3% Afternoon=14.3% Central hours of All hours without Unknown=1.7%
the day=17.6% differences=31.1%
Previous episodes of burning
Yes=82%
No=16.7%
Unknown 0.4%
dermatological centers participating the study was
5.89% (Female to male ratio = 4:1).
The phenotype and phototype of subjects with a
history of PLE was not significantly different from
unaffected people.
The distribution of different types is shown in Table
II.
PLE was almost always characterized by pruritus
(78.2%).
Vol. 141 - N. 3
TABLE II.—Clinical type of PLE.
With multiple
coalescent papules
Plaque type
With small
papules
Vesiculopapular type
36.4%
25.9%
10.5%
7.5%
The trunk is the skin area most frequently affected
(61.1%) while face is interested only in 7.7% of cases.
217
PROCACCINI
TABLE III.—PLE recurrences.
Only one time=19.2%
One day=25.5%
PLE remission
Remission after some days=
45.2%
Improvement after some
days=34.7%
Sometimes=28.9%
2-3 days=35.6%
Every year=31.4%
More than 4 days=9.6%
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Frequency of recurrences
Number of days between
sun exposure and PLE
eruption
Period of recurrences
PLE course
Only during summer=52.7%
Only during other seasons
=0%
Remission only at the end
of the summer=18.0%
No improvement 33.5%
PLE started after a sunlight exposure more intense
then usually in 37.7% of our population, while 42.7%
did not confirm this datum.
PLE appeared even if sunscreens had been used
from the first day of sun exposure (48.1% of people)
and also in skin areas protected by them (47.7% of
subjects).
In 46% of population eruption lasted for 2-3 days.
Data about recurrences are shown in Table III.
Other interesting data collected showed that only
in 20.2% of cases any drug was assumed in the period of PLE eruption, only in 3.8% of cases cosmetics
products had been used and only in 5.9% of cases people had been exposed to surrounding chemical compounds.
On the basis of both the anamnesis and the recognition by subjects interviewed of their eruption being
similar to one of that showed in the photos (Figure 14) the diagnosis of PLE has been done. We think that
only PLE-like lesions expression of a “forme fruste”
of Lupus erythematosus cannot be recognized with
this criterium. On the other side, some rare clinical
variants of PLE, such as the hemorrhagic and the prurigo-like forms, have not been included in our survey, but
statistical data obtained would have not been different.
In Italy the prevalence of PLE (mean of prevalence
among the 8 centers participating in the study) is
5.89%. This prevalence is a little lower than in other
studies 2, 8 in which PLE has been estimated as ranging from 10% to 20% of the population. On the other
hand, PLE has a wide geographical distribution, but its
incidence varies from 15% in UK to 5% in Australia.1
These differences can be due to different UV concentrations as well as to racial differences.
218
During summer and other
seasons=10.1%
Unknown=36.8%
Unknown=20.5%
Unknown=29.3%
Unknown=37.2%
Unknown=31.8%
The most frequent clinical type was characterized
by coalescent papules (36.4%) and the skin area more
frequently affected was the trunk (61.1% of subjects).
There was no statistical difference crossing different clinical types and skin areas affected (χ2 value,
NS).
It is interesting to underline that patients affected
by PLE often expose to sun for recreational activities
(2-3 h a day in 46.9% of subjects) (χ2 value=16.5;
P<0.02) while chronic sun exposures due to work are
rare (no sun exposures due to work in 78.2% of PLE
cases). These data could explain the lack of natural
mechanism of photoprotection in subject with PLE.
PLE patients seem to have a high level of knowledge
about sun exposure modalities worldwide suggested:
actually they sun tan during holidays for a few hours
a day (41.4%), in particular during early hours in the
morning (35.3%). However, 82.2% of cases have previously burned during the life.
It is interesting to underline that 37.7% of cases
experienced a particularly intense sun exposure just
before the first PLE eruption.
The fact that PLE occurred even if sunscreens had
been utilized (48.1% of cases) (χ2 value, NS) demonstrates that sunscreens were inadequated or not well
applied.
PLE, as already known, has a chronic course and it
recurs each year (31.4%). But very often (45.2% of
cases) it improves spontaneously after some days even
if sun exposures continue.
Usually, PLE recurs in particular during summer
(52.7% of cases) and only 7.7% of subjects are affected on the face. These last data, in particular the frequent
sparing of the facial skin, that is chronically sun
exposed, and the gradual improvement of the rash during the summer are possibly related to the development of tolerance mechanisms: suppression of the
Giugno 2006
Risultati. Dei 4 416 soggetti intervistati, 212 avevano una
storia che orientava per una DPS. Pertanto, la prevalenza
della DPS in Italia sembra attestarsi al 5,89%, senza differenze
significative tra i diversi Centri Dermatologici distribuiti nel
territorio nazionale a diverse latitudini.
La varietà clinica di DPS a “papule coalescenti” è la più
comune (36,4%); l’area corporea più colpita sembra essere
il tronco (61,1%), mentre Il viso viene interessato solo in
pochi casi. I soggetti cronicamente esposti al sole tendono a
sviluppare la DPS meno frequentemente di quelli che si
fotoespongono in maniera occasionale. Nel 37,7% la DPS
sarebbe comparsa dopo un’esposizione al sole particolarmente intensa.
Conclusioni. Non esiste alcuna correlazione tra DPS e
assunzione di farmaci né tra DPS e sostanze chimiche
ambientali.
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immune mechanisms of PLE and increased thickening
of the stratum corneum.4, 9
In our data, there is not a clear cut correlation among
sex, absence of lesions on face and improvement of the
eruption during the summer period. Since these 3 criteria have been identified as the main criteria to distinguish a benign summer light eruption from a true
PLE, we agree with Leroy et al.10 These authors state
that the identification of a benign summer light eruption is not correct since PLE is characterized by a continuous spectrum, ranging from the benign eruptions
improving during summer to more severe eruptions
recurring each year with a persistent course during
summer without tendency to amelioration.
Moreover, the last data of the questionnaire show that
there is no correlation between PLE and drugs (only
20.2% of subjects affected took drugs) (χ2 test NS);
PLE and cosmetic substances (3.8% of cases utilized
them before sun exposure) (NS) and PLE and chemical compounds (5.9% of association) (NS).
PROCACCINI
Riassunto
La dermatite polimorfa solare in Italia: caratteristiche
cliniche e dati epidemiologici
Obiettivo. La dermatite polimorfa solare (DPS), la più
frequente fotodermatosi idiopatica, è caratterizzata da un’ampia variabilità clinica e da frequenti recidive.
Scopo di questo studio è stato valutarne la prevalenza in
Italia, le principali caratteristiche cliniche, l’andamento clinico e la recidivanza nella popolazione italiana.
Metodi. Presso 8 Centri Dermatologici italiani sono stati
intervistati 4 416 individui sani. A ciascuno veniva sottoposto un primo questionario con domande inerenti età, fototipo, fenotipo, modalità di esposizione al sole. Agli intervistati
veniva quindi mostrato un set di fotografie di diverse forme
di DPS e, solo a coloro che asserivano di aver manifestato in
passato una patologia cutanea ad esse assimilabile, veniva
somministrato un ulteriore gruppo di domande relative alla
dermopatia.
Vol. 141 - N. 3
Parole chiave: Dermatite polimorfa solare - Fotodermatiti Epidemiologia.
References
1. Pao C, Norris PG, Corbett M, Hawk JLM. Polymorphic light eruption:
prevalence in Australia and England. Br J Dermatol 1994;130:62-4.
2. Morison WL, Stern RS. Polymorphous light eruption: a common
reaction uncommonly recognized. Acta Dermatol Venereol 1982;62:
237-40.
3. Berg M, Ros AM, Berne B. Ultraviolet A phototherapy and trimethylpsoralen UVA photochemotherapy in polymorphous light eruption: a
controlled study. Photodermatol Photoimmunol Photomed 1994;10:
139-43.
4. Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous light eruption. J Eur Acad Dermatol Venereol 2002;16:193-206.
5. Ros A, Wennersten G. Current aspects of polymorphous light eruption
in Sweden. Photodermatology 1986;3:298-302.
6. Epstein S. Studies in abnormal sensitivity to light, IV. Photoallergic
concept of prurigo aestivalis. J Invest Dermatol 1942;5:289-95.
7. Norris PG, Morris J, McGibbon DM, Chu AC, Hawk JLM. Polymorphic light eruption: an immunopathological study of evolving
lesion. Br J Dermatol 1989;120:173-80.
8. Berg M. Epidemiological studies of the influence of sunlight on the
skin. Photodermatology 1989;6:80-4.
9. Honigsmann H. Polymorphous light eruption. In: LIM HW, Soter
NA, editors. Clinical Photomedicine. New York: Marcel Dekker
Inc.;1993.p.167-80.
10. Leroy D, Dompmartin A, Verneuil L, Michel M, Faguer F. Polychromatic phototest sensibility is superior to phototest in polymorphic
light eruptions. Ann Dermatol Venereol 2002:29:860-4.
219
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Sequential treatment of psoriasis
with infliximab followed by cyclosporin
Preliminary results of an open-label prospective study
G. A. VENA 1, N. CASSANO 1, F. LOCONSOLE 1, G. MALARA 2, C. SCIARRONE 2, A. PUGLISI GUERRA 2
Aim. The efficacy and tolerability of a sequential treatment
consisting of infliximab followed by cyclosporin A (CsA) was
evaluated in patients with severe psoriasis, resistant to conventional therapies, including CsA.
Methods. Patients suffered from chronic plaque psoriasis with
psoriasis activity and severity index (PASI) ≥ 16, who had failed
to respond to standard treatments and to CsA 3-5 mg/kg/day,
received intravenous infliximab 5 mg/kg at day 0 and at week
(W) 2. From W2 they were treated with CsA 3 mg/kg/day up to
W24. Apart the days devoted to infliximab treatment, subsequent visits were scheduled at W6, W12 and W24, assessing
PASI and collecting information on tolerability.
Results. Ten patients, with a baseline PASI of 22.25 (range: 1629.4), received and completed the study treatment. The mean
reduction of PASI was 56% at W2 and 82% at W6. At W6 all
patients achieved a PASI-50 response and 7 of them a PASI-75
response. The sequential monotherapy with CsA sustained the
clinical response in most cases, with a constant PASI-50 response
in 9 out of 10 patients (PASI-75 in 6 patients at W12 and 5
patients at W24). The mean improvement of PASI as compared
with baseline was 75% at W12 and 63% at W24. Treatment regimen was well tolerated and no serious adverse events were
observed.
Conclusion. The results of this preliminary prospective openlabelled experience suggest that treatment with only 2 infliximab
infusions caused a striking improvement of psoriasis, which
can be sustained by the sequential use of CsA 3 mg/kg/day in
patients who had failed to respond to CsA ≥3 mg/kg/day. It
can not be ruled out that infliximab can help to restore the
clinical response to conventional treatments previously found
as ineffective.
KEY WORDS: Plaque psoriasis - Infliximab - Cyclosporin A.
Address reprint requests to: Prof. G. A. Vena, Second Dermatology Clinic, University of Bari, Policlinico, Piazza Giulio Cesare 11, 70124 Bari.
Vol. 141 - N. 3
1Department of Internal Medicine
Immunology and Infectious Diseases
2nd Dermatology Clinic, University of Bari, Bari, Italy
2Division of Dermatology, Papardo Hospital, Messina, Italy
I
nfliximab is a chimeric IgG1 antibody which binds
to transmembrane-bound and soluble human tumour
necrosis factor (TNF)-alpha with high specificity,
affinity and avidity,1 and is currently approved for the
treatment of chronic plaque psoriasis refractory to
conventional systemic therapies. Among these,
cyclosporin A (CsA) is one of the most used drugs to
treat moderate to severe psoriasis, whose efficacy and
safety are documented by numerous experimental and
clinical data collected for more than 20 years.2-5
The aim of this open-labelled prospective experience was to study the effects of a short-term treatment
with infliximab followed by maintenance therapy with
low-dose CsA in patients who had previously experienced an inadequate response to CsA.
The patients enrolled in the study were to be adult
subjects with active chronic plaque psoriasis characterized by a psoriasis activity and severity index
(PASI) 6 of at least 16, who had contraindications to or
were intolerant to other conventional systemic thera-
221
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SEQUENTIAL TREATMENT OF PSORIASI WITH INFLIXIMAB FOLLOWED BY CYCLOSPORIN
90
70
60
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Mean PASI improvement
80
made a few days before W2 and then at monthly intervals. Patients were asked to constantly monitor their
blood pressure values. Discontinuation of CsA treatment was required in case of relapse (PASI of at least
50% of the value registered at the baseline) at any
time.
After treatment, patients entered a 24-week observational period, in which rescue treatments were left
at the discretion of dermatologists, and underwent 2
other scheduled visits, at W36 and W48, respectively,
for clinical assessment. Further optional visits were
carried out during the entire 48-week study period, if
needed, for any reason (i.e., worsening of psoriasis,
adverse events, anomalies of laboratory parameters,
willingness of patients to use rescue treatments).
50
40
30
20
10
0
W2
W6
W12
W24
W36
W48
Figure 1.—Mean change of PASI from baseline (%) throught the study
period.
pies and/or had failed to respond to these therapies. All
the patients were to have obtained an inadequate
response (<25% PASI improvement) to standard doses of CsA used for at least 3 months. Exclusion criteria included concomitant inflammatory skin diseases
and other clinical forms of psoriasis other than plaque
psoriasis, any contraindications to the use of infliximab and CsA, previous treatment with infliximab,
concomitant therapy with medications capable of interfering with psoriasis or with CsA metabolism, as well
as nephrotoxic drugs. Any treatment active on psoriasis was to be stopped for an appropriate period of
time prior to the baseline evaluation. Women of childbearing potential and all men had to use medically
approved birth control methods throughout the study
period. After a detailed information about treatment
modalities and characteristics, a written consent was
obtained before the start of infliximab therapy.
Treatment regimen consists of the following sequential phases:
— two intravenous infusions of infliximab 5 mg/kg,
at baseline and at week (W) 2, respectively;
— CsA 3 mg/kg/day, in 2 divided doses after meals,
continuously for 22 weeks, from W2 up to W24.
During the 24-week treatment period, any topical and
systemic therapies active on psoriasis, phototherapy and
sun exposure were considered prohibited. Only nonmedicated emollients and shampoos were allowed.
Visits occurred at the baseline, W2, W6, W12, and
W24, when psoriasis severity was evaluated by means
of PASI and a complete physical examination, with
measurement of vital signs, was performed. After the
screening phase, laboratory routine examinations were
222
Results
A total of 10 patients, 8 males and 2 females with a
mean age of 44 (range: 23-57) and a baseline PASI of
22.25 (range: 16-29.4), were found to meet all the eligibility criteria. As concerns the inadequate response
to prior treatment courses with CsA, 3 patients had
an unsatisfactory effect with doses of 4-5 mg/kg/day
for 3-4 months, whereas the others failed to respond to
CsA 3-3.5 mg/kg/day, which was used after tapering
off the daily dose in order to control the side effects
developed with higher doses (e.g., arterial hypertension,
increase of serum creatinine and liver enzymes, gastric
disturbances). In these cases, the dose of 3-3.5
mg/kg/day notably improved tolerability with complete resolution of adverse events but it was associated with an insufficient clinical response.
All the 10 patients started treatment between October and December 2003 and completed the therapeutic regimen as scheduled, with the visit at W24 taking
place before exposure to sunlight. The therapeutic
effect of the 2 infliximab infusions was dramatic (Figure 1), causing a mean reduction of PASI of 56% at W2
and 82% at W6, 4 weeks after the second infusion and
the start of CsA. At W6 all patients achieved a PASI50 response (≥ 50% improvement in comparison to
baseline) and 7 of these had an improvement of at
least 75% (PASI-75) (Table I). The sequential
monotherapy with CsA 3 mg/kg/day up to W24 sustained the clinical response in most cases, with a constant PASI-50 response in 9 out of 10 patients (PASI75 in 6 patients at W12 and 5 patients at W24, Table I).
The mean improvement of PASI as compared with
Giugno 2006
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baseline was 75% at W12 and 63% at W24. In a case TABLE I.—Distribution of clinical response (PASI change from baseline) throughout the study period.
only, PASI changed less than 50% during CsA
monotherapy but the patient refused to discontinue
% Mean PASI improvement from baseline
(No. of patients)
treatment because he was overall satisfied by treatVisit
ment results, having experienced a notable relief of
25-49%
50-74%
≥75%
pruritus and a discrete improvement of PASI (46% at
Week 2
4
4
2
W12 and 40% at W24).
Week 6
0
3
7
During the follow-up observational period, 4 patients
Week 12
1
3
6
Week 24
1
5
4
used topical drugs as rescue treatment for lesions localWeek 36
1
4
5
ized in critical areas: intermittent use of corticosteroids
Week 48
0
6
3
for face, folds or scalp, vitamin D analogues or keraNo patient experienced an improvement less than 25% from baseline. Total patients
tolitics for scalp, palms or soles. All the patients were evaluable
were 10 at each visit with the exception of W48 when they were 9.
exposed to sunlight for a variable period of time,
including the patient who previously had not achieved
the PASI-50 and who instead obtained a PASI-75
response after sun exposure. Only a patient relapsed at using CsA combined to infliximab in patients in whom
W36 (PASI value=75% of the baseline value) and was methotrexate treatment was contraindicated or adding
in recalexcluded from the subsequent evaluation, requiring CsA to infliximab/methotrexate combination
13-15 It is not known
citrant
cases
of
rheumatoid
arthritis.
systemic treatment. Visit at W48 occurred between
October and December 2004, when a PASI-50 response if CsA may reduce or delay the development of neuantibodies, as shown for
still persisted in the 9 evaluable patients, with 3 patients tralizing anti-infliximab
16, 17
methotrexate.
maintaining a PASI-75.
Our preliminary results suggest that treatment with
Details of PASI change over the 24-week treatment
only
2 infusions of infliximab 5 mg/kg can cause a
period and the subsequent 24-week observational phase
striking improvement of psoriasis which may be susare summarized in Figure 1 and Table I.
Treatment regimen was well tolerated and no seri- tained by the sequential use of CsA 3 mg/kg/day in
ous adverse events were observed. An infusion reac- patients who previously were nonresponders to the
tion was observed only once in a patient receiving the same dosages of CsA or higher. Induction therapy
second infusion: it consisted of mild hypotension and with 3 infusions of infliximab was found to cause per18, 19 but
flushing, and was promptly controlled by slowing the sistent improvement of psoriasis in some cases,
infusion. Laboratory examinations did not reveal any the time of persistence of the clinical response after 2
clinically significant changes in the study population. infusions has never been evaluated. It can not be ruled
out, however, that infliximab can enhance in a synergistic way the activity of CsA or may favour to restore
the response to CsA in patients who failed to respond
to variable dosages of the drug. The therapeutic regiInfliximab is an anti-TNF-alpha chimeric mono- men reported in this paper was designed and used durclonal antibody which is effective as monotherapy for ing a period in which treatment with infliximab had not
refractory moderate to severe plaque psoriasis.7-9 The standardized practical guidelines in psoriasis and was
recommended regimen in this indication consists of not reimbursed, so that the cost of the drug was directintravenous administration of 5 mg/kg at weeks 0, 2 and ly borne by our hospital units, after regulatory approval
6, followed by maintenance infusions at 8-week inter- on a case-by-case basis. Therefore, the assessment of
vals. Treatment with infliximab induced a dramatic this regimen was also aimed to obtain pharmacoecoimprovement of skin lesions, with marked effects nomic data about the possibility of ‘infliximab-sparalready observed after the first infusions. Even a sin- ing’ approaches.
CsA is one of the most used drugs to treat moderate
gle infusion was found to be very effective on psoriatic
skin lesions.10 The long experience gained in rheuma- to severe psoriasis, whose efficacy and safety profiles are
toid arthritis has provided numerous data about the well-established. The daily dosage is of crucial imporcombination of infliximab with methotrexate.11, 12 tance in determining both the clinical response and side
Only a few reports exist supporting the possibility of effects. During treatment with CsA, side effects are
Vol. 141 - N. 3
223
VENA
22,25 (range: 16-29.4) hanno completato il trattamento come
programmato. La riduzione del PASI rispetto al basale è stata pari al 56% a W2 e all’82% a W6. A W6 tutti i pazienti hanno raggiunto una risposta PASI-50 e 7 di questi il PASI-75.
La monoterapia sequenziale con CsA ha consentito il mantenimento della risposta clinica nella maggioranza dei casi,
con una risposta costante PASI-50 in 9 casi (PASI-75 in 6
pazienti a W12 e 5 pazienti a W24). Si è osservato un miglioramento del PASI medio del 75% a W12 e del 63% a W24.
La tollerabilità al trattamento è apparsa positiva.
Conclusioni. Questi risultati preliminari suggeriscono che
già con 2 infusioni di infliximab si ottiene un migliormaneto sensibile della psoriasi, con possibilità di mantenimento
dei risultati in seguito alla monoterapia sequenziale con CsA
3 mg/kg/die in pazienti che avevano precedentemente presentato una risposta insoddisfacente alla stessa CsA a dosi ≥ 3
mg/kg/die. Non si può escludere che infliximab possa favorire il recupero della risposta a terapie convenzionali dimostratesi prima inefficaci.
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usually well controlled by dosage adjustment or temporary interruption, according to their severity. Unfortunately, in some patients, the reduction of the daily
dosage necessary to improve the tolerability may result
in an unsatisfactory therapeutic effect. The dose of CsA
used as maintenance treatment in the regimen herein
presented was well tolerated by all patients and was
never responsible for the dose-related side effects previously experienced by some patients with high dosages.
Although the data of the subsequent 24-week followup period were likely to have been influenced by climatic factors (summer months and related habit of
suntanning), they can suggest some considerations
which can be useful in clinical practice. In fact, most
patients had their psoriasis improved enough to allow
them to expose their skin to sunlight without aesthetic or psycologic problems and all but one did not
relapse up to W48. The use of rescue therapies in the
observational period was limited to topical medications applied to localized skin areas, thus preventing a
relevant interference with total PASI values.
In conclusion, the results of this prospective openlabelled experience suggest that treatment with only
2 infliximab infusions caused significant improvement of psoriasis, which can be sustained by the
sequential use of CsA 3 mg/kg/day in patients who had
obtained an insufficient response to CsA at daily doses ≥ 3 mg/kg. Controlled studies on larger patient
samples are certainly needed to confirm these preliminary results, as well as the chance of recovering
the response to conventional therapies after infliximab treatment.
Riassunto
Trattamento sequenziale della psoriasi con infliximab seguito da ciclosporina: risultati preliminari di uno studio prospettico in aperto
Obiettivo. Lo scopo di questo studio prospettico in aperto è stato valutare l’efficacia e la tollerabilità di uno schema
di terapia sequenziale con infliximab seguito da cisloporina
(CsA), in pazienti con psoriasi severa, con PASI≥16, resistente
a terapie tradizionali, inclusa CsA a dosi ≥3 mg/kg/die.
Metodi. Il trattamento consisteva nell’uso di 2 infusioni e.v.
di infliximab 5 mg/kg, rispettivamente al giorno 0 e alla settimana (W) 2, seguite dalla somministrazione di CsA 3
mg/kg/die da W2 fino a W24. Le visite, che includevano
valutazioni di efficacia e tollerabilità, sono state eseguite al
basale, a W2, W6, W12 e W24.
Risultati. Dieci pazienti, con un valore di PASI basale di
224
Parole chiave: Psoriasi a placche - Infliximab - Ciclosporina A - Terapia sequenziale.
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6. Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a
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7. Chaudari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb
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9. Reich K, Nestle FO, Papp K, Ortonne JP, Evans R, Guzzo C et al.
EXPRESS study investigators. Infliximab induction and maintenance
therapy for moderate-to-severe psoriasis: a phase III, multicentre,
double-blind trial. Lancet 2005;366:1367-74.
10. Chan JJ, Gebauer K. Treatment of severe recalcitrant plaque psoriasis with single-dose intravenous tumour necrosis factor-alpha antibody
(infliximab). Australas J Dermatol 2003;44:116-20.
11. Maini SR. Infliximab treatment of rheumatoid arthritis. Rheum Dis Clin
North Am 2004;30:329-47.
12. Siddiqui MA, Scott LJ. Infliximab: a review of its use in Crohn’s disease and rheumatoid arthritis. Drugs 2005;65:2179-208.
13. Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari
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14. Ferraccioli GF, Assaloni R, Di Poi E, Gremese E, De Marchi G, Fab-
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17. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M et
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Study group. Lancet 1999;354:1932-9.
18. Gottlieb AB, Chaudari U, Mulcahy LD, Li S, Dooley LT, Baker DG.
Infliximab monotherapy provides rapid and sustained benefit for
plaque-type psoriasis. J Am Acad Dermatol 2003;48:829-35.
19. Cassano N, Loconsole F, Amoruso A, Coviello C, Filieri M, Filotico
R et al. Infliximab monotherapy for refractory psoriasis: preliminary
results. Int J Immunopathol Pharmacol 2004;17:373-80.
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ris M. Rescue of combination therapy failures using infliximab, while
maintaining the combination or monotherapy with methotrexate:
results of an open trial. Rheumatology (Oxford) 2002;41:1109-12.
15. Marchesoni A, Puttini PS, Gorla R, Caporali R, Arnoldi C, Atzeni F
et al. Cyclosporine in addition to infliximab and methotrexate in
refractory rheumatoid arthritis. Clin Exp Rheumatol 2005;23:916-7.
16. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD et al. Therapeutic efficacy of multiple intravenous infusions
of anti-tumor necrosis factor a monoclonal antibody combined with
low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum
1998;41:1552-63.
VENA
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Videocapillaroscopic study in psoriatic patients
treated with tacalcitol
G. STINCO, S. LAUTIERI, P. PATRONE
Aim. An analysis was made of the modifications of the superficial capillary bed in a psoriatic plaque and the perilesional
healthy skin during treatment with tacalcitol by means of
video-capillaroscopy (VC).
Methods. Twenty-four patients suffering from psoriasis vulgaris over no more than 15% of the body were studied for a period of 3 months during treatment with 4 mg/g tacalcitol ointment.
Once a psoriatic plaque had been selected, a visual clinical
assessment was made and capillaroscopic measurements were
taken with VC at the time of recruitment (T0), after 4 weeks
(T1), after 8 (T2) and after 12 weeks (T3).
Results. The lesions studied gradually improved and at the
end of the study the psoriatic plaques had disappeared in 12
patients. Even the diameter of the “basket” type capillaries
had reduced significantly (average diameter: 67.64 at the
beginning of the study; 34.08 at the end of the study), but only
in 4 patients did the surface capillary plexus reappear with
altered capillary loops. In the apparently healthy perilesional skin, 14 patients had abnormally elongated capillary loops.
At the end of treatment, only 4 patients still had altered capillary loops.
Conclusion . Tacalcitol proved to be effective in reducing the clinical and capillaroscopic alterations. Nevertheless, the microcirculatory improvement does not perfectly follow the clinical
improvement. We also noted that the tacalcitol action on the
microcirculation is not only limited to the area of application,
but also extends to the surrounding areas.
KEY WORDS: Psoriasis, drug therapy - Microcirculation - Tacalcitol.
Received November 24. 2005.
Address reprint requests to: G. Stinco, Clinica Dermatologica, Università di Udine, c/o Ospedale Civile San Michele, Piazza Rotolone, 33013
Gemona del Friuli, Udine. E-mail: [email protected]
Vol. 141 - N. 3
Institute of Dermatology, Department
of Clinical and Experimental Pathology and Medicine
University of Udine School of Medicine, Udine, Italy
P
soriasis presents well-documented microcirculatory alterations such as the presence of edematous dermal papillae containing tortuous and
dilated capillary loops often with extravasated erythrocytes, mononucleate cells and neutrophils. In
the intrapapilla, the loop does not have a normal
hairpin-like tendency, but it is arranged horizontally in a sinuous manner and appears dilated. The
ascending and descending sections of the loop usually twist once or twice thereby taking on a glomerular aspect. There are no accessory anastomoses
between these dilated glomerular-like capillaries
and the surface vascular plexus. The capillary portion at the papillary crest and the descending portion
are decisively wider than the ascending portion; in
fact it increases from a diameter of approximately
6-9 µm to a diameter of 8-16 µm, even though the
vascular wall thickness remains the same as that of
normal skin capillaries.1
Video-capillaroscopy (VC) helps to identify such
modifications in the microvascular architecture. Dilated, elongated, convoluted capillaries with a glomerular type aspect (i.e. basket-weave form) arranged parallel to the cutaneous surface can be observed in the
psoriatic plaque. At the edge of the psoriatic plaque, the
capillary loops are elongated with a “hairpin” aspect,
227
STINCO
VIDEOCAPILLAROSCOPIC STUDY IN PSORIATIC PATIENTS TREATED WITH TACALCITOL
TABLE I.—Diameters of the “baskets” expressed in Ìm and calibre of
the capillaries forming the network of the superficial capillary
plexus and length of the altered loops expressed in µm during
topical treatment with Tacalcitol.
Tacalcitol
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arranged parallel to the cutaneous surface aligned with
a centripetal tendency. The subpapillary venous plexus
cannot be observed because of acanthosis.2 The calibre of the vessels appears increased, 12-13 µm compared to the 5-6 µm of the capillaries in the healthy skin.
The latter has a “mesh-like” capillaroscopic aspect,
that is the aspect of the surface capillary plexus, as
the papillary capillary loops perpendicular to the cutaneous surface are not visible.3
The first studies relating to modifications of the
microcirculation following treatment for psoriasis
date back to 1981 with Horacek’s electron microscope researches 4 following UVB therapy. In 1985
Klemp and Staberg 5 studied the modifications in
the blood flow during antipsoriatic treatment. In the
same year, Braverman and Sybley 6 described the
modifications of the capillary plexus following treatment with methotrexate and topical steroids. In 1989
Trevisan et al.7 observed the modifications of the
psoriatic microcirculation at the periungual fold following PUVA therapy. In 1994 Strumia et al.8 submitted a preliminary study with VC in which they
observed the reduction in length and tortuosity of
the capillary loops after 6 weeks of tacalcitol treatment. Still in 1994 Berardesca et al. 9 used laser
Doppler velocimetry and trans-epidermal water loss
to compare two drugs such as calcipotriol and clobetasol.
In this study, taking the idea from the work by Strumia et al.,6 the modifications of the superficial capillary bed in a psoriatic plaque and the perilesional
healthy skin during treatment with tacalcitol were
analysed by means of VC.
Twenty-four patients suffering from psoriasis vulgaris involving no more than 15% of the body area
participated in this study: 14 male and 10 female
patients aged between 21 and 64 years (average age:
43 years), who had not been taking any form of treatment for psoriasis for at least 4 weeks.
Excluded from this study were pregnant women or
those who were breast-feeding and patients suffering
from heart disease or severe hepatosis, kidney disorders, hypercalcemia and tumours.
The duration of the study was scheduled over a 12week period. Each patient was recommended to apply
tacalcitol ointment 4 mg/g once a day with precision
228
Basket
diameter
T0
T1
T2
T3
67.64±11.06
48.58±10.42
37.54±9.43
34.08±8.71
Capillary
network
7.16±1.02
6.41±0.51
6.24±0.35
6±0
No.
of patients
Alterated
ansae
14
8
6
4
24.28±8.82
19.66±3.21
17.74±4.43
16±5.65
only on the psoriatic plaques. The use of any cosmetic or topical drug, systemic therapy for psoriasis or
phototherapy was prohibited. Any treatment already in
course for existing pathologies (hypertension, diabetes, disthyroidism) was continued.
At the first visit (T0) the plaque that was going
to be the subject of this study was identified, precise anatomic points were selected, an image of the
anatomic region with the lesion was acquired, likewise a capillaroscopic image of the centre of the
plaque and a capillaroscopic image of the healthy
perilesional skin at a distance of 2 cm from the lesion
edge. From each capillaroscopic image of the centre
of the plaque the diameter of 3 different “baskets”
was measured and the average was then calculated.
In the healthy skin, 3 measurements of the calibre of
the reticular vessels were taken and the average was
calculated. Reference was made to the plaque studied with the VC for the clinical assessment, summing up the values obtained after having assigned a
score of between 0 and 4 to the erythema, infiltration
and scaling.
The clinical assessment and capillaroscopic measurements were repeated by using the noted reference
points on the same site after 4 weeks (T1), after 8
weeks (T2) and after 12 weeks (T3).
A DERMASCOPE® digital capillaroscope was
used for imaging, consisting of a central body with a
100 Watt cold halogen lamp fitted with a manual
luminous intensity control device; a probe consisting
of a 2 m long flexible cable enclosing an optical fibre
bundle, a connection cable between the video signal
processing unit in the central body and the optical
terminal and a video signal processing unit. In turn,
the terminal consisted of a colour microcamera and
a support to hold the various 300x “contact” type
lenses used.
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STINCO
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Figure 1.— Capillaroscopic aspect of the centre of a psoriatic plaque.
Figure 3.— Capillaroscopic “mesh” aspect with abnormally elongated
capillary loops in the skin at 2 cm from a psoriatic plaque.
Figure 2.— Capillaroscopic aspect of the centre of a psoriatic plaque after
3 months of treatment with tacalcitol.
Figure 4.— Capillaroscopic “mesh” aspect of the skin at 2 cm from a psoriatic plaque after 3 months of treatment with tacalcitol.
Before carrying out the capillaroscopic test, a drop
of citron oil was applied to point where the probe was
going to be applied to eliminate any reflections of light
and allow the topmost layers of the epidermis to be
seen.
greater or equal to 30% in the basket diameter as an
effective reduction.
Statistical analysis
The statistic significance of the microcirculatory
reduction and clinical improvement was calculated by
means of Student’s t test, assuming a reduction of
Vol. 141 - N. 3
Results
At the beginning of the study, the average clinical
score of the 24 patients was 7.25±1.86. The lesions
studied improved progressively with a score of
3.91±0.913 at T1, 2.16±0.71 at T2 and 0.5±0.52 at T3.
In 12 patients the psoriatic plaques had disappeared by
229
STINCO
100
80
60
Discussion
Elongated and convolute capillaries with a basketlike appearance at the centre of the plaque and non
observable surface capillary plexus are typical capillaroscopic aspects of psoriasis.2 Such alterations seem
to be the expression, besides a compensatory response,
of the microcirculation to the increased cellular
turnover, as well as a consequence of the expression of
numerous growth factors and chemokines secreted by
the psoriatic keratinocytes. In fact, an increased secretion of Tissue Growth Factor alpha (TGF-α) and Keratinocyte Growth Factor (KGF) has been demonstrated, leading to an increased keratinocyte proliferation
and therefore major metabolic demand, as well as Vascular Endothelial Growth Factor (VEGF) that directly stimulates neoangiogenesis.10
Tacalcitol or 1,24-dihydroxycholecalciferol, a vitamin D analogue with activity for vitamin D receptors
(VDR) of 1.25(OH)2D3, has a marked capacity to induce
differentiation and reduce cellular proliferation.11 Its
230
%
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the time the study had been completed, whereas the
remaining 12 had slight erythema or scaling.
The reduction in the capillaroscopic alterations at the
psoriatic plaque and skin at 2 cm from the lesion are
summarised in Table I.
In all 24 patients at the time of recruitment T0, a psoriatic capillaroscopic pattern was observed at the centre
of the plaque with “basket” like convolute capillaries
(average diameter 67.64) (Figure 1). At the end of the
treatment, significant modifications were observed in the
reduction of the “basket” diameter (average diameter
34.08) (test t=6.83 P>0.01) (Figure 2).
In 4 patients out of the 12 who had clinically healed,
there was a return to the visualisation of the surface capillary plexus, even though altered capillary loops
remained. The other 8 patients in whom the plaque
was no longer objectively observed, typical psoriatic
capillaroscopic alterations were still evident.
At the beginning of the study, in the healthy perilesional skin of 20 patients examined, a mesh-like aspect
was observed, whereas in 4 there were abnormally
elongated capillary loops (Figure 3). Abnormally elongated loops were also visible in 10 patients whose surface capillary plexus was observable. At the end of
treatment, only 4 subjects still had altered capillary
loops, however these were reduced compared to their
size at the beginning of the study (Table I and figure 4).
40
20
0
T0
T1
Basket tacalcitol
T2
T3
Score tacalcitol
Figure 5.— Percentage of average improvement of the clinical score and
percentage of the average reduction of the basket at the psoriatic plaque treated with tacalcitol at the 4 control visits.
activity on psoriasis is also due to an anti-inflammatory and immunomodulating activity that leads to a reduction in the number of polymorphonucleates, CD1+ and
T cells at the psoriatic plaque. Moreover, the drug has
the ability to reduce the number and activity of Langerhans cells, to reduce the release of interleukin-8, to
increase that of interleukin-10 and to regulate the cellular distribution of integrin.12 The capacity to induce
keratinocyte differentiation, thereby reducing cellular
proliferation also reduces the metabolic demands of
the epidermis, eliminating one of the neovascularisation
stimuli. Even the anti-inflammatory and immunomodulating action has an effect on microcirculation by
reducing the chemotactic stimulus as regards the Tcells with a minor induction of epidermal changes.
Further action on the microcirculation is undoubtedly
determined by the capacity to reduce IL-8 release,
known as a neoangiogenetic factor.
In this study, tacalcitol proved to be effective in
reducing the clinical and capillaroscopic alterations.
Nevertheless, microcirculatory improvement did not
perfectly follow clinical improvement (Figure 5).
At the end of the 12 weeks of treatment, the plaque
in 12 patients had clinically healed, but only 4 returned
to a normal capillaroscopic picture.
The reason for this discrepancy could be found in a
slower “restitutio ad integrum”, i.e. full recovery of the
capillary alterations compared to regularisation of keratinocyte proliferation or marked sensitivity of the
endothelial cells to keratinocyte alterations and presence of growth factors. In an apparently clinically
healthy skin, minimum alterations in keratinocyte proliferation or minimum concentrations of growth factors
Giugno 2006
dopo 4 settimane (T1), dopo 8 settimane (T2) e dopo 12 settimane (T3).
Risultati. Le lesioni studiate sono progressivamente migliorate e al termine dello studio in 12 pazienti le chiazze psoriasiche erano scomparse. Anche il diametro dei capillari convoluti tipo “basket” si sono significativamente ridotti
(diametro medio: iniziale 67,64; fine studio 34,08), ma solo
in 4 pazienti si è osservato il ritorno alla visualizzazione del
plesso capillare superficiale con anse capillari alterate. Nella cute perilesionale clinicamente apparentemente sana 14
soggetti presentavano anse capillari abnormemente allungate. Al termine del trattamento, soltanto 4 soggetti presentavano ancora anse capillari alterate.
Conclusioni. Il tacalcitolo si è dimostrato efficace nel
ridurre le alterazioni cliniche e capillaroscopiche. Tuttavia,
il miglioramento microcircolatorio non accompagna perfettamente quello clinico. Abbiamo anche notato che l’azione
del tacalcitolo sul microcircolo non si limita solo alla superficie di applicazione, ma si estende anche alle aree contigue.
PAROLE CHIAVE: Psoriasi, terapia farmacologica - Microcircolazione - Tacalcitolo.
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that are able to maintain the neoangiogenetic stimulus
could still be present.
Although application of the topical drug was carefully limited to the psoriatic plaque, a reduction in the
calibre of the vessels forming the superficial capillary
plexus and a reduction in the length of the altered capillaries in patients who had them was noted on the perilesional healthy skin. This could be the result of the
drug going through the circulatory flow: absorption
of tacalcitol during topical therapy is known 11 and
therefore it is not surprising to see its action away
from the area of application. To be checked is whether
diffusion of the drug at the epidermal level in the surrounding areas of the site of application could have
influenced our observation or whether improvement of
the psoriatic plaque could have determined a reduction
in the production of growth factors and mediators with
a consequent modification in the microcirculatory
alterations in the perilesional skin.
Observation of the discrepancy between clinical
and capillaroscopic improvement and the presence of
microcirculatory alterations in healthy skin and their
reduction following treatment lead to think over the definition of “healed” as far as the psoriatic plaque is
concerned. Can a patient be considered in clinical
remission and therefore suspend treatment when the
clinically visible plaques have disappeared or is necessary to wait for the other components, such as microcirculation, to return to normal? In 1982 Irwin et al.13
demonstrated that there is no epidermal hyperplasia
without vascular proliferation. The VC is certainly an
excellent, fast and comfortable tool to assess microcirculation and therefore it is suggested as the ideal
instrument to decide on the strategy to suspend ongoing treatment of psoriasis.
STINCO
Riassunto
Studio videocapillaroscopico in pazienti psoriasici trattati
con tacalcitolo
Obiettivo. Abbiamo analizzato con videocapillaroscopia
a sonda ottica le modificazioni del letto capillare superficiale nella chiazza psoriasica e nella cute sana perilesionale
durante il trattamento con tacalcitolo.
Metodi. Abbiamo studiato per 3 mesi 24 pazienti affetti da
psoriasi volgare con interessamento non superiore al 15% della superficie corporea durante il trattamento con tacalcitolo
4 mg/g unguento. Scelta una chiazza di psoriasi è stata eseguita una valutazione clinica visiva e misurazioni capillarocopiche con VCSO, al momento dell’arruolamento (T0),
Vol. 141 - N. 3
References
1. Mordovtsev VN, Albanova VI. Morphology of skin microvasculature in psoriasis. Am J Dermatopathol 1989;11:33-42.
2. De Angelis R, Bugatti L, Del Medico P, Nicolini M, Filosa G. Videocapillaroscopic findings in the microcirculation of the psoriatic plaque.
Dermatology 2002;204:236-9.
3. Gilij O. Capillary microscopy in the differential diagnosis of skin
diseases. Acta Dermatol Venereol 1953;33:303.
4. Horacek J. Ultrastructural changes of capillaries by UV in psoriatic
lesions. Z Hautkr 1981; 56: 1218-23.
5. Klemp P, Staberg B. The effects of antipsoriatic treatment on cutaneous
blood flow in psoriasis measured by 133Xe washout method and laser
doppler velocimetry. J Invest Dermatol 1985;85:584-6.
6. Braveman IM, Sibley J. The response of psoriatic epidermis and
microvessels to treatment with topical steroids and oral methotrexate.
J Invest Dermatol 1985;85:584-6.
7. Trevisan G, Magatton Rizzi G, Dal Canton M. Psoriatic microangiopathy modifications induced by PUVA and etretinate therapy. A nailfold capillary microscopic study. Acta Derm Venereol 1989;146S:536.
8. Strumia R, Altieri E, Romani I, Bettoli V, Negrini A, Trimurti S. Tacalcitol in psoriasis: a video-microscopy study. Acta Derm Venereol
1994;186S:85-7.
9. Berardesca E, Vignoli GP, Farinelli N, Vignini M, Distante F, Rabbiosi
G. Non-invasive evaluation of topical calcipotriol versus clobetasol in
the treatment of psoriasis. Acta Derm Venereol 1994;74: 302-4.
10. Nickoloff BJ, Nestle FO. Recent insights into the immunopatogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest
2004; 113:1664-75.
11. Nishimura M, Makino Y, Matugi H. Tacalcitol ointment for psoriasis.
Acta Dermatol Venereol 1994; 186S:166-8.
12. Mommers JM, Castelijns FA, Seegers BA, Van Rossum MM, Van
Hooijdonk CA, Van Erp PE et al. The effect of long-term treatment with
tacalcitol on the psoriatic epidermis. A flow cytometric analysis. Br
J Dermatol 1998;139:468-71.
13. Irwin M, Braverman M.D, Sibley J. Role of the microcirculation in the
treatment and pathogenesis of psoriasis. J Invest Dermatol 1982;78:127.
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Head lice: ex vivo videodermatoscopy evaluation
of the pediculocidal activity of two different topical products
F. LACARRUBBA 1, B. NARDONE 1, M. MILANI 2, G. BOTTA 2, G. MICALI 1
Aim. The aim of this study was to evaluate by videodermatoscopy the efficacy and rapidity of pediculocidal activity in
2 different products indicated in the treatment of head lice.
Methods. Ten tests on 10 adult samples of pediculus humanus
capitis were performed. Head lice were taken from 3 subjects
with active head lice infestation and placed in 10 Petri’s capsules.
After an initial videodermatoscopy observation (of approximately 180 s duration) to evaluate the viability of the parasites, on 5 out of 10 a synergized pyrethrin thermophobic foam
was applied; on the other 5 a coconut and anise oil based-spray
was applied.
Results. In all performed tests with thermophobic foam product the absence of movements of the parasites within 10 s from
the contact with the product was observed, while the absence
of peristalsis was noted within 60 s. On the contrary, with the
essential oil based-product the parasites were alive also after a
continued observation of 120 min after the application of the
product.
Conclusion. Our experience suggests that the videodermatoscopy is a valid researching tool to evaluate the efficacy and
the time of action of topical products with pediculocidal activity.
KEY WORDS: Pediculosis, diagnosis - Videodermatoscopy - Pediculosis, drug therapy.
P
ediculosis is a very frequent disease usually treated with topical compounds with insecticidal activity (pyrethrin, permethrin and malathion) or with so
Received: October 21, 2005.
Accepted for publication: March 15, 2006.
Address reprint requests to: Dr. M. Milani, R&D Mipharm, Via B. Quaranta 12, 20141 Milan, Italy. E-mail: [email protected].
Vol. 141 - N. 3
University of Catania, Catania, Italy
2Medical Direction, Mipharm, Milan, Italy
called natural products with mechanical action (e.g.
essential oil) or with systemic drugs, such as antibiotics
(trimetroprim) or ivermectin.1
However, for many of these products, data about
their real therapeutic efficacy or rapidity of action are
not available at the moment; moreover, evaluation
methods up to now have been based on very simplistic criteria (i.e. clinical examination before and after
treatment).
Videodermatoscopy (VD) is a new instrumental
methodology allowing a rapid, exhaustive and noninvasive in vivo observation of the skin: this tool provides
high quality images with magnifications ranging from
X 4 to X 1000. Both static and dynamic images
obtained trough a colour microvideo camera can be displayed on a monitor and recorded on PC.
A study with VD about the pediculocidal efficacy
and rapidity of action of 2 different products indicated in the treatment of head lice was performed
at the Dermatologic Clinic, University of Catania
(Italy). A formulation of synergised pyrethrin in
thermophobic foam (Milice®; Mipharm) was compared to a coconut and anise oil based-spray, with a
mechanical action obtained by suffocation (Paranix®;
Chefaro).
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HEAD LICE: EX VIVO VIDEODERMATOSCOPY EVALUATION OF THE PEDICULOCIDAL ACTIVITY
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Ten tests were performed on the same number of
adults’ specimens of pediculus humanus capitis taken
in 3 subjects with head lice infestation using a finetooth comb. Each louse was placed in a Petri’s capsule
with gauze on the bottom in order to improve the VD
visualization.
VD examination was performed by a videodermatoscopy Hirox Hi Scope KH 2200 equipped with
zoom lens at magnification ranging from X 10 to X
600.
An initial observation by VD of 180 s duration was
performed to evaluate movements and peristaltic
intestinal activity (that is visible in transparency) as
indicator of lice viability. After this time, a minimal
quantity of pyrethrin thermophobic foam was applied
on 5 parasites and on the other 5 parasites the oil basedspray was applied. The activity of parasites were then
observed and recorded for 120 continuous minutes.
locidal activity is always more frequently described the
appearance of resistance 6 resulting in the inefficacy of
head lice treatment. This phenomenon is more frequent in some geographic area where it is a real problem.7 Furthermore, cross-resistance to permethrin and
malathion was described.8 The cause of therapeutic
failure in head lice treatment is frequently not due to
resistance but to the incorrect use of topical products.
Some products containing a pediculocidal active compound are vehicolated in a formulation not suitable
for this purpose. Clinical evidences show that shampoo
formulations are less effective than cream, lotion or
foam formulations:2 this is due to the low concentration of the active compound and to the very short time
of contact.
VD is a noninvasive diagnostic tool very useful in
dermatology.9 VD is used in a great number of cutaneous diseases thanks to its remarkable versatility
and reliability,9 including cutaneous parasitosis.10, 11
Recently, VD was used in a study to monitor in vivo
the efficacy of a topical antiscabetic treatment and the
optimal timing of this drug application.12 VD can be
used as a diagnostic tool in head and pubic lice infestation: it permits an easy identification of parasite
and eggs when these are not easy to identify to the
naked eye.9 VD permits also an in vivo evaluation of
the movements and physiology of lice and eggs. Isolation of an adult parasite permits in ex vivo conditions (by means of a Petri’s capsule) to observe
through VD the louse and to prove its viability.
Through the isolation of pediculus humanus capitis
(that cannot be reared in laboratory conditions) and
through VD evaluation is also possible to assess the
efficacy and rapidity in pediculocidal activity of topical pediculocides.
In this study pediculocidal action of a synergized
pyrethrin thermophobic foam was highlighted in a
very short period of time: absence of parasite movements were observed within 10 s from the contact with
the product; the absence of peristalsis was noted within 60 s. Data showing in details the time of action of
substances or drugs indicated in head lice treatment,
including pyrethroids substances are not available at the
moment. This study did not assess the evaluation of a
possible ovicidal activity which will be performed in
a future trial.
Our experience suggests that VD represents a valid
research tool for the evaluation of efficacy and time
of action of topical pediculocides. A further and future
Results
In the case of pyrethrin thermophobic foam product,
in all performed tests, the absence of movements of lice
were observed within 10 s from the contact with the
product; the absence of peristalsis were noted within
60 s. With the essential oil based-product the lice were
alive also after a continuous observation of 120 min
after the application of the product (in the packaging
the time for optimal product activity is indicated as
around 15 min).
Pediculosis is due to pediculus humanus capitis, a
blood-sucking insect and specific parasite of humans.2
Pediculosis affects people aged 4-14 years.3 This parasitosis generally does not involve relevant complications, even if it is possible to observe impetigo with
an associated local retro-auricular adenopathy due to
scratching in response to severe itching.4
The evidence based medicine shows that natural
pyrethrin, permethrin and malathion are effective in the
treatment of head lice.5 Synergised natural pyrethrin
and permethrin are the first choice for the topical treatment of head lice thanks to their safety profile. However, also for these molecules with proved pedicu-
234
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HEAD LICE: EX VIVO VIDEODERMATOSCOPY EVALUATION OF THE PEDICULOCIDAL ACTIVITY
per la valutazione dell’efficacia e dei tempi di azione di prodotti topici ad azione pediculocida.
PAROLE CHIAVE: Pediculosi, diagnosi - Videodermatoscopia
- Pediculosi, terapia farmacologica.
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use of VD could be represented by the study of possible lice resistance to commonly used substances
with pediculocidal activity to contribute to the identification of alternative and appropriate therapeutic
options.
LACARRUBBA
References
Riassunto
Pediculosi del capo: valutazione ex vivo tramite videodermatoscopia dell’azione e della rapidità pediculocida di due
differenti preparati topici
Obiettivo. Scopo del presente studio è stato valutare tramite videodermatoscopia l’efficacia pediculocida e la rapidità di azione di 2 differenti prodotti indicati per il trattamento della pediculosi del capo.
Metodi. Sono stati eseguiti 10 esperimenti su altrettanti
esemplari adulti di pediculus humanus capitis, prelevati da
3 soggetti con pediculosi del capo e messi singolarmente in
capsule di Petri. Dopo un’osservazione iniziale in videodermatoscopia di circa 180 s al fine di valutare la vitalità
dei parassiti, su 5 di essi veniva applicato un prodotto a base
di piretrine sinergizzate in formulazione in mousse termosensibile, su altri 5 veniva applicato un prodotto a base di olio
di cocco e anice in formulazione spray.
Risultati. Nel caso del prodotto in mousse è stata osservata
in tutti i test eseguiti l’assenza di movimenti del parassita entro
10 s dal contatto con il prodotto e della peristalsi intestinale entro 60 s. Nel caso del prodotto a base di olio essenziale, i parassiti rimanevano vitali anche dopo un’osservazione
continua di 120 min dopo l’applicazione.
Conclusioni. La nostra esperienza indica come la videodermatoscopia rappresenti un valido strumento di ricerca
Vol. 141 - N. 3
1. Jones KN, English JC 3rd. Review of common therapeutic options in
the United States for the treatment of pediculosis capitis. Clin Infect
Dis 2003;36:1355-61.
2. Chosidow O. Scabies and pediculosis. Lancet 2000;355:819-26.
3. Mumcuoglu KY, Klaus S, Kafka D, Teiler M, Miller J. Clinical observations related to head lice infestation. J Am Acad Dermatol
1991;25:248-51.
4. Frankowski BL, Weiner LB. Head lice. Pediatrics 2002;110:638-43.
5. Dodd CS. Interventions for treating headlice. Cochrane Database
Syst Rev 2001;(2):CDOO1165.
6. Burgess IF. Human lice and their control. Annu Rev Entomol
2004;49:457-81.
7. Hemingway J, Miller J, Mumcuoglu KY. Pyrethroid resistance mechanism in head louse Pediculus capitis from Israel: implications for control. Med Vet Entomol 1999;13:89-96.
8. Downs AM, Stafford KA, Harvey I, Coles GC. Evidence for double
resistance to permethrin and malathion in head lice. Br J Dermatol
1999;41:508-11.
9. Micali G, Lacarrubba F. Possible applications of videodermatoscopy
beyond pigmented lesions. Int J Dermatol 2003;42:430-3.
10. Micali G, Lacarrubba F, Lo Guzzo G. Scraping versus videodermatoscopy for the diagnosis of scabies: a comparative study. Acta
Derm Venereol 1999;79:396.
11. Lacarrubba F, Musumeci ML, Caltabiano R, Impallomeni R, West
DP, Micali G. High-magnification videodermatoscopy: a new noninvasive diagnostic tool for scabies in children. Pediatr Dermatol
2001;18:439-41.
12. Micali G, Lacarrubba F, Tedeschi A. Videodermatoscopy enhances the
ability to monitor efficacy of scabies treatment and allows optimal timing of drug application. J Eur Acad Dermatol 2004;18:153-4.
235
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Combined peel with 25% salicylic acid solution and
10% trichloroacetic acid gel for melasma
M. P. DE PADOVA, S. BELLAVISTA, M. IORIZZO, M. BENTIVOGLI, N. VENTURO, A. TOSTI
Aim. The aim of the study is to evaluate the efficacy and tolerability of a new kind of combined peeling for melasma.
Methods. This new combined peel consists in using salicylic acid
25% in alcoholic solution and trichloroacetic acid 10% in gel, subsequently in the same session. We used this technique to treat 15
female patients, aged from 18 to 45 years, with phototype from
II to IV according to Fitzpatrick scale; they were affected by
epidermic (8 patients), dermal (4 patients) or mixed-depht (3
patients) melasma. For the evaluation of the type and the severity of melasma we used MASI score and Wood’s lamp.
Results. We obtained an excellent esthetic results, in 3-4 settings
at 3-4 weeks interval: in fact, we observed complete resolution in
patients with epidermic melasma, significant regression of the
hyperpigmentation in mixed-depth melasma (more than 50%
decrease in MASI score) and a mild regression in dermal melasma (more than 25% decrease in MASI score). No side effects
were observed. In patients with total resolution no relapses were
observed after 6 months from the end of the treatment.
Conclusion. In this study we have evaluated the efficacy and tolerability of the combined peel, proving that it is useful, reliable and safe in the treatment of the melasma, in all skin types.
KEY WORDS: Melasma - Peel - Salicylic acid - Trichloroacetic
acid.
M
elasma is a common skin hyperpigmentation
disorder, occurring most frequently in adult
females, and with a difficult resolution with dermocosmetic therapy.
Received December 12, 2005.
Address reprint requests to: A. Tosti, Department of Dermatology, St.
Orsola-Malpighi Hospital, Via Massarenti 1, 40138 Bologna, Italy. Email: [email protected]
Vol. 141 - N. 3
Department of Dermatology
University of Bologna, Italy
Until now different peels have been used to treat
melasma; these include salicylic acid, trichloroacetic
acid (TCA), glycolic acid, Jessner’s solution, pyruvic
acid and phenol.1
Results however are not always satisfactory, making
occasionally the melasma worsening, especially
because of postinflammatory hyperpigmentation, persistent erithema and hypertrophic scars.
The aim of our study was to evaluate the efficacy and
tolerability of a combined peel in the treatment of
melasma.
Our combined peel consists in using subsequently
in the same session 2 different chemical agents, salicylic acid 25% in alcoholic solution and TCA 10%
gel.
We enrolled 15 female patients (aged from 18 to 45
years) that were visited at our outpatient consultation
for cosmetic dermatology; their phototype was from II
to VI according to Fitzpatrick scale and they had centrofacial and malar melasma (Table I).
For the evaluation of the severity of melasma we
utilized MASI (Melasma Area and Severity Index) 2
237
DE PADOVA
COMBINED PEEL WITH 25% SALYCILIC ACID SOLUTION AND 10% TRICHLOROACETIC ACID GEL FOR MELASMA
TABLE I.—Patient profiles.
Phototype
Type of melasma
by Wood’s light
Distribution
of melasma
MASI
(before)
MASI
(after)
Duration
of melasma
Race
18 y.
III
E
M
0%
4 months
Caucasian
39 y.
III
E
M
0%
3 years
Caucasian
37 y.
II
E
C
0%
2 years
Caucasian
21 y.
II
E
M
0%
1 year
Caucasian
32 y.
IV
E
C
0%
1 year
Caucasian
39 y.
II
E
C
0%
4 years
Caucasian
42 y.
IV
E
M
0%
3 years
Caucasian
41 y.
VI
E
M
0%
one year
Black
45 y.
III
D
M
Caucasian
II
D
C
40%
(20RM+20LM)
0%
5 years
35 y.
1 year
Caucasian
34 y.
II
D
C
Caucasian
IV
D
M
8 months
Caucasian
40 y.
III
M
M
2 years
Caucasian
42 y.
V
M
C
1 year
Black
45 y.
IV
M
M
75%
(25RM+25LM+25F)
40%
(20RM+20LM)
10%
(5RM+5LM)
25%
(10RM+10LM+5F)
10%
(5RM+5LM)
1 year
37 y.
60%
(30RM+30LM)
60%
(30RM+30LM)
90%
(30RM+30LM+30F)
60%
(30RM+30LM)
75%
(30RM+30LM+15F)
90%
(30RM+30LM+30F)
60%
(30RM+30LM)
60%
(30RM+30LM)
60%
(30RM+30LM)
90%
(30RM+30LM+30F)
90%
(30RM+30LM+30F)
60%
(30RM+30LM)
60%
(30RM+30LM)
75%
(30RM+30LM+15F)
60%
(30RM+30LM)
4 years
Caucasian
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Age
RM = right malar; LM = left malar; F = forehead; E = epidermic; D = dermal; M = mixed-depht; C = centrofacial ; M = malar.
score and Wood’s lamp. To calculate MASI the face
was divided into 4 areas: forhead (30%), right malar
(30%), left malar (30%), chin area (10%).
The examination with Wood’s lamp, used to determine depth of pigmentation, showed an epidermic
melasma in 8 patients (clinically melasma is light
brown and its appearance is enhanced by Wood’s
light), a dermal melasma in 4 patients (clinically
melasma is dark-brown to grey and its appearance
is not enhanced by Wood’s light) and a mixed-depth
melasma in 3 patients (clinically melasma is darkbrown and its appearance is not enhanced by Wood’s
light).
The melasma had developed during pregnancy in
3 patients and during treatment with oral contraceptives
in 4 patients. All patients did not utilized photoprotection.
We treated all the 15 patients with combined peel in
3-4 settings at 3-4 weeks interval. We decided to treat
our patients from October to May, to avoid the risk of
238
a post-peel hyperpigmentation due to the sun exposure in summer.
The used technique includes different phases:
1. pre-peel phase: 3 weeks before the peel the patient
was treated with bleaching agents (Kligman’s trio:
hydroquinone 4%, hydrocortisone 0.5% and retinoic
acid 0.1% in 100 mg of base cream), applying it on the
affected area every evening;
2. cleansing: immediately before applying the chemical peel the skin was cleaned with physiologic solution;
3. salicylic acid application: the alcoholic solution
of salicylic acid 25% was applied using a brush in
order to obtain a uniform and homogeneous dispersion;
4. salicylic acid removal: salycilic acid 25% in alcoholic solution has a limited action since, after the evaporation of the alcohol, in few seconds, the salicylic
acid precipitate remaining on the skin and needs to be
removed with physiologic solution;
5. TCA 10% gel application: the gel was applied
Giugno 2006
DE PADOVA
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Figure 3.— The figure shows a complete regression of the skin hyperpigmentation in a patient with epidermic malar melasma after the treatment
with combined peel.
Figure 1.— A patient with epidermic malar melasma before the treatment.
Figure 2.— A patient with frontal dermal melasma before the treatment.
with a cotton tipped applicator proceeding by single
esthetic-anatomic subunits, to control and modulate
the frosting evolution. We looked for a white-pink
frosting, in order to reach the epidermis and the superficial layers of papillary dermis;
Figure 4.— The figure shows a partial regression of the hyperpigmentation
6. inactivation: since in the epidermic melasma we in a patient with frontal dermal melasma after the treatment with combineed a white frosting, while in dermic or mixed-depht ned peel.
melasma we need a pink frosting, the frosting was
modulated using physiologic solution, to inactivate
— very good response, more than 75% decrease in
the TCA 10% gel;
7. post-peel phase: the post-treatment regiment con- MASI score.
All the 8 patients (100%) with epidermic melasma
sisted of cutaneous hydratation with moisturizers,
and daily use of high-spectrum sunscreen [an ultravi- (Figure 1) obtained a very good response, with a comolet (UV) A/B 50 sunscreen]. After the 10thday, the plete regression of the skin hyperpigmentation (Figure
patient started again to use bleaching agent (Kligman’s 2).
Only one (25%) of the 4 patients with dermal melastrio) applying it every evening in the affected area;
ma
(Figure 3) had a complete clearing, the remaining
8. long term protection phase: patients were instructed to avoid the sun exposure and use a high-spectrum 3 patients (75%) only obtained a mild response (less
than 25%) (Figure 4).
sunscreen.
All the 3 patients with mixed melasma (100%) had
a good response (50% to 75%) with a significant reduction of the hyperpigmentation.
Results
We should underline that at the 3rd day after the
Results were evaluated 3 months after the begin- combined peel, the skin of the patients had a dry and
ning of treatment.
brown colour, lightly wrinkles, minimal limitation of
The response in each patient was graded as:
facial expressions, movements and mild itch. These are
— no response, no change in MASI score at the end not side effects, but consequences of the coagulative
of the treatment;
necrosis of cells in epidermis, that are necessary to
— mild response, less than 25%;
depigmentate the skin affected by melasma.
— moderate response, from 25% to 50%;
All the patients with total resolution (53.3%) and
with mild or good response were examined every
— good response, from 50% to 75%;
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239
DE PADOVA
may have a complete resolution of the hyperpigmentation and patients with dermal or mixed melasma
may improve also, because the combined peel makes
the skin more receptive to topical bleaching regimens.
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month for 6 months and no relapses or worsening were
observed.
Possible side effects of combined peeling are hyperpigmentation, persistent erythema and reactivation
of Herpes Simplex virus infection. No side effects
were observed either during or after the treatment.
Conclusions
Discussion
Already in the past Brody,3 Monheit 4 and Coleman 5
proposed combined peels: in fact, combining a lower
concentration of TCA with another less potent superficial peeling agent, we gain the required level of skin
damage with a lower risk of side effects.
The aim of our combination is to favour penetration of TCA at low concentration, using salicylic acid
as an exfoliant agent. This association has a softer
action than a single strong chemical agent and permits good therapeutic results with minimal risk of
side effects.6
In particular we utilized salicylic acid as a keratinolytic agent to remove epidermal keratinocytes,
including pigmented keratinocytes, and to enhance
the topical penetration of TCA gel 10% which causes
a coagulative necrosis 7, 8 limited to the epidermis and
the superficial layers of papillary dermis.
This induces renewal of the epidermis by accelerating epidermal turnover, by stimulating and increasing the growth of normal and undamaged cells underneath the lesion, thus leading to the resolution of the
cutaneous hyperpigmentation.
Although the epidermis and the papillary dermis
can be regenerated by simply injuring the cornified
layer by superficial peeling, their effect is very slow and
multiple treatments are required to improve pigmentary disorders.9
Utilizing this combined “cold” peel we obtained an
excellent esthetic result in only 3-4 settings separated
each other by 3-4 weeks interval.
Moreover, this technique is ideal for melasma permitting to treat all Fitzpatrick skin types, because the
dynamics of the frosting (intensity, tonality, homogeneity, speed) allows to modulate the deepness of
action, making it possible to use this technique also in
patients with a high phototype.
The main advantage of combined peel is the lack
of inflammatory reaction that could cause a postinflammatory hyperpigmentation.
For this reason patients with epidermic melasma
240
In conclusion, we underline that all the different
phases of our regimen are important for the efficacy of
treatment. In the pre-peel phase the bleaching agents
disperse pigment granules in keratinocytes and interfere with pigment transfer. The combined peel cause
a complete or partial clearing of melasma and without
inflammation. In the post-peel phase the photoprotection permits to avoid relapses.
Riassunto
Peeling di combinazione con una soluzione di acido salicilico al 25% e di gel di acido tricloroacetico al 10% per il trattamento del melasma
Obiettivo. L’obiettivo dello studio è di valutare l’efficacia
e la tollerabilità di un nuovo tipo di peeling di combinazione per il trattamento del melasma.
Metodi. Questo nuovo peeling di combinazione consiste
nell’utilizzo di una soluzione alcolica con il 25% di acido salicilico e di un gel al 10% di acido tricloroacetico, applicate in
successione nella stessa seduta. Abbiamo usato questa tecnica per trattate 15 soggetti di sesso femminile, di età compresa tra 18 e 45 anni, con fototipo Fitzpatrick compreso tra
II e IV, che erano affette da melasma epidermico (8 pazienti), dermico (4 pazienti) o misto-profondo (3 pazienti). Per
valutare il tipo e la gravità del melasma abbiamo utilizzato
il punteggio MASI e la lampada di Wood.
Risultati. Abbiamo ottenuto un eccellente risultato estetico con appena 3-4 sedute ad intervalli di 3-4 settimane.
Infatti, si è avuta risoluzione completa del melasma epidermico, una regressione significativa dell’iperpigmentazione nel caso di melasma misto-profondo (diminuzione del
punteggio MASI superiore al 50%), e una lieve regressione del melasma dermico (diminuzione del punteggio
MASI superiore al 25%). Non sono stati osservati effetti
collaterali. A distanza di 6 mesi dal trattamento, nelle
pazienti con risoluzione totale del melasma non sono state osservate recidive.
Conclusioni. In questo studio abbiamo valutato l’efficacia
e la tollerabilità del peeling di combinazione, provando che
esso è utile, affidabile e sicuro per il trattamento del melasma
in tutti i fototipi cutanei.
PAROLE CHIAVE: Melasma - Peeling - Acido salicilico - Acido tricloroacetico.
Giugno 2006
References
5. Coleman WP, Futrell JM. The glycolic acid + trichloroacetic acid
peel. J Dermatol Surg Oncol 1994; 20:76-80.
6. Iorizzo M, Tosti A, De Padova MP. Melasma. In: Tosti A, Grimes
Pearl E, De Padova MP eds. Color atlas of chemical peels. First edition. Berlin: Springer, Germany, 2005.p.149-59.
7. Cotellessa C, Peris K, Onorati MT, Fargnoli MC, Chimenti S. The use
of chemical peeling in the treatment of different cutaneous hyperpigmentations. Dermatol Surg 1999;25:450-4.
8. Grimes PE. Agents for ethnic skin peeling. Dermatol Ther
2000;13:159-64.
9. Brody HJ. Histology classification. In: Brody HJ ed. Chemical peeling and resurfacing. Second edition. St. Louis, Missouri: Mosby,
1997.p.7-27.
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1. Pazeshky S, Bell FE, Grummer S, McMichael AJ. Therapeutic options
for melasma. Cosmetic Dermatol 2003;16:33-45.
2. Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN et al. Topical retinoic acid (tretinoin) for
melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130:727-33.
3. Brody HJ, Hailey CW. Medium depth chemical peeling of the skin:
a variation of superficial chemosurgury. J Dermatol Surg Oncol
1986;12:1268-75.
4. Monheit G. The Jessner’s + TCA peel: a medium depth chemical
peel. J Dermatol Surg Oncol 1989;15:945-50.
DE PADOVA
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241
REVIEWS
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Advancing vaccination strategies for prevention
and therapy of dermatological diseases
Vaccinology increasingly incorporates the rapidly accumulating new knowledge of the molecular and cellular pathology of
diseases, and of the components and mechanisms of cellular and
humoral immune responses. With the changes in paradigms,
new vaccination strategies are developed and explored for
infectious diseases, cancer, autoimmune disorders and allergies.
While these strategies are still at early stages of development,
vaccination is expected to become an important tool not only for
prevention but also for treatment and management of diseases.
Future vaccines are bound to be molecularly defined and accurately tailored to induce most effective immune responses. Diseases of the skin are, increasingly, targets for vaccine development. Moreover, because of its easy accessibility and its constitution as a major immune organ, future developments will
aim for vaccine designs suitable for delivery via the skin.
KEY WORDS: Allergy - Antigens - Autoimmune diseases - Bacteria - Neoplasms - Epitope - Infections - Parasite - Lymphocytes, T
cells - Toll-like receptor - Vaccines.
E
ver since the successes of the small pox vaccination campaigns were acknowledged by the medical
and scientific communities in the XIXth century, vaccines were viewed as magic bullet for basically every
disease.1 Numerous vaccination attempts were initiated
for both prevention and therapy of infectious diseases,
cancer, allergies and autoimmune disorders. The outcomes of these trials were mostly disappointing.
Nonetheless, following internationally coordinated
Address reprint requests to: P. Walden, Department of Dermatology,
Venerology and Allergy, Clinical Research Group Tumor Immunology, Charité-Universitätsmedizin Berlin, Humboldt University, 10098 Berlin, Germany. E-mail: [email protected]
Vol. 141 - N. 3
P. WALDEN
Department of Dermatology, Venerology and Allergy
Clinical Research Group Tumor Immunology Charité –
Universitätsmedizin Berlin
Humboldt University, Berlin, Germany
vaccination campaigns one major scourge of mankind,
small pox, is considered extinct now. A number of
other infectious diseases could be checked and current campaigns aim at eradicating all vaccine-preventable infectious diseases. Despite these successes,
only 25 infectious diseases are targeted by licensed
vaccines (www.who.int). These are mostly viral infectious and some bacterial toxins. There is no approved
vaccine for prevention of infection by bacteria, protozoa
and helminths. And, despite intense efforts over the
past one and a half century, cancers and autoimmune
diseases are still not controllable by vaccination. On the
other hand, great progress has been made in regard to
allergic disorders with effective hyposensitization protocols now available for a number of type I allergies.
Vaccinology has largely been an empirical discipline developed by trial and error, in most cases, testing the pathogenic agent itself as vaccine, sometimes
with severe side effects. Only recently, knowledge of
antigenic structures recognized by antibodies and T
cells and of the mechanisms of immune regulation
have been incorporated in vaccine development.2 With
the systematic dissection of the immune responses
against infectious diseases, cancer, autoimmune disorders and allergies, and the identification of the rel-
243
WALDEN
VACCINATION STRATEGIES FOR DERMATOLOGICAL DISEASES
ual are the most important safeguards against infection.
For some 25 of the most wide-spread infectious diseases effective vaccines exist. Nonetheless, still many,
especially children, die from these diseases. With
intense international efforts, the World Health Organization (WHO) and Global Alliance for Vaccination
and Immunization (GAVI; www.gavialliance.org) run
and coordinate world-wide vaccination campaigns
aimed at eradicating these vaccine-preventable infectious diseases. But there are many diseases for which
there are no vaccines. Among these are viral diseases
such as AIDS, avian influenza and SARS, protozoal
diseases such as malaria, leishmaniasis and sleeping
sickness, diseases caused by helminths such as river
blindness and schistosomiasis and a large number of
bacterial diseases. Many infections once believed
checked reappear with new epidemics. Among these
are insect-borne diseases such as malaria, leishmaniosis
and sleeping sickness that vigorously recurred with
the ban on the insecticide DTT. New diseases such as
SARS or fatal variants of avian influenza have arisen
and rapidly spread through international traffic. Among
the most prevalent infectious skin diseases that are
primary targets for vaccine development are oral and
genital herpes, and human papilloma virus infections.
Both clusters of diseases are highly immunogenic viral
infections that affect high proportions of the populations in developed and developing countries alike. Various efforts are undertaken to develop vaccines against
herpes and warts 5-7 but there are still enormous problems in the development of vaccines for these causative
agents, not least because of the lack of understanding
of the basic immunology of infections by the large
DNA viruses and of the molecular cell biology of their
long latencies.8 Most individuals respond effectively
with strong humoral and cellular immune responses to
herpes family viruses such as Ebstein Barr virus (EBV)
and Citomegalovirus (CMV), and the infections are
usually well controlled, however, without sterile immunity. Oncogenic subtypes of human papilloma viruses are closely associated with cervical and penile cancers.9 It is generally believed that vaccines against
these viruses can prevent these cancers. Substantial
progress has been made in recent years in the development of vaccines for the human papilloma viruses
HPV 16 and HPV 18 that are thought to be causative
agents for cervical cancers.10-13 The initial observations from a clinical trial with virus-like particle vaccines of the papilloma virus capsid protein L1 are
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evant antigens and immunological epitopes, new concepts and new techniques are being introduced into
vaccinology. This process was pioneered since the
early nineties by the intense efforts in tumor immunology to develop therapeutic cancer vaccines.3 These
changes are expected to accelerate the development
of new vaccines, both for prevention and therapy. All
standard vaccines on the market are designed to induce
neutralizing antibodies. In most diseases, however,
immunity depends on the effective collaboration of
the humoral and the cellular arm of the immune system with helper as well as effector T cells playing
essential parts.2 The intense efforts to develop cancer
vaccines have brought T cell-mediated immunity into
the focus of vaccinology and have introduced a range
of vaccine designs geared towards efficiently inducing
effector T cell responses.
The skin is the largest and most exposed organ of the
body, route of entry for various pathogens and affected by many diseases as primary or secondary site of
manifestation. A number of these diseases are considered possible targets for preventive or therapeutic
vaccination. The skin is also a large immune organ
particularly suited to sense and battle pathogenic intruders and in-born pathologic developments.4 As such,
the skin has moved into the focus of vaccinology as
possible target site for vaccines not only for skin but
also internal diseases, and new strategies for dermal
vaccination are being developed.
This review will sum up some of the most recent
developments in vaccinology with focus on the skin as
site of disease manifestation and vaccination.
Vaccine targets
Infectious diseases
Infectious diseases are still the major burden of
mankind with enormous losses of lives and, for every
individual, of life quality many times and often extensively or continuously during lifetime. Infectious diseases inflict huge economic costs for all countries and
severely block or slow the economic and social developments in regions endemic for protozoal diseases,
HIV, diseases caused by helminths and others. The
vast majority of infectious diseases are not controlled
by vaccination. Rather, hygiene measures such as providing clean drinking water, clearing sewage and waste,
and avoiding unprotected contact to infected individ-
244
Giugno 2006
tions may develop complications by triggering remission or exacerbation of atopic dermatitis.22 Besides
the fact that no preventive vaccine is available yet for
bacterial and fungal infections,2 primary localization
and propagation of many infections at the outer skin
with restricted accessibility for the immune effector
systems is a fundamental problem. It is not clear yet
whether immune interventions or immune prophylaxis can prevent or cure these kinds of infectious diseases. Some other bacterial infections develop inside
the skin and, thereby, are within the reach of the
immune system. Mycobacterium leprae the causative
agent of leprosy induces strong immune responses.
However, these immune responses are not protective
as the disease inevitably progresses with its terribly
disfiguring effects. Animal studies suggest that the
type of helper T cell response might shift the disease
either in direction of disfiguring lepromatous or less
devastating tuberculoid manifestations.
Of even higher complexity is the immunology of
protozoal skin infections caused by the different leishmania species. In the cases of several of the parasites,
the infection is confined to the skin. Always, however, also in cases of visceral or mucosal manifestation,
the skin is the primary port of entry of the parasites. The
immediate local immune responses at this site may
decide whether or not the immune system can fend
off the infection and mount protective immunity. The
quality of the initial cutaneous immune responses,
thus, may be a matter of life or death for the patient. The
skin is also the site of secondary infection by Leishmania donovani after cure from the initial visceral
manifestation of the disease, a condition known as
Post-Kala Azar Dermal Leishmaniasis (PKDL). In
Sudan, PKDL is observed in a large fraction of the
individuals some weeks after they recovered from visceral leishmaniasis. In India the frequency of PKDL is
low and it occurs usually years after the initial visceral disease. In both situations it is a skin disease associated with more or less extensive depigmentation. It
is not clear why the same parasite that is responsible
for the life-threatening visceral leishmaniasis causes a
much milder skin disease at its second appearance but
development of a partial organ-specific immunity during the initial infection might well be part of the explanation. It is also not clear whether PKDL is caused
by reinfection with new parasites or by parasites persisting in the skin. Active immunization in the form of
the age-old practice of leishmanization has been suc-
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induction of neutralizing anti-viral antibodies and
clear-cut reduction of the occurrences of premalignant conditions. These observations, thus, strongly
support the expectations that HPV vaccines can confer protection from HPV-related intraepithelial cervical neoplasia.14, 15 If successful, HPV vaccines will be
the first case of preventive cancer vaccines.11 It is estimated that 20% to 25% of all cancers have a direct or
indirect microbial etiology. Targeting the infections
in these cases by vaccination is believed to interfere
with the malignant development and prevent the cancers. Following-up on the promising observations,
new vaccine designs for HPV are developed and tested that, in addition to neutralizing antibodies, also
induce T cells against epitopes of the oncogenic E6 and
E7 gene products of HPV 16 and 18.16-18 While the
early observations with preventive HPV vaccines seem
to justify the high hopes that prevention of cervical
cancer might be possible, therapeutic vaccines for
these malignancies have failed to show any effect.18
This failure mirrors the observations from animal model experiments with transplantation tumors that vaccines that can prevent the establishment of the tumors
usually have no effects on established tumors.
Bacterial and fungal infections are highly prevalent
and have a great impact on the affected individuals.
These infections are caused by highly pathogenic
microbes as well as common bacteria that can turn
invasive and pathogenic in cases of immune deficiencies or in response to certain cytokines produced by
immune cells. Such induction of bacterial pathogenicity
by immune responses has recently been shown for
Pseudomonas aeruginosa a common bacterium that is
responsible for a large fraction of nosocomial but also
for increasingly occuring community acquired infections with severe courses.19-21 The extent of and the
possible involvement of the skin in such immuneinduced or immune-enhanced pathogenicity of common micro-organisms is currently under intense
research. Bacterial and fungal infections can persist for
a long time, often life-long and cause substantial financial burden for the community. Preventive measures
such as vaccination are of obvious importance and,
taken into consideration the above-indicated interplay
of immune responses and pathogenicity of bacteria,
need to be tailored carefully to avoid exacerbation of
the pathological effects by specific types of immune
responses. Moreover, some of these microbial diseases such as staphylococcal and many fungal infec-
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antibody responses against the promastigote form of
the parasites as they are injected by the bite of the
insect vector. Second, induction of effector T cell
responses against antigens presented by the infected
macrophages that activate these macrophages to kill
their intruders via mechanisms involving active oxygen species.27 The first of these strategies is the only
possibility to prevent entry of the parasites into the
host cell. It is, however, not clear whether neutralizing
antibodies can indeed block the parasites. The latter
goal for anti-parasite vaccines is derived from mouse
model experiments that show that cure from Leishmania donovani infection is correlated with a Th1and Th2-type CD4+, and CD8+ T cell responses 25,
27, 28 and that macrophages induced to oxidative bursts
can kill the parasites. It is hereby particularly important to identify T cell epitopes of parasite antigens that
are presented by infected cells.27, 29-32 Moreover, recent
observations suggest that the course of the infection
may also be influenced by the saliva and immune
responses against salivary components of the insect
vector. Pre-existing immunity against these components seem to support protective immune response.33
If this is confirmed, insect antigens may become relevant constituents of leishmania vaccines. Considering the large body of information on anti-leishmania
immunity and the requirements that leishmania vaccines have to meet, many details of the vaccine design
still need to be worked out before meaningful trials
can be planned.
In summary, the number of infectious diseases that
can be prevented by vaccination is still very limited. It
has become clear that effective preventive or curative
immune responses against infectious agents, especially viruses, and intracellular bacteria and protozoa,
depend on combinations of antibody and effector T
cell responses, and that vaccines have to control the
direction of the helper T cell responses in addition to
inducing the effector cells and cytokines required for
protection.
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cessfully used in the Near East all the way through to
Central Asia to prevent cutaneous leishmaniasis known
as oriental sore. Very recent studies in regions in Northern India that are highly endemic for visceral leishmaniasis or Kala Azar have shown that the frequencies
of seropositivity for the leishmania antigen K39 is
much higher than the prevalence of manifest disease.23
These observations indicate that there is a state of
immunity to leishmaniasis established in the course
of natural infection and strongly support the efforts
to develop leishmania vaccines. But the heterogenous
outcomes of the infections by leishmania parasites
also emphasize that the development of vaccines needs
to incorporate the large body of information on the
immune responses to leishmania infection that has
been accumulated over the past years.24 Infection by
leishmania parasites induces vigorous humoral and
cellular immune responses involving all cell types of
the immune system. The pathology is complicated by
host-disease relationships that are dynamically evolving in the course of infection and during the life-cycle
of the parasites. Key denominators of these relationships are elaborate immune evasion mechanisms enacted by the parasites, the involvement of vector systems
highly specialized for particular leishmania and host
species, the existence of extra-human and obscured
human reservoirs, and explosive propagation of the
parasites. Notwithstanding these complexities, great
progress has been made in understanding the immune
mechanisms associated with protection or with the
failure of the immune defenses.25 Earlier generalizations from studies with mouse models and Leishmania major which is associated with cutaneous leishmaniasis suggested that Th 1-type helper T cell
responses are correlated with resistance to disease and
Th 2-type responses with susceptibility. However,
more recent studies indicate that curative immune
responses involve all arms of the immune system
including innate immune cells, specific antibody
responses and CD4 T cells of both helper T cell types
as well as CD8 effector T cells. From these observations it appears necessary that preventive as well as
therapeutic vaccines against protozoal diseases induce
massive broad-range immune responses with parasite
antigen-specific antibodies, T cells of all helper and
effector types, strong innate immune reactions, and
various immune-regulating and effector cytokines.26 On
this basis, the agenda of vaccine development is
twofold. First, early blockade of infection with strong
246
Autoimmune diseases and allergies
In contrast to other diseases, the goal in cases of
autoimmune diseases and allergies is to specifically
suppress or re-direct on-going pathogenic immune
responses. The therapeutic vaccines should address B
cells, and disease-associated helper and the regulatory T cells rather than effector T cells in these immune
reactions.34, 35 The identification of autoantigens and
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for immune surveillance and tumor rejection.55, 56 But
it took another twenty years, with the discovery of the
first tumor-associated T cell epitopes and antigens,
before it became possible to dissect the specific
immune mechanisms against cancer.57, 58 Today it is
clear that CD8+ T cells are the most important effector cells in tumor immunity and with the identification
of some 300 different tumor-associated epitopes for
these cells derived from about 100 different antigens
we have now a relatively advanced understanding of the
specificities of immune responses against cancer.59, 60
This knowledge has been translated into the design of
vaccines for induction of tumor-specific T cell responses. With that, tumor immunology has transformed vaccinology and has complemented the earlier antibodyfocused approach to vaccine development with new
concepts for T cell vaccines.3, 59, 61, 62 Also, vaccination
in cases of cancer is mostly a therapeutic intervention
despite very encouraging attempts towards prophylactic anti-cancer vaccines for cervical cancer 15 and the
hope that many of the cancers with microbial etiology may be prevented by prophylactic vaccines. As
therapeutic vaccination the specific immune histories
of the patients are expected to impact the outcome of
the treatment and have to be taken into consideration
in vaccine design.
Comparing the specificities of antibody and T cell
responses against tumor cells, the HLA-restricted
mode of antigen recognition allows T cells to scan a
much wider range of antigenicity than accessible to
antibodies. The HLA peptidome of cells, that is the
totality of HLA-bound peptides, reflects not only the
proteome of the cells but also the specific rates of turnover of every protein. It is often phrased that the HLA
present the degradomes of the cells rather than their
proteomes.63-67 The turn-over of the proteins is very
sensitive to the physiological states of the cells, the
HLA peptidomes reflect alterations within as well as
in the environment of the cells. A higher turn-over of
some proteins associated with a higher proliferation rate
will, thereby, result in an altered HLA peptidome compared to resting cells. All this allows T cells to sense
various pathological changes in the cells, a capacity that
can be exploited for vaccine development.64 On the
other hand, the HLA polymorphism significantly complicates the task of developing T cell vaccines in that
the specificities of the responses are far more individualized as it is the case for serological responses. In
effect T cell vaccines need to be designed differently
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the corresponding T cell epitopes, and the characterization of the T and B cell responses in cutaneous
autoimmune diseases such as autoimmune bullous
diseases 35 and systemic lupus erythematosus are key
to the development of autoantigen specific means of
immune intervention for disease prevention and cure.3641 The hope is that it may become possible to utilize T
cell epitopes as specific immune modulators. Upon
suitable modifications, they may be used as antagonists
of the CD4+ T cells that drive the pathogenic immune
responses. Alternatively, the T cell receptor families of
the pathogenic T cells can be attacked by vaccination
to raise cytolytic T cell responses against the autoimmune T cells.42-45 These two strategies have been tested in mouse and rat models and the corresponding
attempts to prevent or reverse autoimmune disease
yielded some interesting successes. The translation of
these approaches into therapies for autoimmune diseases in man, however, is still far off. In contrast to
the situation with autoimmune diseases, there is rapid
progress in the development of therapeutic vaccination
strategies against allergies. These strategies of immune
desensitization, meaning immune modulation and
immune tolerization, for the treatment of allergies 46 are
increasingly being based on identified T cell epitopes.47,
48 The use of such epitopes, rather than unfractionated allergen preparations, will substantially improve
the quality of therapeutic vaccines and help to control the effects of the immune interventions. Many of
these attempts are based on the hypothesis that a disbalance of Th1/Th2-type immune responses is responsible for allergies 49, 50 and, consequently, aim at redirecting the polarization of the helper T cell responses
in order to correct the disbalanced immune states.51
Other concepts aim at inducing regulatory T cells
(Treg) responses to down-regulate aberrant T cell reactivities, both in cases of autoimmune diseases and
allergies. 52-54
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Cancers
The hypothesis that the immune system is responsible for protection against cancer and plays an important part in rejection of tumors has already been proposed in the XIXth century, however, it was not until the
late sixties and seventies of the twentieth century that
the instruments of anti-tumor immune responses began
to become unraveled. Macfarlane Burnet was the first
to propose that thymus-dependent, viz, as we know
today, T cell-dependent immune reactions are the basis
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natural epitopes, can be designed to recruit and activate
tumor-specific T cells most efficiently. The potentials
of such mimotopes have been demonstrated in animal
models for melanoma as well as in clinical applications
as therapeutic vaccines for cutaneous lymphoma.82-86
The tumor-associated antigens known to date are,
with very few exceptions, normal self-antigens.60 Antigens such as the melanoma-associated antigens tyrosinase, tyrosinase-related proteins (TRP), MART1/Melan A and S100 constitute the most numerous
group followed by the cancer-testis antigens. For some
tumors, for instance hepatocellular carcinoma or colon
carcinoma, embryonic antigens like α-fetoprotein
(AFP) or carcinoembryonic antigen (CEA), respectively, have been found aberrantly expressed. Tumors
with viral involvement express viral antigens that, as
foreign antigens, are ideal targets for cancer vaccines.
The most relevant examples here are, as mentioned
above, human papillomavirus antigens in cervical carcinoma. For melanoma, the latter two categories of
tumor-associated antigens play no role. Tumor-specific neoantigens that once were believed to be the
main focus of anti-tumor immune response have rarely
been found. A mutation in cdk4 of melanoma cells of
a patient is one of the few examples.87 It, thus, seems
that mutations giving rise to such neoantigens play no
relevant role in tumor immunology. The exceptions
might be idiotype sequences of the T cell receptor of
T cell lymphomas and of the immunoglobulins of B
cell lymphoma that are explored as possible targets
for cancer vaccines in cases of lymphoma, also cutaneous T and B cell lymphomas.88 In any case, tumorspecific neoantigens are individualized and not suited
for widely applicable vaccines. By and large, the tumorassociated antigens and T cell epitopes known to date
classify tumor-specific immune responses as autoimmune responses.89 Notwithstanding the fact that nearly all tumor-associated antigens are not tumor specific but also expressed and presented by non-malignant
cells, these antigens can be and are being used for cancer vaccines.
With the identification of tumor-associated T cell
epitopes, new techniques for detection, characterization and enumeration of T cell responses against these
antigens have been developed and are being used for
immune monitoring in the context of clinical vaccination trials. These new tools include HLA oligomers
loaded with the T cell epitope of interest that are used
to detect all T cells with given specificity, and intra-
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than vaccines for antibody-based immunity.62 The
physiology of antigen-presenting cells and the molecular mechanism of antigen processing have to be
incorporated in the vaccine design as well as the specific requirements for the collaboration of the precursors of tumor-specific cytolytic effector cells with T
helper cells.3, 68-72
The first tumor-associated antigens and HLA class
I-restricted T cell epitopes for human cancers were
determined by expression cloning of cDNA from tumor
cells of a melanoma patient together with HLA genes
into COS cells, testing these doubly transfected cells
with T cells of the same patient and sequencing the
cDNA of transfectants that specifically induce T cell
responses. The first identified antigen was MAGE, a
member of a new class of proteins whose expression
is confined to tumor cells and testis.57, 73 In the following years different families of these so called cancer-testis antigens were identified but, despite intense
efforts, no functions have yet been determined for the
MAGE proteins. Testis is an immune-privileged organ,
meaning, it is not accessible to CD8+ T cells. The
antigens, therefore, are relatively tumor-specific and
considered preferred antigens for cancer vaccines.
Now, different technologies are employed to identify cancer-associated antigens and T cell epitopes.
The most successful approach involves bioinformatics
to predict potential T cell epitopes in the sequences
of identified or suspected tumor-associated antigens
that then are validated in T cell assays.74-76 Powerful but
technically very demanding alternatives are biochemical approaches that involve extraction and
sequencing by mass spectrometry of peptides bound to
the HLA of tumor cells.77-80 These analyses of HLA
peptidomes provide new insights into the physiology
of the tumor cells and allow to identify antigens that are
relevant for the pathology of the tumors.80 For use in
cancer vaccines, some tumor-associated T cell epitopes were modified to improve HLA binding and,
thereby, the efficiency of T cell activation.81 Such
altered epitopes are more efficient than their natural
counterparts in inducing responses by specific T cells,
however, in some cases it turned out that T cells
induced by such altered epitopes did not or only inefficiently recognize and destroy tumor cells that present
the natural epitope. Such problems can be circumvented by complete de novo design of peptides that
efficiently activate T cells originally raised against the
tumor cells. Such so called mimotopes, mimetics of
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more than twice that expected from clinical experiences and a high fraction of the patients experienced
stable disease.96, 109 Therapeutic vaccination, thus,
seems to be suited for maintenance therapy where cure
is not possible. Since the adverse effects of vaccination
therapy are minimal and restricted to slight inflammatory responses at sites of vaccine injection, vaccination could become an alternative to conventional
treatment modalities for maintenance in advanced
stage cancer patients.
Despite some reports of vaccination-induced complete responses in advanced stage cancer patients, it is
questionable whether therapeutic vaccination will
become a dependable curative therapy for late stage
cancers. The basic problem that limits the efficiency of
cancer vaccination is the heterogeneity of the tumor
cells that increases with tumor mass and time of tumor
development. With their heterogeneity the immune
evasion capacity of the tumor cells increases with time.
Therapy failures due to the selection of therapy-resistant tumor cell variants is also reported for chemotherapy and radiotherapy. To circumvent these problems
combinations of different but compatible and mutually
complementing therapeutic principles 110, 111 should
be considered. In contrast to advanced disease stages,
early stages of cancer might be less prone to immune
evasion and more sensitive to therapeutic vaccination.
At early cancer stages curative therapeutic vaccination is conceivable. However, no sufficiently informative clinical trials with early stage cancer patients
have been conducted yet to test these options.
In addition to melanoma, initial studies have demonstrated that cutaneous lymphoma is susceptible to therapeutic vaccination.83, 84 Due to a lack of identified
tumor-associaed antigens and T cell epitopes, other
skin cancers have not yet been addressed with therapeutic cancer vaccines. Nonetheless, there is indirect
and very suggestive evidence that they could be targeted by vaccination therapy as well. Among the observations supporting this notion are tumor regression in
cases of basal cell carcinoma upon applications of
immune modulators such as imiquimod and CpG that
are known to act via Toll-like receptors (TLR) to activate antigen-presenting cells.112-114 This option is currently tested for actinic keratosis as well and has yielded very promising initial results. The exact immunological, cellular and molecular mechanisms of these
clinical responses upon treatment with TLR agonists
still need to be worked out.
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cellular cytokine staining with subsequent flow cytometry as well as ELISpot that detect T cells specifically responding to their cognate antigens.90-92 With the
help of these tools natural anti-cancer immune responses as well as the immunological effects of vaccination and other therapeutic interventions are analyzed.
As most tumor-associated antigens have been identified for melanoma, melanoma research is the forerunner in tumor immunology and cancer vaccinology
and the vast majority of the clinical vaccination trials
have been and are being conducted with melanoma
patients.61, 93-95 In most cases these were advanced
stage patients with metastasized tumor and a history of
repeated treatment failures. Such patients are generally
not expected to respond well to therapeutic vaccination.
Nonetheless, the trials have yielded significant evidence for the potential effectiveness of vaccination
therapy for the treatment of cancer. Cancer vaccines
regularly induce tumor-specific T cell responses and,
in some cases, also clinical responses in cancer
patients.72, 96, 97 However, despite frequent induction of
tumor-specific T cells in the vaccinees, these immunological responses only in a few cases correlate with
clinical responses.96, 98, 99 These failures of the tumorspecific T cells to exert an effect on the tumors have
been correlated with immune evasion by the tumor
cells with either loss of antigenicity or immune suppression.84, 96, 100-102 To reduce the risk of antigen loss,
vaccines with complex antigenicity have been designed
and tested in clinical trials.72, 96, 103-105 Hybrid cell vaccination that uses fusions of a patient’s tumor cells
with allogenic dendritic cells as vaccines, is the most
extensively studied vaccine design that represent a
complex tumor antigenicity.72, 96, 106-108 Multiantigen
immune monitoring of these hybrid cell vaccination trials demonstrate induction of high frequencies of tumorspecific T cells with a broad range of specificities for
tumor-associated antigens.96 Nonetheless, the frequencies of objective clinical responses was not significantly improved. Instead, immune escape variants
of the tumor cells were detected in tumor lesions progressing under therapy that have lost expression of
multiple antigen, of HLA or of the transporter associated with antigen processing (TAP). It thus seems that
multiantigen tumor vaccines efficiently induce broad
immune specificities that select tumor cells with a correspondingly broad pattern of immune evasion.
Although only few objective clinical responses were
recorded, the median survival time of the patients was
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tions depends on efficient antibody as well as CD8+
effector T cells responses. This is particularly true for
the immune reactions involved in recovery and cure
from disease.2 Immunity to cancer is mostly T cellmediated immunity,3 antibodies play no relevant part.
Only in the case of cancers with microbial etiology,
both antibody and T cell responses are expected to be
important for immunity. For induction of both types of
immune responses, humoral responses mediated by
B cells through antibodies and effector-cellular immune
responses by CD8+ T cells, T cell help is required.68,
116-118 T cells do not respond to antigen directly but to
processed antigen presented by the HLA molecules
of the antigen-presenting cells. It has become clear
now that antigen-presenting cells involved in the induction of immune responses need to fulfill specific
requirements and, besides presenting the antigenic
epitopes for the T cells in the correct HLA contexts,
HLA class I molecules for CD8+ and HLA class II
molecules for CD4+ T helper cells, they have to provide additional signals via specific sets of costimulatory receptors and counter receptors as well as
cytokines such as IL-12. Although all cells that express
HLA class II molecules can serve as antigen-presenting cells, dendritic cells are best equipped for the task
and need to be addressed by vaccines.119, 120 The dendritic cells are critical in induction and orchestration of
cellular immune responses. In all, molecularly defined
vaccines should contain three essential constituents.
First, epitopes or antigens for the effector cells, cytotoxic CD8+ T cells or B cells, second, epitopes or antigens for helper T cells, third, adjuvants for active modulation of the antigen-presenting cells. In addition,
vaccines composition should include adjuvants with
reservoir functions to control the bio-availability of
the vaccine.
Different vaccine formulations have been proposed
to incorporate these constituents. Besides whole viruses or pathogenic cells, complete lysates, subunit preparations from the pathogens or tumor cells, recombinant
proteins, peptides, virus-like particles, DNA and RNAbased vaccines were developed and are being tested,
mostly in animal models, few already in clinical trials.121, 122 Epitopes for HLA class I-restricted effector CD8+ T cells are peptides of eight to ten amino
acids which are products of limited proteolysis from
proteins expressed by the cell. These peptides are
bound by HLA class I molecules and presented at the
cell surfaces.59 Epitope for HLA class II-restricted T
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Although natural anti-cancer immune responses are
mainly mediated by T cells, it may well be possible to
induce antibodies against tumor cells with therapeutic
effects. Tumor cells often have an altered molecular
composition of their surfaces, in particular, altered
glycosylation patterns. The identification of such
altered glycosylations may be exploited to develop
strategies for active antibody-directed immunization
against tumor-specific cell surface molecules.115 Antibody-based therapies may be interesting alternatives
and complementation of T cell-based strategies. Moreover, for cancer with microbial etiologies such as papilloma viruses in cervical or some head-and-neck cancers, hepatitis B and C viruses in hepatocellular carcinoma, human T lymphotrophic virus in T cell lymphoma, EBV in lymphoma or nasopharyngeal carcinomas or Helicobacter Pylory in MALT lymphoma,
prevention of infection by neutralizing antibodies may
contribute to immune protection.11-15 In these cases, as
for other infectious diseases, vaccines should induce
neutralizing antibody as well as cytolytic T cell
responses.
Vaccine design and delivery
All commercial vaccines are for infectious diseases
and aim at the induction of neutralizing antibodies
against the infectious agent itself, this is the case for all
anti-viral vaccines, or toxins produced by bacteria.
They were all developed empirically and consist of
either the inactivated, sometimes attenuated, infectious agent or a subunit thereof. Usually, alum is added
as an adjuvant to enhance the efficacy of the immune
induction. With the elucidation of the specificities of
the immune reactions over the past two decades and the
identification and dissection of immune dominant epitopes for B cells and T cells, the development of vaccines of molecularly defined components has become
possible. As yet however, only few such molecularly
defined vaccines have been tested in clinical trials,
none has been approved yet for routine application.
Besides the antigenic determinants recognized by the
T and B cells, the requirements of the regulatory cell
interactions in the induction of immune responses
need to be considered in the development of new vaccines. Challenging the antibody-focused approaches to
vaccine development, recently reported studies indicate
that protective immunity against many infectious diseases such as viral, mycobacterial or protozoal infec-
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riority of complex antigens in inducing immune
responses to the tumors. In all cases where T cells are
to be addressed by the vaccines, complex antigenicity is essential to sufficiently cover the HLA immunogenetics of the human target populations.
Infectious agents used as vaccines have often sufficient immune-stimulatory capacity to induce protective immune responses. Nonetheless, the effectiveness of the vaccines can be enhanced by addition of
adjuvants. When defined components, especially synthetic products are used as vaccine antigens, however,
activators of the dendritic cells can be essential for
the vaccination effects. The recent discovery of Tolllike receptors (TLR) in mammals 123-125 and the finding that their ligands often are compounds of long
known immune stimulators used as adjuvants has made
it possible to develop molecularly defined modulators
of antigen-presenting cell functions. TLR are ancient
and highly conserved key components of the innate
immune system that share structural elements with
the Toll protein of drosophila. They are differentially
expressed by different cells of the immune system
including B cell, monocytes, macrophages and dendritic cells, but not by T cells. The signaling pathways
addressed by the TLR concurs in parts with the interleukin-1 signaling pathway and involves the transcription factor NF-ÎB.125, 126 The effects of signaling
through TLR is expression of costimulatory molecules and proinflammatory cytokines. The resulting
innate immune responses attract various cells of the
immune system including T cells. Particularly important is the activation of dendritic cells with their functions in the induction and coordination of T cell-mediated immune responses.
So far 11 mammalian TLR have been identified,
and their cellular distributions and ligand specificities unraveled.124 The natural ligands are microbial
products of diverse chemical classes. As examples,
TLR2 binds, among many other molecules, lipopeptide of various pathogens and peptidoglycans of Grampositive bacteria.127, 128 TLR3 binds double-stranded
viral DNA, TRL4 lipopolysaccharide, TLR7 and 8
single stranded viral RNA 129 and TLR9 unmethylated CpG motifs of bacterial DNA.130-132 TRL8 had initially been found to bind synthetic imidaziquinolines
such as imiquimod that is in clinical use for treatment
of warts and tested in clinical trials for treatment of
basal cell carcinoma and actinic keratosis.112,114 TLR
1, 2, 4, 5 and 6 are expressed at the cell surface where-
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helper cells have eleven and more amino acids and
are derived from internally expressed as well as extracellular antigens. While the epitopes for T cells are
peptides, antibodies can bind molecules of virtually any
chemical class. Often they recognize conformational
rather than simple linear determinants. Based on the
elucidation of the structure of the antigenic determinants for many antibodies, various strategies for the
synthesis of conformationally defined vaccine components are being developed. However, these strategies
have not been translated into synthetic vaccines yet.
More often, recombinant proteins are prepared and
tested as vaccine antigens. Most successfully, virus-like
particles (VLP) are explored for this purpose. VLP
can also be altered chemically or by gene-technological means to include additional epitopes besides the
determinants of the viral core proteins.
To enable T-B cell collaborations, the epitopes for
both cell types need to be in one molecule. This notion,
known as the epitope linkage concept, is one of the
basic concepts of immunology. It is based on experiments that have shown that for induction of secondary
antibody responses which involve antibody class
switch, haptens as model antigenic determinant for
the B cells need to be covalently linked to a carrier
protein that contains epitopes for T helper cells. For TT cell collaboration, that is the interaction of T helper
cells and precursors of CD8+ cytolytic T cells there is
also an epitope linkage requirement. However, in contrast to T-B cell interaction the epitopes for the two T
cell types need not be covalently linked. They have to
be presented by the same antigen-presenting cell.68
Helper T cell antigens for efficient induction of CD8+
T cells can be part of the vaccine antigen but in many
situations it may improve the potency of the vaccines
if other antigens are added. Recall antigens like tuberculin, potent foreign antigens like KLH or allogeneic
HLA class II molecules have been used as helper antigens for the iduction of CD8+ T cells. Whatever the
design of the vaccine, it is advantageous to include a
large number of epitopes for the targeted immune cells
in order to cope with the heterogeneous immunogenetics of human populations and to broaden the
scope of the immune responses. Complex antigens,
mixtures of antigens or peptides and polyvalent epitopes, called polytopes,103 have been developed for
this purpose. In cancer vaccinology, comparisons of
single epitope vaccines with complex vaccine antigens carrying various epitopes have shown the supe-
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cinoma model.135 Recent results of studies with women
treated with topical imiquimod for cervical intraepithelial neoplasia indicate that imiquimod induces T cell
responses with broadened specificity of the responding CD8+ T cells.113 Different TLR differ in their
capacity to induce specific CD8 responses. Studies
with ligands for TLR 2 and 4 have produced conflicting results, in some experiments efficient induction
of CD8+ T cells was achieved, in others not. Ligands
for TLR3, 5 and 7 have moderate adjuvant effects
whereas TLR9 most dramatically increased CTL
responses.141 Despite such promising data, it still needs
to be established what the optimal dose and timing is
for the application of TLR agonists as adjuvants in
therapeutic or prophylactic vaccination. Further studies are needed especially in the light of recent reports
of extensive TLR engagement leading to immunological anergy and the respective adverse effects.
The route of delivery is crucial for the success of
vaccination. Most vaccines available to date have to be
injected, in some few cases oral application is possible but not used anymore. Such invasive vaccinations
are problematic. Not only that they cause discomfort
for the vaccinees and may be traumatic experiences
especially for children. In many developing countries
the needles and syringes are used several times for
different individuals. WHO reports that in some regions
more than 80% of the vaccination equipment is reused
(www.who.int). This practice born from poverty and
restricted resources bears a substantial risk of spreading infections. Especially in regions with high prevalence of HIV and hepatitis virus infections the risk of
vaccination-related dissemination of disease is very
high. WHO, therefore, calls for intense research to
replace the current invasive vaccination practices by
non-invasive applications.142 Besides some attempts in
direction of oral vaccines, transdermal routes are being
explored and transdermal vaccination is high up on
the agenda of vaccine development. These developments build on the new techniques for delivering substances through the skin, some pioneered by cosmetics industry. The skin, thereby, is not only an easily
accessible site and transdermal application, not only a
convenient route for vaccination, it is also a major
immune organ that provides all the cellular requirements for efficient utilization of the vaccines. In contrast to muscle, currently the main target organ for
vaccine application, the antigen-presenting cells
required for induction of all aspects of protective
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as TLR 4, 7, 8 and 9 are found in endosomes and bind
viral or microbial components that become accessible only upon disintegration of the viruses, bacteria
or protozoons. Depending on the cellular distribution
of TLR expression, different cytokines and different
other cell types are induced.133 In humans TLR 7, 8 and
TLR9 are expressed by plasmacytoid dendritic cells
that, when activated by the corresponding TLR ligands, mature to potent antigen-presenting cells with
increased expression of HLA class II molecules and
costimulatory molecules, and secretion of T cell-stimulatory cytokines including IL-12.134-137 Activation of
B cells by TLR9 stimulation results in strong enhancement of antibody production.
Lipopolysacharide, lipopeptides, CpG and
imiquimod have already been tested as vaccine adjuvants.127 The TLR 7/8 agonist imiquimod as well as
other imiquidazochinolines were tested successfully in
animal models as vaccine constituent for induction of
immune responses against viral infections such as
Herpes Simplex and transplantation tumors, both for
prophylaxis or therapy.113 Similarly, the TLR9 agonist CpG (CpG-ODN) has strong adjuvant activity in
vaccines for infectious diseases and tumors.134-137 It
is well established now that the efficacy of DNA vaccines, at least in parts, depends on the presence of
CpG motifs in their sequences.121, 122 A hepatitis B
vaccine that includes CpG oligonucleotides has been
tested successfully in orangutans that developed efficient protective antibody responses. Vaccine without
the CpG oligonucleotides was not effective.138 Other
examples for the efficacy of CpG in supporting induction of antigen-specific immune responses are mouse
model experiments with the E7 protein of the oncogenic papilloma virus HPV-16 that resulted in induction of E7-specific cytotoxic T cells and protection
from HPV 16-related cancers.132 Currently, the first
clinical trials with hepatitis B virus envelop proteins
plus CpG-ODN are being conducted.134 Besides induction of CD8 T cells via enhancing the co-stimulatory
capacity of dendritic cells, down-regulation of regulatory T cells (Tregs) is discussed as possible principle of TLR activity.139 TLR agonists can stimulate
dendritic cells via TLRs such that regulatory T cell
function becomes blocked and, thereby, immune
responses against pathogens unblock.140
Some pioneering work on the potential clinical application of imiquimod and other TLR agonists has
focused on tumor models such as a murine colon car-
252
Giugno 2006
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immune responses are present in abundance and the
lymphocytes to be activated are readily recruited to
the skin. It is foreseeable that future vaccinations
involve application of patches or crèmes rather than the
use of needles. Moreover, almost all vaccines available
to date require prime-boost schemes that cause enormous logistic problems. To overcome these problems
intense research is on-going to develop simplified
schemes that combine immediate and delayed antigen release so that priming and boosting vaccines can
be delivered simultaneously.
In conclusion, while today vaccines in clinical use
as well as the recent developments tested in clinical
trials are complex natural products, future vaccines
are expected to be defined synthetic products containing the above-discussed constituents. The skin,
thereby, is not only the site of manifestation of diseases that in future may be preventable by vaccination. It is also the immunologically well-equipped
outer wall of immune defense against infections and,
therefore, prospectively the site for transdermal vaccine delivery.
WALDEN
Acknowledgement.—The authors wishes to thank Patricia Zambon for
her expert assistance in preparing this manuscript.
Riassunto
Strategie avanzate di vaccinazione per la prevenzione e la
terapia della patologie dermatologiche
La vaccinologia incorpora sempre più le nuove conoscenze che rapidamente si stanno ascumulando sulla patologia molecolare e cellulare delle malattie e sui componenti e meccanismi delle risposte immunitarie cellulomediate e umorali. Con le modificazioni dei paradigmi,
sono state sviluppate nuove strategie vaccinali per le malattie infettive, il cancro, i disturbi autoimmunitari e le allergie. Mentre queste strategie sono ancora in fase iniziale di
sviluppo, ci si attende che la vaccinazione diventi un importante strumento non solo per la prevenzione ma anche per
il trattamento e la gestione delle malattie. I futuri vaccini
deriveranno dalle conoscenze della biologia molecolare e
saranno costruiti per indurre le risposte immuni più efficaci.
Le patologie dermatologiche rappresentano, sempre di più,
un possibile bersaglio per lo sviluppo dei vaccini. Inoltre,
grazie alla sua facile accessibilità e alla sua costituzione quale organo immune maggiore, i futuri sviluppi consentiranno di disegnare dei vaccini in grado di essere somministrati tramite la cute.
PAROLE CHIAVE: Allergia - Antigeni - Malattie autoimmuni Batteri - Neoplasie - Epitope - Infezioni - Parassiti - Linfociti T - Toll-like receptor - Vaccini.
Vol. 141 - N. 3
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Lore K, Betts MR, Brenchley JM, Kuruppu J, Khojasteh S, Perfetto
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A
UVA1 phototherapy
R. CAPEZZERA, C. ZANE, P. G. CALZAVARA-PINTON and GIFDE*
Non ionizing radiations with wavelengths ranging from 340 to
400 nm (UVA1 waveband) have peculiar photophysical, photobiological and phototherapeutical effects. UVA1 penetrates
deeply into the skin and modulates the biological and immunological activity of both dermal and epidermal circulating as
well as resident cells. Unlike UVB (260-320 nm) and UVA2
(320-340 nm), UVA1 photobiological effects are mediated exclusively by oxidative photochemical processes leading to the formation of singlet oxygen and other reactive oxygen species
(ROS). The main targets of ROS are cell membranes and cytoplasmic organelles, particularly mitochondria, that are rich
of structural molecules with several double bonds, e.g. lipids and
aminoacids. UVA1 phototerapy proved to be an effective and
well tolerated therapeutic option in the treatment of atopic
dermatitis, localized scleroderma, mastocytosis, systemic lupus
erythematosus, mycosis fungoides, chronic graft versus host
disease and a growing number of other skin diseases, characterized by dermo-epidermal infiltrates of normal as well as
neoplastic lymphocytes, mastocytes and/or eosinophils as well
as alterated metabolism of collagen. There is no general agreement on the optimal treatment protocol. UVA1 is delivered at
fixed doses without progressive dose adjustments. However,
protocols differ in the UVA1 dosage, the number of weekly
exposures, and total number of exposures. UVA1 therapy is
*) Gruppo Italiano di Fotodermatologia (GIFDE): T. Lotti, P. Cappugi,
R. Rossi, C. Senesi (Florence), G. Monfrecola, E. Procaccini (Naples), A.
Peserico, S. Piaserico (Padua), G. Leone, M. Picardo (Rome), P. Amerio
(Chieti), M. Guarrera, A. Hazini (Genoa), A. Gasparetto (Treviso), G.
Fimiani, P. Rubegni, M. Pellegrino, L. Flori (Siena), D. Schena, C.A
Cagalli (Verona), V. Brazzelli (Pavia), S. Di Nuzzo (Parma), D. Calista
(Cesena), P. Zampieri (Merano), S. Percivalle (Milan), A. Nazari (Rapallo).
Address reprint requests to: Prof. PG. Calzavara-Pinton, Dermatological University Clinic, P.le Spedali Civili 1, Brescia, Italy.
Vol. 141 - N. 3
Department of Dermatology II
University of Brescia, Brescia, Italy
always well tolerated and episodes of erythemogenic reaction
are rare. Long term adverse effects are unknown but the hazard of skin carcinogenicity seems negligible because UVA1
does not damage directly DNA.
KEY WORDS: UVA1 - Phototherapy - ROS - Cytokines - Dermatitis, atopic.
I
n 1981, a novel filtered metal halide lamp with high
output strictly confined to the UVA1 (340-400 nm)
waveband was invented.1
In the following years, substantial progress was
made in clarifying the photobiological, photophysical and phototherapeutical effects induced by this particular waveband.
Mechanisms of action
In comparison to UVB (280-325 nm) and UVA2
(320-340 nm), UVA1 penetrates deeper into the dermis and affects the biological and immunological
activity of both epidermal and dermal cells, whether circulating or resident.
The mechanisms of action are also different. Unlike
UVB and UVA2, UVA1 is not able to isomerize urocanic acid and does not cause direct anaerobic effects.
257
CAPEZZERA
UVA1 PHOTOTHERAPY
It mainly works through photochemical aerobic reactions leading to the generation of singlet oxygen and
other reactive oxygen species (ROS), i.e. superoxide
anions, hydroxyl radicals and hydrogen peroxide.
These activated molecules damage aminoacids through
oxidation, particularly tryptophan, tyrosine, histidine,
methyonine and cysteine leading to the denaturation of
structural proteins, enzymes and receptors.
The auto-catalytic process of peroxidation of unsatured membrane phospholipids and cholesterol leads
to the formation of hydroxide derivatives of these
lipids and a broad group of aldeidic compounds, the
most important of which being malonyldialdeidis.2, 3
DNA bases damaged through oxidation produce
many photoproducts,4 such as 8-hydroxiguanine, 5hydroxicytosine and tymine glycol. However, their
mutagenic activity is held low because the base excision repair (BER) enzymatic system is able to repair
the DNA damages quickly and efficiently. This enzymatic system consists of a glycosidase, the replication protein A (RPA), and an endonuclease (adenyl
AP) together with the proliferating cell nuclear antigen
(PCNA). In addition, UVA1 induces pyrimidine
dimers, though in negligible amounts without biologic importance.
UVA1 exposures also induce cross-links between
DNA strands and proteins as well as breaking singlestrand DNA through a Fenton reaction.4 Since these
DNA alterations do not inhibit cell growth, they are
considered transient products of the repairing process.5
UVA1 exposures may result in immunomodulatory
effects such as the modification of transcription and
release of several cytokines, the enhancement of the
expression of cell-surface receptors and adhesion molecules and the selective induction of apoptosis of
immunocompetent cells.6
Increased m-RNA and protein expression of IL-1α,
IL-6, IL-8, IL-10, TNF-α 7-9 and proopiomelanocorticotropin (POMC)-derived peptides, including αMSH,10 may be observed in UVA1 irradiated keratinocytes. α-MSH has many anti-inflammatory
effects, e.g. inhibition of IL-1 or TNF-α-mediated
proinflammatory effects, and immunosuppressive
effects, e.g. inhibition of cell-mediated immune
responses.11
UVA1 exposures enhance the expression of nitric
oxide synthase-2 (NOS-2) in endothelial cells of normal human skin and in keratinocytes of psoriatic skin.
The extent of the enhancement is comparable with the
258
expression achieved by stimulation with pro-inflammatory cytokines IL-1β, TNF·α and IFNγ.12
UVA1 enhances the synthesis of prostaglandins
(mainly PGE2) and leukotrienes, activates phospolipase, and promotes the growth of Langerhans cells
and dendritic cells. PGE2 is a potent immunosuppressant that affects the expression of co-stimulatory molecules on the surface of antigen presenting
cells and thereby prevents the activation of selected
T cell subsets, especially Th1-like cells.13 It has also
been demonstrated that the improvement of skin status in patients with atopic dermatitis treated with
medium-dose UVA1 is associated with the modulation of the expression of cathepsin G in the dermal
inflammatory infiltrate.14 This is a serine protease
that may attack laminines, proteoglycanes, collagen
I and insoluble fibronectine, inducing several biological effects: provocation of pro-inflammatory
events, degradation of the basement membrane,
destruction of the tissue inhibitor of matrix metalloproteinases (MMP) and enhancement of the endothelial permeability.
UVA1-induced upregulation of ICAM-1 expression
on the surface of keratinocytes is mediated by an oxidation mechanism 8, 9 which may be modulated through
cellular glutathione levels. UVA1-induced transcription
of AP-1, c-Fos, c-Jun and NF-kB not only affects several inflammatory and immune activities but also the
activation of metalloproteinase.15
ROS and singlet oxygen generation cause a so called
“early” or pre-programmed cell death through an apoptotic mechanism that does not require de novo protein synthesis, takes less than 20 min and acts on the
proteins which constitute the mitochondria, such as
cytochrome-C.16 This process leads to the immediate
opening of the cycloporine A-sensitive (“S” site) mitochondrial megapore.
Such early cell death of neoplastic lymphocytes has
been observed in B and T-cell lymphoma skin infiltrate.
The apoptotic process also leads to the release of IFNÁ. The following immunomodulation and the increased
number of T-lymphocytes can partially explain the
phototherapeutic efficacy of UVA1 in the treatment
of immune diseases.17
Like PUVA and UVB, UVA1 can also kill keratinocytes by a “delayed” or programmed cell death.
This apoptotic mechanism takes at least 4 h, and works
by damaging the DNA, and the subsequent up-regulation of p53 (with the activation of Bax and 8-cas-
Giugno 2006
UVA1 PHOTOTHERAPY
CAPEZZERA
pase, and down-regulation of bcl-2), transcription of
AP1 and expression of Fas-L.18-20
However, in vivo trials showed that 3xMED of UVA1
irradiation causes far fewer apoptotic sunburn cells
than 3xMED of NB-UVB or solar irradiation.21
We can see a correlation between the decrease of
bcl-2, the increased expression of p53 and the considerable reduction of either normal or pathological
T-lymphocytes. These events are probably critical in
the successful treatment of atopic dermatitis, mycosis
fungoides and other T-cell mediated dermatosis.22, 23
Unlike UVB, UVA1 cannot significantly reduce the
number of epidermal Langerhans cells even if it can
reduce their size.24
Furthermore, UVA1 increases the number of CD34+
dermal dendritic cells and causes their accumulation
in the draining lymph nodes by a mechanism that
requires only IL1-β.25 This contrasts with UVB activity where the presence of TNF-α is also required.
Therefore, it is likely that, unlike PUVA and UVB,
UVA1 targets dermal dendritic cells and not Langerhans cells.26
Unlike UVB, UVA1 radiation induces the synthesis
and the expression of metalloproteinases (e.g. MMP1, MMP-2 and MMP-3) in human dermal fibroblasts
27-29 through an autocrine mechanism involving the
UVA1 inducible cytokines IL-1 and IL-6. Thus UVA1
phototherapy-induced softening and disappearance of
sclerotic lesions such as morphea and keloids may
result from induction of MMP.11 Finally UVA1 does not
reduce only the release of hystamine from basophils
and mastocytes, but also the number of dermal mast
cells present.30
UV sources and action spectrum
Nowadays, UVA1 irradiation sources are equipped
with both fluorescent and filtered metal halide lamps.
The fluorescent lamps have a low irradiance (5-10
W/cm2 at skin level) and deliver low UVA1 doses (usually around 10-30 J/cm2) within 30-60 min. High-output metal halide sources have a much greater irradiance
(80 W/cm2 at skin level) and can irradiate medium
(40-70 J/cm2) or high doses (up to 130 J/cm2) in treatment sessions of 30-45 min.31
Unfortunately, metal halide UVA1 irradiation units
are very expensive to buy and operate. In addition,
they require elaborate cooling systems and careful
maintenance. Therefore, their use is limited to a few
Vol. 141 - N. 3
highly specialized centers of phototherapy in Europe
and the USA.32
Unlike UVB and PUVA phototherapies, UVA1 is
delivered at fixed doses without progressive dose
adjustments.33
Clinical indications
UVA1 phototherapy has proved to be an effective and
well-tolerated therapeutic option in the treatment of a
growing number of inflammatory diseases, (characterized by dermo-epidermal infiltrates of normal or
neoplastic T-cells, mastocytes and/or eosinophils) and
diseases where the metabolism of collagen is altered.3438 The efficacy of UVA1 has been demonstrated by
randomized and controlled studies in the treatment of
atopic dermatitis and LES (unfortunately, the LES
studies come from a single source and a low number
of patients were enrolled).
As regards dosages, different regimens have been
proposed: low (10-20 J/cm2), medium (50-60 J/cm2),
and high (100-130 J/cm2) doses,39 though at present
there is no general agreement about which would be
best.
In controlled clinical trials for the treatment of acute
and severe atopic dermatitis, medium doses of UVA1
proved to be superior to low doses while being just as
effective as high doses.40, 41 Combined UVA-B phototherapy was found more effective than low-dose
UVA1 42, 43 but inferior both to medium 44 and high
dose UVA1. High doses of UVA1 were also found
more effective than the topical application of fluocortolone.45
Medium doses of UVA1 are more effective than
NB-UVB in the treatment of acute lesions of atopic
dermatitis but less effective in the treatment of chronic manifestations.46
UVA1 is just as effective as topical PUVA in the
treatment of chronic atopic dermatitis but it is preferable in that it is easier to perform.46-54
The reduction of skin inflammation and the improvement of the disease condition are closely linked to the
significant decrease of the eosinophilic count in the
blood, 47 serum levels of the eosinophilic cationic protein (ECP) 48 and soluble IL-2 (sIL-2R) and IL-4 (sIL4R) receptors 44, 48-51 and a reduction of dermal mast
cells and intraepidermal IgE-bearing Langerhans
cells.52, 53
Low doses of UVA1 have been used in the treat-
259
CAPEZZERA
UVA1 PHOTOTHERAPY
ment of skin lesions associated with LES because they
not only modify the pathogenetic mechanisms inducing immediate apoptosis, but promote the repair of
UVB and UVA2-induced DNA damage, interfere with
the translocation of extractable nuclear antigens (e.g.
RoSSA), and reduce the IL12 levels (through the
release of IL10) as well as the eosinophil serum levels.37, 55
An improvement of several extra-cutaneous clinical
parameters has also been observed these patients, e.g.
morning stiffness, headache, arthralgia, asthenia and
some laboratory parameters considered as disease
activity markers (leukopenia and serum iter of antinuclear antibodies).37
However, patients affected with LES should be carefully monitered in order to opportunely diagnose phototoxicity.
In the treatment of other diseases, the efficacy of
UVA1 is supported only by single case reports or controlled trials enrolling small numbers of patients. Therefore, until we have further information, UVA1 phototherapy must be administered exclusively to patients
that are resistant to or do not tolerate standard therapies.
UVA1 irradiation proved to be effective in the treatment of patients affected by cutaneous T-cell lymphoma (CTCL) not only in 1A and 1B stages of the disease, but also in the tumoral and erythrodermic stages.
UVA1 appears particularly useful for patients showing
gastrointestinal or systemic toxicity due to oral psoralen
administration.56-60
Medium dose UVA1 was found effective also for
large-plaque parapsoriasis,59 pityriasis lichenoides et
varioliformis acuta 61 and pityriasis lichenoides chronica.62, 63
In these skin diseases, the therapeutic activity of
UVA1 seems to be related to direct effects on the cutaneous inflammatory infiltrate since unexposed lesions
do not respond.63
UVA1 phototherapy quickly reduces itching and
clears skin lesions in patients affected by sub-erythrodermal pityriasis rubra pilaris 64 and Netherton
Syndrome.65
Although UVA1 phototherapy showed some efficacy in the treatment of psoriasis, it can be considered a viable alternative to either UVB or PUVA only
in the case of HIV+ patients since it does not induce
promoter genes of HIV replication.66
In anecdotal case reports, medium or high dose UVA1
phototherapy proved to be effective in the treatment
260
of inflammatory diseases characterized by dermal infiltrate such as idiopathic mucinosis follicularis,67 cutaneous sarcoidosis,68, 69 hypereosinophilic syndrome,70
generalized granuloma annulare 71, 72 and extragenital
lesions of lichen sclerosus et atrophicus 73, 74 (this last
seems to be responsive also to low-dose UVA1 75).
Both low-dose and medium-dose UVA1 phototherapy are effective in the management of patients affected by maculo-papular mastocytosis 76 although pigmentary changes do not disappear. Clinical improvement is accompanied by a marked reduction of both
lesional skin mast cells and histamine levels present in
the urine.
Prolonged treatment cycles with high-dose UVA1 are
effective for localized scleroderma 77 in adults and
pansclerotic morphoea in children,78 while low-dose
UVA1 is less effective,25 ,79, 80 but results are very good
if associated with b.i.d. application of calcipotriol
cream.81
Medium 82 or low-dose 83 UVA1 exposures cause
progressive softening of the skin 82 and healing of
peripheral piecemeal necrosis 83-85 in patients affected
by systemic sclerosis (SSc).86 These patients showed
a progressive improvement of functional parameters
related to disease activity, including passive joint
mobility, skin temperature, and cutaneous elasticity.
This clinical improvement is also accompanied by
improvements in ultrasonic parameters and histological features. The therapeutic effects of UVA1 may be
demonstrated by immunohistochemical investigations
that show the induction of collagenases and a reduction of the lymphocyte infiltrate.83 ,86-88
A recent case-report indicates that UVA1 phototherapy may improve keloids and hypertrophic scars
84 and some clinical symptoms related to POEMS syndrome such as sclerodactily, flexion contractures, and
skin thickness.89
Medium-dose UVA1 phototherapy was found effective also in the treatment of sclerodermic as well as
lichenoid lesions caused by graft-versus-host disease
(GVHD).90, 91 Futhermore, UVA1-induced clinical
improvement has permited the use of immunosuppressive therapies by reducing the risk of drug induced
toxicity and opportunist infections.92, 93
Protocol of treatment
Before engaging in a new treatment cycle patients
must sign a written consent form that informs them
Giugno 2006
UVA1 PHOTOTHERAPY
CAPEZZERA
of the possible risks of the therapy as well as their
alternative therapeutic options.
UVA1 phototherapy must be absolutely excluded
when one or any of the following criteria are present:
congenital DNA-repair defects; porphyrias; congenital defects of skin pigmentation; dysplastic nevus syndrome; former cutaneous melanoma; severe heart disease; therapy with photosensitizing drugs.
Other though minor criteria for the exclusion of this
therapy are: under age patients; a personal or family history of non-melanoma skin cancer; family history of
melanoma; severely sun damaged skin; former radiotherapy; therapies with arsenic and BCNU; poor compliance.
Treatment protocols are very simple: UVA1 is delivered at fixed and sub-erythemigenic doses without
progressive dose adjustments. A phototest for the determination of the erythematous threshold as well as a
photoprovocative test are recommended only if a photodermatosis is suspected.94
Even if there are no comparative trials currently
available for most of the possible applications of UVA1
phototherapy, a medium-dose seems to be just as effective as high-dose UVA1 phototherapy. Therefore medium-dose regimens are preferentially delivered because
of lower cumulative dosages, costs and side effects.
Low-dose regimens are exclusively recommended
in the treatment of LES, because medium and highdose UVA1 could trigger the disease.
Five exposures a week are indicated in the case of
atopic dermatitis while 3 exposures a week on alternate
days are suggested for other dermatoses.
Treatment should be continued until complete clearing occurs, or, in the case of partial improvement, until
there is no further amelioration in spite of one additional week of treatment. Alternatively, other authors
suggest a predetermined number of exposures: 15 in the
case of atopic dermatitis and 30 for dermal sclerosis.94
There is no evidence tso show whether maintenance
cycles of treatment are useful in preventing recurrences. Therefore, they should be avoided not only
because of cost, but more importantly because of the
greater risk of cumulative skin toxicity.
Side effects
Skin dryness and mild itch are often reported by
patients undergoing UVA1 phototherapy, but are usually responsive to emollient creams. Other acute side
Vol. 141 - N. 3
effects are uncommon and limited to the exacerbation
of latent photosensitive diseases or relapse of a herpes
simplex infection.
The major potential long-term adverse effects are
photoaging and skin cancer.
UVA1 induces photoaging through photobiological mechanisms that are not completely known;
although mitochondrial DNA mutations may play a
relevant role.95
UVA1 induces SCC-like tumours in chronically
exposed mice.96-98 UVA1 induced cancerogenesis
involves biological mechanisms that seem to be different from UVB even if the resulting skin tumours are
the same. In particular, a wide spectrum of p53 mutations are observed after UVB but not after UVA1 exposures.99
However, the magnitude of this risk in UVA1 treated patients is still unknown and long term trials
enrolling a wide range of patients would be needed
in order to clearly understand the risks involved.
Nonetheless it is generally agreed that a standardization of dosage regimens and an accurate dosimetry
would reduce these potential long term hazards.39
Conclusions
After a review of published trials and single case
reports the following guidelines can be suggested:
— UVA1 mainly induces type II, oxygen-dependent photochemical reactions;
— unlike UVB and PUVA, UVA1 penetrates into the
dermis and modulates the biological and immunological activities of both epidermal cells and dermal cells;
— UVA1-induced biological and immunological
effects are different from those induced by UVA2,
UVB and PUVA;
— UVA1 phototherapy is expensive because of the
high costs of UVA1 irradiation units and the high power consumption (up to 24 KW); this machinery requires
constant and careful maintenance; a single treatment
session may last up to 50 min even with the most powerful irradiation units;
— before starting a new treatment cycle, patients
must sign a written consent form that informs them
of the possible risks of the therapy and their eventual
therapeutic options;
— treatment protocols are very simple: a preventive phototest is not required; UVA1 is delivered at
261
CAPEZZERA
UVA1 PHOTOTHERAPY
fixed, sub-erythemigenic doses without progressive
dose adjustments.
— comparative studies have shown that mediumdose UVA1 regimens (50-60 J/cm2) are as effective
as high-dose regimens (100-130 J/cm2) and more effective than low-dose regimens (10-39 J/cm2) in the treatment of atopic dermatitis. As far as other therapeutic
indication are concerned, medium-dose UVA1 seems
as effective as high-dose UVA1 even if no comparative
studies are available. Since there is no evidence that
confirm the higher efficacy of high-dose UVA1, medium-dose regimens are preferred because of their lower cumulative dosages, costs and side effects. Neither
medium-dose nor high-dose regimens are recommended in the treatment of LES;
— the real risk of long term side effects, e.g. photoaging and skin cancer, is not at present known;
— randomized and controlled studies supporting
UVA1 efficacy have been reported only for atopic dermatitis and LES (however good results in the treatment of LES come from a single source and the number of studied patients was low);
— UVA1 phototherapy is preferable over NB-UVB
in the treatment of acute exacerbations of atopic dermatitis but not for chronic lesions;
— LE affected patients must be treated with lowdose regimens and must be carefully monitored in
order to opportunely diagnose phototoxicity or systemic clinical manifestations;
— in other suggested indications, the use of UVA1
is supported only by single case reports or uncontrolled or small trials. Therefore UVA1 phototherapy
should be administered exclusively to patients who
do not tolerate, or are not responsive to standard therapies;
— therapeutical results reported in the treatment of
diseases characterized by lymphocyte or mastcells
dermal infiltrate or by deficiencies in fibroblastic activity are particularly relevant and promising;
— for the treatment of psoriasis, UVA1 must be
reserved for HIV+ patients only;
— criteria for the absolute exclusion of UVA1 phototherapy are: congenital DNA-repair defects; porphyrias; congenital defects of skin pigmentation; dysplastic nsevus syndrome; former cutaneous melanoma;
severe heart diseases; photosensitizing drugs;
— contraindications that require an evaluation
between risk and benefit are: under age patients; per-
262
sonal history of epitheliomas; family history of
melanoma; numerous UV exposures in the past; former radiotherapy or therapies with arsenic and BCNU;
poor compliance.
Riassunto
Fototerapia UVA1
Le radiazioni ionizzanti con lunghezza d’onda compresa
tra 340 e 400 nm (UVA1) hanno effetti fotofisici, fotobiologici e fototerapeutici peculiari. Gli UVA1 penetrano profondamente nella cute e modulano l’attività biologica e immunologia sia delle cellule dermiche ed epidermiche circolanti che di quelle residenti. Diversamente dagli UVB (260320 nm) e dagli UVA2 (320-340 nm), gli effetti fotobiologici
degli UVA1 sono mediati esclusivamente da processi fotochimici ossidativi che portano alla formazione di ossigeno
singoletto e di altre specie di ossigeno reattivo (ROS, da
reactive oxygen species). Il bersaglio principale delle ROS
è rappresentato dalle membrane cellulari e dagli organuli
citoplasmatici, in particolar modo dai mitocondri, che sono
ricchi di molecole strutturali con diversi doppi legami, quali i lipidi e gli aminoacidi. La fototerapia UVA1 si è dimostrata
essere un’opzione terapeutica efficace e ben tollerata per il
trattamento della dermatite atopica, dello sclerodermia localizzato, della mastocitosi, del lupus eritematoso sistemico, della micosi fungoide, della malatia cronica da rigetto del trapianto verso l’ospite. Essa inoltre si è dimostrata efficace
per un numero crescente di altre patologie cutanee, caratterizzate da infiltrati dermo-epidermici di linfociti normali o
neoplastici, mastociti e/o esosinofili, così come per le alterazioni metaboliche del collagene. Al momento non c’è un
accordo generale su quale sia il protocollo ottimale di trattamento. Gli UVA1 vengono somministrati a dosi fisse, senza aggiustamento progressivo del dosaggio. Tuttavia, i protocolli differiscono per quanto riguarda il dosaggio, il numero di esposizioni settimanali e il numero totale di esposizioni. La terapia UVA1 è sempre ben tollerata e sono rari gli episodi di reazione eritematosa. Gli effetti collaterali a lungo termine non sono noti, ma il rischio di carcinogenicità cutanea sembra trascurabile, dal momento che gli UVA1 non
danneggiano direttamente il DNA.
PAROLE
CHIAVE:
UVA1 - Fototerapia - ROS - Citochine - Der-
matite atopica.
References
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M
C IN
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P R
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H E
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A
Human immunodeficiency virus and dermatology a focus on special diseases and a review of the literature
H. BELTRAMINELLI, P.H. ITIN
Cutaneous disorders can be seen in any stage of the human
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), including a wide spectrum of diseases
which, owing to the rapid development of anti-HIV drugs,
have changed relevance during the history of HIV infection.
With the advent of highly active antiretroviral therapy,
many skin disorders have improved or disappeared completely, whereas others may even worsen as the patient's
immune status begins to recover, a phenomenon known as the
immune reconstitution syndrome. Disorders such as Kaposi's
sarcoma and oral hairy leukoplakia are typical but not specific for HIV infection. When recognized, HIV infection
needs to be determined serologically. Seborrhoic dermatitis
or atypic herpes simplex are commonly associated with HIV
infection but they can often be present without the infection. Dermatological manifestations such as generalized skin
rash are a presenting feature in 40% of cases of acute HIV
infection. In 10% of HIV patients, stomatologic findings are
the first clinical sign of the disease and can help to establish
a diagnosis of HIV infection. Most cutaneous disorders in the
setting of AIDS share common features: an unusual presentation with atypical localization, widespread eruption,
sudden exacerbations, resistance to treatment and often a
chronic course; some reflect the patient's underlying immune
status; manifestations of disseminated and extensive disease typically co-present with laboratory findings of lower
CD4+ cell count and/or high viral load. Some HIV-associated
systemic fungal infections (without skin correlations) and
some adverse drug reactions (with evident skin manifestations) may be life-threatening. Moreover, many drugs can
produce several adverse effects and possible interactions.
Hence, in the setting of HIV, a high index of suspicion is a
Address reprint requests to: H. Beltraminelli, MD, Universitätsspital
Basel, Dermatologie, Petersgraben 4, CH-4031 Basel.
Vol. 141 - N. 3
Dermatology Unit, University Hospital, Basel, Switzerland
vital for establishing early diagnosis and instituting prompt,
effective treatment.
KEY WORDS: Human immunodeficiency virus - Acquired immunodeficiency syndrome - Antiretroviral therapy - Marker lesionSkin.
History and epidemiology
T
he history of human immunodeficiency virus
(HIV) infection began in 1981 when an outbreak
of an unusual combination of Pneumocystis carinii
pneumonia and mucosal candidiasis was observed in
healthy young men in Los Angeles, California.1 The
HIV was later identified, and a growing number of
patients showed typical disease patterns associated
with impaired cellular immune function.
Taking a systematic approach to skin diseases in
the setting of HIV, this article focuses on diseases
associated with highly active antiretroviral therapy
(HAART), which has been widely used in western
Europe since 1996-1997.
The HIV infection pandemic was initially limited to
communities such as men who have sex with men
(MSM)-in fact, the acquired immunodeficiency syndrome (AIDS) was first called gay-related immunodeficiency (GRID), injection drug users, commercial
sex workers and the poor. Current trends indicate,
267
BELTRAMINELLI
HUMAN IMMUNODEFICIENCY VIRUS AND DERMATOLOGY-A FOCUS ON SPECIAL DISEASES AND A REVIEW£W
however, an increasing shift in the incidence of HIV to
heterosexuals. Noteworthy is that systematic screening of blood donations since 1985 virtually eliminated the risk of HIV transmission through blood transfusion.
The epidemiology of HIV and HIV-related diseases
and the social problems they cause have changed over
the course of the history of the disease. In the past,
when treatment was unavailable, HIV patients were
socially discriminated and isolated from the community. As new treatment modalities became available,
however, discrimination diminished and epidemiologic data shifted parallel with the introduction of
modern drugs. But in recent years, a new clinical situation, the so called immune restoration syndrome,
has been observed in patients with good response to
HAART, where diseases like herpes zoster or
Mycobacterium avium intracellular infections flare
up because of the patient's better immunological
response to the microorganism. HAART has led to a
marked decrease in HIV-related morbidity and mortality: the annual AIDS mortality has dropped by 75%
since 1995; opportunistic infections in general, and
serious cases in particular, are less frequent; mucocutaneous diseases have declined dramatically. Despite
this good news, new problems such as the fat redistribution syndrome have emerged, along with a rise in the
incidence of skin cancers (e.g. squamous cell carcinoma, basalioma and Bowen's disease).
With the implementation of interventions to reduce
the risk of vertical transmission of HIV in pregnant
women, the rate of vertical transmission in Europe
fell from 15.5% by 1994 to 2.6% after 1998.2
Worldwide about 40 million people (17.5 million
women, 2.3 million children) are currently living with
HIV infection; more than 25 million have died since
1981; about 4.9 million new infections occurred in
2005 alone.3 Globally, HIV is now the fourth leading
cause of death; 3.1 million people died from HIV in
2005. There is a large gap in the data between the poor
and the rich countries. While all report an increasing
number of people living with AIDS, in the former this
is because of a lack of prevention campaigns and a
result of not using a condom during sex, either of
which may be associated with particular cultural,
socioeconomic, linguistic and administrative barriers.
In the latter, HAART reduced HIV-related mortality to
levels comparable with the rates in non-HIV-infected
reference populations. So people feel healthier and
268
are more sexually active. In addition, the number of
non-HIV-infected persons at risk for the infection may
be increasing among a young generation now sexually active who did not experience the initial AIDS epidemic and are either unaware or simply ignore the risk
of HIV infection. Swiss data, like those from other
western countries, show an increase in AIDS and HIV
infections during the late 1990s, followed by a decrease
that has stabilized since 2002. More recently, however, the rate of new infections is increasing again.4 The
largest group of HIV-infected persons are those who
have heterosexual contact (about 60% in total); this
increase probably reflects the general upward trend
in infections attributed to heterosexual sexual contact
in the developed countries; regrettably the incidence of
HIV infection among MSM is still rising.5
General considerations
During the last 20 years, the spectrum of HIV-related skin manifestations has changed, subsequently
influencing dermatological differential diagnosis.6
HIV-positive patients have more skin problems (92%
of HIV cases) 7 than a similar non-HIV-infected collective. Stern 8 showed that on average HIV-positive
patients have 3.7 different dermatological diagnoses.
Dermatologic clinical findings can be markers and
sometimes detectors of hidden HIV infection. The
common features of the majority of skin diseases in
HIV-positive patients are the unusual clinical presentation, with atypical and wider localization, sometimes mimicking other dermatologic diseases,9 uncharacteristic course with treatment resistance and relapses. Because of this atypical presentation, skin biopsy
for histological analysis is recommended to verify
clinical diagnosis; when there is clinical suspicion of
infection, a microbiological study should be ordered
as well, particularly in nodular, pustular or ulcerated
clinical presentations. Knowledge of the spectrum of
these skin disorders is a challenge for daily clinical
practice.
A frequent clinical observation is that the incidence
and severity of skin disorders occurs more often as
the body's immune function deteriorates; however,
statistical data confirming this observation are limited,
and the correlation between the two is still controversial. One study showed a statistically significant correlation between a low CD4 cell count in HIV patients
with various skin disorders and a higher CD4 cell
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BELTRAMINELLI
Figure 2.—Oral hairy leukoplakia.
Figure 1.—Herpes simplex; erosive destruction of the nail.
Figure 5.—Severe, diffuse candida stomatitis.
Figure 3.—Kaposi's sarcoma; blue-brownish nodules on a leg. Figure 4.—
Hemorrhagic herpes zoster; confluent hemorrhagic blisters on erythematous skin in dermatome L1-L2.
count in asymptomatic HIV patients.10 A study from
Thailand showed that during the early stage of HIV
infection (CD4 cell count >500/µL), patients may typically have xerosis and seborrheic dermatitis, and in
advanced stages (CD4 cell count <200/µL) patients
have more opportunistic infections such as multidermatomal herpes zoster and penicillinosis (typical in
tropical countries). Interestingly, no cases of Kaposi's
sarcoma or skin tumors were identified in this study,11
perhaps because of the low prevalence of Kaposi's sar-
Vol. 141 - N. 3
coma among Asians, and the prevalence of drug eruptions was unexpectedly low.
A study from Spain 12 on a cohort of 1161 HIV-positive patients (74% were injection drug users) showed
some correlations between advanced stages of HIV
disease with lower CD4 cell count and certain dermatoses associated with an increased risk of developing AIDS and increased mortality. Oral candidiasis
and seborrheic dermatitis were the most common disorders, followed by xerosis, drug eruptions, dermatophytosis, papular eruption of AIDS; others included
genital herpes, herpes simplex (Figure 1), oral hairy
leukoplakia (OHL) (Figure 2), molluscum contagiosum, verruca vulgaris, onychomycosis, folliculitis in
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BELTRAMINELLI
candidiasis, staphylococcal folliculitis, abscesses,
Kaposi's sarcoma (Figure 3), idiopathic pruritus, diffuse alopecia, psoriasis, skin hyperpigmentation,
mucosal hyperpigmantation. Although herpes zoster
(Figure 4) did not appear to be associated with impaired
immunity, it could, however, be considered a marker
of poor prognosis as it was associated with higher
mortality. Most of these results were in line with those
of other studies from the 1990s.
Jordan et al.13 showed that in adults, and particularly
in children, HIV-specific CD8 cells lack perforin, an
important CD8 cell component which, when lost, may
be associated with progressive HIV disease, suggesting
that a lack of effector cell properties in HIV-specific CD8
cells contributes to a lack of immune control in HIV.
Increased serum IgE levels and eosinophilia have
been almost exclusively described in HIV patients
with low CD4 cell count. Paganelli et al.14 showed that
CD8 cells functionally mimic Th-2 type CD4 cells and
may account for hyper-IgE and eosinophilia in the
absence of CD4 cells.
Data from a prospective Swiss cohort study from
1996 15 on 357 HIV patients showed tinea (43.7% of
patients) as the most frequent dermatological problem, followed by xeroderma (37.8%), seborrhoic dermatitis (32.5%), candida stomatitis (Figure 5), verruca vulgaris, folliculitis, herpes simplex, condyloma
acuminatum and molluscum contagiosum. These data
are similar to those from other cohort studies of German-speaking Europe.16 It is well known that xerosis, OHL, molluscum contagiosum, oral candidiasis and
Kaposi's sarcoma are cutaneous markers of HIV disease with an important immunodeficiency.17
Before and after highly active antiretroviral
therapy
During the 1990s, a series of new antiviral drugs
and combinations of various active compounds profoundly changed the approach to treating HIV patients.
After treatment failure or resistance, the therapeutic regimen was usually replaced with new medications and/or
new combinations. After zidovudine monotherapy of
the early 1990s, combination therapy with other reverse
transcriptase inhibitors became available; after 1995
HIV-1 protease inhibitors with potent anti-HIV activity became widely available and were added to these
combinations. There are 4 different classes of antiretroviral drugs: nucleoside reverse transcriptase
270
inhibitors (NRTI), non-nucleoside reverse transcriptase
inhibitors (NNRTI), protease inhibitors (PI) and fusion
inhibitors (FI). Modern HAART is a combination of at
least 3 drugs, typically including either a PI, or a nonnucleoside analogue reverse transcriptase inhibitor,
and 2 nucleoside analogue reverse transcriptase
inhibitors. The goal of this treatment is to achieve
maximum viral suppression for as long as possible,
while minimizing side effects and preventing the development of drug resistance. With the introduction of
HAART, the prevalence of several HIV-associated
opportunistic infections and malignancies changed
remarkably, including regression of oral candidiasis,
Kaposi's sarcoma and OHL,18 except for mycobacterial diseases,19 oral condylomata and herpes simplex
virus infection, this last of which seems to persist. The
morbidity and mortality of AIDS patients declined
dramatically. Sterne et al.4 showed that HAART, compared with no treatment, was more beneficial with
longer duration of treatment, but was less effective in
patients whose presumed mode of transmission was
injection drug use. The reason for the clinical improvement was probably the result of partial immune reconstitution with improved cellular immune system, as
demonstrated by the more persistent, higher CD4 cell
count as compared with previous antiviral monotherapy. The decreasing incidence of opportunistic infections may also have been be due to advances in prophylactic treatments. The prevalence of most noninfectious skin diseases did not change after the introduction of HAART.20
Prins et al.21 showed that in the developed countries there is little evidence for sex differences in the rate
of disease progression before and during the HAART
era. Notably, with the availability of effective treatment, HIV-infected women of reproductive age have
increasingly decided to have children.
Seoane Reula et al.22 observed a significant decrease
in the prevalence of mucocutaneous manifestations
during HAART treatment in HIV-infected children
(follow-up every 3 months over 22 years); some children had no treatment at the beginning of the study, others received antiviral monotherapy followed by combined therapy, and then by HAART. During HAART
an increase in the CD4 cell count was observed, while
during monotherapy or combination therapy there was
no decrease in cell count and even a small increase in
mucocutaneous manifestations.
Maurer et al.23 studied the effect of HAART on
HIV-infected women in the U.S.; studies on women
Giugno 2006
TABLE I.—Epidemiology of the most frequent skin diseases before
and after highly active antiretroviral therapy (HAART). Results of
the Swiss cohort study.
Candida stomatitis
Oral hairy leukoplakia
Seborrheic dermatitis
Folliculitis
Reactive syphilis serology
Before HAART (%)
After HAART (%)
41.7
34.2
32.5
21.8
18.5
12
4.3
13.0
10.9
10.9
with HIV infection are important because their proportion of the population living with HIV infection is
rising (17.5 million women worldwide of a total of
40.4 million people);3 the women receiving HAART
had less eczema, folliculitis, tinea pedis and xerosis
than those who did not receive HAART, independently
of CD4 cell count.
The incidence of Kaposi's sarcoma dropped precipitously after the introduction of HAART.24 HAART
may prevent the risk of developing non-Hodgkin's
lymphoma 25 but not that of Hodgkin's lymphoma or
other nonacquired immunodeficiency syndrome-defining cancers. HIV patients are at high risk for human
papilloma virus (HPV) related cancers (i.e., cervical
and anal cancers) and they are not clearly affected by
CD4 cell count or HAART; nonmelanomatous skin
cancer, which is also associated with cutaneous HPV
types, was found to be three-fold higher in a Swiss
HIV cohort study, but the number of HIV patients with
this tumor is still about 10-fold less than among organ
transplant recipients. Other data on the impact of
HAART on the natural history and outcome of HIVassociated malignancies are limited.
In our previous study 26 we found that the prevalence of seborrheic dermatitis is influenced neither by
initial CD4 cell count nor by antiretroviral treatment.
Epidemiological data from a Swiss cohort study of
the most frequent skin diseases before and after
HAART are shown in Table I.27
Interestingly, herpes zoster appeared more frequently
after HAART; this rise was attributed to the immune
reconstitution phase. Another interesting observation
is that eosinophilic folliculitis appeared not only in
patients with low CD4 cell count but also in those who
had successfully completed HAART. This dermatosis
is another new addition to the immune reconstitution
syndrome. Other diseases that show a flare-up after
starting HAART are infections from herpes viruses,
cytomegalovirus, mycobacteria, cryptococci, inflamed
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BELTRAMINELLI
cutaneous warts, molluscum contagiosum demodex folliculitis and inflammatory diseases such as sarcoidosis,
eosinophilic folliculitis, atopic dermatitis and tattoo
intolerance. The immune reconstitution syndrome is
a transitory worsening of disease that appears generally
3 to 6 months after HAART has been started.
Although the overall survival of HIV patients since
the introduction of HAART has improved, mortality
remains higher among HIV-positive patients than in the
general Swiss population.28
Caution is warranted when interpreting these data
because the long-term effect of HAART is still unclear.
In most studies that have reported successful treatment, follow-up was limited to 1 year or less, and most
trials focused on increased CD4 cell count and viral
response to treatment. But these outcome measures
are not the only ones that correlate with AIDS improvement or death, since other elements such as improved
medical care, early detection of HIV patients and the
increasing use of prophylactic drugs may also play a
critical role. For ethical reasons, placebo-controlled
studies versus HAART are not possible.
Antiretroviral drugs and cutaneous side effects
HIV patients have a higher incidence of drug reactions than those unaffected by HIV. The reasons for this
difference are many: first, HIV patients take many different drugs daily (antiretrovirals, antibiotics, antimycotics, and other medications) over years, so they are
concurrently exposed to several substances with various potential interactions; second, it is known that
viral infection in general, and HIV in particular, predisposes to skin reactions; third, drug reactions are
more common in the setting of immunosupression.29
In addition, HIV-infected patients have more CD8 cells
in their otherwise normal skin compared with controls. There are short- and long-term side effects, the
risk varies from drug to drug, from drug-class to drugclass, from interactions among different drugs and
from patient to patient. Certain antiretroviral agents are
associated with specific cutaneous manifestations. The
most common NRTI-induced dermatological side
effects are hypersensitivity (with multisystem involvement) to abacavir and hyperpigmentation (reversible
and relatively dose-dependent) from zidovudine. Cutaneous problems account for a significant portion of
NNRTI-related adverse events, including mild rash or
severe exanthema (Stevens-Johnson syndrome, [SJS])
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BELTRAMINELLI
from nevirapine, pruritic rash from delavirdine; major
side effects caused by PI are retinoid-like effects (recurrent paronychia, pyogenic granulomas, curly hair,
alopecia), lipodystrophy from indinavir, and mild skin
rash from amprenavir. The most common cutaneous
side effect of the newest class of antiretrovirals (FI) is
injection site reactions (98% of patients!). These and
other less frequent HAART side effects have been
described in detail by Kong and Myers.30
A major adverse effect of HAART is the lipodystrophy syndrome, which includes loss of peripheral
fat (lipoatrophy) in the face, limbs and buttocks,
and/or central obesity; other characteristic features are
dorsocervical obesity (buffalo hump), lipomas and
breast hypertrophy; some HAART agents such as
stavudine (d4T), and PI in general, are more likely to
induce lipodystrophy. Typically, the symptoms appear
within 6 to 12 months after the start of treatment.
The pathogenesis of lipodystrophy is poorly understood, but recent studies have shown an association
with mitochondrial-DNA depletion caused by NRTI.31
Partial reversibility of lipoatrophy was obtained after
switching from the agent zidovudine or stavudine
(d4T) to abacavir, but other features of the lipodystrophy syndrome showed no improvement from the
switch.32
Sexually transmitted infections
Preventing and treating sexually transmitted infections (STIs) reduces the risk of HIV transmission,
especially among persons with numerous sexual partners, such as sex workers and their clients. Infection
with syphilis, gonorrhea, Chlamydia, trichomoniasis
and genital herpes, which cause breaks in mucosal tissues and inflammation, increase the chance of HIV
transmission during unprotected sex. The broken mucocutaneous barrier in the lesions of these infections
plays an important role. In 2001 Auvert et al.33 demonstrated a strong association between HIV and herpes
simplex type 2. McFarland et al.34 and Del Mar et al.35
suggested that the 2 viruses favor each other, with
each boosting the odds that a person will contract and
transmit the other.
Wearing a latex condom is the most efficient way to
reduce the sexual transmission of HIV and other STIs.
Most people in general, and young persons in particular, tend to know very little about STIs, hence part of
HIV awareness campaigns should be specifically
272
addressed to young people and promoted as an example of youth-friendly services. We believe that the
ignorance about STIs in general and about HIV infection and AIDS in particular is the main reason for the
rise in the number of infected patients in the developed countries. People know that the risk of dying
from HIV infection is much less now than it was during the first years of the history of HIV. Some believe
AIDS can be definitively cured or managed and survived, while forgetting that the risk of transmission, and
hence of contracting HIV infection is lifelong. In addition, the risk of infection by heterosexual contact is
underestimated, owing to the misconception that HIV
infection is only a risk for particular communities such
as sex workers, injection drug users and MSM. Some
HIV-infected persons stop using a condom, believing
that a low viral load renders them noninfectious. A
different kind of prevention campaign showing a generally healthy looking HIV-positive patient maybe just
that kind of new message to raise awareness.
Focus on particular noninfectious HIV-related
cutaneous disorders
Early human immunodeficiency virus manifestations
and the skin
Acute or primary HIV infection (i.e. acute retroviral syndrome, HIV seroconversion syndrome, primary HIV infection) is a transient (a)symptomatic illness with a broad spectrum of clinical manifestations.
In the majority of cases a high index of suspicion is
needed to diagnose it. Most patients (40-90%) present with mononucleosis-like symptoms in the first
week of acute HIV infection, but symptoms are often
unspecific, and some patients have an asymptomatic
seroconversion. Although more than 50% of patients
with acute HIV infection are symptomatic, over 90%
go undiagnosed at the first medical visit.36 Misdiagnosed cases miss the chance to institute early treatment; furthermore, early diagnosis is important because
administration of antiretroviral treatment during acute
HIV infection has been demonstrated to improve the
subsequent clinical course of the disease and to boost
the CD4 cell count.37 HAART initiated during primary virus infection may reduce the number of longlived, latently infected lymphocytes that act as a reservoir for HIV.38 Patients with acute HIV infection seem
to have a more heterogeneous spectrum of the virus
Giugno 2006
BELTRAMINELLI
Figure 7.—Pruritic papular eruption; many single excoriations with elevated,
infiltrated erythematous borders. Figure 8.—Eosinophilic folliculitis; multiple erythematous papules and pustules, mostly associated with a follicle.
Figure 6.—Erythema of the proximal nailfold; periungual erythema of
the toe with telangiectasia.
than those with chronic infection, thus potentially
improving their response to HAART. Early recognition
of HIV infection is important for preventing the spread
of the disease, since primary infected patients have
high titers of HIV virus in the blood 39 and genital
secretions, and are also particularly contagious. Many
new HIV infections occur during this early phase from
contact with persons with high viral load. The signs and
symptoms of acute HIV infection usually present within days to weeks after initial exposure and last about
2 weeks. The commonest nondermatological signs are
fever, fatigue, headache, lymphadenopathy, pharyngitis, myalgia, arthralgia, weight loss, gastrointestinal troubles and night sweats.40 Interestingly, 87% of
HIV-infected persons remember symptoms which
could be associated with an acute retroviral syndrome.41
Erythema of the proximal nailfold
In a previous study, we analyzed skin diseases associated with HIV infection in addition to those discussed above; 2.4% of the patients showed asymptomatic marked periungual redness,42 2 of which had
dilated capillaries. Periungual erythema (Figure 6) is
an unspecific finding which may be found in systemic
lupus erythematosus, dermatomyositis and scleroderma; it can be a very early manifestation of diabetes
mellitus, other rare associations such as the sequelae
of cytotoxic therapy, atopy or of working on coffee
plantations. Periungual erythema has been reported
repeatedly in several conditions with severe immun-
Vol. 141 - N. 3
odeficiency such as graft-versus-host disease, Langerhans' cells histiocytosis and Wiskott-Aldrich syndrome.
In 1989 we reported the first patient with HIV infection, periungual lichenoid papules and marked erythema.43 The pathogenesis of periungual erythema is
unknown. Ruiz-Avila et al.44 suggested that angiogenetic factors produced by HIV, which are implicated in the pathogenesis of Kaposi's sarcoma and bacillary angiomatosis, may be responsible for the telangiectasias seen in HIV patients; these factors included
the Tat protein, interleukin-6 and oncostatin M.
Pruritic papular eruption
The pathogenesis of pruritic papular eruption (PPE),
despite 2 decades of reports, is still unclear. Clinical
manifestations are a severe pruritus associated with
firm, discrete, erythematous urticarial papules localized
on the extremities, the face and sometimes the trunk;
the excoriated papules heal with scarring hyperpigmentation (Figure 7). Histopathologic findings show
a mild to moderate dermal perivascular and periadnexal lymphomononuclear infiltrate with eosinophils
and mast cells (which could justify the intense pruritus), immunohistochemical characterization of T-cell
subpopulations show a clear predominance of CD8
cells 45 compared with healthy skin; the predominance
of CD8 cells in PPE lesions does not simply represent
a reflux of peripheral blood, as the number of CD8
lymphocytes in the lesions is higher than in healthy
skin. Pathophysiologically, PPE has been linked to
insect bite reactions 46 as a hyperallergic response
against mosquito saliva 47 or against another antigen.
The incidence of the disease increases as the CD4 cell
count decreases, so PPE can be regarded as a cuta-
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BELTRAMINELLI
neous marker of advanced HIV infection,48 nevertheless, there are cases of PPE as an initial manifestation
of HIV. In Brazil for example, PPE has been found in
11.7% of patients with HIV infection and is considered
there as a marker of HIV infection.49 Most patients
have been described in Haiti, Brazil, Thailand and
Africa, but rarely reported in Europe and North America. The differential diagnosis of this disease includes
staphylococcal folliculitis, eosinophilic folliculitis,
demodex folliculitis, drug eruptions, arthropod bite
reactions, photodermatitis, crusted scabies and secondary syphilis. Because of the evident scarred excoriations similar to prurigo, HIV patients with PPE suffer additional stigmatization. The persistent pruritus is
usually refractory to topical steroids and oral antihistamines.
Eosinophilic folliculitis
Eosinophilic folliculitis (EF) develops in the setting of abnormal host immunity, mostly in individuals
with end-stage HIV infection with low CD4 cell count,
and it is a marker for individuals with a high risk of
developing opportunistic infections.
Unlike some authors who believe that EF and PPE
are the same entities, we think they constitute 2 different diseases because of clinical and pathological
differences and by a different course during HIV infection,.
EF is a disease of the immune reconstitution syndrome and shows flare-ups after HAART is begun.50
Paradoxically, it has even been thought to improve
with HAART.51
The clinical manifestation of EF is a pruritic papulopustular eruption involving the trunk, limbs and face
(Figure 8). The bulk of documented cases are MSM.
Often there is a peripheral blood eosinophilia.52
The pathophysiological mechanism underlying EF
is unknown. The suggested cause is a hypersensitivity reaction against Demodex folliculorum and Pityrosporum or against some constituent of sebum acting
as an autoantigen. This last hypothesis is supported
by histological evidence for a lytic degeneration of
the sebaceous glands.53 Other histological findings
are follicular inflammation with lymphocytes,
eosinophils and neutrophils. Immunohistology shows
a T-cell lymphocytic infiltrate with marked CD8 cell
predominance.
EF should be differentiated from other types of folliculitis, Ofuji's disease and PPE.
274
Treatment of EF is frustrating; some patients improve
with topical steroids, antihistamines, antimycotics,
retinoids and UV-therapy. Currently there is no gold
standard. Recent studies have reported a positive effect
of topical tacrolimus.54 In our experience, administration of systemic retinoids is the most efficient therapy.
Oral lesions and human immunodeficiency virus
Oral lesions are readily visible; oral inspection is a
simple and a highly important step in assessing dermatological status. When HIV status is unknown and
HIV testing is difficult, as in developing countries,
certain oral lesions provide a strong indication of the
possible presence of HIV infection;55 they can also be
considered early clinical features. OHL and oral/pharyngeal candidiasis are indicators of a depleted immune
system and signs of progression to AIDS,56 for this
reason they are included in the CDC classification criteria. Oral candidiasis, Kaposi's sarcoma and lymphoma were among the earliest described lesions of
AIDS seen in homosexual and bisexual men.
Most HIV-related oral lesions correlate chiefly with
HIV viral load, independently of CD4 cell count;57, 58
nevertheless, studies have shown an evident association of oral candidiasis and OHL with low CD4 cell
count.59 Many have confirmed that oral lesions are
remarkably reduced under the effect of HAART, probably as a result of an expression of a reconstituted
immune system;60 a reduction in opportunistic infections was also demonstrated.61
Many oral diseases are similar in clinical appearance, making the right diagnosis difficult. With an
atypical presentation, as in HIV patients, the differential diagnosis 62 includes pseudo-OHL, chronic
hyperplastic candidiasis, herpes simplex, lichen planus,
graft-versus-host reaction, idiopathic leukoplakia,
white sponge nevus, leukokeratosis nicotinica, geographic tongue, marked edema and trauma. The diagnostic steps are microscopic study for mycosis, viral
scraping for microbiological determination or punch
biopsy. We recommend serological HIV test for lesions
suggestive of HIV infection.
Future
There is new evidence that the prevention programs
initiated in many countries are finally helping to bring
Giugno 2006
down the HIV prevalence in Kenya and Zimbawe, as
well as in urban Haiti. Another success story that
should serve as an example that prevention campaigns
can make a significant difference is that of Thailand,
where the incidence of HIV infections has dropped
dramatically. Most efforts need to be done in subSaharan Africa, the area hardest hit by HIV infection,
followed by the Caribbean. In addition to these areas,
a growing epidemic with another kind of patients is on
the march in Eastern Europe and Central and East
Asia.
In the past 2 years, worldwide access to the expensive antiretroviral treatment has improved markedly.
Despite the progress witnessed in some regions, however, the situation has changed slowest in the poorest
countries of Latin America and the Caribbean, vast
parts of Asia and virtually all of sub-Saharan Africa.3
Indications are that some treatment gaps will narrow
further, but not as quickly as to contain the emergency
of the epidemic. Universal change of current conditions
will require the coordination of many different
approaches to treatment, prevention and care, all of
which needs to be done urgently. But this is part of a
larger long-term challenge that will require overcoming such serious problems as stigma, discrimination,
gender inequalities and other human rights violations,
together with the social injustices caused by AIDS.
These are extraordinary challenges that demand extraordinary responses and, very importantly, long term
vision.
A special direction in future prevention campaigns
in western Europe will be to target HIV information to
different groups at risk for HIV infection such as immigrants from countries with a high prevalence of
HIV/AIDS (notably sub-Saharan Africa), young people, persons with multiple sex partners, and other
groups (e.g. MSM and bisexual men) that have shown
a recent rise in the incidence of new infections.
Riassunto
Virus dell'immunodeficienza umana e dermatologia - patologie particolari - una revisione della letteratura scientifica
Le manifestazioni cutanee osservate in qualsiasi stadio
della sindrome da virus dell'immunodeficienza umana/immunodeficienza acquisita (HIV/AIDS) comprendono un ampio
spettro di patologie che hanno visto cambiare la loro importanza nel decorso dell'infezione da HIV, principalmente grazie al rapido sviluppo dei farmaci antiretrovirali. Con l'av-
Vol. 141 - N. 3
BELTRAMINELLI
vento della terapia antiretrovirale altamente efficace molte
manifestazioni cutanee sono migliorate o completamente
scomparse e altre possono persino peggiorare quando si ha
la ripresa dell'immunità dell'ospite, un fenomeno conosciuto come sindrome da ricostituzione immunitaria.
Alcune manifestazioni quali il sarcoma di Kaposi e la leucoplachia orale villosa sono tipiche (ma non specifiche) dell'infezione da HIV, tanto che, in loro presenza, è consigliabile eseguire il test sierologico per la ricerca di anticorpi
anti-HIV. Anche altre manifestazioni cutanee, quali la dermatite seborroica o l'herpes simplex possono comunemente associarsi all'infezione da HIV, ma spesso compaiono in
assenza di questa infezione; alcune manifestazioni dermatologiche, quali l'esantema cutaneo generalizzato, sono presenti nel 40% dei casi di infezione acuta da HIV. Nel 10% dei
pazienti HIV-positivi le lesioni del cavo orale rappresentano
il primo segno clinico di malattia e consentono di porre diagnosi di infezione da HIV. La maggior parte delle manifestazioni cutanee in corso di AIDS hanno una presentazione
insolita, con localizzazioni atipiche, eruzioni disseminate, esacerbazioni improvvise, resistenza al trattamento e spesso
hanno in comune un decorso cronico; alcune di queste riflettono lo status immunitario sottostante del paziente, le manifestazioni disseminate compaiono solitamente con conte
cellulari CD4+ molto basse e/o con alte cariche virali. Alcune infezioni fungine sistemiche HIV-associate (senza interessamento cutaneo) e alcuni effetti collaterali dei farmaci
(con presenza di manifestazioni cutanee) possono essere
pericolose per la vita, ed è necessario che il medico ne tenga conto per poterle diagnosticare precocemente e per poterle trattare efficacemente. Non bisogna dimenticare che il
trattamento dell'infezione da HIV prevede molti farmaci,
con diversi effetti collaterali e una miriade di possibili interazioni tra di loro.
PAROLE CHIAVE: Virus dell'immunodeficienza acquisita Terapia antiretorvirale - Marker di lesione - Cute.
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29. Coopman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and
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30. Kong HH, Myers SA. Cutaneous effects of highly active antiretroviral therapy in HIV-infected patients. Dermatol Ther 2005;18:58-66.
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35. del Mar Pujades Rodriguez M, Obasi A, Mosha F, Todd J, Brown D,
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36. Flanigan T, Tashima KT. Diagnosis of acute HIV infection: it's time
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37. Kinloch-De Loes S, Hirschel BJ, Hoen B, Cooper DA, Tindall B,
Carr A et al. A controlled trial of zidovudine in primary human immunodeficiency virus infection. N Engl J Med 1995;333:408-13.
38. Lori F, Jessen H, Lieberman J, Finzi D, Rosenberg E, Tinelli C. Treatment of human immunodeficiency virus infection with hydroxyurea,
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infection. N Engl J Med 1998;339:33-9.
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1996;125:257-64.
42. Itin PH, Gilli L, Nuesch R, Courvoisier S, Battegay M, Rufli T et al.
Erythema of the proximal nailfold in HIV-infected patients. J Am
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papular dermatosis with nail changes in acquired immunodeficiency
syndrome: clinical, histological and immunohistochemical considerations. Dermatologica 1989;179:99-101.
44. Ruiz-Avila P, Tercedor J, Rodenas JM. Periungual erythema in HIVinfected patients. J Am Acad Dermatol 1997;37:1018-9.
45. Rosatelli JB, Soares FA, Roselino AM. Pruritic papular eruption of the
acquired immunodeficiency syndrome: predominance of CD8+ cells.
Int J Dermatol 2000;39:873-4.
46. Resneck JS Jr, Van Beek M, Furmanski L, Oyugi J, LeBoit PE, Katabira E et al. Etiology of pruritic papular eruption with HIV infection in
Uganda. JAMA 2004;292:2614-21.
47. Penneys NS, Nayar JK, Bernstein H, Knight JW. Chronic pruritic
eruption in patients with acquired immunodeficiency syndrome associated with increased antibody titers to mosquito salivary gland antigens. J Am Acad Dermatol 1989;21:421-5.
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cutaneous hypersensitivity to insect antigens in the pruritic papular
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hairy leukoplakia and oral candidiasis as predictors of HIV viral load.
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Patton LL. Sensitivity, specificity, and positive predictive value of
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Schmidt-Westhausen AM, Priepke F, Bergmann FJ, Reichart PA.
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CLINICAL CASES
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In vivo nifedipine-induced acantholysis
L. ROSSIELLO 1, E. RUOCCO 1, M. D. MIGNOGNA 2, A. BARONI 1, A. LO SCHIAVO 1
Acantholytic changes may be induced in vivo and in vitro by a
growing list of drugs. Nifedipine (a widely used antihypertensive drug acting as a calcium channel blocker) seems to have an
acantholytic effect in vitro. We report a case of a 74-year-old
man, affected with intermediate basal cell carcinoma of his
right clavicular area, in whom the histologic examination
showed suprabasal acantholytic clefts in the perilesional epidermis. The patient’s history revealed only a mild arterial
hypertension that had been treated with 10 mg nifedipine for
10 years. Long-term administration of nifedipine, the absence
of fixed intercellular antibodies by direct immunofluorescence (DIF) and circulating anti-Desmoglein-1 and anti-Desmoglein-3 (anti-Dsg 1-3) autoantibodies by ELISA, the lacking of
any blisters or erosive lesions, and the histologic findings suggest a diagnosis of in vivo nifedipine-induced acantholysis.
KEY WORDS: Acantholysis - Nifedipine - Pemphigus - Carcinoma, basal cell.
A
cantholytic changes may be induced in vivo and
in vitro by a growing list of drugs. Nifedipine is
a widely used antihypertensive drug with an acantholytic effect in vitro.1
The complex and still partially understood action
mechanism seems to be related to an inhibitory interference of the drug with enzymes involved in the keratinogenesis and calcium-dependent adhesion moleReceived May 20, 2004.
Accepted for publication April 3, 2006.
Address reprint requests to: L. Rossiello, MD, Seconda Università degli
Studi di Napoli, Via Sergio Pansini 5, 80131 Napoli, Italy.
Vol. 141 - N. 3
Second University of Naples, Naples, Italy
2Unit of Oral Medicine
Department of Odontostomatological
and Maxillofacial Sciences
Federico II University of Naples, Naples, Italy
cules like desmogleins.1-3 Furthermore, as described by
Kim et al., nifedipine may cause the outcome of
pemphigus mainly in genetically predisposed subjects.2
Case report
A 74-year-old retired man had been suffering for 3 years
from an asymptomatic irregularly roundish neoformation
located on his right clavicular region. Over the years the
lesion had ulcerated and covered with crusts, and enlarged to
reach a diameter of about 2 cm. He was referred to our department.
The patient’s clinical history did not reveal any significant
finding except a mild arterial hypertension that had been
treated with 10 mg nifedipine per day for 10 years.
Clinical examination showed a nodular ulcerated lesion
suggesting a diagnosis of basal cell carcinoma.
An excisional biopsy was performed and histologic examination displayed masses of basaloid cells, areas of squamous metaplasia with concentric keratinization (Figures 1,
2), leading to a diagnosis of intermediary basal cell carcinoma.
Unexpectedly, the histologic picture also showed areas of
suprabasal acantholysis with acantholytic cells in the perilesional epidermis (Figure 1).
279
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IN VIVO NIFEDIPINE-INDUCED ACANTHOLYSIS
Figure 1.—Suprabasal acantholysis(*) and edge of basal cell carcinoma(?) [hematoxylin-eosin, 250×].
Figure 2.—Masses of basaloid cells and areas of squamous metaplasia
with concentric keratinization (horn pearls) [hematoxylin-eosin, 250×].
Neither acantholytic genodermatoses (Hailey-Hailey disease, Darier disease) were revealed by the clinical history nor
clinical signs of pemphigus or other acquired acantholytic
diseases (Grover’s disease) were present.
Direct immunofluorescence (DIF), using fluoresceinlabelled antibodies to human IgG, IgA, IgM, and C3, of the
perilesional biopsy specimen did not display any intercellular
deposits. In addition, no anti-Desmoglein-1 and anti-Desmoglein-3 (anti-Dsg 1-3) autoantibodies were detected by immunoenzymatic assay (ELISA). HLA typing did not reveal any
pemphigus correlated antigens.
In addition we ruled out by histologic evaluation the other
benign or precancerous cutaneous lesions characterized by
localized acantholysis such as acantholytic actinic keratosis,
acantholytic seborrheic keratosis, acantholytic acanthoma
and warty dyskeratoma. Acantholytic actinic keratosis is
mainly characterized by the presence of hyperkeratosis with
parakeratosis, loss of underlying granular layer, epithelial
dysplasia and solar elastosis. These morphological features
are not identifiable in the present case.
In acantholytic seborrheic keratosis, the acantholysis is
generally focal, but the lesion elsewhere shows the characteristic morphologic picture including horny cysts, variable
proliferation of basaloid and squamous cells, acanthosis,
papillomatosis and hyperkeratosis.
Acantholytic acanthoma should be easily differentiated
from our case because this lesion displays acanthosis, papillomatosis, hyperkeratosis and dyskeratosis.
Likewise, we ruled out the warty dyskeratoma because it
is composed of widely dilated cystic lesion, often associated
to hair follicle, containing keratinous debris mixed with
grains of Darier.
A further biopsy was carried out, after the patient’ s infor-
med consent, on apparently healthy skin of his back, but
histologic examination did not show acantholysis or other
morphologic changes.
The patient’s history (nifedipine long-term administration), the absence of fixed intercellular antibodies by DIF
and circulating anti-Dsg 1-3 autoantibodies by ELISA, the
lacking of any blisters or erosive lesions, and the histologic
findings suggested a diagnosis of in vivo nifedipine-induced acantholysis in a non genetically pemphigus pronepatient.
The patient was advised to change nifedipine with an
other antihypertensive drug and to undergo periodical checkups.
280
Discussion
Acantholysis is a morphofunctional change occurring in stratified epithelia, characterized by the loss
of intercellular cohesion with subsequent disjunction
of epithelial cells.
An exhaustive explanation on the mechanisms involved in acantholysis is lacking at present. Nevertheless, several data 3-8 indicate that acantholysis can be
induced both in vivo and in vitro by 2 main mechanisms: a) immune acantholysis induced by specific
pemphigus antibodies which, binding to antigens target on keratinocyte cell membrane, cause the activation of proteinases leading to cellular dyshesion; b)
biochemical acantholysis induced by some drugs and
Giugno 2006
IN VIVO NIFEDIPINE-INDUCED ACANTHOLYSIS
chemical substances able to link with keratinocyte cell
membrane and to interfere with cell-cell adhesion
molecules thus producing a disjunction of keratinocytes.
The acantholytic potential of nifedipine has been
documented in vitro 1, 3 as well as the possibility that
it may cause the outbreak of pemphigus foliaceus.2
The process of keratinogenesis needs the presence
of certain enzymes, such as keratinocyte transglutaminase and gamma-glutamyl transpeptidase, whose
activity requires free calcium ions.9-11 These enzymes
seem to play a pivotal role in cell-cell cohesion and
aggregation of keratinocytes to form a stratified epithelium. Nifedipine, acting as a calcium channel blocker
inhibiting transmembrane calcium ion influx,1-3 may
interfere with calcium availability thus provoking biochemical acantholysis.
In the present case, factors supporting the hypothesis of biochemical acantholysis are the presence of a
HLA genotype not related to pemphigus and the absence of fixed intercellular antibodies by DIF and circulating anti-Dsg 1-3 autoantibodies by ELISA.
ROSSIELLO
Riassunto
Acantolisi indotta in vivo dalla nifedipina
L’acantolisi può essere indotta in vivo e in vitro da una crescente lista di farmaci. La nifedipina, farmaco anti-ipertensivo di largo uso, agisce bloccando i canali del calcio e sembra avere in vitro attività acantolitica.
In questo lavoro viene descritto il caso di un paziente di 74
anni, affetto da carcinoma basocellulare in regione clavicolare destra, in cui l’esame istologico rivelava la presenza di
aree acantolitiche soprabasali nell’epidermide adiacente al
tumore.
La storia clinica del paziente evidenziava soltanto una
moderata ipertensione arteriosa che era stata trattata per 10
anni con 10 mg al giorno di nifedipina.
L’immunofluorescenza diretta era negativa e nel siero non
si riscontravano con il metodo ELISA anticorpi anti-Desmogleina-1 e anti-Desmogleina 3 (anti-Dsg 1-3).
Tali dati, unitamente all’assenza di lesioni erosive o bollose e ai reperti istologici, consentivano di porre la diagnosi di acantolisi indotta in vivo da nifedipina.
PAROLE CHIAVE: Acantolisi - Nifedipina - Pemfigo - Carcinoma basocellulare.
References
Conclusions
The lacking of a genetic predisposition might explain
the presence of acantholysis only, with no clinical
signs of pemphigus.
The association of acantholysis with intermediary
basal cell carcinoma is intriguing. In fact, a similar
case was reported in the literature,12 concerning the
finding of an intermediate basal cell carcinoma adjacent to suprabasal acantholytic clefts, where acantholysis was linked with the use of another antihyperthensive drug (enalapril).
We hypothesize that, in the case presented, besides
nifedipine, additional factors might have influenced
skin susceptibility to acantholysis, such as a locally
immunodepression (locus minoris resistentiae) and
antigen subtle changes on keratinocyte cell membrane induced by the presence of the near basal cell carcinoma. In fact, our case displayed acantholytic changes only in the skin area adjacent to the basal cell carcinoma, whereas no morphological changes were
detectable in other cutaneous sites.
Further clinical observations and investigations are
needed to completely elucidate the pathogenic mechanisms of induced acantholysis.
Vol. 141 - N. 3
1. Brenner S, Ruocco V, Bialy-Golan A, Tur E, Flaminio C, Ruocco E
et al. Pemphigus and pemphigoid-like effects of nifedipine on in
vitro cultured normal human skin explants. Int J Dermatol
1999;38:36-40.
2. Kim S-C, Won JH, Ahn SK. Pemphigus foliaceus induced by nifedipine. Acta Derm Venereol (Stockh) 1993;73:210-1.
3. Ruocco V, Brenner S, Ruocco E, de Angelis F. Lombardi ML. Different patterns of in vitro acantholysis in normal human skin samples
explanted from different sites of the body. Int J Dermatol 1998;37:1822.
4. Brenner S, Bialy-Golan A, Ophir J, Ruocco V. Drug-induced pemphigus. Does a relationship exist between inducing drug and lesion topography? J Eur Acad Dermatol Venereol 1997;9:155-8.
5. Singer KH, Hashimoto K, Lazarus GS. Pathophysiology of pemphigus. Dermatol Clin 1983;1:179-86.
6. Ruocco V, Pisani M, de Angelis E, Lombardi ML. Biochemical
acantholysis provoked by thiol drugs. Arch Dermatol 1990;126:
965-6.
7. Brenner S, Golan H, Bialy-Golan A, Ruocco V. Lesion topography in
two cases of nifedipine-related pemphigus. J Eur Acad Dermatol
Venereol 1999;13:123-6.
8. Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. I. A survey.
Clin Dermatol 1993;2:501-5.
9. Ruocco V, Pinto F, D’Avino M, Baroni A, Ruocco E. L’acantolisi
biochimica in vitro. Ann Ital Dermatol Clin Sper 1996;50:155-64.
10. Esposito C, Ruocco V, Cozzolino A, Lo Schiavo A, Lombardi ML, Porta R. Are acantholysis and transglutaminase inhibition related phenomena? Dermatology 1996;193:221-5.
11. Lorand L, Conrad SM. Transglutaminases. Mol Cell Biochem
1984;58:9-35.
12. Lo Schiavo A, Guerrera V, Cozzani E, Aurilia A, Ruocco E, Pinto F.
In vivo enalapril-induced acantholysis. Dermatology 1999;198:
391-3.
281
TECHNICAL NOTES
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Mohs surgery in Italy today
P. BOGGIO 1, M. GATTONI 1, G. BORRACINA 1, P. FARINELLI 1, G. LEIGHEB 1
R. L. BOLDORINI 2, A. RAMPONI 2, G. MONGA 2
Mohs surgery is a surgical and anatomo-pathological technique that permits complete eradication of malignant skin
tumors, namely basal cell carcinomas, with an extensive local
growth and without metastatic diffusion. This is obtained
through an examination of the whole perimeter thanks to horizontal sections of the specimen after careful mapping. The
practical procedure is described and the possible variants of
Tübingen method and the delayed technique are discussed.
Indications and limits of this technique are discussed with some
clinical cases. Finally, considerations are made about the
increasing need of this technique due to spreading inappropriate nonsurgical treatments for basal cells carcinomas. Much
more clinical centers in Italy are needed in the future that can
use Mohs surgery.
KEY WORDS: Mohs surgery - Basal cell carcinoma - Tübingen
method - Delayed technique.
M
ohs surgery (MS) or microscopic controlled
surgery is a particular technique with peculiar
executive and histopathologic modalities. This method,
in fact, is the only one able to eradicate malignant skin
tumors, without metastatic diffusion (namely basal
cell carcinomas) with an extensive local growth, with
a percentage of eradication higher than with conventional surgical techniques (from 97% to 99%) and a
saving of healthy tissue otherwise not obtainable.
Received: September 9, 2004.
Accepted for publication: May 23, 2006.
Address reprint requests to: Dr. P. Boggio, Clinica Dermatologica,
Ospedale Maggiore della Carità, Corso Mazzini 18, 28100 Novara.
Vol. 141 - N. 3
Ospedale Maggiore della Carità
School of Medicine and Surgery, A. Avogadro Eastern
Piedmont University, Novara, Italy
2Unit of Pathological Anatomy and Histology
Ospedale Maggiore della Carità
School of Medicine and Surgery, A. Avogadro Eastern
Piedmont University, Novara, Italy
Discussion
At the beginning, MS, conceived by F. Mohs in
1930, provided tumoral tissue chemical fixation in
vivo followed by excision for histologic examination,
after mapping. Histologic examination was executed
with horizontal cutting plans.1, 2 Difficulties in the
management of zinc chloride’s caustic effects in some
weak anatomic sides, the pain after its application and,
in particular, the evolution of cryostatic techniques,
permitted the passage to the fresh tissue techniques,
now used.
MS, often used in the United States, expecially in private clinics, probably has not been sufficiently understood in Europe. This poor interest is due to technical,
economical and logistic reasons as much as to its high
costs. Moreover, the lack in specialised medical and
technical staffs, the inadequate organisation between
surgical and anatomo-pathological phases (that must
be simultaneous and tightly binded) and the ignorance
of best oncological treatments in dermatology lead to
283
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of Italy, in order to avoid too much expenses travels for
patients needing MS.
Execution principles and method
Figure 1.—Traditional sections: The vertical cuts “random” can not evidence points in which the neoplasia exceeds the margins of exeresis.
undervalue the potential aggressiveness of basal cell
carcinoma.3
All those behaviours lead to wrong treatments and
increasing relapsing lesions that will need MS for
complete eradication.4
Today in USA private practice, the technique is
often used mainly for small lesions and the dermatologist is the only protagonist including the histologic
examination. In Italy and in other European countries,
because of sanitary laws, histological examination
must be done only by anatomo-pathology specialists.
So, a tight collaboration between these specialists and
the dermatologists is needed.
In Italy, the only public centre practicing MS regularly is the Dermatologic Clinic of Novara. In our hospital this treatment has been used for over 15 years
with more and more frequency, increasing to a hundred
of cases every year, with a total number of more than
900 surgical treatments (regularly registered) with the
collaboration between us and the Anatomo-Pathology
Unit.
This outcome, obtained with the improvement of
procedure, technical and human resources, led to an
increasing number of patients coming from all Italian
regions due to the diffusion of information about our
activity.
The great number of patients causes a long waiting
time, so we hope that more clinics in the National
Health System will be able to perform MS in the future.
The best solution could be the establishment of more
centres, at least one in the center and one in the South
284
MS technique is based on the observation that the
tridimensional development of neoplasia is often irregular and unpredictable, if it is based only on its clinical macroscopic aspect.5, 6
In these conditions, surgical respect limits can be
excessive in some points but insufficient in others.
Neoplastic topography can not be solved by normal
diagnostic instruments used in vivo (for example cutaneous echography): microscopic dimensions of the
irregular limits of some neoplasias need, necessarily,
a histologic examination.
Complete eradication can be obtained by the observation of all the boundaries of surgical sample. This is
not guaranteed using normal histological sections
because of randomised vertical and perpendicular cuts
normally used (Figure 1).
Complete perimeter examination, obtainable by sectioning vertically all the sample, does not permit localization of neoplasia persistence in vivo.
The innovation of MS was to perform horizontal
sections of the sample maintaining orientation during
histopahologic phases permitting the correlation with
the correspondent point mapped on the surgical
wound.7, 8
Thus, each histologic point corresponds to a surgical wound point in vivo (Figures 2, 3). Practical application of this technique is characterized by different
phases.9-11
A) Mapping of the lesion in vivo: the observational examination permits to identify the clear or suspected clinical limits of the neoplasia. Then, the surgical limits should be defined by using a dermographic
pen, drawing them a few millimetres from clinical
edges (normally a 1-2 mm distance is used) (Figure 4).
This aim of this minimal distance is to save the majority of normal tissue as possible (expecially in some
esthetic regions such as face) and it can be done thanks
to histologic support. The behaviour in conventional
surgery is different because of the wider security limits requested.
After perimeter delimitation, the main axes of the
area can be drawn, with dermographic pen, usually
vertical and horizontal, obtaining 4 quadrants.
Giugno 2006
BOGGIO
Figure 3.—Comparison between the 2 possible histologic answers in the
same lesion applying the traditional method or the technique of Mohs:
“radical excision” in the first case and “...t he neoplasia reaches the depth
and a margin” in the second.
Figure 2.—Horizontal cuts in the Mohs technique from depth towards the
surface: every point in which the neoplasia exceeds the margins of exeresis is evidenced.
If the area of each quadrant is greater than 1 cm, it
would be better to perform other subdivisions following a quadrangular network.
B) Mapping on documentation support: the picture
obtained should be drawn schematically on a paper
that will be put into clinical diary as a document used
for the following procedures and for carrying the sample to the histological examination (Figure 5).
Documentation can be taken also with a camera or
polaroid for the same purpose.
It is then possible to proceed to numbering the projected pieces and draw the colour of the margins.
C) Local anesthesia by infiltration or regional (if
there are great lesions).
D) “Bowl shaped” cut along the perimeter using a
No. 5 blade lancet. Before the complete excision of
the lesion from its seat, make incisions along the
lines previously drawn by dermographic pen, being
Vol. 141 - N. 3
careful to create the marks also on the surrounding
skin, for an easy orientation in the subsequent phases (Figure 6).
E) Dressing of surgical wound is done after a careful hemostasis, waiting for histological examination.
F) The specimen, carefully oriented, is placed on
the mapped supporting paper and then cut as previously planned. Each piece is numbered (tidily arranged
on the drawn plan) and each edge is pictured by a different colour in order to obtain a perfect orientation
(Figure 7).
Special colours, freezing and histology-colouring
resistant, are used to paint specimens.
G) Specimens are then sent to the Pathology Unit on
their paper support. Here, they are inverted (bottom up)
and put in special containers and frozen. Histological
cryostatic sections, are stained with hematoxylin and
eosin. The first sections will be representative of deeper situation (also of the edges).
The first sections will mainly give a picture of the
deep situation and the precise detection of the possible persistence of tumor on the bottom of the operating rubble.
The following sections allow to observe the whole
perimeter of the lesion showing where the tumor reaches the colored margins (Figure 2).
The specimens are completely cut horizontally from
the bottom to the epidermic surface.12
285
BOGGIO
3
2
4
1
Black
5
Right nostril
6
8
7
Mohs 1 st cut
Figure 4.—Mapping in vivo of the lesion to take-off with the scheme of the
fields of division.
Figure 5.—Outline on paper with the map of the lesion and programming
of the divisions and their coloration.
H) After examination of all pieces sections, the
pathologist marks on the attached paper-map the points
in which the tumor reaches bottom or sides, and sends
back the drawing to the surgeon.
I) The drawing allows to establish in which exact
points it is necessary to widen the excision. Any new
removal is 4-5 mm wide from the margin (Figure 8).
A new map is drawn showing the correspondent
increases, the numbering of pieces (continuing from the
previous ones) and the plan of coloration of the margins of new pieces removed.
L) New pieces are carefully laid down on the prepared map sheet with the relevant numeration and then
the margins are painted (Figure 9). In order to maintain orientation and due to irregular shapes of the new
specimens, only the margin of the external cut is
marked using different colours.
M) The pathologist proceeds to new frozen sections
from the depth towards the surface and to microscopic examination.
N) The procedure is repeated till the external margins are negative for neoplasm.13
O) The most suitable dermosurgical reconstruction
is chosen (direct suture, flaps or graft).
286
Different techniques
Method of Tübingen
When the specimen is of remarkable dimensions in
extension and thickness, the conventional technique is
difficult to perform due to the very high number of
sections needed. In order to overcome such a disadvantage, a variation in the technique has been proposed by the University of Tübingen, allowing the
same precise indication on margins and depth with a
limited number of sections.14 This technique, also
named “the cake method”, has the entire piece horizontally cut only in the lower layer obtaining, therefore,
indications of the invasion in depth with the examination of the first sections. The margins are cut tangentially in a vertical way in order to have a clear view
of the possible peripheral persistence of neoplastic
expansions (Figure 10).
Giugno 2006
BOGGIO
Figure 6.—Surgical gap after removal of the lesion. The radial cutaneous
incisures are made in correspondence to the division of the removed fragments.
Figure 8.—Plan of increase in 2 fields on histologic indication.
Right
Upper right
Right
4
5
5
3
2
4
1
5
1
2
3
5
Black
4
8
7
Nostril
6
6
4
3
Black
5
8
7
6
5
Mohs 1st cut
Figure 7.—Fragments of the specimen are positioned on a paper sheet
with the map having cure to maintain the correct guideline and coloring the
margins in differentiated way.
Vol. 141 - N. 3
Mohs 2nd cut
Figure 9.—Positioning of pieces of increase on map with the coloration of
the margins.
287
BOGGIO
Figure 10.—Tübingen method. Horizontal examination of the deep margin of the piece: its mapping with coloration and cuts like in traditional
Mohs. Vertical and tangential cuts of the circular margins: their guideline
coloration and tangential histologic sections. Precise evidence, with the minimal number of sections, of the points of persistence of the neoplasia.
The “deferred” method
Another possible variation of the technique is the so
called “deferred Mohs”. This option is an expedient due
to the technical impossibility to obtain from the pathologist reports in short times or in the same day. In this
case, the technique is the same as the one of the traditional MS. Numbered and coloured pieces are normally fixed and examined in some days (but with the
typical horizontal sections of Mohs).4 The main disadvantage of this method is represented by the necessity to maintain open the surgical gap for more days
waiting for the pathologist’s response. The formation
of granulation tissue makes the reading of possible
new cuts more difficult and uncertain. Moreover,
remarkable expansions of operating times (logistics
and surgical) give to this method a second choice position.
a. sclerodermiform basal cell carcinomas often have
badly defined limits and irregular and unpredictable
radial extension;
b. nodular basal cell carcinomas can infiltrate underlying structures and muscular layers;
c. also other neoplasms with unpredictable infiltrating modality of expansion (i.e. dermatofibrosarcoma protuberans and extramammary Paget) can take
benefit from this technique. Particularly dermatofibrosarcoma, usually needing very large precautionary demolitions is better cured with this method also
thanks to histochemical help to detect any neoplastic
fragment left;15
d. delicate and esthetic sites of the face need the
maximum saving of healthy tissue (i.e. periorificial
regions, nose, eye, etc.), but also other critical rgions
can take benefit from this technique (for instance external genitalia);16
e. recurrent tumors (in great part due to previous
incomplete excisions or wrong treatments without
histopathologic examination) often show an anomalous spreading modality along the previous scars or
along anatomical plans in depth and are scarcely valuable only on clinical examination. Only MS allows
an exact ablation.
Limits of Mohs surgery
The limits of MS are represented by the impossibility to remove with reasonable certainty all the
tumor when it reaches layers of other tissues or organs
that cannot be removed, oriented and examined under
frozen sections (like in case of invasion of bones,
deep organs, nervous structures, nasal and oral cavities, eye etc.).
Another limit is represented by tumors with tendency to metastasize (i.e. squamous cell carcinoma,
melanoma, merkelomas, sarcomas etc.)
Indications for Mohs micrographic surgery
As we have seen, MS has great costs in terms of
human and economic expenses: an accurate selection
of treatable cases is, therefore, needed in public health
structures.
The choice criteria will first of all take care of the
probability for a determined tumor to overcome the
clinical limits, of particular anatomical locations where
maximum saving of tissue is needed, and of the possible recurrence of some types of tumors, for instance:
288
Conclusions
In conclusion, we hope that a greater awareness of
necessity and importance of radical excisions in dermatological oncology will spread in dermatologist’s
practice. We confirm the necessity of an important
place for MS, also with its limits, in the National Health
System and in dermosugical practice.
This occurrence will be able to reduce remarkably
Giugno 2006
BOGGIO
the morbidity and mortality still observed for basal
cell carcinomas. Meanwhile, any effort should be
made not only in oncologic prevention campaigns
but also in the sensibilization of the Sanitary Administrations to demonstrate the social benefits of this
technique of treatment in spite of its great economic engagements.
Riassunto
Chirurgia di Mohs oggi in Italia
La chirurgia di Mohs è una tecnica chirurgica in grado di
eradicare neoplasie maligne cutanee non metastatizzanti in
fase di crescita estensiva locale. I principi su cui essa si basa
sono: l’esame di tutto il perimetro dell’exeresi mediante
sezioni orizzontali del pezzo asportato e la mappatura precisa
del pezzo stesso. Vengono descritte in dettaglio le procedure adottate nell’esecuzione pratica con il supporto di alcuni
casi esemplificativi e le sue possibili varianti tecniche (metodo di Tübingen e metodica “differita”). Vengono discussi le
indicazioni e i limiti all’applicazione della chirurgia di Mohs
con considerazioni sui campi di impiego anche al di fuori delle indicazioni classiche. Si considerano, infine, i possibili
sviluppi dell’applicazione della metodica con una sempre
più ampia richiesta di utilizzo a causa della diffusione di
trattamenti non chirurgici per gli epiteliomi e, quindi, la
necessità di aumentare in Italia il numero di centri che pratichino la chirurgia di Mohs.
PAROLE CHIAVE: Chirurgia di Mohs - Carcinoma basocellulare - Metodica di Tübingen - tecnica di Mohs differita.
Vol. 141 - N. 3
References
1. Mohs FE. Chemosurgery for skin cancer. Fixed tissue and fresh tissue techniques. Arch Dermatol 1976;11:211-6.
2. Mohs FE. Chemosurgery: microscopically controlled surgery for skin
cancer. Past, present, future. J Dermatol Surg Oncol 1978;4:41-54.
3. Leigheb G. Basaliomi in “sedi critiche”. Dermochirurgia: trattamento di elezione. G Ital Chir Derm Oncol 1986;1:1-21.
4. Leigheb G. La tecnica di Mohs in dermochirurgia. Dermatologia
Oggi 1986;1:31-4.
5. Tulli A. La chirurgia di Mohs. In: Leigheb G, Tulli A editors. Manuale
di Dermochirurgia. Milano: Cilag SpA; 1990. p. 325-8.
6. Mikhail GR. Mohs Micrographic Surgery. Philadelphia: Saunders;
1991.
7. Lawrence CM. Mohs’ micrographic surgery for basal cell carcinoma.
Clin Exp Dermatol 1999;24:130-3.
8. Drake LA, Dinehart SM, Goltz RW, Graham GF, Hordinsky MK,
Lewis CW et al. Guidelines of care for Mohs micrographic surgery.
J Am Acad Dermatol 1995;33 (2 Pt 1):271-8.
9. Roenigk SJ, Roenigk HH. Dermatologic surgery: principles and practice. New York: Marcel Dekker; 1989.
10. Tromovitch TA, Stegman SJ. Microscopically controlled excision of
skin tumors: chemosurgery (Mohs): fresh tissue technique. Arch Dermatol 1974;110:231-2.
11. Robins P. Chemosurgery: my 15 years of experience. J Dermatol Surg
Oncol 1981;7:779-89.
12. Breuninger H. Histologic control of excised tissue edges in the operative treatment of basal cell carcinomas. J Dermatol Surg Oncol
1984;10:724-8.
13. Picoto AM, Picoto A. Technical procedures for Mohs fresh-tissue
surgery. J Dermatol Surg Oncol 1986;12:134-8.
14. Kopke LF, Konz B. [Micrographic surgery. A current methodological
assessment] Hauthartz 1995;46:607-14. German.
15. Hobbs ER, Wheeland RG, Bailin PL, Ratz JL, Yetman RJ, Zins JE.
Treatment of dermatofibrosarcoma protuberans with Mohs micrographic surgery. Ann Surg 1988;207:102-7.
16. Mikhail GR, Farah RN. Surgery of the skin of the male genitalia. In:
Epstein E, Epstein E Jr editors. Skin Surgery. 5th ed. vol 2. Springfield,
IL: Charles C. Thomas; 1982. P. 518-33.
289
LETTERS TO THE EDITOR
TABLE I.—Modification of hematochemical tests during follow-up.
M
C IN
O E
P R
Y V
R A
IG M
H E
T ® DI
C
A
Regression induced by highly active
antiretroviral therapy
of a psoriasiform dermatitis
revealing HIV-infection
A. VIRGILI, E. ALTIERI,
M. M. LAURIOLA, M. CORAZZA
Section of Dermatology, Department of Clinical
and Experimental Medicine,
University of Ferrara, Ferrara, Italy.
Dear Sir,
A
54 year-old man presented a non-itchy dermatitis characterized by erythematous scaly papules and plaques
on the limbs (Figure 1). The dermatitis, starting since 3
months, was unresponsive to topical steroids.
During the previous year, the patient was admitted to the
Hematology Center for acute thrombocytopenia (11 000
The paper has already been presented at the 1° Congresso Regionale Dermatologi Emiliano-Romagnoli. Bologna, March 20, 2004.
CD4+ (mm3)
CD4/CD8
Viremia (mL)*
PLT (mm3)
Before
HAART
After 1 month
of therapy
After 3
months
32
0.04
>100 000
< 76 000
85
66
0,08
<50
171 000
1 880
77 000
*) HIV-RNA/mL copies.
TABLE II.—Histopathology of HIV-associated psoriasis.
Classic form
Psoriasisform dermatitis
— Parakeratosis
— Focal parakeratosis
— Regular acanthosis
— Irregular acanthosis
— Neutrophils within the horny
layer (Munro microabscesses)
and the Malpighian layer (spongiform pustules of Kogoj)
— Fewer Munro microabscesses
— Absence of the granular layer
(agranulosis)
— Slight spongiosis
— Elongation of dermal papillae
— Mild papillomatosis
— Perivascular infiltrate (lymphocytes, histiocytes, neutrophils)
in the upper dermis
— Perivascular and diffuse lymphocytic infiltrate with occasional macrophages and multinucleated giant cells
Figure 1.—Psoriasiform dermatitis of the thigh in HIV-positive patient. Figure 2.—Skin biopsy showing focal parakeratosis and acanthosis, perivascular infiltrate of lymphocytes, neutrophils and plasma cells in the upper dermis. HE-20×.
Vol. 141 - N. 3
291
PLT/mm3). Since Werlhof disease (acute autoimmune thrombocytopenia) had been diagnosed, the patient had been assuming systemic steroids (prednisone at an initial dose of 75
mg/die for 2 weeks, then reduced to 12 mg/die) for 1 year.
A slight asthenia and weight loss were reported; on examination, only a moderate enlargement of superficial inguinal nodes was appreciated.
Routine haematochemical tests showed: PLT 76 000/mm3,
total leucocytes 6 100/mm3 with 16.6% of lymphocytes.
Coagulation, liver and kidney tests, glycemia, ESR were
normal and a syphilis test was negative. Beta-2-microglobulin
was increased (4.1 mg/L; n.v. 1.42-3.21) and both the blood
copper and ferritinemia showed a slight increase; seric LDH
was normal. Lymphocyte typing showed a decrease of the
CD4+ count that was 32/mm3 and 3.2% (n.v. 500-1300/mm3;
32-52%), CD8+ count 770/mm3 and 77% (n.v. 220-900/mm3;
20-40%) and CD4/CD8 ratio 0.04 (n.v. 0.8-2).
On the basis of these values an HIV test was performed;
both enzyme-linked immunosorbent assay (ELISA) and
Western Blot (HIV1-2 positive; p18, p24, p31, gp41, p55,
p66, gp120, gp160: positive) confirmed the seropositivity.
According to the classification revised by the CDC (Centers for Disease Control in 1993, the patient was considered
HIV+, symptomatic, class B3.
A cutaneous biopsy revealed a psoriasiform dermatitis
showing a focal parakeratosis and acanthosis, a perivascular
and periadnexial T-lymphocytic infiltrate in the upper dermis
with occasional exocytosis (Figure 2).
The patient was treated with a combined therapy (Highly
Active Antiretroviral Therapy, HAART) of 2 nucleoside
reverse transcriptase inhibitors (zidovudine and lamivudine) plus 2 protease inhibitors (lopinavir and ritonavir) and trimethoprim-sulfametoxazole for the prophylaxis of the respiratory apparatus infections when CD4+ count <200/mm3.
The systemic steroid for thrombocytopenia was suspended and after a few weeks of the antiretroviral therapy
(HAART), the laboratory parameters greatly improved (Table
I).
We observed a drastic clinical improvement and, 3 months
after the beginning the HAART, the remission of the cutaneous disease.
In our case, the absence of a personal history of psoriasis,
the patient’s age at the appearance of the dermatosis, its
eruptive character, the clinical pattern and the drastic improvement after only a few weeks from beginning the antiretroviral therapy, all pointed to a HIV-related psoriasiform
dermatitis.
A similar dermatological pattern can be included among
the papulosquamous eruptions, common cutaneous manifestations of HIV infection.1 In the seropositives subjects, the
prevalence of psoriasis vulgaris does not seem to increase, but
during infection, psoriasis is often more severe, unresponsive
to treatment and with a higher prevalence of psoriatic arthritis.2, 3
All the clinical forms of psoriasis are possible in HIVpositive subjects and several disease patterns may coexist
in the same patient.1, 2
292
Two histopathological patterns of HIV-associated psoriasis are recognized: the classic form and a so called psoriasiform dermatitis (Table II). Some authors 1 underline that
lymphocytoclasis, dermal cellular infiltrate, mainly CD8+
lymphocytes and macrophages, relative decrease of T
lymphocytes and increase of plasma cells within the inflammatory infiltrate have been considered peculiar histological
aspects of HIV-related psoriasis.
HIV infection induces CD4+ T-cell depletion, nevertheless
in cutaneous inflammatory infiltrates of psoriasis reactive
B cells, namely plasma cells, are increased.1, 4 In fact, in
patients with acquired immunodeficiency there is a polyclonal B cell expansion and an expression of plasma cells in
peripheral tissues with unknown functional significance.4
Therefore, the presence of numerous plasma cells within the
biopsy of a psoriatic lesion may indicate an underlying HIV
infection.1, 4
In our case, the histological features and the presence of
plasma cells in the dermal infiltrate were suggestive of psoriasiform dermatitis.
In the therapy of HIV-related papulosquamous disorders,
topical drugs (steroids, tars and dithranol) are unsatisfactory and systemic treatments are debated (UVB, PUVA) or
even dangerous (immunosuppressive drugs).1, 5
However, zidovudine (AZT) is effective in the treatment
of HIV-associated psoriasis.1, 2, 5 In addition to inhibition of
the HIV reverse transcriptase, AZT also interferes with DNA
synthesis repressing keratinocyte proliferation. This antipsoriatic effect is dose-dependent, long-lasting, though longterm relapses may occur.1, 5
In our case, thrombocytopenia was correlated with HIV
infection and underwent an evident improvement after the
beginning of HAART. Thrombocytopenia can be seen in
60% of the HIV-positive patients. Its pathogenesis is debated: in addition to an autoimmune hypothesis, a direct viral
action can be supposed on the megakaryocytopoiesis.6
Thrombocytopenia, often unrecognized, should be considered a clue to suspect HIV infection, especially when associated with other signs.
In conclusion, recognition of an associated skin disease
may lead to early HIV diagnosis, thereby reducing the risk
of transmission, initiating appropriate antiviral therapy and
prolonging the disease-free interval prior to the development of AIDS.
References
1. Montazeri A, Kanitakis J, Bazex J. Psoriasis and HIV infection. Int J
Dermatol 1996;35:475-479.
2. Garman ME, Tyring SK. The cutaneous manifestations of HIV infection. Dermatol Clin 2002;20:193-208.
3. Namazi MR. Paradoxical exacerbation of psoriasis in AIDS: proposed explanations including the potential roles of substance P and
gram-negative bacteria. Autoimmunity 2004;37:67-71.
4. Horn TD, Herzberg GZ, Hood AF. Characterization of the dermal
infiltrate in human immunodeficiency virus-infected patients with
psoriasis. Arch Dermatol 1990;125:1462-1465.
Giugno 2006
5. Duvic M, Crane MM, Conant M, Mahoney SE, Reveille JD, Lehrman
SN. Zidovudine improves psoriasis in human immunodeficiency viruspositive males. Arch Dermatol 1994;130:447-451.
6. Castoldi GL. Malattie del sangue e degli organi ematopoietici. Milano: McGraw-Hill; 2001. p. 444-454 and 612.
Address reprint requests to: Dr. A. Virgili, Dipartimento di Medicina Clinica e Sperimentale, Sezione di Dermatologia, Università di Ferrara, Via
Savonarola 9, 4100 Ferrara. E-mail: [email protected]
Figure 1.—Patient P.R. Ulcerative and vegetant lesions in the perianal
area.
Chronic hypertrophic perianal herpes
in HIV-infected individuals
A. DI CARLO 1, L. M. MUSCARDIN 2, M. GIULIANI 1,
A. MAINI 1, G. PALAMARA 1, L. MANENTE 3
1Infective Dermatology Unit
S. Gallicano Dermatological Institute, IRCCS, Rome, Italy
2Cutaneous Histopathology Unit
S. Gallicano Dermatological Institute, IRCCS, Rome, Italy
3Anatomical Pathology Unit
S. Filippo Neri Hospital, Rome, Italy
Dear Editor,
G
enital herpes is particularly frequent in HIV-1 infected
individuals, showing rather an ulcerative than vescicular or erosive aspect.1 Less frequently, it can assume a combined aspect, both ulcerative and vegetant.2 During these
last years, we have seen 4 HIV-infected individuals presenting under this last appearance (Figure 1). They were all men
who had sex with men (MSM) and were naïve for high active antiretroviral therapy (HAART), in spite of a long time
from HIV-1 disease diagnosis. In all the subjects the lesions
were localized in the perianal region. Immunological data
showed a lymphocyte CD4+ count that ranged from the
lowest values of 54/mm3 of a subject, to the highest ones of
384/mm3 of another, while the HIV-RNA viral load varied
from 27 900 copies/mL to 94 700 copies/mm3 (Table I). To
exclude condylomata lata, external genital warts, mycobacteriosis, chancroid, herpetic lesions or neoplasms, we performed a panel of examinations and a biopsy.3 In the first group,
only the Tzanck test resulted positive in all the patients.4
The histological examination revealed in all cases an ulcerated
Vol. 140 - N. 3
Figure 2.—Patient P.R. A partially eroded epidermis, with a dense plasmacellular infiltrate in the dermis (EE 100×).
lesion with a chronic telangiectatic tissue of granulation and
a large number of plasma cells and eosinophils; at the borders
of the ulcer, multinucleated keratinocytes were observed
with greyish nuclei and a marginated chromatin, within a
hyperplastic epidermis (Figure 2). In 2 subjects, the lesions
showed a marked pseudoepitheliomatous hyperplasia of the
epidermis. Finally, a dense infiltrate mainly plasmacellular
was often seen throughout the dermis. The immunohistochemical examination revealed polyclonality for the k and λ
293
TABLE I.—Clinical, immunological and virological parameters of the patients with perianal genital herpes at the time of the first observation.
Patient
Sex
Age
Risk
No. of
lesions
Duration
of symptoms
(months)
CD4/mm3
HIV-1 RNA
c/mL
HAART
P. R.
G. A.
Z. M.
M. M.
M
M
M
M
60
35
35
32
MSM
MSM
MSM
MSM
2
1
3
4
12
12
12
12
384
176
54
120
27 900
1 300
59 300
94 700
no
no
no
no
light chains of the plasmacytoid cells. Lastly, all 4 patients
showed a poor response to oral acyclovir, as reported in the
literature (5% of HIV-infected persons), so they underwent
a treatment with acyclovir i.v. (5 mg/kg/every 8 h daily)
combined with HAART, with a partial response.5
In conclusion, the presence of nodular or nodulo-ulcerated chronic lesions in the perianal or genital region in HIVpositive patients should lead the clinicians to exclude the
herpetic aetiology and differently, they should invite the
patients with an unknown HIV serostatus presenting similar
lesions to perform a HIV test.
2.
3.
4.
5.
fested by chronic perianal ulcerative herpes simplex lesions. N Engl
J Med 1981;305:1439-44.
Samaratunga H, Weedon D, Musgrave N, Mccallum N. Atypical presentation of herpes simplex (chronic hypertrophic herpes) in a patient
with HIV infection. Pathology 2001;33:532-5.
Tong P, Mutasim DF. Herpes simplex virus infection masquerading as
condilomata acuminata in a patient with HIV disease. Br J Dermatol
1996;134:797-800.
LeBoit PE, Limova M, Yen TSB, Palefsky JM, White CR Jr, Berger
TG. Chronic verrucous varicella-zoster virus infection in patients
with the acquired immunodeficiency syndrome (AIDS). Histologic and
molecular biologic findings. Am J Dermatopathol 1992;14:1-7.
Erlich KS, Mills J, Chatis P, Mertz GJ, Busch DF, Follansbee SE et al.
Acyclovir-resistant herpes simplex virus infections in patients with the
acquired immunodeficiency syndrome. N Engl J Med 1989;320;
293-6.
References
1. Siegal FP, Lopez C, Hammer GS, Brown AE, Kornfeld SJ, Gold J et
al. Severe acquired immunodeficiency in male homosexuals, mani-
294
Address reprint requests to: Dr. A. Di Carlo, Direttore S.C. Dermatologia
Infettiva, Istituto Dermatologico S. Gallicano (IRCCS), Via S. Gallicano
25 A, 00153 Roma, Italy. E-mail: [email protected]
Giugno 2006

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