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OFFICIAL JOURNAL OF THE SOCIETÀ ITALIANA DI DERMATOLOGIA MEDICA,
CHIRURGICA, ESTETICA E DELLE MALATTIE SESSUALMENTE TRASMESSE (SIDeMaST)
VOLUME 149 - No. 3 - JUNE 2014
GIORNALE ITALIANO DI
DERMATOLOGIA E VENEREOLOGIA
Official Journal of the “Società Italiana di Dermatologia Medica, Chirurgica,
Estetica e delle Malattie Sessualmente Trasmesse (SIDeMaST)”
Honorary Editor
Mario PIPPIONE
Editor in Chief
Andrea PESERICO
Assistant Editors
Nicola PIMPINELLI - Pietro Quaglino
Honorary Members and Editorial Committee
M. Bagot (Paris, France) - L. Borradori (Bern, Switzerland) - R. Cerio (London, UK) - K. D. Cooper (Cleveland, USA)
P. M. Elias (San Francisco, USA) - J. Hercogova (Prague, Czech Republic) - F. Kerdel (Miami, USA) - C. Paul (Tolouse, France)
M. R. Pittelkow (Rochester, USA) - R. Schwartz (Newark; USA) - W. Sterry (Berlin, Germany) - E. Tschachler (Vienna, Austria)
Editorial Board
P. Amerio (Chieti) - G. Argenziano (Reggio Emilia) - A. Belloni Fortina (Padova) - N. Cassano (Bari) - A. Costanzo (Roma)
E. Cozzani (Genova) - M. C. Fargnoli (L’Aquila) - F. Lacarrubba (Catania), D. Linder (Padova) - I. Neri (Bologna)
F. Rongioletti (Genova) - F. Sampogna (Roma) - C. Tomasini (Torino) - M. Venturini (Brescia) - G. Zambruno (Roma)
Società Italiana di Dermatologia Medica, Chirurgica, Estetica
e delle Malattie Sessualmente Trasmesse (SIDeMaST)
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Andrea Peserico (President) - Gianfranco Altomare - Emilio Berti - Sergio Chimenti - Clara De Simone
Alberico Motolese - Aurora Parodi - Giovanni Pellacani
Nicola Pimpinelli - Carlo Pincelli - Anna Virgili
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Alberto OLIARO
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Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique of
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International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Ann Int Med
1988;108:258-65.
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Payne DK, Sullivan MD, Massie MJ. Women’s psychological reactions
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Publishers; 1986. p. 132-58.
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Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam:
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Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med [Internet]. 2006 Jul 4
[cited 2007 Jan 4];145(1):62-9. Available from:
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GIORNALE ITALIANO DI
DERMATOLOGIA E VENEREOLOGIA
Vol. 149
June 2014
No. 3
CONTENTS
DRUG ERUPTIONS - Part II
317
281
Grasso V., Vassallo C., Croci G., Brazzelli V.
Guest Editors: G. BORRONI, C. TOMASINI
Acute generalized exanthematous pustulosis: report of
five cases and systematic review of clinical and histopathological findings
Vassallo C., Derlino F., Brazzelli V., D’Ospina R. M.,
Borroni G.
Tyrosine kinase inhibitors: muco-cutaneous side
effects at the microscope
329
Thalidomide-induced granuloma annulare
Ferreli C., Atzori L., Manunza F., Pau M., Caddori A.
335
291
Histopathologic spectrum of Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS): a diagnosis that needs clinico-pathological correlation
Borroni G., Torti S., Pezzini C., Vassallo C., Rosso R.,
D’Ospina R. M., Tomasini C., Brazzelli V.
ORIGINAL ARTICLES
Topical lactoferrin can improve stable psoriatic plaque
Saraceno R., Gramiccia T., Chimenti S., Valenti P., Pietropaoli
M., Bianchi L.
341
301
Drug-induced lupus erythematosus
Clinically and/or histologically pigmented poromas
in Caucasian patients
Marzano A. V., Tavecchio S., Menicanti C., Crosti C.
Betti R., Bombonato C., Cerri A., Moneghini L., Abramo P.,
Menni S.
311
347
Inflammatory/infectious cutaneous side effects of
biological drugs in patients with psoriasis: a general
review with personal data
Rongioletti F., Burlando M., Parodi A.
Vol. 149 - No. 3
In vivo and in vitro evaluation of topical formulations containing physiological lipid mixture for
replacement of skin barrier function
Barba C., Parra J. L., Coderch L., Semenzato A.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
XV
CONTENTS
355
372
Crosta M. L., Caldarola G., Fraietta S., Craba A., Benedetti C.,
Coco V., Janiri L., Rinaldi L., De Simone C.
Lo Schiavo A., Brancaccio G., Romano F., Caccavale S.
Psychopathology and eating disorders in patients
with psoriasis
Lymphangiomas arising on lymphedema: first step of
malignant development
374
A rare association between neurofibromatosis type 1
and vulvar sarcoma
363
CASE REPORTS
Periungual pyogenic granulomas due to topical tazarotene for nail psoriasis
Piraccini B. M., Venturi M., Patrizi A.
Miraglia E., Pecorella I., Persechino F., Visconti B., Calvieri S.,
Giustini S.
376
A clinical case of cutaneous silica granuloma
367
Onesti M. G., Fino P., Amorosi V., Piro F., Pedace D., Carella
S., Latini C.
Carlesimo M., Pennica A., Muscianese M., Bottoni U.,
Abruzzese C., Giubettini M., Pranteda G., Pranteda G.
378
Multiple skin ulcers due to Serratia marcescens in a
immunocompetent patient
Merkel cell carcinoma of the lower limb
De Paola M., Poggiali S., Miracco C., Pisani C., Batsikosta A.,
Bilenchi R.
371
CORRESPONDENCE
A case of superimposed segmental giant melanocytic
nevus
Piccolo V., Russo T., Picciocchi R., Ametrano O., Moscarella E.
XVI
381
Yellow urticaria in a patient with hepatic cirrhosis
Chiba T., Hayashi F., Shinmura M., Kiyomatsu M., Tatematsu
S., Nakao M., Furue M.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

DRUG ERUPTIONS - Part II
Guest Editors: G. Borroni, C. Tomasini
G ITAL DERMATOL VENEREOL 2014;149:281-90
Acute generalized exanthematous pustulosis: report of five cases
and systematic review of clinical and histopathological findings
C. VASSALLO, F. DERLINO, V. BRAZZELLI, R. M. D’OSPINA, G. BORRONI
Acute generalized exanthematous pustulosis (AGEP) is a rare,
drug-related pustular eruption usually starting from folds
with edema and erythema and with subsequent spreading.
Clinically AGEP is characterized by the sudden appearance of
dozen of sterile, non follicular, small pustules on erythematous
and edematous skin. Mild non erosive mucosal involvement,
mostly oral, may sometimes occur. Fever, neutrophilia and peripheral blood eosinophilia (in a third of patients) are present.
Other skin signs such as facial edema, purpura, target-like
lesions and blisters have been described but are not typical
for AGEP. Diagnostic criteria for AGEP were established by
an international committee of experts, the European Study of
Severe Cutaneous Adverse Reactions (EuroSCAR). The most
relevant histopathological feature is represented by the detection of non-follicular subcorneal and/or intracorneal spongiform pustules that are usually large, contiguous and tend to
coalesce. After elimination of the causative drug, pustules usually spontaneously disappear in a few days with desquamation and the reaction fully resolves within 15 days. Internal
organs are not usually involved and no systemic treatment is
required. Withdrawal of the culprit drug is mandatory. Although AGEP is a self-limiting disease with a favourable prognosis, secondary infections are a not infrequent complication
in patients in poor general medical conditions. The reported
mortality is about 5%. The most severe cases are associated
with drug rechallenge.
Key words: Acute generalized exanthematous pustulosis - Pathology - Diagnosis.
A
cute generalized exanthematous pustulosis
(AGEP) is a rare, acute, febrile eruption, characterized by the occurrence of numerous small, nonfollicular, sterile pustules, arising within large areas
Corrisponding author: C. Vassallo, MD, Department of Dermatology,
University of Pavia, Policlinico San Matteo IRCCS Foundation, Viale C.
Golgi 19, 27100 Pavia, Italy. E-mail [email protected]
Vol. 149 - No. 3
Dermatology Unit, Department of Clinical‑Surgical
Diagnostic and Pediatric Sciences, University of Pavia
Policlinico San Matteo IRCCS Foundation, Pavia, Italy
of oedematous erythema, associated with peripheral
blood leukocytosis. In 1968 Baker and Ryan identified 5 patients with drug-related pustular eruptions
with an acute course, who had no history of psoriasis.
Over time, cases with similar clinical characteristics
have been described using different names, such as
“generalized toxic pustuloderma”, “blistering drug
eruptions”, and “generalized pustular dermatosis”.1
The term acute generalized exanthematous pustulosis (AGEP) was first introduced by Beylot et al. in
1980.2, 3 AGEP was better defined later by Roujeau
et al.4 and Chang et al.5
In most cases (more than 90%) it arises as an adverse drug reaction even if other rarer toxical and
infectious causes have been reported (Table I). The
incidence of AGEP is estimated at one to five cases
per million people per year, even though this figure
may be underestimated and misdiagnosed as pustular psoriasis.6, 7 Although AGEP is generally accepted as a distinct entity, clinical, etiologic and histopathologic features may hardly be distinguished
from drug-induced psoriasis and, to a lesser extent,
from other pustular widespread neutrophilic dermatosis.
Materials and methods
We conducted a retrospective study of all patients
admitted to our department for AGEP between 2008
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
281
VASSALLO
ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS
Table I.—Some of the most frequently involved drugs causing AGEP.
Group
Specific Agent
Antibiotics
Amoxicillin (with or without clavulanic acid) propicillin, imipenem, cephalexin and cephradine, co-trimoxazole,
doxycycline, chloramphenicol, ciprofloxacin, norfloxacin, ofloxacin, teicoplanin, streptomycin, isoniazid, metronidazole
Terbinafine, fluconazole, itraconazole, nystatin
Sertraline, chlorpromazine, nitrazepam
Diltiazem, captopril, enalapril, furosemide, hydrochlorothiazide
Hydroxychloroquine, pyrimethamine, salazopyrine, mesalazine, azathioprine, cytarabine, piperazine ethionamate, pseudoephedrine, allopurinol, dextropropoxyphene, icodextrin, mexiletine, morphine, acetylsalicylic
acid, naproxen, deltaeparin, intravenous non-ionic contrast agents
Antimycotics
Anticonvulsant
Antihypertensive
Others
and 2013 (6-year period): a series of seven patients
has been considered. All the patients were rated with
the EuroSCAR score and five out of seven were
classified as affected by AGEP. Three male and two
female patients are reported (mean age 66.6). All
the patients had different comorbidities requiring a
therapy with a specific drug that in each case was of
recent introduction. In each case reported the patient
presented a rather abrupt occurrence of erythematous patches quickly followed by the appearance of
dozens of millimetric non follicular, monomorphous
pustules, associated with a burning sensation and
pruritus. In all cases lesions had focal distribution
with a tendency to spread rapidly and to coalesce.
In two patients, a palmar involvement was observed,
while in one woman mucosal (oral) involvement
was evident. Admission to our in-patient department
was required in two cases. Patients were all investigated for laboratory findings, including full blood
count, creatinine, transaminases, bilirubin, gammaglutamyl peptidase and inflammatory markers. In
each case two punch biopsies were performed, respectively for histopathological examination and
direct immunofluorescence; a pustular smear was
made from a recent lesion in order to exclude an infectious etiology. In all cases the culprit drug was
suspended and a systemic and/or topical corticosteroidal therapy was started. Resolution of cutaneous
lesions with superficial desquamation was observed
in all cases.
Results
Results are reported and summarized in Table II,
where clinical features, causative drugs, histopathological and immunopathological findings are reported for each patient. Microbiological examinations
from pustular smears always proved negative. In all
cases direct immunofluorescence was negative and
histopathological examination (Table III) was always consistent with a diagnosis of AGEP presenting with subcorneal and intracorneal pustules with
only scant spongiosis and few necrotic keratinocytes.
Rare eosinophils in superficial dermis were evident
in three patients.
Table II.—Main clinical features of five patients affected by AGEP.
Patient
gender
age
1 (CR), F
70 yrs-o
2 (CG), M
76 yrs-o
3 (DL), M
60 yrs-o
4 (CG), F
68 yrs-o
5 (GF), M
59 yrs-o
282
Main comorbidities
Causative drug
Cutaneous involvement
Rheumatoid arthritis Hydroxychloroquine Trunk, arms, legs, face
Mucosal
involvement
Systemic involvement
Lips
Fever, 38 °C, leukocytosis
with neutrophilia, elevation of
inflammatory markers (hospitalized)
Leukocytosis with neutrophilia,
elevation of inflammatory markers
Fever; rhabdomyolysis (hospitalized)
Dermatomyositis
Hydroxychloroquine
Arms, legs, palms
//
Hairy cell leukaemia
Pentostatin
Neck, trunk, legs
//
Diabetes mellitus
arthrosis
Hypertension
Naproxen sodium
Trunk, palms
//
Amoxicillin + clavulanic acid
Face, trunk (folds)
//
Leukocytosis with eosinophilia, slight
elevation of inflammatory markers
Slight elevation of inflammatory
markers
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Table III.—Histopathological findings in five patients affected by AGEP.
Immunopathological
features
Histopathological features: epidermal changes
Histopathological features: dermal changes
1
DIF negative
2
DIF negative
Basket-wave corneum, scant sub/intraepidermal
non spongiform pustules, spongiosis, neutrophilic
exocytosis
Subcorneal pustules, focal spongiosis, neutrophils at
dermo-epidermal junction
3
DIF negative
Parakeratosis, focal scale-crust, subcorneal pustules,
spongiosis, rare single necrotic keratinocytes
4
DIF negative
Subcorneal pustules, scant focal spongiosis, neutrophils exocytosis, rare single necrotic keratinocytes
5
DIF negative
Confluent subcorneal pustules, slight spongiosis,
neutrophils along the dermo-epidermal junction
Slight edema of papillary dermis, scant interstitial
inflammatory infiltrate composed of lymphocytes,
neutrophils, and few eosinophils
Edema of sub-papillary dermis, extravasation of
erythrocytes, interstitial infiltrate of neutrophils
and lymphocytes, no eosinophils
Slight edema of papillary dermis, scant inflammatory infiltrate composed of lymphocytes,
neutrophils and many eosinophils. Erythrocytes
extravasation
Edema of sub-papillary dermis, erythrocytes
extravasation, interstitial infiltrate of neutrophils
and lymphocytes, few eosinophils
Scarce infiltrate of lymphocytes and neutrophils
in an oedematous superficial dermis. No eosinophils
Patient
Clinicopathologic correlations in the five AGEP pa‑
tients considered
Case 1
A 70-year-old woman, affected by rheumatoid arthritis developed erythematous and edematous patches, quickly covered by pustular lesions. She was in
treatment with hydroxychloroquine for one month
before cutaneous eruption. These manifestations began on the trunk and rapidly spread to legs, arms,
face and oral mucous membranes (lips) (Figure 1).
These widespread cutaneous lesions were associated
with fever (38 °C), pruritus and burning sensation
and altered blood clotting analysis. Hospitalization
was necessary. Laboratory findings showed leucocytosis with neutrophilia and elevation of inflammatory markers. No other internal organ involvement
was documented. A pustular smear from a new lesion was performed and allowed us to exclude an
infectious cause of lesion. Two punch biopsies were
performed, on for direct immunofluorescence (negative) and one for histopathologic examination, confirming the clinical diagnosis of AGEP. In particular
basket-wave corneum, scant sub/intraepidermal non
spongiform pustules, spongiosis, neutrophilic exocytosis were observed. The dermis was characterised
by slight oedema of papillary dermis, scant interstitial superficial inflammatory infiltrate composed of
lymphocytes, neutrophils, and few eosinophils.
Case 2
Figure 1.—AGEP: mucous membrane involvement. Mucosal
localization is reported in only one third of cases, being almost
exclusively oral. Pustular lesions evolve into superficial erosions.
Vol. 149 - No. 3
A 76-year-old man affected by dermatomyositis in
therapy with systemic corticosteroids started also a
therapy with hydroxychloroquine, developing within some days erythematous and edematous patches
with small, monomorphous pustular lesions all over
the body surface (Figure 2) with even a palmar involvement. No mucosal localization was present and
good clinical general conditions were documented.
Only leukocytosis with neutrophilia and slight elevation of inflammatory markers were detectable.
A pustular smear was performed from a recent lesion and resulted negative for micro-organisms.
Two punch biopsies were taken: the first one for
DIF proved negative and the other one was consistent with a diagnosis of AGEP. The histopathologic
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Figure 3.—Subcorneal pustule filled by several neutrophils (hematoxylin-eosin).
Figure 2.—AGEP: early stage. Presence of erythematous and
oedematous patches on the neck and on the trunk. Lesions were
associated with hitch. Within a few hours the occurrence of several, monomorphous, millimetric pustules could be documented.
features presented with subcorneal pustules (Figure
3), focal spongiosis, neutrophils at dermo-epidermal
junction (Figure 4), edema of sub-papillary dermis,
extravasation of erythrocytes, interstitial infiltrate of
neutrophils and lymphocytes, no eosinophils.
Case 3
A 60-year-old man affected by hairy cell leukemia
started chemotherapy with granulocyte colony stimulating factors (GCSF) and pentostatin. About 15
days later he developed erythematous patches covered by small, monomorphous pustules, localized
284
Figure 4.—Neutrophils along dermal-epidermal junction (hematoxylin-eosin).
to trunk, neck and legs. Mucous membrane was not
involved. A systemic involvement was documented
by the presence of fever (>38 °C), elevation of inflammatory markers and rhabdomyolysis, that could
be interpreted as due to chemotherapy. The patient
was admitted to our in-patient department. Pustular
smear was performed and resulted negative as well as
direct immunofluorescence. Histopathology showed
parakeratosis, focal crusty lesions, subcorneal pustules, spongiosis, rare single necrotic keratinocytes,
slight oedema of papillary dermis, extravasation of
erythrocytes scant inflammatory infiltrate composed
of lymphocytes, neutrophils and many eosinophils.
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Case 4
A 68-year-old woman affected by diabetes mellitus and arthrosis took naproxen sodium because of
joint pain and developed within some hours a diffuse
burning and itchy sensation associated the following day to the occurrence of erythematous patches
mainly localized on the trunk and on arms with also
a palmar involvement, and covered by tiny confluent pustules. These pustular lesions were extremely
fragile and were associated to a scaling evolution
(Figure 5), particularly marked on palms. Neither
mucosal nor systemic involvement was observed.
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Laboratory findings showed a slight elevation of inflammatory markers and moderate leukocytosis. A
pustular smear from a new lesion was performed and
allowed us to exclude an infectious cause of lesion.
Two punch biopsies were performed for direct immunofluorescence, resulted negative, and histopathological examination. Histopathology revealed the
presence of subcorneal pustules (Figure 6), scant
focal spongiosis, neutrophils exocytosis, rare single
necrotic keratinocytes, oedema of sub-papillary dermis, erythrocytes extravasation, interstitial infiltrate
of neutrophils and lymphocytes, few eosinophils.
Case 5
A 59-year-old patient affected by hypertension, after the intake of amoxicillin and clavulanic acid for a
Figure 5.—AGEP: late stage. After the withdrawal of the culprit
drug the disease usually resolves spontaneously with superficial
desquamation within fifteen days. Here typical involvement of
arm fold is reported.
Vol. 149 - No. 3
Figure 6.—Patient 4: a small, subcorneal pustule associated with
parakeratosis (hematoxylin-eosin).
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Figure 8.—Histopathological findings are characterized by confluent pustules and underlying psoriasiform epidermal hyperplasia (hematoxylin-eosin).
Figure 7.—Patient affected by amoxicillin and clavulanic-induced
AGEP with confluent pustules on his left thigh.
dental abscess, within a few hours developed an erythematous papulo-pustular eruption on trunk, with
a peculiar distribution on folds (Figure 7), quickly
involving his face. The patient was apyretic and laboratory examinations did not reveal any significant
alteration. Histopathological findings were characterized by confluent subcorneal pustules (Figure 8),
slight spongiosis of epidermis, neutrophils along the
dermo-epidermal junction, a scarce infiltrate of lymphocytes and neutrophils in an oedematous superficial dermis. No eosinophils were present.
Discussion
AGEP is a rare, acute, pustular, usually febrile
eruption. The current estimated incidence rate of
AGEP is one to five cases per million per year.6, 8
Previous studies have shown that AGEP can occur
at any age, also in childhood, even if the mean age
of occurrence has been assessed between the fourth
and the fifth decade.8 AGEP affects men and women
equally, even if a trend toward female predominance
would be revealed by more recent studies,4, 5, 6, 9 being perfectly consistent with the recognized female
predominance in drug eruption in general.8 These
data are consistent with those observed in our study,
even if in our series of cases patients were older than
the mean age reported in literature. According to lit-
286
erature seasonality would play a role in AGEP occurrence since a clustering of cases in the summer
has been reported in a series of cases from Israel, albeit further studies would be necessary to clarify this
finding.9, 10 As far as we know from our observation
seasonality does not play a relevant role since our
patients developed AGEP in months different from
summer, even showing a predilection for autumn and
winter. Clinically, pustular manifestations usually
occur rapidly: from hours (usually within 24 hours)
to few days after drug intake. Lesions usually start
on face on flexural areas and disseminate over few
hours with development of systemic symptoms. The
pustular eruption is represented by dozens to hundreds of small (pinhead sized, 5 mm) non follicular,
sterile pustules, arising on an strongly erythematous
and oedematous skin surface. Sometimes confluence
of pustules and their evolution with desquamation
may mimic a positive Nikolsky’s sign simulating,
in severe cases, toxic epidermal necrolysis (TEN).
The occurrence of lesions is usually associated to a
burning sensation or to pruritus or both. Other skin
signs like marked edema of the face, purpura lesions
(especially on the legs), Stevens-Johnson-syndromelike “atypical targets”, blisters and vesicles have
been observed in more than 50% of patients with
AGEP, even if they are not typical for it. Mucous
membrane involvement may occur in about 20% of
the cases but usually is mild and remains limited to
one location (mostly oral). Systemic symptoms are
almost always presents and include: fever above 38
°C, lymphadenopathy and leukocytosis with blood
neutrophil count above 7 X109/L. Hypocalcaemia
can be detected and a mild to moderate eosinophilia
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may be present in about one third of the patients.7 In
about 30% of cases a slight reduction of the creatinine clearance, leading in some cases to a transient
renal failure, may be detected. A mild elevation of
aminotransferases may also be found.9 Cutaneous
lesions last 1 to 2 weeks after the withdrawal of the
involved drug and are followed by a desquamation.7
The course of the disease is usually favourable with
a spontaneous regression of cutaneous and systemic
symptoms (even if topical steroid and systemic antipyretics may help). In some rare cases a widespread
TEN-like picture can develop with a more severe
prognosis that can be worsened also by secondary
infections. Rare fatalities are documented: reported
mortality rate is about 5%.8 These clinical manifestations and this clinical behaviour are perfectly
consistent with those observed in our case series,
therefore their stereotypical features, associated to
the acute and abrupt onset have to be recognised in
order to immediately suspect a diagnosis of AGEP
facing a pustular manifestation of sudden appearance. Histopathology of AGEP, despite its relative
aspecificity, is a useful means of diagnostic integration with the history of patients and their clinical
features. Biopsy specimen should be obtained from
early pustular lesions. A relevant histopathological
feature is the presence of non-follicular subcorneal
and/or intracorneal spongiform pustules encompassing more than 15 keratinocytes. Pustules may coalesce. These pustular lesions are typically sterile and
no bacterial, viral or fungal proliferation can be detected at haematoxylin-eosin staining or PAS stain.
In a wide histopathological study performed in 2010
on 102 patients with a definite or probable diagnosis
of AGEP (according to AGEP validation score), 23%
of cases also presented with follicular pustules that
are not typical of AGEP, although the diagnosis could
not be excluded for this.8 We could not observe any
follicular pustule in our cases. Other relevant epidermal features typically associated to pustular lesions
in AGEP are the presence of necrotic keratinocytes
and neutrophil exocytosis. In our series of patients,
two had few, single necrotic keratinocytes and one
neutrophilic exocytosis. In two cases presence of
neutrophils along the dermo-epidermal junction was
detectable. The main dermal features were papillary
oedema and mixed superficial, interstitial, and mid/
deep-dermal infiltrates containing neutrophils and
eosinophils. No sign of vasculitis is usually evident,
even if in more than 50% of cases leukocytoclasia
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and erythrocyte extravasation can be detected with
their misinterpretation as vasculitis and with a consequent diagnostic confusion of AGEP with pustular vasculitis.8 In three out five of our patients it was
possible to observe erythrocyte extravasation. Additional features that can be observed are: parakeratosis and rete-ridges elongation (mild to moderate);8 in
our patient affected by hairy cell leukaemia, parakeratosis could be seen, but probably is to address to
previous chemotherapy that he received.
Despite the neutrophilic inflammation observed
in AGEP is unusual in allergic drug reactions, many
of the other mentioned aspects are typical of drug
adverse reactions, such as the prominent presence
of eosinophils in the skin of patients, both within
the pustules and in the dermis, but also blood eosinophilia, observed in about a third of patients with
AGEP, is a hallmark of many drug-induced allergic
reactions, suggests that AGEP is a hypersensitivity
reaction. Furthermore the mid/deep-dermal perivascular infiltrates and extravasation of erythrocytes,
the absence of vasculitis and especially the presence
of necrotic keratinocytes in AGEP has been reported
also in other drug eruptions including exanthematic
drug eruptions and drug eruptions characterized primarily by interface dermatitis such as lichenoid drug
eruptions, such as Stevens-Johnson syndrome (SJS),
TEN and fixed drug eruptions.8 In more than 90% of
cases AGEP is caused by drug intake.7 The onset of
AGEP is rapid, often occurring within 24 hours after drug intake. Recently, a large-scale multinational
case-control study (the EuroSCAR study) pointed out
that the latent period is different for each drug, being
for instance, shorter (about 24 hours) for antibiotics
and longer (even 11 days) for other drugs.9 Longer
latent periods (1-3 months to 1 year), were reported
in a few AGEP cases with an underlying malignancy,
that conceivably would play a role in extending latent
period.10, 11-13 Spontaneous resolution usually begins
once the causative drug is no longer used, even if
in exceptional cases a severe evolution in TEN-like
picture has been reported.13 A prior sensitization (including a contact sensitization) to the inducing drug
may explain the short interval between drug administration and the onset of the eruption; the short interval suggests an immunologic recall phenomenon
in a patient with strong prior sensitization. According to this hypothesis, in many cases there may be
a positive patch test reaction to the suspected drug.
Other than this, a genetic predisposition has also
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been documented, since HLA-B5, -DR11 and -DQ3
have been found more frequently in patients with
AGEP.7 Among drugs antibiotics are the most frequent causative agents, especially penicillins or macrolides (ampicillin/amoxicillin±clavulanic acid and
pristinamycin), quinolones, anti-infective sulphonamides, terbinafine, and spiramycin±metronidazole,
even if also other drugs such as (hydroxy)chloroquine, diltiazem, carbamazepine have been frequently mentioned as responsible agents. In the table 1 we
list all the main drug that have been associated with
AGEP during years. The absolutely relevant role of
drugs in determining AGEP is underlined also by
ours case series where eache patient had an history
of recent drug intake. Besides drug intake which is
the most frequent cause, AGEP can occur also after
viral infections (e.g., enteroviruses parvovirus B19,
cytomegalovirus and Coxsackie B4), UV radiation, heavy metal exposure (e.g., hypersensitivity to
mercury) and spider bites.12, 13 Pathogenetic mechanisms are now quite known and have been mainly
elucidated by patch and in vitro tests. The first step
would be represented by activation, expansion and
subsequent migration of drug specific CD4 and CD8
cells to the skin. Presentation of the drug bound to
major histocompatibility complex (MHC) class I by
keratinocytes to T CD 8 cells result in apoptosis of
keratinocytes derived from the release of granzyme
and perforin by TCD8 cells and in a subsequent formation of subcorneal vescicles. Infiltration of TCD4
cells would also contribute to this process, since the
presentation of the drug bound to major histocompatibility complex (MHC), class II, by keratinocytes
to drug-specific TCD4 cells determine the release
of CXCL-8 and of granulocyte macrophage-colony
stimulating factor (GM-CSF), respectively able to
induce the recruitment of neutrophils and to prevent
of neutrophils apoptosis. This result in the conversion of subcorneal vescicles into sterile pustules.
CD4 cells also release interferon (IFN-γ), which
stimulates keratinocytes to secrete CXCL-8 and interleukin-5, which contributes to the eosinophilia observed in some patients. Resident Langerhans cells
may present drug antigens to CD4 cells and keratinocytes may act as antigen presenting cells to CD8
cells, increasing the neutrophil-mediated inflammatory response.14 AGEP diagnosis is based on clinical,
histopathological and immunopathological features
but also on personal history (e.g. history of psoriasis, history of recent drug intake). In a retrospective
288
analysis of 63 cases of AGEP, performed in 2001,
suggested five criteria for AGEP recognition: 1) several dozens of small, mostly non follicular pustules
arising on a widespread oedematous erythema; 2)
typical histopathologic change; 3) fever (38 °C); 4)
blood neutrophil count above 7 X 109/L and 5) acute
evolution with spontaneous resolution of pustules in
less than 15 days, elaborating then even a more sophisticated score system for AGEP diagnosis (AGEP
validation score).15, 16
The AGEP validation score is a standardized scoring system composed of a set of data related to clinical features (morphology and clinical course) and
histopathology. On the basis of this score is possible to categorize cases as no AGEP, possible AGEP,
probable AGEP and definite AGEP.8-12 The AGEP
validation score has been used to diagnose AGEP in
many case reports and case series but in everyday
clinical practice the five criteria first suggested can
be often satisfactory in order to make a diagnosis.
Once suspected AGEP, other more specific tests such
as in vivo and in vitro tests can be performed for the
identification of culprit drugs, always keeping in
mind that they are consistent in some cases but not
in others.17
In vivo tests consist on patch tests that are considered well-tolerated (although a generalized AGEPlike reaction has been reported) 12 and, over recent
years, have been created for a wider and wider variety of medications and chemicals, proving strongly
positive in more than 50% of AGEP cases. Concerning in vitro tests, drug specific CD4+ and CD8+ T
cells can be isolated and cultured from patch test
sites and blood from AGEP patients. A positive diagnostic sign was represented by the observation of
the in vitro release of the Th1-type cytokine IFNγ,
of the lymphokine macrophage migration inhibition
factor and of the mast cell degranulation test. Differential diagnosis of AGEP includes a wide number of
vescico-pustular dermatoses. The main differential
diagnoses according to clinical and histopathological features are represented by: pustular psoriasis
(von Zumbusch type), subcorneal pustular dermatosis (Sneddon-Wilkinson disease), pustular vasculitis,
drug hypersensivity syndrome and toxic epidermal
necrolysis.
Distinction of AGEP from pustular psoriasis (von
Zumbush type) is probably the hardest and still most
debated differential diagnosis because of their clinical and histopathological similarity diseases so that
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ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS
to be considered in some cases a same entity. In this
case, the history of the patient proves fundamental.
Usually in pustular psoriasis a positive history of
pre-existent and even long-dating psoriasis is often
present, while in AGEP is possible but not so frequent, a positive history for recent drug intake is
uncommon and systemic symptoms and cutaneous
manifestation are referred by the patient to have a
longer duration. Moreover, from a clinical point of
view in pustular psoriasis, pustules and erythema
usually have a more generalized distribution and
show a tendency to persist until a therapy is started. On the contrary, in AGEP, pustular lesions are
mainly localized, with a particular predominance in
the folds and have a more fading behaviour/course,
since they often spontaneously resolve with drug
withdrawal. Moreover, even though both AGEP and
pustular psoriasis at histopathological examination
show a spongiform subcorneal and/or intraepidermal
sterile pustule, in pustular psoriasis more typical aspects, such as papillomatosis and regular acanthosis
can be detected. Finally in AGEP the presence of an
inflammatory infiltrate of both neutrophils and eosinophils on the one hand differentiate from psoriasis
and on the other hand underline once again AGEP
nature as drug-adverse reaction. Recent genetic studies on pustular psoriasis underline the presence of recessive mutations of IL36RN in generalized pustular
psoriasis; the same defect was also find in some patients affected by AGEP, suggesting that the two condition might have in common at least one pathway.18
Sneddon-Wilkinson’s subcorneal pustular dermatosis may resemble AGEP, especially for its
prevalent folds involvement. Despite that SneddonWilkinson’s disease have a less acute course and
at histopathological examination pustular lesions,
that are also wider than in AGEP, are not spongiform. Considering the spectrum of bullous diseases
also pemphigus foliaceus/IgA pemphigus and toxic
epidermal necrolysis have to be excluded. Usually
pemphigus foliaceus and IgA pemphigus have a less
acute course, more diffuse distribution, present with
subcorneal bullous lesions with a scant neutrophilic
infiltrate and have a positive direct immunofluorescence.
On the other hand in some cases the presence of
“atypical” target lesions and the confluence of pustules mimicking a positive Nikolsky-sign may suggest the diagnosis of TEN in severe cases of AGEP.
In these cases a distinction can be made because usu-
Vol. 149 - No. 3
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ally AGEP presents a more superficial epidermal detachment and mucous membrane involvement is less
pronounced. Whereas differentiation in some cases
might be difficult on clinical grounds alone, histology is significantly different in TEN typically showing full thickness epidermal necrosis and only a very
sparse inflammatory infiltrate. Yet, even some overlap
cases might exist that fulfil the criteria for both diseases both clinically and histologically. Drug hypersensitivity syndrome, also referred to as DRESS (an
acronym for drug rash with eosinophilia and systemic
symptoms) may also show papulo-vesicles and/or papulo-pustules, the pustular component being usually
less pronounced than in AGEP. In addition patients
usually show show more severe systemic symptoms
with: fever, lymphadenopathy, eosinophilia, and often severe visceral involvement like hepatitis, nephritis, pneumonitis, and/or myocarditis. Also pustular
vasculitis should be excluded, since bullous and/or
pustular lesions may arise in purpura lesions of leukocytoclastic vasculitis. In addition there seems to be
a special variant of leukocytoclastic vasculitis which
is characterized by the development of many small
pustules which, as opposed to AGEP, are localized
mainly on the dorsum of the hands and which might
also be drug-induced. A marked leukocytoclastic
vasculitis, not detectable in AGEP, can be observed
in histology. The occurrence of systemic symptoms
like fever, lymphoadenomegaly and blood leukocytosis with neutrophilia, associated with an elevated
amount of neutrophils detectable at histopathology
should lead also to rule out an infection (bacterial or
fungal) presenting as primary or secondary on a preexistent dermatosis. Bacterial folliculitis, dermatophyte infections, pyoderma vegetans, Kaposi’s varicelliform eruption, impetigo, impetiginized eczema
and staphylococcal scalded skin syndrome have to be
excluded performing a pustular smear.
Conclusions
AGEP is a rare, acute, pustular, usually febrile
eruption induced by drugs. All our patients with
AGEP improved within a few days after drug withdrawal, symptom management and systemic/topical
corticosteroids. None of our patients died, despite
two required hospitalization for systemic involvement. All of them presented comorbidities, and three
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autoimmune diseases. Hydroxychloroquine-induced
AGEP was observed in two out of five patients. One
patient presented pentostatin-induced AGEP, never
described before. The histopathological findings
were consistent with AGEP in all cases and in two of
them a new histological feature could be described,
namely the presence of neutrophils along the dermoepidermal junction. Clinicopathological correlation
allows a specific diagnosis in most of cases, albeit
the rapid evolution of pustules may sometimes infer
in obtaining a representative biopsy of the process,
making more difficult the diagnosis.
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11. Tamir E, Wohl Y, Mashiah J, Brenner S. Acute generalized exanthematous pustulosis: a retrospective analysis showing a clear predilection for women. Skinmed 2006;5:186-8.
12. Halevy S, Kardaun SH, Davidovici B, Wechsler J; EuroSCAR and
RegiSCAR study group. The spectrum of histopathological features
in acute generalized exanthematous pustulosis: a study of 102 cases.
Br J Dermatol 2010;163:1245-52.
13. Peermohamed S, Haber RM. Acute generalized exanthematous
pustulosis simulating toxic epidermal necrolysis: a case report and
review of the literature. Arch Dermatol 2011;147:697-701.
14. Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol 2012;53:87-92.
15. Roujeau JC, Bioulac-Sage P, Bourseau C, Guillaume JC, Bernard P,
Lok C et al. Acute generalized exanthematous pustulosis. Analysis
of 63 cases. Arch Dermatol 1991;127:1333-8.
16. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute
generalized exanthematous pustulosis (AGEP) -a clinical reaction
pattern. J Cutan Pathol 2001;28:113-9.
17. Mashiah J, Brenner S. A systemic reaction to patch testing for the
evaluation of acute generalized exanthematous pustulosis. Arch
Dermatol 2003;139:1181-3.
18. Sugiura K. The genetic background of generalized pustular psoriasis: IL36RN mutations and CARD14 gain-of-function variants. J
Dermatol Sci 2014;14:S0923-1811
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

G ITAL DERMATOL VENEREOL 2014;149:291-300
Histopathologic spectrum of Drug Reaction
with Eosinophilia and Systemic Symptoms (DRESS):
a diagnosis that needs clinico-pathological correlation
G. BORRONI 1, S. TORTI 1, C. PEZZINI 1, C. VASSALLO 1, R. ROSSO 2
R. M. D’OSPINA 1, C. TOMASINI 3, V. BRAZZELLI 1
Drug Reaction with Eosinophilia and Systemic Symptoms
(DRESS) is characterized by an heterogeneous group of severe dermatologic manifestations and systemic involvement,
due to several groups of medicaments. A series of 9 consecutive cases, observed from 2008 to 2013 in the Department of
Dermatology, University of Pavia, is reported, all satisfying
the clinical, hematological and systemic diagnostic criteria
of DRESS. Clinically, 4 out of 9 patients had an urticarial
and papular eruption, 2 an erythema-multiforme-like (EMlike) pattern, 2 erythroderma and 1 had an erythematous
and macular reaction. Aim of the study was to describe the
histopathologic features of DRESS and to trace a possible
correlation between the four clinical recognized types of
the syndrome and the histopathological patterns. Predominantly, a superficial perivascular lymphocytic infiltrate,
extravasation of erythrocytes, and focal interface changes
characterized DRESS cases. Less frequently, histopathology revealed the presence of necrotic keratinocytes; surprisingly, only in 2 cases the presence of rare dermal eosinophils
was detected, even if all the patients had significant peripheral eosinophilia. A histopathological diagnosis of DRESS
seems per se, according to our data, not feasible, since the
main histopathological changes (interface changes, superficial perivascular dermatitis, focal spongiosis, lichenoid
infiltrate, rare presence of necrotic keratinocytes) can be
interpreted generically as a drug induced dermatitis. The
above mentioned histopathological changes, however, when
associated with clinical information on cutaneous and systemic involvement of the patient, allow the pathologist or
the dermatopathologist to make a diagnosis of DRESS with
a reliable margin of certainty.
Key words: Drug hypersensitivity syndrome - Diagnosis Drug-related side effects and adverse reactions.
Corresponding author: G. Borroni, MD, Department of Dermatology,
University of Pavia, Fondazione IRCCS Policlinico San Matteo, Viale
C. Golgi 19, 27100 Pavia, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1Department of Clinical‑Surgical,
Diagnostic and Pediatric Sciences
Dermatology Section, University of Pavia
Foundation IRCCS Policlinico San Matteo, Pavia, Italy
2Anatomic Pathology
Foundation IRCCS Policlinico San Matteo
University of Pavia, Italy
34th Section of Human Pathology
Training‑Centre in Dermatopathology
San Giovanni Battista University Hospital, Turin, Italy
T
he syndrome characterized by cutaneous Drug
Reaction with Eosinophilia and Systemic Symptoms, defined by the acronym DRESS, has been
firstly described by Bocquet et al. in 1996.1 The
syndrome encompasses an heterogeneous group of
severe and systemic reactions (liver, kidney, heart,
lung, central nervous system, blood, lymph nodes),
caused by different drugs, associated with fever and
extensive skin manifestations.
The genetic susceptibility factors of DRESS have
not yet been fully identified. However, some HLA
alleles have been correlated with DRESS in some
ethnic groups, but not in others. In fact, in Japanese
patients with carbamazepine induced DRESS a correlation with HLA-B*4801 have been demonstrated. An association between allopurinol and HLAB*5801 has not been found in Japanese patients with
DRESS.2 On the contrary, some other alleles, such as
HLA-A*31:01 showed a significant association with
carbamazepine-induced DRESS both in European
and Chinese population.3-7
The role of causal drugs 8 and susceptibility
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HISTOPATHOLOGIC SPECTRUM OF DRESS
to viruses, such as HHV-7,9 Epstein-Barr Virus
(EBV),10 cytomegalovirus (CMV),11 HHV-6 and
Varicella-Zoster Virus (VZV),12 reactivated during
the relatively long period of drug administration
(from 3 weeks to 2 month), and T-cell response 13
are as many factors that play a crucial role in the
complex pathogenesis of the syndrome.
The severity of systemic signs and symptoms
have, to some extent, put aside the dermatological
features. Cutaneous eruption, however, is one of the
main diagnostic criteria of DRESS.
Despite its protean dermatological presentation,
four main clinical patterns have been proposed:1, 14
I) urticarial and papular manifestation; II) erithemamultiforme-like reaction (EM-reaction); III) macular
and erythematous features; and IV) erythrodermalike pattern.
Histopathologic findings of DRESS have been
referred as polymorphous, to the point of making a
diagnosis of DRESS on the histopathologic grounds
alone, virtually impossible to the pathologist.
The EM-like reaction has been related to a poorer
prognosis, with more severe hepatic involvement.14
ered in RegiSCAR grading system for DRESS,15
were used in our cases.
Histopathology showed a wide spectrum of
changes including 1) necrotic keratinocytes; 2) exocytosis of lymphocytes; 3) spongiosis/vesciculation;
4) focal interface changes with vacuolar alterations;
5) superficial perivascular lymphocytic infiltrate; 6)
atypical lymphocytes; 7) eosinophils in the dermis;
8) lichenoid infiltrate; 9) dilated blood vessels; and
10) extravasation of erythrocytes. They have been
graded according to their presence (%) and severity
(scoring), with an evaluation of every change from 0
to 3. Low grade incidence of changes was defined by
a total score <0.30; slight changes were defined by
a scoring between 0.30 and 0.60; moderate changes
between 0.60 and 0.90; high grade of changes >0.90.
Aim of the study was to investigate the histopathological findings of DRESS, to describe the main
characteristics, and to trace a correlation between the
clinical presentation and histopathological pattern.
Every patient was assessed by two dermatologists
at least and by one pathologist for the above mentioned purposes, and assisted in the clinical course
by several specialists of different medical disciplines.
Material and methods
Over a 6-year period (2008-2013) a series of nine
consecutive cases of DRESS, all satisfying the clinical, haematological and systemic criteria of the Syndrome, have been considered.
Six male and three female patients, all Caucasians,
are reported (mean age: 59.5).
Four cases had urticarial and papular manifestations, two had a diffuse EM-reaction, one had a
macular and erythematous eruption and two had an
erythroderma-like pattern.
In every case medical history showed previous and
recent exposure to drugs (from two weeks to two
months), and a sequential series of worsening clinical findings in the development of the disease.
Patients were all investigated for laboratory
findings, including full blood count, creatinine,
transaminases (AST, ALT) and gamma-glutamyl
transpeptidase, bilirubin and virological analyses
(HIV, hepatitis B and C, Epstein-Barr Virus, Human
Herpes Virus 6 and 7, Cytomegalovirus), ECG and
chest Rx. Biopsies were taken after patients consent
and processed for routine histopathology.
All the clinical and laboratory findings, consid-
292
Results
Results are reported and summarized in Table I,
were clinical features, causative drugs, systemic involvement and peripheral eosinophilia percentage
have been reported for every patient.
Clinicopathologic correlations in the nine DRESS
patients considered
Case 1
A 40-year-old man, presented with widespread, erythematous-papular confluent lesions, involving more
than 50% of the body surface and affecting trunk and
extremities (Figure 1A). He had been in treatment with
allopurinol for 3 weeks, before cutaneous manifestation. Afterwards, he developed also hepatic and renal
dysfunction, fever and diffuse lymphadenopathy and
he was hospitalized. The peripheral eosinophilia was
>20%. Histopathology revealed a superficial dense
perivascular lymphocytic dermatitis, with several lymphocytes with hyperchromatic nuclei, focal interface
changes, mild exocytosis and slight focal spongiosis.
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HISTOPATHOLOGIC SPECTRUM OF DRESS
BORRONI
Table I.—Clinical features, causative drug, systemic involvement in the 9 patients observed.
Patient’s
gender
and age
Type and % of cutaneous clinical involvement
1
M
40 y-o
Diffuse macular and erythematous eruption
>50%
2
M
58 y-o
Diffuse urticarial persistent erythematous eruption
>50%
3
F
35 y-o
Implicated drug/drugs
Systemic involvement
Eosinophilia
Allopurinol
Hepatic dysfunction
Renal dysfunction
Lymphadenopathy
Fever
>20%
Carbamazepine
Hepatic dysfunction
Acute pancreatitis
Lymphadenopathy
Fever
>20%
Erythroderma and confluent EM-like eruption
>50%
Diclofenac
Hepatic dysfunction
Lymphadenopathy
10-19%
4
M
65 y-o
Diffuse erythematous erythroderma-like reaction
Extent >50%
Allopurinol
Hepatic dysfunction
Renal dysfunction
Lung involvement
Pericarditis
Fever
>20%
5
M
72 y-o
Diffuse erythematous erythroderma-like reaction with
facial HSV infection
Extent >50%
Carbamazepine
Hepatic dysfunction
Renal dysfunction
Lymphadenopathy
Fever
>20%
6
M
67 y-o
Severe and persistent urticarial reaction
Extent >50%
Valproic Acid
Hepatic dysfunction
Lymphadenopathy
10-19%
7
F
58 y-o
Diffuse papular and erythematous eruption
Extent >50%
Amoxicylline +
Clavulanic Acid
Hepatic dysfunction
Lymphadenopathy
Fever
10-19%
8
F
76 y-o
EM-like eruption
Extent >50%
Hydroxychloroquine
Hepatic dysfunction
Lymphadenopathy
Fever
>20%
9
M
65 y-o
Diffuse papular and erythematous eruption
Extent <50%
Perindopril +
Indapamide
Hepatic dysfunction
>20%
A
B
Figure 1.—A) Diffuse erythematous and macular eruption, involving more than 50% of the body surface; B) dense superficial perivascular and interstitial lymphocytic infiltrate, with focal exocytosis and slight spongiosis. Erythrocyte extravasation in the upper part
dermis, (H&E).
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HISTOPATHOLOGIC SPECTRUM OF DRESS
Erythrocyte extravasation was seen in the upper dermis. No eosinophils were present in the inflammatory
infiltrate (Figure 1B).
Case 2
A 58-year-old male patient, with personal history of carbamazepine medication 4 weeks before,
showed a diffuse urticarial erythematous eruption
from the onset involving upper trunk, with later involvement to limbs and face, associated with intense
pruritus, asthenia and fever (Figure 2A). During
hospitalization, he developed hepatic dysfunction
A
and acute pancreatitis and we detected a peripheral
eosinophilia >20%. A skin biopsy from the trunk
was taken. Histopathology was characterized by a
lichenoid lymphocytic infiltrate, involving focally
dermo-epidermal junction and dermal interstitium.
Furthermore, a dense perivascular lymphocytic infiltrate was seen around superficial blood vessels, with
many hyperchromatic nuclei. Slight vasodilation
with few extravasated erythrocytes, no eosinophils
in the dermal infiltrate. Epidermal changes were
characterized by incipient and frank focal spongiosis
with exocytosis of lymphocytes, without necrotic keratinocytes (Figure 2B).
B
Figure 2.—A) Diffuse urticarial persistent erythematous eruption (>50%); B) relatively dense lichenoid lymphocytic infiltrate, and
dense superficial perivascular lymphocytic infiltrate with many hyperchromatic nuclei. Focal epidermal spongiosis, (H&E).
A
B
C
Figure 3.—A) Erythroderma-like pattern of DRESS involving trunk and proximal arms; B) EM-like features of DRESS in the same patient on upper arms and lower legs (>50%); C) absence of necrotic keratinocytes, vacuolar changes at dermo-epidermal junction, with
a hint of sub-epidermal vesiculation and a dense mid-dermal perivascular and interstitial lymphocytic infiltrate, without eosinophils
(trunk), (H&E).
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HISTOPATHOLOGIC SPECTRUM OF DRESS
Case 3
A 35-year-old woman developed diffuse figurate
targetoid, discrete and confluent erithema-multiforme-like lesions, with erythroderma-like reaction,
involving neck, face, trunk and extremities (Figure
3A, B), about 3 weeks after diclofenac treatment.
Moreover, she developed hepatic dysfunction and
diffuse lymphadenopathy; peripheral eosinophilia
was 16%. A biopsy was taken, and histopathology
revealed absence of necrotic keratinocytes with a
dense perivascular superficial lymphocytic infiltrate,
and some atypical lymphocytes with hyperchromatic
nuclei, focal interface vacuolar changes and a hint
of sub-epidermal vesiculation. No eosinophils were
detectable in the inflammatory infiltrate (Figure 3C).
Case 4
A 65-year-old man showed a diffuse erythematous
eruption with oedema and focal vesiculation, with
later diffuse desquamation (Figure 4A, B). He was
treated with allopurinol since one month for hyperuricemia. Few days after hospitalization, he developed
a renal and hepatic dysfunction, with lung involvement and pericarditis. Peripheral eosinophilia was
>20%. A skin biopsy was done from his left thigh.
Histopathology was characterized by a true spongiotic dermatitis with intraepidermal vesiculation and
focal and confluent necrotic keratinocytes, either immediately beneath the stratum corneum and within
the spongiotic foci. Oedema of the sub-papillary dermis was prominent. In the dermis a mild perivascular
A
B
BORRONI
lymphocytic infiltrate with rare hyperchromatic nuclei, without eosinophils, was seen, associated with
moderate erythrocyte extravasation (Figure 4C).
Case 5
A 72-year-old-male patient was in treatment
with carbamazepine for bipolar disorder. After 6
weeks of carbamazepine therapy, he developed
a macular confluent and erythroderma-like reaction, involving more than 50% of the skin (Figure
5A, B). For the appearance of hepatic and renal
dysfunction, the patient was hospitalized. His peripheral eosinophilia was >20%. A skin biopsy
was taken and histopathology revealed epidermal
atrophy with necrotic keratinocytes and interface
changes, a lymphocytic superficial perivascular
infiltrate with some hyperchromatic nuclei. The
stratum corneum was characterized by hyperkeratosis with parakeratosis and scale crusts with neutrophils (Figure 5C).
Case 6
A 67-year-old-man showed a severe erythematomacular and confluent urticarial reaction, involving
more than 50% of cutaneous surface (Figure 6A,
B). The drug involved was valproic acid, which the
patient had been taking for 3 weeks. Moreover, he
developed severe hepatic dysfunction and lymphadenopathy and he had peripheral eosinophilia 17%. A
skin biopsy was taken from the trunk. Histopatholo-
C
Figure 4.—A, B) Diffuse erythroderma-like reaction (>50%); C) spongiotic dermatitis, with oedema of the papillary dermis and mild
perivascular lymphocytic infiltrate with hyperchromatic nuclei, without eosinophils. Few extravasated erythrocytes, (H&E).
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HISTOPATHOLOGIC SPECTRUM OF DRESS
A
B
C
Figure 5.—A, B) Erythroderma-like diffuse reaction (>50%), with late stage HSV-infection on the face; C) Epidermal atrophy with few
necrotic keratinocytes and focal interface changes. Lymphocytic superficial perivascular infiltrate with hyperchromatic nuclei (H&E).
A
B
C
Figure 6.—A, B) Severe and persistent urticarial-like reaction (>50%); C) dense and diffuse lymphocytic superficial perivascular infiltrate, with few necrotic keratinocytes, in touch with lymphocytes, (H&E).
gy was characterized by a dense diffuse lymphocytic
superficial perivascular dermatitis, incipient spongiosis with rare necrotic keratinocytes, surrounded by
lymphocytes (Figure 6C).
Case 7
A 58-year-old female patient developed erythematous confluent oedematous lesions, involving more
than 50% of the body surface and confluent widespread papular eruption (Figure 7A, B). She had a
personal history of amoxicylline + clavulanic acid
treatment for a previous dental work about 20 days
before. The patient was hospitalized for the development of hepatic dysfunction, fever and diffuse
lymphadenopathy. She had a peripheral eosinophilia
13%. A skin biopsy was taken from her right leg.
Histopathology was characterized by compact and
296
basket waved orthokeratosis and parakeratosis, slight
atrophy of the epidermidis, focal interface changes
without necrotic keratinocytes, lymphocytic exocytosis, oedema of the papillary dermis, and a perivascular superficial and mid-dermal lymphocytic infiltrate, with some interstitial changes, vasodilatation
and erythrocytes extravasation. No eosinophils were
detected (Figure 7C).
Case 8
A 76-year-old woman showed an EM-like reaction, involving more than 50% of body surface about
6 weeks after starting therapy with hydroxychloroquine for dermatomyositis (Figure 8A). In few days,
the patient developed hepatic dysfunction and fever,
so she was hospitalized. Her peripheral eosinophilia
was >20%. Histopathology (left forearm), revealed
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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HISTOPATHOLOGIC SPECTRUM OF DRESS
A
BORRONI
B
C
Figure 7.—A, B) Diffuse papular and confluent erythematous and oedematous features (>50%); C) Focal interface changes, without
necrotic keratinocytes, lymphocytic exocytosis, oedema of the papillary dermis, and superficial and mid-dermal lymphocytic infiltrate,
with some eosinophils and extravasation of erythrocytes, (H&E).
A
B
Figure 8.—A) Confluent EM-like lesions, involving more than 50% of the body surface; B) moderate atrophy of the epidermis, focal
interface changes, no necrotic keratinocytes, mild perivascular lymphocytic infiltrate, with eosinophils and erythrocytes extravasation
(left upper arm), (H&E).
moderate atrophy of the epidermis, focal interface
changes, without necrotic keratinocytes, superficial
perivascular lymphocytic infiltrate, with eosinophils,
vasodilatation and moderate erythrocytes extravasation (Figure 8B).
dermis. No eosinophils were detected in the infiltrate
(Figure 9B).
Case 9
On the basis of the clinical classification of DRESS
into four main patterns,1, 14 4 out of 9 patients had
diffuse urticarial and papular eruption, 2 had erythroderma, 2 EM-like reaction and 1 erythematous and
macular pattern. However, at least 6 of our patients
had, to some extent, overlapping mixed features, and
only 3 had either defined papular or urticarial diffuse lesions. Allopurinol (2 cases), carbamazepine (2
cases) and diclofenac, valproic acid, amoxicylline +
clavulanic acid, hydroxychloroquine, perindopril +
indapamide (1 case respectively) were the causative
About a month after starting treatment with perindopril-indapamide, a 65-year-old man developed a
diffuse urticarial and papular eruption and hepatic
dysfunction (Figure 9A). He had peripheral eosinophilia >20%. A skin biopsy from the trunk was
taken, and histopathology revealed slight atrophy of
the epidermis, without necrotic keratinocytes, scant
interface changes, moderately dense lichenoid lymphocytic infiltrate in the papillary and sub-papillary
Vol. 149 - No. 3
Discussion
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HISTOPATHOLOGIC SPECTRUM OF DRESS
A
B
Figure 9.—A) Diffuse urticarial and papular eruption (<50%); B) Irregular acanthosis, no necrotic keratinocytes, focal interface changes and moderately dense lichenoid lymphocytic infiltrate in the papillary and sub-papillary dermis, (H&E).
drugs of DRESS in our series. Hepatic dysfunction
and eosinophilia were found in 100% of the cases,
while fever (>38 °C) was recorded in 6 out of 9 cases and lymphadenopathy in 7 out of 9. Some rarer
clinical features, such as pericarditis and acute pancreatitis, were recorded in cases 4 and 2. None of the
patients died of the disease. In case 9, a particularly
long course was characterized by the resolution of
systemic signs and symptoms, but by the persistence
of an erythroderma-like appearance at several month
after diagnosis of DRESS.
The patient 1 with diffuse macular erythema-
Table II.—Histopathologic changes found in the epidermis and dermis of the 9 DRESS patients.
Case
1
2
3
4
5
6
7
8
9
Sc
%
Av Sc
Necr
KC
0
0
0
2
2
1
0
0
0
5
33.3
0.55
Exoc
Lymph
1
2
0
2
0
1
2
0
0
8
55.5
0.88
Spong
Vesic
1
2
1
3
0
1
0
0
0
8
55.5
0.88
Focal
Interface
Changes
Lymph
Sup Periv
Infiltrate
1
2
1
0
2
0
2
1
1
10
77.7
1.1
3
3
3
1
1
3
2
0
0
16
77.7
1.7
Atyp
Lymph
0
2
2
1
1
0
0
0
0
6
44.4
0.66
Eos
0
0
0
0
0
0
1
2
0
3
22.2
0.33
Lichenoid
infiltrate
0
1
0
0
1
0
0
0
2
4
33.3
0.44
Dilated
blood
vess
1
2
0
1
1
0
2
1
0
8
66.6
0.88
Extrav
erythr
2
1
0
1
0
0
2
1
0
7
55.5
0.77
Score (Sc) expresses the sum of the severity of every single histopathological change out of the total cases considered.
Percentage (%) defines the relationship between the number of the cases showing that specific histopathologic change out of the total number of the
patients considered for that change.
Average Score (Av Sc) represent the ratio between the scoring of a single histopathologic change and the total number of the cases.
Legend:
Necr KC: necrotic keratinocytes.
Exoc Lymph: exocytosis of lymphocytes.
Spong Vesic: spongiosis and vesiculation.
Focal Interface Changes: focal interface changes.
Lymph Sup Periv Infiltrate: lymphocytic superficial perivascular infiltrate.
Atyp Lymph: atypical lymphocytes.
Eos: eosinophils.
Lichenoid infiltrate: lichenoid infiltrate.
Dilated blood vess: dilated blood vessels.
Extrav eryth: extravasation of erythrocytes.
298
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HISTOPATHOLOGIC SPECTRUM OF DRESS
tous eruption had histopathology characterized by
a dense superficial perivascular lymphocytic infiltrate with a mixture of changes of the interface and
spongiosis.
The EM-like clinical presentation had histologically either a dense perivascular superficial infiltrate with focal interface changes and atypical lymphocytes (case 3) and slight focal interface changes
with eosinophils (case 8). None of the 2 cases had
necrotic keratinocytes.
Erythroderma-like pattern (cases 4 and 5) had
both atypical lymphocytes in the dermal infiltrate
and a moderate number of necrotic keratinocytes.
Spongiosis characterized case 4, while focal interface changes characterized mostly case 5.
The urticarial clinical pattern was mostly associated with a superficial perivascular lymphocytic infiltrate (3 out of 4 cases) and spongiosis (2 out of
4) and by focal interface changes (3 out of 4). An
inconstant presence of lichenoid infiltrate, dilated
blood vessels, extravasation of erythrocytes and
necrotic keratinocytes was found in an erratic way
throughout the four cases.
A constant relationship between the clinical type
of DRESS and the histopathologic pattern could not
be traced in our patients. This does not mean that
DRESS has no histopathologic specific changes.
Histopathological features (Table II) were mostly
characterized by focal interface changes, with slight
vacuolar alteration of basal layer (seven out of nine
patients; 77.7%, with an average score of 1.1) and by
a superficial variably dense perivascular lymphocytic
infiltrate (7 out of 9 patients; 77.7%, average score
1.5). Atypical lymphocytes, with hyperchromatic
nuclei, were a relatively common feature, found in
4 out of 9 cases (44.4%, average score 0.66). Spongiosis, as well as exocytosis of lymphocytes, were
both found in 55.5%, average score 0.88. Necrotic
keratinocytes were found only rarely (33.3%, average score 0.55). On the contrary, dilated blood vessels in the upper part of the dermis and a variable degree of extravasation of erythrocytes were found in
about 66% of the cases, with an average score 0.88.
True lichenoid infiltrate was found only in 2 cases.
Eosinophils were surprisingly a rare histopathological finding (2 cases with very few cells), while all
the 9 patients had constant peripheral eosinophilia.
We have no reliable explanation of this dissociation
between the peripheral eosinophilic pattern and the
virtual absence of the eosinophils in the skin.
Vol. 149 - No. 3
BORRONI
Conclusions
Our data cannot confirm a more severe prognosis for patients with EM-like clinical presentation,
as reported by some authors.14 The most severe and
prolonged course characterized, on the contrary, the
erythroderma-like presentation in cases 4 and 5, and
in case 9, who had long lasting erythroderma-like
changes. In those 3 cases, the severe course of the
disease could be referred to a series of several preexisting comorbidities. One of the patients (case 5)
also showed HSV vesiculation and crusting on his
face.
The well known attitude of drugs in inducing
a vast and variegate number of clinical reactions
(erythematous, exanthema-like, urticarial, EMlike, erythrodermal, papular, macular and oedematous, vesico-bullous) and histopathological variants
(spongiotic, bullous, lichenoid, interface dermatitis,
perivascular superficial dermatitis with or without
necrotic keratinocytes), is confirmed by this study
on histology of DRESS. An aspecific diagnosis of
drug induced dermatitis may be suspected and done
on histopathologic grounds alone, but a specific histopathologic diagnosis of DRESS does not seem feasible for the pathologist or the dermatopathologist,
without mandatory and accurate clinical information.
References
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  2. Kano Y, Hirahara K, Asano Y, Shiohara T. HLA-B allele associations with certain drugs are not confirmed in Japanese patients with
severe cutaneous drug reactions. Acta Derm Venereol 2008;88:6168.
  3. Genin E1, Chen DP, Hung SI, Sekula P, Schumacher M, Chang PY
et al. HLA-A*31:01 and different types of carbamazepine-induced
severe cutaneous adverse reactions: an international study and meta-analysis. Pharmacogenomics J 2013 [Epub ahead of print].
  4. McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė
D, Carrington M et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med
2011;364:1134-43.
  5. Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL,
Spreen W et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121-2.
  6. Gonçalo M, Coutinho I, Teixeira V, Gameiro AR, Brites MM, Nunes R
et al. HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and
Stevens-Johnsonsyndrome/toxic epidermal necrolysis in a Portuguese
population. Br J Dermatol 2013;169:660-5.
  7. Amstutz U1, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura
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HISTOPATHOLOGIC SPECTRUM OF DRESS
H et al. Recommendations for HLA-B*15:02 and HLA-A*31:01
genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions. Epilepsia 2014 [Epub ahead of print].
  8. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs.
N Engl J Med 1994;331:1272-85.
  9. Seishima M, Yamanaka S, Fujisawa T, Tohyama M, Hashimoto K.
Reactivation of human herpesvirus (HHV) family members other
than HHV-6 in drug-induced hypersensitivity syndrome. Br J Dermatol 2006;155:344-9.
10. Kano Y, Hiraharas K, Sakuma K, Shiohara T. Several Herpesviruses
can reactivate in a severe drug-induced multiorgan reaction in the
same sequential order as in graft-versus-host disease. Br J Dermatol
2006;155:301-6.
11. Kano Y, Shiohara T. Sequential Reactivation of herpesvirus in
drug-induced hypersensitivity syndrome. Acta Derm Venereol 2004;84:484-5.
12. Kano Y, Horie C, Inaoka M, Tadashi I, Mizukawa Y, Shiohara T.
300
Herpes Zoster in patients with drug-induced hypersensitivity syndrome/DRESS. Acta Derm Venereol 2012;92:206-7.
13. Gerber BO, Pichler WJ. Cellular mechanisms of T cell mediated
drug hypersensitivity. Curr Opin Immunol 2004;16:732-7.
14. Walsh S, Diaz-Cano S, Higgins E, Morris-Jones R, Bashir S, Bernal W et al. Drug reaction with eosinophilia and systemic symptoms: is cutaneous phenotype a prognostic marker for outcome?
A review of clinicopathological features of 27 cases. Br J Dermatol 2013;168:391-401.
15. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, Halevy S, Davidovici
BB, Mockenhaupt M et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS
syndrome really exist? Br J Dermatol 2007;156:609-11.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

G ITAL DERMATOL VENEREOL 2014;149:301-9
Drug-induced lupus erythematosus
A. V. MARZANO, S. TAVECCHIO, C. MENICANTI, C. CROSTI
Drug-induced lupus erythematosus (DI-LE) is defined as an
entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic
lupus but which is temporally related to drug exposure and
resolves after withdrawal of the implicated drug. Similarly to
idiopathic lupus, DI-LE can be divided into systemic LE, subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE)
and cutaneous LE tumidus. DI-SCLE is the most frequent
variant of drug-induced cutaneous LE and presents mainly
with annular-polycyclic lesions; the clinical picture is often
widespread, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are typically present, whereas antihistone antibodies are uncommonly found. We have recently addressed the
question whether DI-SCLE differs significantly from its idiopathic counterpart by virtue of clinical features and, based on
our findings, we have suggested that the frequent occurrence
of malar rash and bullous, erythema multiforme-like and
vasculitic manifestations can be regarded as the hallmark of
DI-SCLE. In contrast, the histology is not a useful diagnostic
criterion for DI-SCLE, considering that the typical pattern of
lichenoid interface dermatitis is seen only in the early stage
of disease and tissue eosinophilia does not represent a differentiating histopathological feature. DI-CCLE and DI-LE
tumidus, albeit possibly misdiagnosed, are rarely observed
and are characterized by classic discoid lesions and erythematous-oedematous plaques on sun exposed areas, respectively.
Management of DI-LE is based on the discontinuation of the
offending drug; topical and/or systemic corticosteroids and
other immunomodulating/immunosuppressive agents should
be reserved for resistant cases.
Key words: Lupus erythematosus - Antibodies, antinuclear Antibodies - Dermatitis - Drug eruptions.
Corresponding author: A. V. Marzano, Operative Unit of Dermatology, Department of Pathophysiology and Transplantation, University of
Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,
via Pace 9, 20122 Milan, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
Operative Unit of Dermatology
Department of Pathophysiology and Transplantation
University of Milan, Fondazione IRCCS Ca’ Granda
Ospedale Maggiore Policlinico, Milan, Italy
D
rug-induced lupus erythematosus (DI-LE) was
first reported in 1945 in association with sulfadiazine.1 It is defined by the following diagnostic
criteria: 1) absence of signs and symptoms of lupus
erythematosus (LE) before exposure to a drug; 2)
appearance of one or more clinical manifestations
of LE in combination with antinuclear antibodies
(ANA) positivity after exposure to it; 3) resolution
of clinical symptoms accompanied by reduction or
reverting to normal of ANA titers following drug
withdrawal; 4) and recurrence of symptoms once
the implicated drug is retaken.2 There are a number
of reports in literature concerning patients with preexisting LE in whom the drug acts as a factor inducing exacerbation of the disease or unmasking latent
lupus; in these cases, there is lack of resolution of
LE symptoms and signs in spite of drug discontinuation.3, 4 As for idiopathic LE, DI-LE may present
with systemic symptoms (with or without cutaneous
manifestations) or with predominant skin involvement; the cutaneous variants include subacute cutaneous lupus erythematosus (SCLE) and chronic
cutaneous lupus erythematosus (CCLE) or discoid
LE; there are only few reported cases of cutaneous
lupus erythematosus tumidus (DI-LE tumidus) induced by drugs.3-7 This review discusses the dermatological aspects of DI-LE, focusing on its cutaneous
variants, particularly the most common presentation,
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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MARZANO
Drug-induced lupus erythematosus
DI-SCLE, suggesting that the latter differs clinically
from the idiopathic counterpart; moreover, we provide an update on postulated pathomechanisms for
the DI-SCLE skin lesion and DI-LE in general as
well as on triggering drugs.
Pathogenesis of DI-LE
The pathogenesis of DI-LE is not fully understood
yet and available data suggest that there is no single mechanism responsible for the induction of autoimmunity. Four main pathomechanisms have been
hypothesized:8 1) the drug (or its metabolite) binds
itself to a “self” protein making it “foreign” and
triggering an autoreactive immune response against
this autoantigen by virtue of the so-called molecular
mimicry phenomenon;9 2) reactive drug metabolites
cause cell death by direct cytotoxicity;10, 11 3) disruption of the central immune tolerance occurs;12,
13 4) autoreactive T-lymphocytes develop owing to
DNA hypomethylation;14, 15 all the aforesaid pathomechanisms could co-exist and cross-talk. Some
drugs such as anti-tumor necrosis factor (TNF)-alpha agents deserve a separate discussion. Indeed, it
has been suggested that these drugs alter the regulatory role of TNF-alpha on antigen presenting cells,
inhibiting apoptosis of potentially autoreactive T
cells;16 in addition, TNF-alpha blockers could impair the activity of cytotoxic T cells with functions
of immunosurveillance, leading to production of
pathogenic autoantibodies.14, 17 Another hypothesis
is that these drugs inhibit the function of regulatory
T (Treg) lymphocytes which are responsible for immunosurveillance. It has also been demonstrated that
during treatment with TNF-alpha antagonists there is
a reduced expression of CD44 antigen, which contributes to inducing apoptosis of autoreactive T cells.
Moreover, the inhibition of T helper (Th) 1 immune
response by anti-TNF-alpha agents can determine a
shift to a predominantly Th2 response; finally, infections in patients under anti-TNF-alpha therapy may
lead to a polyclonal activation of B cells with consequent production of autoantibodies.18, 19
Pathogenesis of DI-SCLE skin lesion
The pathogenesis of the DI-SCLE skin lesion remains speculative too. Immune response to skin an-
302
tigens modified by drugs (or ultraviolet radiations)
and Fas-dependent apoptosis of epidermal basal keratinocytes are currently proposed as pathomechanisms for inducing and perpetuing skin lesions in
SCLE,20-22 as well as in other drug-induced immunemediated cutaneous disorders such as StevensJohnson syndrome, toxic epidermal necrolysis and
erythema multiforme (EM).23 The release of soluble
pro-inflammatory epidermal and dermal mediators
(which may be genetically regulated) and increased
expression of cellular adhesion molecules on keratinocytes and subepidermal endothelial cells are also
involved. In particular in SCLE, nuclear antigens
such as Ro/SSA, translocated to the keratinocyte
surfaces, possibly involving the heat-shock proteins
are targeted by circulating anti-Ro/SSA antibodies
and cytotoxic T cells. These mechanisms are able to
upregulate cellular apoptosis.24 An additional pathomechanism may consist in a reduced expression of
Bcl-2, a protein known as blocking apoptosis, which
has been demonstrated by means of immunohistochemical methods along the epidermal basal layer in
lesional skin from patients with LE compared with
normal skin.22 Low number of Treg cells has recently been demonstrated in skin lesions of patients with
cutaneous LE,25 suggesting that a defective global
function of these cells may trigger a crescendo of
autoimmunity potentially culminating in the skin illness. In fact, Treg lymphocytes are responsible for
immunologic self-tolerance by suppressing potentially autoreactive T cells. Thus, although the exact
role of the offending drug in triggering keratinocyte
apoptosis and recruiting inflammatory cells into the
DI-SCLE skin lesion remains to be elucidated, the
above findings suggest that the extent of both epidermal apoptosis and inflammation may correlate with
the chronological development and severity of LE
skin lesions.
DI-SCLE
Idiopathic SCLE was recognized in 1979 as a distinct subtype of cutaneous LE with unique clinical,
immunological and genetic features.26, 27 Clinically,
SCLE typically presents with nonscarring annular
or papulosquamous eruptions on sun exposed skin,
mainly the upper back, chest, dorsal arms and lateral
neck. However, a number of unusual variants have
been described, including pityriasiform, bullous,
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Drug-induced lupus erythematosus
erythrodermic, poikilodermatous, toxic epidermal
necrolysis-like and erythema multiforme (EM)-like
subtypes.28-33 Anti-Ro/SSA antibodies are classically
regarded as the serological marker for this subset.34,
35 DI-SCLE was described for the first time in 1985
by Reed et al.36 in association with hydrochlorothiazide; they reported 5 patients with DI-SCLE, one of
whom was affected by systemic LE since 25 years
without skin lesions and another one complained
of arthralgias.36 Several drugs have been reported
as causative agents of DI-SCLE, including antihypertensive drugs such as diuretics, calcium channel
blockers and angiotensin converting enzyme inhibitors, antifungals such as terbinafine,37-39 statins and
chemotherapeutics;16, 40-47 recently, there were several reported cases of SCLE induced by TNF-alpha
antagonists and their number is progressively increasing 48, 49 (Table I). From a meta-analysis of the
literature published by Lowe et al. in 2011 50 comes
that there were 117 reported cases of DI-SCLE with
a prevalence in females (72% of cases) and a mean
age at disease onset of 58 years; in this study, the
mean incubation period for all drug classes combined was 27.9 weeks (range: 3 days to 11 years) and
the mean overall time to resolution of DI-SCLE after
drug discontinuation was 7.3 weeks (range: 1 week
to 32 weeks). These authors concluded that there
was adequate published experience to suggest that
DI-SCLE did not differ clinically, histopathologi-
MARZANO
cally or immunologically from idiopathic SCLE.50
We have seen and followed-up in our department 11
cases of DI-SCLE between 2001 and 2010, whose
clinical features, immunological findings, course
and therapy are summarized in Table II. The cutaneous features were compared with those of our 79
patients with idiopathic SCLE to address the question whether DI-SCLE differs significantly from its
idiopathic counterpart.51
Clinical manifestations
Unlike the literature data coming from the metaanalysis by Lowe et al.,50 DI-SCLE manifested as
widespread skin lesions involving also lower extremities in nine out of eleven patients of our case
series (82%), while generalized involvement was
observed in only five out of our 79 patients with
idiopathic SCLE (6%).51 In eight patients (73%),
DI-SCLE presented with annular-polycyclic eruptions, while in two patients it was characterized
by papulosquamous lesions (18%); coexistence of
annular-polycyclic and papulosquamous features
was observed in only one patient (9%). Unlike the
data reported by Lowe et al.,50 in our case series DISCLE significantly differed from idiopathic SCLE
by virtue of distinctive cutaneous features, particularly the frequent occurrence of malar rash and bullous, EM-like and vasculitic manifestations. Indeed,
Table I.—Drugs associated with drug-induced subacute cutaneous lupus erythematosus.
Thiazidic diuretics
Calcium channel blockers
ACE inhibitors
β-blockers
Statins
Biologics
Antibiotics
Chemotherapics
Antifungals
NSAIDs
Antidepressant
Proton pump inhibitors
Anticonvulsants
Antiaggregants
Immunosuppressants
Antihistamines
Antiemetics
Ranitidine
Hydroclorothiazide
Diltiazem, verapamil, nifedipine, nitrendipine
Cilazapril
Acebutolol
Simvastatin
TNF-α antagonists (infliximab, etanercept, adalimumab, golimumab), efalizumab, rituximab
Rifabutin/rifamycin, doxycycline
Gemcitabine, doxorubicin, capecitabine, fluorouracil, tamoxifen, docetaxel, paclitaxel, interferon β,
interferon α, leuprorelin
Terbinafine, griseofulvin
Piroxicam, naproxen
Bupropion
Lansoprazole, pantoprazole, esomeprazole, omeprazole
Carbamazepine, sodium valproate, lamotrigine, phenytoin
Ticlopidine
Leflunomide
Cinnarizine
Thiethylperazine
ACE: angiotensin converting enzyme; NSAID: non-steroidal anti-inflammatory drugs; TNF: tumor necrosis factor.
Vol. 149 - No. 3
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Drug-induced lupus erythematosus
Table II.—Summary of the clinical features, immunological findings, course and treatment in our 11 cases of drug-induced subacute
cutaneous lupus erythematosus (modified from Marzano AV et al.51).
Patient Sex
Age at
onset
(years)
Offending drug
Incubation
time
(weeks)
Cutaneous
features
Annularpolycyclic;
bullous
Annularpolycyclic;
bullous;
EM-like;
malar rash
Papulosquamous
Annularpolycyclic;
bullous;
purpuric;
malar rash
Annularpolycyclic;
EM-like;
purpuric;
malar rash
Annularpolycyclic;
EM-like;
purpuric;
malar rash
Annularpolycyclic;
EM-like;
malar rash
Annularpolycyclic;
bullous;
purpuric and
necroticulcerative
Annularpolycyclic;
bullous;
EM-like;
purpuric and
necroticulcerative
Papulosquamous
Annularpolycyclic/
papulosquamous
overlap
1
M
66
Nitrendipine
3
2
F
24
Leflunomide
3
3
F
70
Etanercept
3
4
M
60
Piroxicam
3
5
F
80
Allopurinol
4
6
M
62
Amoxicillin plus
clavulanic acid
2
7
F
72
Hydroxychloroquine
6
8
F
85
Ramipril
4
9
M
90
Carbamazepine
2
10
F
68
Enalapril
6
11
F
58
Hydroxychloroquine
6
Immunological
findings
Treatment
Resolution
time
(weeks)
Follow-up
(years)
ANA; Ro/SSA;
La/SSB; AHA;
Sm; aCL; LAC
ANA
None
4
9
Pred
3
4
ANA; Ro/SSA
None
3
4
ANA; Ro/SSA
Pred
24
5
ANA; Ro/SSA
None
3
3
Absent
ANA; Ro/SSA;
La/SSB; AHA
None
3
2
Absent
ANA; Ro/SSA;
La/SSB
None
8
3
Absent
ANA; Ro/SSA;
La/SSB; RNP;
Scl-70
None
8
1
Absent
ANA; Ro/SSA;
La/SSB; aCL
Pred
10
1
ANA; Ro/SSA
None
4
6
ANA; Ro/SSA
None
4
5
Extracutaneous
involvement
Absent
Absent
Absent
Absent
Absent
Absent
Absent
M: male, F: female; EM: erythema multiforme; ANA: antinuclear antibodies; Ro/SSA: Ro/Sjögren’s syndrome associated antigen; La/SSB: La/Sjögren’s
syndrome associated antigen B; AHA: antihistone antibodies; aCL: anticardiolipin antibodies; LAC: lupus anticoagulant; RNP: anti-ribonucleoprotein
antibodies; Sm: Smith antigen; pred: oral prednisone.
bullous lesions, typically occurring over the edge of
annular-polycyclic eruptions (Figure 1A), were observed in five of 11 patients with DI-SCLE (45%)
and in only one patient with idiopathic SCLE (1%).
304
Five of 11 patients with DI-SCLE (45%) presented
with targetoid EM-like lesions (Figure 1B), which
were present in only one patient with idiopathic
SCLE (1%). Vasculitic manifestations, namely only
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Drug-induced lupus erythematosus
purpuric (Figure 1C) or purpuric and necrotic-ulcerative lesions, on the lower legs were seen in five of
11 patients with DI-SCLE (45%); in contrast, only
two of 79 patients with idiopathic SCLE (3%) exhibited vasculitic lesions. Finally, malar rash (Figure
1D) was evident in five of 11 patients with DI-SCLE
(45%), while it was seen in five of 79 patients with
the idiopathic counterpart (6%). As regards systemic
symptoms and signs, arthralgias or arthritis, serositis
and other visceral involvement as well as Raynaud
phenomenon were lacking in all our 11 patients with
DI-SCLE; on the other hand, in none of the 11 patients were the American College of Rheumatology
criteria 52 for the diagnosis of systemic LE fulfilled.51
Histopathological aspects
In the early stages of disease, skin biopsy specimens taken from both annular-polycyclic and papulosquamous lesions show a typical pattern of lichenoid interface dermatitis: it consists in an upper
dermal lympho-histiocytic infiltrate invading the dermoepidermal junction with hydropic degeneration of
the epidermal basal cell layer; numerous necrotic keratinocytes are also present (Figure 2A). In papulosquamous lesions there is also psoriasiform hyperplasia of the epidermis. Dermoepidermal detachment
is seen in patients having annular-polycyclic lesions
associated with blisters. In EM-like lesions, the histological picture is similar to that found in DI-SCLE
but with stronger hydropic degeneration of the basal
layer. Purpuric as well as necrotic-ulcerative lesions
reveal typical histopathological features of leukocytoclastic vasculitis. In the late stages of disease,
nonspecific changes are usually observed, namely
mononuclear cell inflammatory infiltrates in the upper dermis without epidermal alterations.51 Some
authors have recently reviewed skin biopsy specimens of 59 patients with SCLE, 15 of whom were
drug-induced and 44 idiopathic, concluding that tissue eosinophilia does not represent a differentiating
histopathological feature of DI-SCLE.53
MARZANO
Laboratory findings
It is well known that SCLE is characterized by distinctive immunological profile consisting in positivity
of ANA (81-100% of cases) and Ro/SSA (81-90% of
cases); SSB/La positivity is observed in a lesser percentage of cases (45-48%);3, 50, 51 antihistone antibodies can be detected in 33% of cases and, unlike druginduced systemic LE, are not considered a serological
marker of DI-SCLE.54, 55 According to Lowe et al.,50
anti-Ro/SSA antibodies, re-evaluated in clinical remission, remain positive in 66.7% of cases; in our case
series however, these autoantibodies were negative in
73% of patients when re-assessed at least one year after
DI-SCLE resolution.51 Antidouble stranded (ds) DNA
antibodies are usually absent, whereas anticardiolipin
antibodies in combination with anti-beta2-glycoprotein I and lupus anticoagulant have been found in one
case reported by ourselves.56 Anemia, leukopenia and
thrombocytopenia are rarely reported.3, 51
Treatment and course
The management of DI-SCLE consists in the discontinuation of the implicated drug. Pharmacological treatment should be reserved for either severe or
refractory cases, these last sometimes representing a
preexisting lupus exacerbated by the offending drug.
Systemic corticosteroids at the doses commonly used
for idiopathic SCLE are the first-choice therapy; topical steroids and/or hydroxychloroquine may be associated. In more resistant cases, other immunomodulating/immunosuppressive agents such as thalidomide,
azathioprine, cyclophosphamide or mycophenolate
can be used.3 In our case series, DI-SCLE healed upon
drug discontinuation after a mean resolution time of
7 weeks (range 3–24); the three patients showing the
most severe clinical presentation were given oral prednisone 0.5 mg/kg/day at progressively tapering dosages until stopping after SCLE resolution. At the time of
writing, all patients were alive and free of disease after
a mean time of follow-up of 4 years (range 1-9), with
neither relapses nor evolution into idiopathic systemic
LE having occurred.51
Direct immunofluorescence features
Direct immunofluorescence on sun exposed skin
usually reveals granular deposits of immunoglobulin
(Ig) M (Figure 2B) and/or IgG and/or complement
(C) 3 at the dermoepidermal junction.51
Vol. 149 - No. 3
DI-CCLE
DI-CCLE is a rare entity originally reported as
caused by fluororuracile agents like tegafur and
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MARZANO
Drug-induced lupus erythematosus
A
C
B
D
Figure 1.—A) Bullae evolved in crusts covering the edge of annular polycyclic lesions on the lower extremities in a patient with druginduced subacute cutaneous lupus erythematosus (DI-SCLE); B-D) DI-SCLE patients. Targetoid erythema multiforme-like lesions extensively involving the back and gluteal regions (B). Vasculitic features manifesting as purpura on the legs (C). Typical malar rash (D).
306
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Drug-induced lupus erythematosus
A
MARZANO
B
Figure 2.—A) Skin biopsy specimens taken from a patient with drug-induced subacute cutaneous lupus erythematosus (DI-SCLE)
showing a lichenoid interface dermatitis histopathological pattern (hematoxylin-eosin stain; original magnification, x 200); B) direct
immunofluorescence studies on sun exposed lesional skin of a DI-SCLE patient revealing immunoglobulin (Ig) M deposits along the
dermoepidermal junction (fluoresceine isothiocyanate stain; original magnification, x 200).
uraciltegafur (UFT).57 More recently, some cases triggered by TNF-alpha antagonists, such as infliximab
or etanercept, have been described.4, 16, 44-47, 58 The
clinical features are those of the idiopathic counterpart, namely classic discoid lesions presenting with
a photosensitive distribution on the face, upper trunk
and arms. Systemic symptoms such as fever, arthralgia or myalgia are typically lacking. Concerning immunological findings, ANA have been reported to
be present in 66% of cases whereas anti-extractable
nuclear antigen (ENA) and anti-dsDNA antibodies
are usually absent as well as antihistone antibodies.
As for idiopathic CCLE, anaemia, leukopenia and
thrombocytopenia are generally not found.3
Treatment and course of DI-CCLE and DI-LE tumidus
The treatment of choice for DI-CCLE and DI-LE
tumidus consists in the withdrawal of the implicated
drug. Cutaneous manifestations usually heal within
8 weeks; sometimes the complete resolution can be
slower, making useful a drug treatment. Hydroxychloroquine at the doses commonly used for the
idiopathic counterparts, in combination with topical corticosteroids, is the first-line therapy. Systemic
corticosteroids or thalidomide can be used in resistant cases.3
Conclusions
DI-LE tumidus
To the best of our knowledge, only six cases of
DI-LE tumidus presenting with typical erythematous-oedematous plaques on sun exposed areas have
been reported: three cases were due to TNF-alpha
blockers, two triggered by bortezomib, a proteasome
inhibitor approved for the treatment of multiple myeloma, and another one occurred following assumption of an angiotensin-converting enzyme inhibitor.
Extracutaneous involvement was lacking in all the
aforesaid cases.4, 47, 58-62
Vol. 149 - No. 3
DI-SCLE is the most frequent variant of druginduced cutaneous LE and presents mainly with
annular-polycyclic manifestations; the clinical
picture is often generalized, with involvement of
the lower legs that are usually spared in idiopathic
SCLE. ANA and anti-Ro/SSA antibodies are usually present, whereas antihistone antibodies are
uncommonly found. We have recently addressed
the question whether DI-SCLE differs significantly
from its idiopathic counterpart by virtue of clinical aspects and, on the basis of our findings, we
have suggested that the frequent occurrence of ma-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
307
MARZANO
Drug-induced lupus erythematosus
lar rash and bullous, EM-like and vasculitic manifestations can be considered distinctive features
marking the drug-induced variant. In contrast, the
histology is not a verifying criterion for DI-SCLE,
considering that the typical pattern of lichenoid interface dermatitis is seen only in the early phase of
disease. DI-CCLE, albeit possibly misdiagnosed, is
rarely observed and its picture is characterized by
the occurrence of classic discoid lesions typically
involving sun exposed sites; aspects of lupus tumidus, whose actual incidence may also be underestimated, have rarely been reported, particularly
in patients treated with TNF-alpha antagonists. In
conclusion, although DI-SCLE seems to represent
a subset different clinically from the idiopathic
counterpart, careful review of a patient’s drug history in correlation with clinical findings remains
the standard for identifying a drug as an etiologic
or exacerbating factor in patients with LE.
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15.Yung R, Chang S, Hemati H, Johnson KJ, Richardson BC. Mechanism of drug-induced lupus. Comparison of procainamide and
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16. Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to
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17.Yung R, Powers D, Johnson K, Amento E, Carr D, Laing T et
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18. William EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus.
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19. Caramaschi P, Biasi D, Colombatti M, Pieropan S, Martinelli N,
Carletto A et al. Anti-TNFalpha therapy in rheumatoid arthritis and
autoimmunity. Rheumatol Int 2006;26:209-14.
20. Bennion SD, Middleton MH, David-Bajar KM, Brice S, Norris DA.
In three types of interface dermatitis, different patterns of expression of intercellular adhesion molecule-1 (ICAM-1) indicate different triggers of disease. J Invest Dermatol 1995;105:71-9.
21. Norris D, Bennion S, David-Bajar K. Pathomechanisms of cutaneous lupus erythematosus. In: Wallace DJ, Hahn BH, editors.
Dubois’ lupus erythematosus. 5th ed. Baltimore, MD: Williams &
Wilkins; 1997. p. 549-67.
22. Baima B, Sticherling M. Apoptosis in different cutaneous manifestations of lupus erythematosus. Br J Dermatol 2001;144:958-66.
23. Marzano AV, Frezzolini A, Caproni M, Parodi A, Fanoni D, Quaglino P et al. Immunohistochemical expression of apoptotic markers
in drug-induced erythema multiforme, Stevens–Johnson syndrome
and toxic epidermal necrolysis. Int J Immunopathol Pharmacol
2007;20:557-66.
24. Nyberg F, Stephansson E. The role of T cells and adhesion molecules in cutaneous lupus erythematosus. In: Kuhn A, Lehmann P,
Ruzika T, editors. Cutaneous lupus erythematosus. Berlin: Springer-Verlag; 2005. p. 267-81.
25. Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J et
al. Low number of regulatory T cells in skin lesions of patients with
cutaneous lupus erythematosus. Arthritis Rheum 2007;56:191020.
26. Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus
erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979;115:1409-15.
27. Sontheimer RD, Maddison PJ, Reichlin M, Jordon RE, Stastny P,
Gilliam JN. Serologic and HLA associations in subacute cutaneous
lupus erythematosus, a clinical subset of lupus erythematosus. Ann
Intern Med 1982;97:664-71.
28. Sontheimer RD. Subacute cutaneous lupus erythematosus. A quarter century’s perspective. In: Sarzi-Puttini P, Doria A, Girolomoni
G, Kuhn A, editors. The skin in systemic autoimmune disease. Amsterdam: Elsevier; 2006. p. 65-86.
29. Marzano AV, Facchetti M, Alessi E. Poikilodermatous subacute cutaneous lupus erythematosus. Dermatology 2003;207:285-90.
30. Marzano AV, Berti E, Gasparini G, Caputo R. Lupus erythematosus
with antiphospholipid syndrome and erythema multiforme-like lesions. Br J Dermatol 1999;141:720-4.
31. Caproni M, Cardinali C, Salvatore E, Fabbri P. Subacute cutaneous
lupus erythematosus with pityriasis-like cutaneous manifestations.
Int J Dermatol 2001;40:59-62.
32. Torchia D, Caproni M, Massi D, Chella A, Fabbri P. Paraneoplastic
toxic epidermal necrolysis-like subacute cutaneous lupus erythematosus. Clin Exp Dermatol 2010;35:455-6.
33. Aydogan K, Karadogan S, Balaban Adim S, Tunali S. Lupus erythematosus associated with erythema multiforme: report of two
cases and review of the literature. J Eur Acad Dermatol Venereol
2005;19:621-7.
34. Lee LA, Roberts CM, Frank MB, McCubbin VR, Reichlin M. The
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autoantibody response to Ro/SSA in cutaneous lupus erythematosus. Arch Dermatol 1994;130:1262-8.
35. Marzano AV, Lazzari R, Polloni I, Boneschi V, Crosti C. Rosacealike cutaneous lupus erythematosus: an atypical presentation responding to antimalarials. Acta Derm Venereol 2013;93:106-7
36. Reed BR, Huff JC, Jones SK, Orton PW, Lee LA, Norris DA. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985;103:49-51.
37. Bonsmann G, Schiller M, Luger TA, Stander S. Terbinafine-induced
subacute cutaneous lupus erythematosus. J Am Acad Dermatol
2001;44:925-31.
38. Farhi D, Viguier M, Cosnes A, Reygagne P, Dubertret L, Revuz J
et al. Terbinafine-induced subacute cutaneous lupus erythematosus.
Dermatology 2006;212:59-65.
39. Callen JP, Hughes AP, Kulp-Shorten C. Subacute cutaneous lupus
erythematosus induced or exacerbated by terbinafine: a report of 5
cases. Arch Dermatol 2001;137:1196-8.
40. Cassis TB, Callen JP. Bupropion-induced subacute cutaneous lupus
erythematosus. Australas J Dermatol 2005;46:266-9.
41. Fenniche S, Dhaoui A, Ammar FB, Benmously R, Marrak H,
Mokhtar I. Acebutolol-induced subacute cutaneous lupus erythematosus. Skin Pharmacol Physiol 2005;18:230-3.
42. Dam C, Bygum A. Subacute cutaneous lupus erythematosus induced or exacerbated by proton pump inhibitors. Acta Derm Venereol 2008;88:87-9.
43. Marzano AV, Ramoni S, Del Papa N, Barbareschi M, Alessi E.
Leflunomide-induced subacute cutaneous lupus erythematosus with
erythema multiforme-like lesions. Lupus 2008;17:329-31.
44. DeBandt M, Sibilia J, Le Loet X, Prouzeau S, Fautrel B, Marcelli C
et al. Systemic lupus erythematosus induced by anti tumor necrosis
factor alpha therapy: a French national survey. Arthritis Res Ther
2005;7:R545-51.
45. Bentley DD, Graves JE, Smith DI, Hefferman MP. Efalizumabinduced subacute cutaneous lupus erythematosus. J Am Acad Dermato 2006;54:S242-3.
46. Spillane AP, Xia Y, Sniezek PJ. Drug-induce lupus erythematosus in a patient treated with adalimumab. J Am Acad Dermatol
2007;56:S114-6.
47. Chen JK, Chen TS, Lim P, Iqbal M. Drug-induced subacute cutaneous lupus erythematosus associated with doxorubicin. J Am Acad
Dermatol 2012;67:273-5.
48. Marzano AV, Borghi A, Meroni PL, Crosti C, Cugno M. Immunemediated inflammatory reactions and tumors as skin side effects of
inflammatory bowel disease therapy. Autoimmunity 2014 [E-pub
ahead of print].
49. Wilkerson E, Hazey MA, Bahrami S, Callen JP. Golimumab-exacerbated subacute cutaneous lupus erythematosus. Arch Dermatol
2012;148:1186-90.
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50. Lowe G, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A
systematic review of drug-induced subacute cutaneous lupus erythematosus. Br J Dermatol 2011;164:465-72.
51. Marzano AV, Lazzari R, Polloni I, Crosti C, Fabbri P, Cugno M.
Drug-induced subacute cutaneous lupus erythematosus: evidence
for differences from its idiopathic counterpart. Br J Dermatol
2011;165:335-41.
52. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF
et al. The 1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 1982;25:1271-7.
53. Hillesheim PB, Bahrami S, Jeffy BG, Callen JP. Tissue eosinophilia.
Not an indicator of drug-induced subacute cutaneous lupus erythematosus. Arch Dermatol 2012;148:190-3.
54. Sontheimer RD, Henderson CL, Grau RH. Drug-induced subacute
cutaneous lupus erythematosus: a paradigm for bedside-to-bench
patient-oriented translational clinical investigation. Arch Dermatol
Res 2009;301:65-70.
55. Callen JP. Drug-induced cutaneous lupus erythematosus, a distinct
syndrome that is frequently unrecognized. J Am Acad Dermatol
2001;45:315–6.
56. Marzano AV, Borghi A, Mercogliano M, Facchetti M, Caputo R.
Nitrendipine-induced subacute cutaneous lupus erythematosus. Eur
J Dermatol 2003;13:213-6.
57.Yoshimasu T, Hiroi A, Uede K, Furukawa F. Discoid lupus erythematosus (DLE)-like lesion induced by uracil. Eur J Dermatol
2001;11:54-7.
58. Vezzoli P, Violetti SA, Serini SM, Muratori S, Berti E, Crosti C. Cutaneous lupus erythematosus induced by adalimumab. J Dermatol
2011;38:283-4.
59. Aguayo-Leiva I, Vano-Galvan S, Carrillo-Gijon R, Jaén-Olasolo
P. Lupus tumidus induced by bortezomib not requiring discontinuation of the drug. J Eur Acad Dermatol Venereol 201;24:13634.
60. Schneider SW, Staender S, Schlüter B, Luger TA, Bonsmann G.
Infliximab-induced lupus erythematosus tumidus in a patient with
rheumatoid arthritis. Arch Dermatol. 2006;142:115-6.
61. Schepis C, Lentini M, Siragusa M, Batolo D. ACE-inhibitorinduced drug eruption resembling lymphocytic infiltration (of
Jessner-Kanof) and Lupus erythematosus tumidus. Dermatology
2004;208:354-5.
62. Böckle BC, Baltaci M, Weyrer W, Sepp NT. Bortezomib-induced
lupus erythematosus tumidus. Oncologist 2009;14:637-9.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
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G ITAL DERMATOL VENEREOL 2014;149:311-6
Inflammatory/infectious cutaneous side effects of biological drugs
in patients with psoriasis: a general review with personal data
F. RONGIOLETTI 1, 2, M. BURLANDO 1, 2, A. PARODI 1, 2
In recent years, the use of biologic drugs has greatly changed
the therapy of psoriasis and psoriatic arthritis, but they have
some adverse effects. In particular, skin lesions induced by
anti-tumor necrosis factor (TNF) and anti-interleukin (IL)
12/23 drug (ustekinumab) have been reported with an increased incidence, highlighting the importance of the skin as
a major target of the side effects of these drugs. There is a
wide spectrum of skin lesions of different morphology and
etiology that includes skin lesions directly related to drug
administration, the development of cutaneous immune-mediated conditions and cutaneous infections. The aim of this
review is to revisit the literature data on inflammatory/infectious skin adverse effects of biologics both anti-TNF-α inhibitors and anti-IL 12/23 antagonists and to report and update
our personal data on inflammatory/infectious side effects in
patients with psoriasis/psoriatic arthritis treated with biologics.
Key words: Biological products - Drug-related side effects and
adverse reactions - Psoriasis.
T
he advent of biological drugs such as anti-tumor
necrosis factor (TNF)-a and anti-interleukin (IL)
12/23 inhibitors in recent years has provided an important armamentarium in the treatment of various
dermatologic diseases, especially psoriasis.1 However, even if well tolerated, increasing use of these
medications in clinical practice has led to the recognition of a variety of dermatologic adverse drug
reactions. There is a wide spectrum of skin lesions of
different morphology and etiology induced by biologics that includes skin lesions directly related to
drug administration, the development of cutaneous
Corresponding author: F. Rongioletti, MD, Clinica Dermatologica,
Viale Benedetto XV 7, Genoa, Italy. E-mail: [email protected]
Vol. 149 - No. 3
1IRCCS,
San Martino‑IST University Hospital
Genoa, Italy
2Section of Dermatology
DISSAL University of Genoa, Genoa, Italy
immune-mediated conditions and cutaneous infections (Table I).
This paper is divided into two parts. The first is
a general review of all the inflammatory/infectious
dermatologic side effects related to biological drugs
including both anti-TNF-a and anti CD 12/23 inhibitors. The second part deals with our personal experience with the inflammatory/infectious skin adverse
reactions observed in treating psoriatic patients at the
Section of Dermatology, University of Genoa, Italy
by both anti-TNF-a blockers (infliximab, etanercept,
adalimumab, golimumab) and IL-12/23 antagonist
(ustekinumab).
Overview of cutaneous adverse events
related to TNF-α inhibitors
The main inflammatory skin adverse reactions
reported during therapy with anti-TNF-a inhibitors
are “toxic/allergic” reactions and immune-mediated
skin diseases, “autoimmune” skin diseases including
interface dermatitis (lichenoid reactions, erythema
multiforme, lupus and lupus-like disease), cutaneous
vasculitis, bullous diseases, granulomatous dermatitis, eczematous reactions (atopic-like dermatitis), alopecia and psoriasiform dermatitis, which represents
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INFLAMMATORY SIDE EFFECTS OF BIOLOGICS IN PATIENTS WITH PSORIASIS
Table I.—Main cutaneous adverse events associated to treat‑
ment with TNF-alpha antagonists.
1.Skin lesions related to the administration of treatment
–– Toxic/allergic reactions
–– Acute infusion reactions
–– Delayed exanthematous rash
–– Injection site reactions
2.Immune-mediated diseases
–– New onset psoriasis and exacerbation of prior psoriasis
–– Eczematous reactions (atopic-like dermatitis)
–– Lupus-like syndromes and cutaneous lupus
–– Vasculitis
–– Lichenoid reaction
–– Erythema multiforme, Stevens-Johnson syndrome
–– Alopecia areata/psoriasiform alopecia
–– Granulomatous reactions (sarcoid-like)
–– Bullous diseases
–– Miscellanea
3.Cutaneous infections
–– Bacterial infections: cellulitis, folliculitis
–– Viral infections: herpes zoster, herpes simplex
–– Fungal infections: candidiasis, pityriasis versicolor
a paradoxical side effect.2, 3 Each cutaneous eruption
improved or resolved with switching to a different
TNF-a inhibitor, discontinuation of the anti-TNF-a
agent, and/or topical or systemic steroids. The mechanism for such diverse cutaneous eruptions among
this class of medications remains poorly understood.
The spectrum of cutaneous injections is quite variable, depending on the type of TNF-a blocker used
and include bacteriae, viral, fungal and protozoan
infection.
Skin lesions related to the administration of treat‑
ment
Toxic/allergic reactions
The most frequent side effects of TNF-α inhibitor
drugs are: i) acute infusion reactions and delayed exanthematous rash with infliximab; and ii) injection
site reactions (ISRs) to subcutaneously administered
etanercept, adalimumab and golimumab.
Infusion reactions to infliximab occurs in 16%
of treated patients compared with 6% of placebo.
The acute reaction occurs during or within 24 hours
while the delayed reaction occurs from 24 hours to
14 days after administration. The risk is also linked
to the presence of human antichimeric antibodies but
may be lessened by concomitant use of methotrexate, azathioprine. Most of these reactions are mild or
312
moderate with hypertension, pruritus, sudden flush,
vomiting, tachycardia or bradycardia, shivers and fever. Only few reactions are severe and are characterized by urticaria, Quincke’s edema, tickling throat,
dyspnea, and hypotension. In the former, reducing
the infusion rate to 60-80 mL/h (20-30 drops/min)
led to disappearance of symptoms while in the latter
the infusion should be immediately stopped giving
appropriate drugs (steroids, adrenaline).4
Patients treated with TNF-α inhibitors such as
etanercept, adalimumab and golimumab can develop
ISRs around the sites of injections. The mechanism
resides mainly in type IV delayed type reaction with
recruitment of CD8+ cytotoxic lymphoid cells (TH1lymphocyte- reaction). Well syndrome-like reaction
with dermal infiltrate of eosinophils and recall ISRs
have also been reported. Recall ISRs are reaction at
sites where anti-TNF-a was previously injected after
the last injection. Biopsy specimens from recall ISRs
demonstrates that the dermal infiltrate was predominantly composed of CD4+ T lymphocytes. Clinically, these reactions consist of erythema, edema,
pruritus, pain, indurated plaque and occur within the
first 2 months, usually 1 to 2 days after the last injection and heals within a few days. Discontinuation of
therapy is usually not necessary.5, 6
Long-term studies are necessary to determine the
durability of response and the real risk of ISRs with
golimumab and certolizumab pegol.7
Immune-mediated disorders
The use of anti-TNF-α is associated with a growing number of autoimmune or immune-mediated
diseases which include psoriasiform reactions, interface dermatitis (lichenoid reactions, lupus and
lupus-like syndrome, erythema multiforme/StevensJohnson syndrome), cutaneous vasculitis, granulomatous dermatitis, eczematous reactions, alopecia
and bullous diseases.8
Psoriasiform reactions (new onset psoriasis
and exacerbation of prior psoriasis)
The development of psoriasis or the exacerbation
of a pre-existent psoriasis is a paradoxal phenomenon that have been described in patients treated with
TNF-a inhibitors such as infliximab, etanercept,
adalimumab.9-12 The incidence of induced psoriasis is estimated at 2.3-5%. In a study of the Mayo
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INFLAMMATORY SIDE EFFECTS OF BIOLOGICS IN PATIENTS WITH PSORIASIS
RONGIOLETTI
Clinic dealing with patients seen from 1998 to 2010,
56 patients (73% females, mean age 48 y) presented
with a psoriasiform reaction. They were affected by
Crohn’s disease in 39% of cases and rheumatoid
arthritis in 25%. New-onset or worsening psoriasis
occurred after a mean treatment duration of 17.1
months with infliximab in 54% of cases, adalimumab in 34% and etanercept in 12%. The clinical presentation included: plaque psoriasis (N.=27), palmoplantar pustulosis (N.=25), scalp psoriasis (N.=12),
generalized pustular psoriasis (N.=7), erythrodermic
psoriasis (N.=2), and inverse psoriasis (N.=2). Several patients were treated with more than a single
TFN-a inhibitor.12 As for the treatment, stopping
TNF blocking therapy should be decided on individual basis. In cases of mild or non-acute reactions,
topical corticosteroids and phototherapy ± acitretin
seem to be effective. For more severe or acute systemic reactions, addition of cyclosporine or methotrexate should be evaluated. We have to consider
that switching to a different TNF inhibitor may well
worsen the lesions as this paradoxical response appears to be a class effect. The underlying pathogenesis of induction of psoriasis or psoriasiform reactions
by TNF-a inhibitors remain elusive but the disruption of balance between TNF/INF-a (YANG & YIN
theory) is one of the most reputed hypothesis. In fact,
TNF influences expression of many other cytokines
including INF-a which is produced by plasmacytoid
dendritic cells, involved in early lesions of psoriasis.
The blockade of TNF-α receptors by the drugs results in deregulated overproduction of INF-α which
could be responsible of the paradox of worsening or
inducing psoriasiform reactions.13
antibodies to double-stranded DNA (dsDNA).14-16
Antihistone antibodies are present in 17-57%. The
positivity of anti dsDNA seems not to be related to
clinical manifestations. As for pathogenesis, the accumulation of nuclear debris (nucleosomes) from
apoptotic cells could promote autoantibody production; however, inhibition of cytotoxic T cells by
anti-TNF-α therapy reduce the elimination of autoantibody-producing B cells with a shift to TH1 to
TH2 response. Another paradoxical phenomenon is
the disappearance of subacute cutaneous lupus erythematosus by the use of etanercept in several cases.
Anti-TNF-α is rarely associated with dermatomyositis that usually causes inflammatory rash and
muscle weakness; these symptoms may persist after
discontinuation of anti-TNF-α but respond to corticosteroid and immunosuppressive treatments.17
Lichenoid reactions with an interface pattern have
been reported and considered as a relevant classeffect.18
Five cases of erythema multiforme, 2 of StevensJohnson syndrome and 1 overlap during anti-tumor
necrosis factor treatment for plaque psoriasis have
been described.19 The Stevens-Johnson syndrome,
when associated with adalimumab administration
can show severe mucositis, peripheral rash, desquamation, and concomitant fever; these manifestations
are characterized by high morbidity and mortality
and can respond to intravenous hydrocortisone.20
This is another paradoxical phenomenon as resolution of toxic epidermal necrolysis with anti-TNFa treatment is found in the literature.21
Lupus erythematosus and interface disorders
Leukocytoclastic vasculitis is the most frequent
type of vasculitis, and purpura is the most frequent
cutaneous lesion associated with anti-TNF-a agents;
vasculitis, moreover, can be associated also with an
extracutaneous implication in one-quarter of patients, especially renal involvement.22 Infliximab
and etanercept are more involved than adalimumab.
The anti-TNF-α and especially infliximab induce
the development of systemic lupus erythematosus
(SLE) and can also worsen a pre-existent discoid
lupus erythematosus. The disease develops within a
few months of starting therapy but also after 4 years.
Infliximab is implicated in 37% of cases, etanercept
in 33% and adalimubab in 25%. Women in their fifth
decade of life are more involved. Forty-five per cent
of cases have “limited cutaneous lupus” (subacute)
while more than 50% develop SLE characterized by
maculopapular and butterfly rash, alopecia, photosensitivity, hypocomplementemia, fever, renal disease
and high prevalence of antinuclear antibodies and
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Vasculitis
Granulomatous dermatitis
Granulomatous dermatitis has also been associated with anti-TNF-a inhibitors, especially etanercept and mostly considered as cases of sarcoid-like
granulomatosis or complete sarcoidosis with pulmonary and cutaneous involvement.23 This is intriguing
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RONGIOLETTI
INFLAMMATORY SIDE EFFECTS OF BIOLOGICS IN PATIENTS WITH PSORIASIS
because TNF-α antibody drugs have also been used
successfully to treat sarcoidosis. The incidence is
estimated in ~1/2800. Dermatological patients may
present with nodular lesions, tattoo inflammation
and erythema nodosum. The mean delay between
induction therapy and the development of the disease is 12 months. It seems that anti TNF treatment
enhances the level of triggering infectious antigens
and/or modifies the cytokine environment. Anecdotal cases of interstitial granulomatous dermatitis associated with the use of TNF-a inhibitors have been
described.24 Paradoxically, also in this setting, additional casesof interstitial granulomatous dermatitis
have been successfully treated with etanercept.25
Eczematous reactions
Eczematous reactions have been diagnosed as
dyshidrotic, contact, nummular, atopic, papular,
and nonspecific eczema. Histopathology showed a
spongiotic dermatitis and rarely a mild psoriasiform
dermatitis with additional keratinocyte necrosis. Discontinuation of therapy led to remission and recurrence occurred when the biological drug was restarted. Treatment consisted mostly of topical steroids.26
Alopecia
Non cicatricial alopecia, usually presenting as alopecia areata-like reaction occurring 2-24 months after
starting therapy with anti-TNF have been described as
a significant association. This adverse drug reaction
appears to be a class effect as all TNF-a inhibitors
including also certolizumab have been considered as
culprit.27 Anti-TNF-a may induce also psoriasiform
eruptions with severe scalp involvement and alopecia.
Histopathology revealed epidermal psoriasiform
changes and dermal infiltrate with plasma cells and
eosinophils.28 Remission of alopecia areata was observed after stopping therapy as well as with continued treatment with biological drugs. Topical steroids
seems to improve alopecia. However, psoriasiform
alopecia may evolve into a cicatricial form.
Bullous diseases
Anecdotal cases of autoimmune bullous diseases such pemphigoid and pemphigus have been described with anti TNF-a inhibitors 29 as well as cases
of multiple lesions of focal cutaneous mucinosis,30
314
pseudolymphomatous reactions,31 morphea,32 vitiligo 33 and neutrophilic dermatoses (neutrophilic eccrine hidradenitis-like and Sweet’s-like syndrome).34
Cutaneous infections
A review of the German register for use of biologics in rheumatoid arthritis found a cutaneous infection rate of 7.2% with TNF blockade therapy. The
spectrum of cutaneous infectious is quite variable,
depending on the type of TNF-α blocker used and include bacterial, viral, fungal and protozoan infections.
Thus, in a prospective study in patients affected by
rheumatoid arthritis that analyzed the incidence and
type of skin side effects associated with anti-TNF,
the most frequent were cutaneous infections.35 The
most frequently associated skin condition is bacterial
cellulitis, erysipelas and abscess formation occurring
in less than 0.1% to 7% of patients with TNF inhibition followed by infection with herpes simplex and
herpes zoster seen in 0.8% to less than 5% of TNFinhibited patients. Cutaneous fungal infections are
found from 1% to 6.9% of patients. Skin infections
are also the second most common infection seen in
patients receiving anti-TNF therapy accounting for
21% of all infections, only preceded by the respiratory tract infections. Since TNF-α is a proinflammatory cytokine that plays an important role in innate
immunity and protection against bacterial, viral and
parasitic diseases, it is likely that its inhibition may
increase the risk of infection, especially at the levels
of skin and soft tissues compared with other areas.16
Additional skin infections that has been linked to
anti TNF-a includes folliculitis, pytiriasis versicolor,
and granulomatous infectious diseases (tuberculosis,
histoplasmosis, leshmaniasis and nontuberculous
mycobacteria).36 In relation to the type of anti-TNF
drugs related to the development of infection, infliximab has been shown to be associated with higher
incidence of skin infection than other drugs.37
Overview of cutaneous adverse events related
to il-12/23 antagonist (ustekinumab)
Ustekinumab is a human monoclonal antibody
that binds to the shared p40 subunit of IL-12 and
IL-23. Since the drug is on the market for less time
than anti-TNF-a inhibitors, data on its side effects
are less evident. However, it has been implicated in
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
INFLAMMATORY SIDE EFFECTS OF BIOLOGICS IN PATIENTS WITH PSORIASIS
similar skin reaction as anti-TNF-a such as injection
site erythema that seems the most frequent side effect, psoriasiform eruptions including pustular and
arthritic flares, alopecia areata, autoimmune bullous
diseases such as linear IgA dermatitis, eczematous
drug reactions, pseudolymphomatous reactions.38-43
RONGIOLETTI
Ustekinumab (9 patients)
No inflammatory/infectious skin adverse reaction
has been observed. One patient with only cutaneous
psoriasis developed a severe arthritis.
Conclusions
Personal experience
We have treated 109 psoriatic patients with biologics at the DISSAL, Section of Dermatology, University of Genoa from 2006 to 2013. Forty-six patients
have been treated with etanercept, 33 with adalimumab, 16 with infliximab, 9 with ustekinumab and 4
with golimumab. Side effects have been divided into
serious (leading to ceasing the therapy) and slight
reactions (therapy has been maintained and patients
have been accurately monitored).
Etanercept (46 patients)
We observed seven skin adverse reaction: two serious side effect characterized by one case of recurrent flares of erysipela (3 times in 3 months) and one
of purpuric vasculitis and five slight effects including: 1 injection-site reaction, 1 lichenoid reaction, 1
urticaria, 1 cheilitis and 1 alopecia areata.
References
Infliximab (16 patients)
We observed seven infusion reactions with two
serious side effects characterized by 2 hypotension,
seizures, angioedema; one of the 2 patients showed a
subsequent worsening of his psoriasis with the development of a generalized pustular erythrodermic psoriasis. In addition we saw 4 slight infusion reactions.
Adalimubab (34 patients)
Four slight side effects including 1 injection side
reaction, 1 pyodermitis vegetans, 1 alopecia and 1
urticaria have been observed.
Golimumab (4 patients)
One patient developed a pyoderma gangrenosum
of the right flank that resolved after treatment with
cyclosporine
Vol. 149 - No. 3
As the use of biologics (anti-TNF and anti IL12/23)
continues to increase, diagnosis and management
of skin adverse reactions will become an important
challenge. The overall rates of inflammatory adverse
events is more or less similar between the different
TNF-a inhibitors. The main difference are referred
more to the rates of specific events. Infusion reactions with infliximab and injection site reactions
with etanercept and adalimubab are the most common side effects. Although an increased incidence
of infections with the use of TNF-a inhibitors has
been reported, we could not confirm these data. Curiously, IL12/23 inhibitor ustekinumab is associated
with similar skin side effects than TNF-a inhibitors.
Discontinuation of the anti-TNF-α treatment should
be evaluated on individual basis. A greater number
of patients treated with longer courses of therapy,
coupled with careful observations and reporting, will
better define risks and benefits of biologic agents.
  1. Menter A, Gottlieb A, Feldman SR, Van Voorhees AS et al. Guidelines of care for the management of psoriasis and psoriatic arthritis:
Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008;58:82650.
  2. Moustou AE, et al. Cutaneous side effects of anti-tumor necrosis
factor biologic therapy: a clinical review. J Am Acad Dermatol
2009;61:486-504.
  3. Nagy G, Lukács K, Sziray A, Fazekas K, Florián A, Tamási L,
Károlyi Z. Adverse events during biological therapy - focusing on
dermatological side-effects. Orv Hetil 2011;152:212-20.
  4. Lequerrè T, Vittecoq O, Klemmer N, Goeb V, Pouplin S, Menard JF
et al. Management of infusion reaction to infliximab in patients with
rheumatoid arthritis orspondyloarthritis: experience from an immunotherapy unit of rheumatology. J Rheumatol 2006;33:1307-14.
  5. Paltiel M, Gober LM, Deng A, Mikdashi J, Alexeeva I, Saini SS
et al. Immediate type I hypersensitivity response implicated in
worsening injection site reactions to adalimumab. Arch Dermatol
2008;144:1190-4.
  6. Benucci M, Manfredi M, Demoly P, Campi P. Injection site reactions to TNF-a blocking agents with positive skin tests. Allergy
2008;63:138-9.
  7. Zidi I, Bartegi A, Ben AN. Dermatologic adverse events: golimumab, friend or foe? Pharmazie 2011;66:5-10.
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  8. Borchers AT, Leibushor N, Cheema GS, Naguwa SM, Gershwin
ME. Immune-mediated adverse effects of biologicals used in the
treatment of rheumatic diseases. Autoimmun 2011;37:273-88. 101.
  9. de Gannes GC, Ghoreishi M, Pope J, Russell A, Bell D, Adams S
et al. Psoriasis and pustular dermatitis triggered by TNF-{a} inhibitors in patients with rheumatologic conditions. Arch Dermatol
2007;143:223-31.
10. Wollina U, Hansel G, Koch A, Schönlebe J, Köstler E, Haroske G.
Tumor necrosis factor-a inhibitor-induced psoriasis or psoriasiform
exanthemata: first 120 cases from the literature including a series of
six new patients. Am J Clin Dermatol 2008;9:1-14.
11. Joyau C, Veyrac G, Dixneuf V, Jolliet P. Anti-tumour necrosis factor a therapy and increased risk of de novo psoriasis: is it really a
paradoxical side effect? Clin Exp Rheumatol 2012;30:700-6.
12. Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and
palmoplantar pustulosis associated with tumor necrosis factor-α inhibitors: The Mayo Clinic experience, 1998 to 2010. J Am Acad
Dermato 2012;67:e179-85.
13. Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J. Crossregulation of TNF and IFN-a in autoimmune diseases. Proc Natl
Acad Sci USA 2005;1:3372-7.
14. De Bandt M, Sibilia J, Le Loët X, Prouzeau S, Fautrel B, Marcelli C et al. Systemic lupus erythematosus induced by anti-tumor
necrosis factor a therapy: a French national survey. Arthritis Res
2005;7:545-51.
15. Costa MF, Said NR, Zimmermann B. Drug-induced lupus due
to anti-tumor necrosis factor a agents. Semin Arthritis Rheum
2008;37:381-7.
16. Levine D, Switlyk SA, Gottlieb A. Cutaneous lupus erythematosus
and anti-TNF-a therapy: a case report with review of the literature.
J Drugs Dermatol 2010;9:1283-7.
17. Klein R, Rosenbach M, Kim EJ, Kim B, Werth VP, Dunham J.
Tumor necrosis factor inhibitor-associated dermatomyositis. Arch
Dermatol 2010;146:780-4.
18. Garcovich S, Burlando M, Rongioletti F, Garcovich A, Parodi A,
Amerio P. Cutaneous drug eruption with an interface dermatitis pattern due to anti-tumour necrosis factor-a agents: a relevant classeffect. Acta Derm Venereol 2010;90:311-2.
19. Ahdout J, Haley JC, Chiu MW. Erythema multiforme during antitumor necrosis factor treatment for plaque psoriasis. Am Acad Dermatol 2010;62:874-9.
20. Mounach A, Rezqi A, Nouijai A, Ghozlani I, Achemlal L, Maghraoui AE et al. Stevens-Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease. Rheumatoll Int
2013;33:1351-3.
21. Hunger RE, Hunziker T, Buettiker U, Braathen LR, Yawalkar N.
Rapid resolution of toxic epidermal necrolysis with anti-TNF-a
treatment. Allergy Clin Immunol 2005;116:923-4.
22. Ramos-Casals M, Brito-Zerón P, Muñoz S, Soria N, Galiana
D, Bertolaccini L et al. Autoimmune diseases induced by TNFtargeted therapies: analysis of 233 cases. Medicine (Baltimore)
2007;86:242-51.
23. Skoie IM, Wildhagen K, Omdal R. Development of sarcoidosis following etanercept treatment: a report of three cases. Int
2012;32:1049-53.
24. Deng A, Harvey V, Sina B, Strobel D, Badros A, Junkins-Hopkins JM et al. Interstitial granulomatous dermatitis associated
with the use of tumor necrosis factor a inhibitors. Arch Dermatol
2006;142:198-202.
25. Ahmed ZS, Joad S, Singh M, Bandagi SS. Interstitial granuloma-
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tous dermatitis successfully treated with etanercept. Am J Case Rep
2014;15:94-6.
26. Bonnet N, Guis S, Koeppel MC, Roudier J, Grimaud JC, Jean-Pastor MJ, Berbis P. Cutaneous events during anti-TNF a therapy: a
prospective observational study of 41 cases. Ann Dermatol Venereol
2010;137:12-20.
27. Bene J, Moulis G, Auffret M. Alopecia induced by tumour necrosis
factor-a antagonists: description of 52 cases and disproportionality
analysis in a nationwide pharmacovigilance database. Rheumatology (Oxford) 2014 [Epub ahead of print].
28. Doyle LA, Sperling LC, Baksh S, Psoriatic alopecia/alopecia areata-like reactions secondary to anti-tumor necrosis factor-α
therapy: a novel cause of noncicatricial alopecia. Am J Dermatopathol 2011;33:161-6.
29. Boussemart L, Jacobelli S, Batteux F, Goulvestre C, Grange P, Carlotti A et al. Autoimmune bullous skin diseases occurring under
anti-tumor necrosis factor therapy: two case reports. Dermatology
2010;221:201-5.
30. Duparc A, Gosset P, Lasek A, Modiano P. [Multiple lesions of focal
cutaneous mucinosis: a side-effect of anti-TNF a therapy?]. Ann
Dermatol Venereol 2010;137:140-2.
31. Guis S, Schiano de Colella JM, Bonnet N, Andrac-Meyer L, Balandraud N, Mattei JP et al. Cutaneous pseudolymphoma associated with a TNF-a inhibitor treatment: etanercept. J Dermatol
2008;18:474-6.
32. Stewart FA, Gavino AC, Elewski BE. New side effect of TNF-a
inhibitors: morphea. Skinmed 2013;11:59-60.
33. Maruthappu T, Leandro M, Morris SD. Deterioration of vitiligo and
new onset of halo naevi observed in two patients receiving adalimumab. Dermatol Ther 2013;26:370-2.
34. Hryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range
of adverse cutaneous eruptions in patients on TNF-a antagonists. J
Cutan Pathol 2012;39:481-92.
35. Gottlieb AB, Kerbleski JF. Cutaneous infections Dermatological
complications and safety of anti-TNF treatments. Gut 2009;58:10339.
36. Laquer V, Ta T, Nguyen T, Tan B. Mycobacterium porferae infection in a psoriasis patient on anti-TNF-α therapy. Dermatol Online J
2013;19:196-209.
37. Hernández MV, Meineri M, Sanmartí R. Skin lesions and treatment with tumor necrosis factor a antagonists. Reumatol Clin
2013;09:53-61.
38. Stamell EF, Kutner A, Viola K, Cohen SR. Ustekinumab associated
with flares of psoriatic arthritis. JAMA Dermatol 2013;149:1410-3.
39. Wenk KS, Claros JM, Ehrlich A. Flare of pustular psoriasis after
initiating ustekinumab therapy.J Dermatolog Treat 2012;23:212-4.
40. Verros C, Rallis E, Crowe M. Alopecia areata during ustekinumab
administration: Co-existence or an adverse reaction? Dermatol Online J 2012;18:14.
41. Becker JG, Mundi JP, Newlove T, Mones J, Shupack J. Development of linear IgA bullous dermatosis in a patient with psoriasis
taking ustekinumab. J Am Acad Dermatol 2012;67:e150-1.
42. Jung J, Levin EC, Jarrett R, Lu D, Mann C. Lymphomatoid drug
reaction to ustekinumab. Arch Dermatol 2011;147:992.
43. Pernet C, Guillot B, Bessis D. Eczematous drug eruption after
ustekinumab treatment. Arch Dermatol 2012;148:959-6.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
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G ITAL DERMATOL VENEREOL 2014;149:317-27
Tyrosine kinase inhibitors:
muco-cutaneous side effects at the microscope
V. GRASSO 1, C. VASSALLO 1, G. CROCI 2, V. BRAZZELLI 1
In the past recent years, treatments that target receptors with
kinase activity, involved in the transmission of neoplastic proliferation signals, had revolutionized cancer therapy. Imatinib mesylate has been the first of this novel family of drugs
approved for the treatment of hematologic malignancies. Afterwards, other second-generation kinase inhibitors, such as
dasatinib and nilotinib, have been introduced to circumvent
resistance to imatinib. These target therapies have a better
tolerability profile than standard chemotherapy, but their
range of activity is not simply directed at tumor cells, and
a wide spectrum of systemic side effects is now recognized.
In particular, muco-cutaneous side effects represent the most
frequent non-hematological adverse events. Due to the need
of a prompt recognition of these toxicities, diagnosis is usually
made on clinical grounds, and an accurate histological characterization is generally lacking. The aim of this paper was to
focus on the histopathological findings of cutaneous reactions
related to tyrosine kinase inhibitors use. We propose a differentiation between specific and non-specific cutaneous side
effects, through an analysis of the possible etiopathogenetic
mechanisms of actions of the drug, clinical aspects and major
histological features. A review of the literature has been integrated by our personal experience, highlighting the importance of clinico-histological correlation, necessary to make a
proper diagnosis.
Key words: Chemotherapy - Cancer - Regional perfusion Skin diseases - Exanthema.
C
ancer chemotherapy has been one of the major
medical advances in the last few decades, and
the field of targeted therapies, small molecule drugs
directed against cancer-specific signalling pathways,
Corresponding author: V. Brazzelli, Department of Clinical-Surgical,
Diagnostic and Pediatric Sciences, Institute of Dermatology, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
E-mail: [email protected]
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1Department of Clinical-Surgical,
Diagnostic and Pediatric Sciences
Institute of Dermatology, University of Pavia
and Foundation IRCCS Policlinico San Matteo
Pavia, Italy
2Department of Human Pathology, University of Pavia
and Foundation IRCCS Policlinico San Matteo
Pavia, Italy
marked a turning point in terms of therapeutic responses and allowed to increase the selectivity of
drug action and limit systemic side-effects.
Tyrosine kinase inhibitors (TKIs) block the ATPbinding site and autophosphorylation of the tyrosine
residues of several proto-oncogenes. This mechanism finally inhibits the activation of intracellular
signal-transduction pathways in tumour cells, responsible for deregulation of key cell functions such
as proliferation and differentiation.1-5
The first-generation TKI was imatinib mesylate
(Gleevec®, STI571), approved for the treatment of
chronic myeloid leukemia (CML) and gastrointestinal stromal tumours (GISTs).6 The development of
polyclonal resistance to imatinib gave birth to a second generation of multikinase inhibitors, dasatinib
(Sprycel®, BMS-354825) and nilotinib (Tasigna®,
AMN107).7-14 Today, these drugs can be used up
front in newly diagnosed patients and the registration of new TKIs is proceeding remarkably fast.5, 15
The availability of highly potent TKIs has really
broadened the treatment armamentarium in cancer
therapy and frequent updates are mandatory for the
physicians treating oncologic patients and for those
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Tyrosine kinase inhibitors
dealing with systemic adverse events related to their
employ.
During the last years, growing attention has been
paid to tolerance and toxicity profiles of these new
drugs. In particular, cutaneous reactions are one of
the most commonly reported adverse events associated with TKIs administration, being mostly mild to
moderate in severity and often transient and self-limiting, even if severe life-threatening reactions have
been described.16-18
The heterogeneity of reactions to TKIs proves
that these drugs exert different effects on the skin,
but much remains to be elucidated about their pathophysiology.
Considering our personal experience and the most
relevant papers in the literature, we can support the
concept of differentiation between specific mucocutaneous side effects, since a drug-related pathogenetic mechanism of action or peculiar clinical and
histopathological findings may be recognised, and
non-specific adverse events, whose clinico-histological features and biological activity of the drug are
unlikely to be related.
Despite the high incidence of cutaneous side effects reported in several clinical trials, an accurate
diagnostic investigation and categorization has never
been carried out, because diagnosis is often made
on clinical grounds alone. Nevertheless, a cutaneous
biopsy and histopathological examination are necessary to make a precise diagnosis and offer a dermatological in-depth analysis in terms of biological
activity of the drug, pathogenesis of a particular side
effect and need for therapy.
In this paper, we review the most frequent specific
and non-specific muco-cutaneous side effects associated to the use of first- and second-generation TKIs,
focusing on the histologic findings and highlighting
the importance of the integration of both clinical and
histopathologic data to make a proper diagnosis.
Specific muco-cutaneous side effects
Hypopigmentation and hyperpigmentation
Many case reports evidenced the occurrence of
pigmentary changes during TKIs treatment.19-21
Clinically, they appear with localized hypopigmented patches (Figure 1), or with diffuse depigmentation
of the skin. Hair depigmentation may present as well.
318
Figure 1.—Clinical findings of vitiligo-like hypopigmented
patches with irregular and undefined borders on the back, in a 44year-old female patient with CML treated with imatinib. Other
similar lesions were present on the legs and arms, and appeared
two months after the beginning of the therapy. In the center of the
hypochromic patch, a small scar corresponding to the skin biopsy
is evident.
In a study conducted by Arora et al., depigmentation
appeared in 41% of 118 patients treated with imatinib, and the median time of onset was four weeks.22
We reported the development of vitiligo-like lesions and generalized lightening of the skin in a
pediatric patient treated with imatinib, assessing
the skin colour changes by means of a colorimetric
measurement over a period of four months.23 We also
described the case of another pediatric patient treated with dasatinib, who developed achromic patches
on his neck and the dorsal surfaces of his hands, and
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Photoinduced dermatoses
Figure 2.—Histopathological features of vitiligo-like hypopigmentation, showing irregular epidermal hyperplasia, with absence of melanocytes in the basal layer. Scanty perivascular inflammatory infiltrates are detectable in the superficial dermis. The
reduction of melanocytes has been confirmed by S100 staining
(Hematoxylin&Eosin, x20).
complete depigmentation of his hair, eyelashes and
eyebrows.24
The cases described emphasize the role of the c-kit
pathway in melanocyte biology. TKIs-induced skin
depigmentation is thought to be caused by blockade
of c-kit signalling, which may occur via direct inhibition of c-kit mediated gene activation.25-28 The link
between the c-kit receptor and melanogenic genes
probably occurs through the microphtalmia transcription factor (MITF), which is crucial for melanocyte development.29
A clue to histological diagnosis includes a reduction or complete absence of melanocytes in association with a partial or total loss of epidermal pigmentation. Superficial perivascular and perifollicular
lymphocytic infiltrates are generally absent (Figure 2).
Paradoxically, the same drug can induce darkening of the skin and hyperpigmentation, though less
frequently. Etienne et al. reported hair repigmentation in 9 of 133 patients and Valeyrie et al. in 8 of 54
patients treated with imatinib.19, 30
How the same drug can induce two opposite cutaneous adverse events remains unclear, and further
studies on TKIs effects on the c-kit-transduced signal and regulation of MITF will help to explain the
complex molecular mechanisms involved in melanocyte differentiation.
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Photosensitization and photoinduced dermatoses
most likely represent specific TKIs-related cutaneous adverse reactions.
Rousselot and colleagues described 8 cases of
photosensitization in patients receiving imatinib
therapy. Sunburn intensity varied from painless to
painful erythema, limited to exposed skin.31
The photosensitivity risk related to genetic polymorphisms of human ATP-binding cassette (ABC)
transporter ABCG and its inhibition by drugs have
been studied in vitro. Imatinib can inhibit the ATPbinding cassette subfamily G member 2 (ABCG2)mediated porphyrin transport inducing a significant
enhancement of the cellular photosensitivity through
the disruption of porphyrin homeostasis. It can be
hypothesized that certain genetic polymorphisms
and/or inhibition of ABCG2 by imatinib can increase
the potential risk of drug-induced phototoxicity.32, 33
Like imatinib, both nilotinib and dasatinib decreased ABCG2 surface expression, supporting the
hypothesis that all three TKIs are substrates of ABC
transporters and that, at higher concentrations, TKIs
overcome transporter function.34
At the same time, skin protection against ultraviolet
rays is altered because of the impaired melanogenesis
induced by TKIs via an inhibition of c-kit activity.
We studied two patients who presented with photoinduced erythematous eruption limited to photoexposed areas during imatinib treatment (Figure 3).35 In
both cases, histopathological examination revealed
Figure 3.—Clinical presentation of photoinduced rash in sun-exposed area in a 52-year-old female patient with CML and receiving imatinib.
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Figure 5.—Tense bullae, erosions and crusts on erythematous
background after four months of imatinib therapy in a 45-yearold male patient affected by CML. Other similar lesions were evident in photo-exposed areas of both forearms, highly suggestive
of pseudoporphyria.
Figure 4.—Histopathological features of photoinduced dermatitis, showing interface dermatitis with scattered necrotic keratinocytes, focal exocytosis, perivascular inflammatory infiltrates in
the superficial dermis and vasodilation of capillaries and venules
(Hematoxylin&Eosin, x10).
interface dermatitis, scattered necrotic keratinocytes,
focal exocytosis, perivascular inflammatory infiltrates
in the superficial dermis composed by lymphocytes
and scattered eosinophils, and mild dermal elastosis.
Vasodilation of superficial capillaries and venules
was evident between collagen bundles (Figure 4).
The appearance of such a cutaneous side effect may
be attributed to the biological activity of the drug.
Pseudoporphyria
Imatinib has been also reported to induce pseudoporphyria. In a case report, the patient developed
tense, sometimes hemorrhagic blisters without surrounding erythema on the dorsa of the hands and
ankles. Histology of a biopsy taken from a blister
showed a subepidermal bulla, along with dermal
320
edema and a scant lymphohistiocytic perivascular infiltrate with sporadic eosinophils. Type IV collagen
was found to be localized to the floor of the blister.
A subsequent biopsy of peribullous skin showed
slightly thickened upper vessel walls with some
amorphous eosinophilic material; moreover, a duplication of the basal membrane with type IV collagen
stain was seen, without PAS positivity.36, 37
We studied a patient with a history of skin fragility
aggravated by photoexposition, appeared during imatinib therapy. On clinical examination, widespread
erosions and crusted lesions on erythematous background located on the dorsal surface of both hands
and forearms were evident (Figure 5). Porphyrin metabolism abnormalities were not detected.
Histologic features were characterized by a subepidermal blister with dermal papillae protruding in the
lumen, scant dermal inflammatory infiltrates (Figure
6), and the presence of diastase-resistant, PAS positive material deposited around capillary vessels with
thickened walls (Figure 7), all features consistent
with a diagnosis of porphyria cutanea tarda or pseudoporphyria.
Recently, Pérez and colleagues described a patient
treated with imatinib who developed multiple tense
hemorrhagic blisters, erosions, crusts, and scars on
both hands. The histological examination revealed
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Figure 6.—Histological findings of imatinib-induced pseudoporphyria, characterized by cell-poor, subepidermal blister with dermal papillae protruding in the lumen, scant inflammatory infiltrates and dermal elastosis. Thickened vessel walls are evident in
the superficial dermis (Hematoxylin&Eosin, x10).
Figure 7.—High power view of superficial vessels showing diastase-resistant, PAS positive, homogeneous material deposited
around thickened walls (Periodic acid-Schiff, x40).
subepidermal vesicles and positive PAS staining of
the blood vessel walls.38
As described in true photoinduced dermatoses,
similar pathophysiologic mechanisms may be proposed for TKIs-related pseudoporphyria. In particular, the enhanced cellular photosensitivity induced
by the alteration of intracellular porphyrin levels
may be responsible for the development of this peculiar cutaneous side effect.
Pityriasiform eruptions
A series of three male patients on imatinib who
developed an erythematous macular eruption on
the trunk and arms has been reported by some of
us.39 The lesions presented a peripheral collarette of
desquamation and a vaguely parallel distribution to
Langer’s skin lines, suggesting a clinical diagnosis
of pityriasis rosea-like drug eruption (Figure 8).
Other authors reported similar clinical features as
a side effect of imatinib therapy.40, 41
We suggest that this kind of eruption represent a
specific drug-related side effect since many histological hallmarks can be recognised. In all specimens,
Vol. 149 - No. 3
Figure 8.—Pityriasis rosea-like eruption in a 50-year-old male
patient with CML after one month of imatinib treatment. Widespread, monomorphous, slightly pruritic, erythematous patches
with a collarette of scales are evident.
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Figure 9.—Histological findings of pytirasis rosea-like eruption
include orthokeratotic hyperkeratosis, interface dermatitis with
scattered necrotic keratinocytes, focal exocytosis and lymphocytic
inflammatory infiltrates in the dermis. A remarkable vasodilation
of blood capillaries, venules and lympathic vessels with elongated
shapes is detectable (Hematoxylin&Eosin, x10).
histological findings included interface dermatitis
with scattered necrotic keratinocytes and focal exocytosis, superficial and mid-dermal lymphocytic inflammatory infiltrates with perivascular and periadnexal accentuation (Figure 9).
A constant peculiar finding that can be considered
a clue for the diagnosis of TKIs-related pityriasiform
eruptions, is the presence of a remarkable dilation
of lymphatic vessels and blood capillaries. Some of
these vessels are telangiectases, and notable perivascular infiltrates without signs of vasculitis may be
seen (Figure 10).
These histopathological findings may be correlated to the specific drug’s inhibition of growth
factors, like platelet-derived growth factor receptor
(PDGF-R), a growth factor involved in interstitial
fluid homeostasis. This inhibition may lead to an increase in dermal interstitial fluid pressure, through
a dysregulation of the tension between endothelial
cells and the extracellular matrix.
Pasmatzi et al. described a case of disseminated
erythematous and pityriasiform plaques with similar
histopathological features.42
Psoriasiform eruptions
Valeyrie et al. reported a psoriasiform rash localized on the scalp, trunk and arm in 4 of 54 imatinib-
322
Figure 10.—Typical histopathological features of pityriasis rosealike eruption, with interface dermatitis, focal vacuolar changes at
the dermo-epidermal junction, superficial lymphocytic inflammatory infiltrates with perivascular accentuation. Dilated superficial
vessels with bizarre, elongated shapes and no signs of vasculitis
are evident (Hematoxylin&Eosin, x10).
treated patients.19 In other reports, the eruption can
present with psoriasiform palmoplantar hyperkeratosis.43
Imatinib has been related to psoriasis induction in
some patients with CML.44-46 A case of psoriasis vulgaris developing during nilotinib treatment has been
recently described.47
Histological examination showed pathological
features of psoriasis, including epidermal hyperkeratosis and acanthosis with parakeratosis, and perivascular lymphocytic infiltration in the superficial dermis.
The mechanisms underlying psoriasiform eruptions are still unclear. An interference with cytokine
production and T cell proliferation induced by the
drug could be hypothesized. In particular, TKIs inhibit the function of CD4+ CD25+ regulatory T cells
(Treg) and block intracellular signalling of effector T
cells, so it is possible that the balance of these effects
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leads to the development or exacerbation of pre-existing psoriasis.48, 49
Superficial edema
Superficial edema is another common cutaneous
reactions associated with TKIs, with an incidence
of 55.9% reported in the IRIS study.50 It mainly affects the face, especially the periorbital area, but it
can also affect the legs. The incidence of peripheral
edema varies from 5% to 18% for dasatinib.51, 52
The diagnosis of this cutaneous adverse event
is generally made on the basis of clinical aspects,
and histological examinations are poorly described.
Common histological findings include superficial
edema with ectasis of lymphatic and blood vessels,
without alteration of endothelial cells, without inflammatory cells.
The specific chronic inhibition of PDGF-R and
other growth factors may impair pericyte function
and lead to weakening of the vessel wall.
The same process of vasodilation is found in other
TKIs specific side effects, suggesting that this represents a major histological feature and a clue to diagnosis.
Non-specific muco-cutaneous side effects
Erythematous maculopapular rashes
The occurrence of erythematous maculopapular rashes is frequently reported in clinical trials
and case series. These rashes are usually labelled
as “non-specific” and initially manifest as erythematous macules and papules or erythema alone;
they can mimick morbilliform eruptions and may
eventually become purpuric or progress to erythroderma. The lesions are generally located on the
trunk and proximal segments of arms and tend to
be mild and self-limiting. The lower extremities,
intertriginous areas, and face are less frequently
involved.17, 19
The incidence of erythematous skin rashes associated to imatinib was 33.9% in the IRIS study, 17% in
the DASISION study, 22% in the ENESTnd study,
and ranging from 19% to 66.7% in the most relevant
case series.19, 50, 53-55 Maculopapular eruptions and
exfoliative rashes are also the most frequent dasatinib-related cutaneous side effect.51, 52 As concerns
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nilotinib, skin rashes are reported with an incidence
ranging from 2-20% to 41-47%.12, 54
According to a meta-analysis conducted by
Drucker et al., the incidence of all-grade skin rash
with nilotinib was 34.3%, higher than with dasatinib,
whose incidence was 23.3%.56
Histologically, hyperkeratosis with parakeratosis
is generally observed, together with focal spongiosis,
discrete lymphocytic exocytosis and necrotic keratinocytes. The papillary dermis shows a variable degree
of edema and lympho-histiocytic perivascular infiltrate, with eosinophils and few neutrophils. An irregularity of the dermoepidermal junction with scattered
melanophages may also be detected. These findings
are consistent with a drug eruption, but not specific
for a TKIs-induced skin rash.57, 58 Sometimes, clinical
findings are more suggestive for a specific skin rash
induced by TKIs, such as the presence of erythematous follicular papules and perifollicular lesions, including lesions resembling keratosis pilaris.
The pathogenetic mechanism of rash has thus far
not been studied and remains elusive. It may be hypothesized a direct inhibitory effect against other
kinases, which are active in the skin. Nevertheless,
their inhibition has a putative role in rash development that needs further study.
Muco-cutaneous lichenoid eruptions
The clinical appearance of muco-cutaneous lichenoid eruptions induced by TKIs can be heterogeneous. The eruption may be mild to extensive,
generally characterized by dark purple, pruriginous,
lichen planus-like papular lesions. Cases of widespread eruptions with papules and plaques have been
described.59-64 Mucosal lesions are less frequent and
may be characterized by white plaques with a reticulated pattern, grey-violaceous plaques or reddish
macules and erosions.65-67
We studied two cases of oral lichenoid reactions
during imatinib therapy. One patient presented white
lesions on the oral mucosa and the tongue, characterized by fixed radiating striae.35 The other patient
showed white striae on the oral mucosa only (Figure
11). A mucosal biopsy showed acanthosis with mild
parakeratosis of the epithelium, vacuolar degeneration of the basal layer, lymphocytic perivascular
infiltration of upper dermis and capillary vasodilation (Figure 12). Despite the absence of histological
clues, a mild vasodilation is detectable.
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Tyrosine kinase inhibitors
Figure 11.—Clinical findings of lichenoid drug eruption of the
oral mucosa characterized by asymptomatic, white fixed striae, in
a 55-year-old male patient after three months of imatinib therapy
for CML.
Kuraishi et al. reviewed fourteen patients with
cutaneous lichenoid eruptions due to imatinib, highlighting the fact that these eruptions are clearly doserelated.68
It is proposed that these lesions may be closely
correlated with the drug-induced altered expression of epidermal markers and changes in epidermal
homeostasis, but the exact pathogenetic mechanism
remains unclear.
Neutrophilic dermatoses
The appearance of neutrophilic dermatoses has
been sparsely reported in the literature. Sometimes,
the adverse cutaneous reactions have been classified
under precise diagnoses; otherwise, they have been
simply described as pustular eruptions because of the
lack of consistent clinical and histological criteria.69
Ayirookuzhi et al. described a patient who developed an abrupt onset of tender and painful erythematous plaques and nodules on the dorsal aspects of both
hands and forearms, preceded by the use of imatinib.
The histological examination showed neutrophilic
dermatosis with epidermal sparing and intradermal
abscess formation involving both the superficial and
deep dermis, consistent with Sweet syndrome.70
Two patients with imatinib-induced acute generalized exanthematous pustulosis have been described.71, 72 Both patients exhibited an acute generalized pustular eruption with multiple painful
pruritic pustules on an erythematous and edematous
324
Figure 12.—Histopathological features of oral lichenoid drug
eruption include acanthosis with mild parakeratosis, focal vacuolar degeneration of the basal layer, lymphocytic perivascular
infiltration in the lamina propria and mild capillary vasodilation
(Hematoxylin&Eosin, x10).
background, beginning in the face and later spreading to the trunk and extremities. The histological
examination showed intraepidermal pustules with
parakeratosis, interstitial cellular infiltration of neutrophils, exocytosis of abundant eosinophils and apoptotic neutrophils, without signs of vasculitis.
A case of neutrophilic eccrine hidradenitis during
imatinib treatment has also been reported.73 The patient developed a progressive, erythematous, papular
rash most prominent over the medial thighs and volar
wrists and also involving the palmoplantar surfaces.
A skin biopsy demonstrated necrosis and squamous
metaplasia of the eccrine glands and ducts associated
with an infiltrate of lymphocytes and neutrophils.
Considering the uncommon and heterogeneous
presentation of these eruptions, they may not be considered drug-specific and no pathogenetic mechanism has been proposed. Furthermore, the appearance of neutrophilic dermatoses can ben related to
the primary hematological disease.
Panniculitides
Ugurel et al. described a patient treated with imatinib and presenting with recurrent skin lesions characterized by erythematous, swollen and deeply indurated nodules on the upper and lower limbs.74
Biopsy of lesional skin showed a mild, nonspecific
mononuclear perivascular infiltrate throughout the
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Tyrosine kinase inhibitors
GRASSO
dermis. In the subcutaneous tissue, numerous macrophages, neutrophils and lymphocytes were present
between the adipocytes throughout the fatty tissue
lobules and closely to small blood vessels, without
septal involvement. Focal necrotic adipocytes were
also detected. The clinical and histopathological data
were consistent with a diagnosis of imatinib-induced
panniculitis.
Even dasatinib can induce similar cutaneous reactions. Two patients presenting with painful subcutaneous nodules with overlying erythema on the lower
limbs have been described.75 The histological examination revealed a lobular panniculitis, with massive
infiltration by polymorphonuclear leukocytes, without signs of vasculitis.
No precise pathogenetic mechanism has been suggested and their uncommon occurrence may justify
their categorization as non-specific drug-related adverse events.
Other rare cutaneous side effects
Clark and colleagues reported a case of mycosis
fungoides-like reaction in a patient treated with imatinib.76 On clinical examination, the patient showed
a diffuse skin eruption characterized by slightly erythematous and pruritic macules which extended in a
centripetal way. A skin biopsy revealed the presence
of a mild superficial and mid-perivascular cellular
infiltrate consisting of epidermotropic, large, hyperchromatic lymphocytes with focal vacuolar changes
of basal keratinocytes and scattered eosinophils. The
immunohistochemical studies showed 80% of cells
expressing CD3 with approximately equal numbers
of CD4+ and CD8+ lymphocytes, supporting the diagnosis of a mycosis fungoides-like reactive infiltrate.
In another report, a patient developing a facial
eruption characterized by symmetrical, slightly erythematous and indurated plaques after the initiation
of imatinib treatment has been described.77 The histological examination showed reticular degeneration
of the pilosebaceous follicles with the formation of
cystic spaces associated with presence of mucin, and
perifollicular infiltrates of mononuclear cells and eosinophils, with slight atypia of some lymphocytes. Immunohistochemistry showed that most of the infiltrating cells were CD3+ and CD4+, CD20- and CD68-,
confirming the diagnosis of follicular mucinosis.
Plana and colleagues reported a case of pityria-
Vol. 149 - No. 3
sis rubra pilaris-like reaction induced by imatinib,
characterized by large orange-red plaques with areas of uninvolved skin between them, marked follicular hyperkeratosis and waxy keratoderma on the
palms and soles.78 On histological examination, irregular hyperkeratosis with alternating vertical and
orthoparakeratosis was seen, and hair follicles with
keratinous plugs were also a distinctive feature.
Battistella and colleagues reported a case of handfoot syndrome in a patient receiving imatinib.79 Clinically, the patient experienced painful palmoplantar
erythema with edema, spreading over the lateral aspects of the feet and dorsal surfaces of the fingers
and toes. A skin biopsy showed upper epidermal necrosis and many necrotic keratinocytes of the underlying layers, a moderate inflammatory lymphocytic
infiltrate in the papillary dermis and some slight interface dermatitis.
Conclusions
We analyzed the most frequent muco-cutaneous
side effects associated with the employ of first- and
second-generation TKIs, with a focus on the histological findings and the need for integration between
the clinical and histopathological data in order to
make a proper diagnosis.
The tolerability profile of first- and second-generation TKIs is overall comparable, but even low-grade
side effects affect quality of life and adherence to
therapy. In particular, muco-cutaneous side effects
represent the most common non-hematological adverse reactions and their great heterogeneity mirrors
the different targets of TKIs. The incidence of many
cutaneous reactions appears to be related to the cumulative dosage, which further supports a specific
pharmacological effect of the drug rather than immunologic or allergic mechanisms.
Here, a distinction between specific and non-specific muco-cutaneous adverse events is proposed,
considering the pathological mechanisms of action of
the drug, the clinical aspects and histological features.
Many of these specific cutaneous toxicities may
be regarded as potential indicators of responsiveness
to therapy, or even direct markers of treatment outcome, because they indicate biological activity. Furthermore, the increasingly specificity of new molecules will emphasize the need for a more accurate
categorization of these peculiar cutaneous reactions,
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Tyrosine kinase inhibitors
considering that specific effects of the drug in the
skin are reflected in a broad spectrum of clinico-histological findings.
Dermatologists play a central role in recognizing
and treating these side effects, and the adaptation of
the treatment to the clinical conditions. The timely
reporting of severe complication is recommended.
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Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
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G ITAL DERMATOL VENEREOL 2014;149:329-33
Thalidomide-induced granuloma annulare
C. FERRELI 1, L ATZORI 1, F. MANUNZA 1, M. PAU 2, A. CADDORI 3
Granuloma annulare (GA) is an acquired, usually self-limiting, asymptomatic granulomatous skin disease with well
recognized clinical and histological features that occurs
in children and adults generally before the age of 30. Five
clinical types are described including the localized, generalized, subcutaneous, perforating, and patch forms. The
possible role of immune dysregulation has been pointed out
in the pathogenesis of GA, as it has been reported in association with several diseases and conditions like diabetes,
thyroid diseases, malignancies, tuberculosis, human immunodeficiency, Epstein Barr and hepatitis C virus infection.
Drug-induced GA is a rare presentation, that can appear
similar or identical to idiopathic GA. We present a 75-yearold Caucasian man with a violaceous ring-like firm, papular
eruption, localized on the dorsal aspect of both hands, with
histological features of GA, which subsequently resolved
with the discontinuation of thalidomide he had started 1
month earlier for the treatment of a multiple myeloma. The
lesions appeared with renewed intensity after resuming a
therapy cycle. Jones’s algorithm for the diagnosis of adverse
drug reactions (ADR) showed a certain association, thus the
final diagnosis of thalidomide-induced GA was made.
Key words: Granuloma annulare - Thalidomide - Drug-related side effects and adverse reactions.
D
rug induced GA is a rare entity, firstly described
by Rothwell in 1980 induced by gold therapy.1
Since then, besides gold,2 it has been described in
association with a number of medications, among
them allopurinol,3-5 diclofenac,6 calcium channel
blockers,7 antidepressants,8 anticonvulsants,9, 10
interferon.11 More recently, case reports came out
Corresponding author: C. Ferreli, M. Aresu Department of Medical
Science, University of Cagliari, Via Ospedale 54, 09124 Cagliari, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1Unit of Dermatology
M. Aresu Department of Medical Science
University of Cagliari, Cagliari, Italy
2Unit of Dermatology, AOU Cagliari, Cagliari, Italy
3Unit of Internal Medicine, SS. Trinità Hospital
ASL 8, Cagliari, Italy
in the literature about the association between antitumor necrosis factor alpha (TNF-alpha) drugs and
the occurrence of GA.12-17 The paradox of this last
observation is that TNF inhibitors can be used for
the treatment of refractory GA.18
Case report
A 75-year-old Caucasian male was admitted to our
hospital because of the recent onset of erythematous ringlike firm papular lesions, mostly in annular configuration
with clear centre and slightly elevated borders, localized
on the dorsal aspect of both hands. The eruption occurred
15 days after the start of thalidomide therapy, at the starting dosage of 100 mg/day, then increased to 150 mg/day,
for multiple myeloma. Dermatologic examination revealed asymptomatic multiple erythematous papules and
annular plaques localized on lateral and dorsal aspect of
both hands and fingers (Figure 1). No rash was present
elsewhere. The mucous membranes, hair and nails were
normal.
Laboratory examination of complete blood count, serum chemistries, liver and kidney function tests showed
normal results, as well as rheumatoid factor, anti doublestranded DNA, antinuclear antibodies, CRP, pANCA and
cANCA. The patient was otherwise healthy, no arthralgias, or autoimmunity disorders were present. The past
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FERRELI
THALIDOMIDE INDUCED GRANULOMA ANNULARE
Figure 1.—Papular eruption on the dorsal aspect of both hands
and fingers.
Figure 2.—Resolution of the rash after drug withdrawal.
Figure 3.—Palisading infiltrate of histiocytes surrounding areas
of collagen degeneration with a dense perivascular lymphocytic
infiltrate (H&E 10X).
Figure 4.—Palisading granulomas around degenerated collagen
(H&E 40X).
330
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
THALIDOMIDE INDUCED GRANULOMA ANNULARE
FERRELI
association (certain), and the diagnosis of drug-induced
GA was made.
Discussion
Figure 5.—Mucin deposition in areas of interstitial histiocytic infiltrate (Alcian blue 40X).
medical history was remarkable for multiple myeloma related pathological fractures on D12, L2-L5 and duodenal
bulb disease. Histopathological examination of a biopsy
taken from the dorsum of the hand showed a palisading
infiltrate of histiocytes, surrounding areas of necrobiotic
collagen fibres and a dense perivascular lymphocytic infiltrate with few eosinophils, without vasculitis (Figures
3, 4). There was also a prominent interstitial histiocytic
infiltrate and mucin deposition (Figure 5), with no evidence of interface dermatitis. Neither lymphoid atypia
nor giant histiocytes were observed.
Thalidomide administration was suspected to have induced the lesions as its discontinuation produced a dramatic improvement within one month (Figure 2). A rechallenge with thalidomide 100 mg/day associated with
prednisone 25 mg/bid three months later resulted in the
recurrence of lesions within two weeks. Thalidomide was
definitely stopped with complete and persistent resolution of the rash. Jones’s algorithm for the diagnosis of
adverse drug reactions 19 confirmed the highly probable
Vol. 149 - No. 3
GA is a relatively common idiopathic disorder
occurring in all races and ages more frequently affecting women under 30 years of age. Five clinical variants are described, localized, generalized,
subcutaneous, perforating, and patch forms, with
often overlapping clinical features. The proposed
pathogenetic mechanisms are many: they range
from IFN-gamma producing lymphocytes in the
setting of a Th1 inflammatory reaction,20 to type IV
delayed hypersensitivity,21 lymphocytes mediated
monocytes’ activation 22 and elastic fibers degeneration.23 Several etiologic factors have been suggested, such as viral infections (HSV, EBV, HBV,
HCV and HIV), insect bites and trauma,24 TB testing and sunlight 25 and neoplastic disorders,26 although they are still unproven.27 Drug induced GA
has been described after exposure to a number of
drugs and, more recently, anti TNF-alpha drugs
have been added to the list.12-17
TNF-alpha is a cytokine that plays an important
role in the normal host defence 28 but, when overproduced, it is implicated in the pathogenesis of
several inflammatory conditions and autoimmune
disorders by inducing and maintaining inflammation through lymphocytes’ activation and cytokine production.29 Thalidomide has re-emerged
as a novel antineoplastic agent with antiangiogenic
activities and it has been shown to down regulate
the production of TNF-alpha, both in vivo and in
vitro, suggesting its immunomodulatory role.30 In
our patient thalidomide was administered for the
treatment of multiple myeloma and the temporal
relationship among the development of the dermatosis, its resolution upon drug discontinuation
and its recurrence upon rechallenge of this drug,
confirmed the iatrogenic nature of the rash. The
chance that idiopathic GA had occurred in association with multiple myeloma is unlikely as our patient did not have clinical evidence of GA prior to
thalidomide treatment. Moreover, to the best of our
knowledge, GA has never been reported in patients
affected with multiple myeloma. Besides, there are
several potentially drug induced entities that clinically resemble GA that should be regarded in the
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
331
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THALIDOMIDE INDUCED GRANULOMA ANNULARE
differential diagnosis, such as interstitial granulomatous dermatitis (IGD),31 palisaded neutrophilic
and granulomatous dermatitis (PNGD),32 interstitial granulomatous drug reaction (IGDR),33 and a
GA in the setting of systemic disease.34 In the case
reported herein histologic features supporting the
diagnosis of GA included collagen necrobiosis, interstitial histiocytosis and abundant mucin deposition, in the absence of interface dermatitis and lymphoid atypia, features generally found in IGDR.
The occurrence of drug induced GA following
anti-TNF-alpha treatment has been primarily described in patients with collagen vascular diseases,
mainly rheumatoid arthritis, after administration
of new “biologic” anti-TNF-alpha agents,35 but it
has not yet been described in association with thalidomide therapy. Conversely, thalidomide, an old
anti-TNF-alpha inhibitor, and its derivative lenalidomide, have been reported to induce IGDR 29, 36
suggesting that there is a spectrum of drug induced
granulomatous reactions with often subtle clinical findings and variable histopathologic pictures.
The pathogenesis of the granulomatous reaction
developing in the course of TNF-alpha inhibitors
could be related to some specific hystiocyte and/or
lymphocyte activity regulated by this cytokine and
the immunologic burden in genetically predisposed
individuals. Further reports might unravel the question and convey new insights on this unusual cutaneous adverse drug reaction.
Conclusions
The occurrence of GA during the administration
of TNF-alpha inhibitors has been described mainly
in patient affected by rheumatoid arthritis, and has
encouraged the hypothesis that this drugs can promote a disease specific reaction. Our case occurred
in absence of rheumatoid arthritis, therefore suggesting that the drug is primarily responsible for the
cutaneous reaction due to a kind of immunologic
suppression induced by this class of drugs.
References
  1. Rothwell R. S, Schloss E H. Granuloma Annulare and Gold Therapy Arch Dermatol 1980;116:863
  2. Martin N, Belinchón I, Fuente C, Vélez A, Sánchez-Yus E. Granuloma annulare and gold therapy. Arch Dermatol 1990;126:1370-1.
332
  3. Singh SK, Manchanda K, Bhayana AA, Verma A. Allopurinol induced granuloma annulare in a patient of lepromatous leprosy. J
Pharmacol Pharmacother 2013;4:152-4.
  4. Becker D, Enk A, Bräuninger W, Knop J. Granuloma anulare disseminatum as a rare side effect of allopurinol. Hautarzt
1995;46:343-5.
  5. Goihman-Yahr M Disseminated granuloma annulare and intranasal calcitonin. Int J Dermatol 1993;32:150.
  6. Le Corre Y, Léonard F, Fertin C, Kalis B. Granuloma-annulare
type photosensitivity disorder caused by diclofenac. Ann Dermatol Venereol 1992;119:932-3.
  7. Lim AC, Hart K, Murrell D. A granuloma annulare-like eruption associated with the use of amlodipine. Australas J Dermatol
2002;43:24-7.
  8. Álvarez-Pérez A, Gómez-Bernal S, Gutiérrez-González E, Rodríguez-Granados MT, Toribio J. Granuloma annulare photoinduced by paroxetine. Photodermatol Photoimmunol Photomed
2012;28:47-9.
  9. Lagier L, Dunoyer E, Estève E. Topiramate: a new inductor of
granuloma annulare? 2011;138:141-3.
10. Cassone G, Tumiati B. Granuloma annulare as a possible new adverse effect of topiramate. Int J Dermatol 2014;53:259-61.
11. Kluger N, Moguelet P, Chaslin-Ferbus D, Khosrotherani K, Aractingi S. Generalized Interstitial Granuloma Annulare Induced by
Pegylated Interferon-Alpha. Dermatology 2006;213:248–249
12. Ratnarathorn M, Raychaudhuri S P, Naguwa S Disseminated
granuloma annulare: a cutaneous adverse effect of anti-tnf agents
Indian J Dermatol 2011;56:752-754.
13. Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare response to adalimumab. Int J Dermatol 2010;49:45760
14. Voulgari PV, Markatseli TE, Exarchou SA, Zioga A, Drosos AA.
Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis 2008;67:567-70.
15. Viguier M, Richette P, Bachelez H, Wendling D, Aubin F Paradoxical cutaneous manifestations during anti-TNF-alpha therapy.
Ann Dermatol Venereol 2010;137:64-71.
16. Devos SA, van den Bossche N, De Vos M, Naeyaert JM. Adverse
skin reactions to anti-TNF-alpha monoclonal antibody therapy.
Dermatology 2003;206:388-90.
17. Lebas D, Staumont-Sallé D, Solau-Gervais E, Flipo RM, Delaporte
E. Cutaneous manifestations during treatment with TNF-alpha
blockers: 11 cases. Ann Dermatol Venereol 2007;134:337-42.
18. Kozic H, Webster GF. Treatment of widespread granuloma annulare with adalimumab: a case report. J Clin Aesthet Dermatol
2011;4:42-3.
19. Jones JK. Criteria for journal reports of suspected drug reactions.
Clin Pharm 1982;1:554-5.
20. Fayyazi A, Schweyer S, Eichmeyer B, Herms J, Hemmerlein
B, Radzun HJ et al. Expression of IFNgamma, coexpression of
TNFalpha and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare. Arch Dermatol
Res 2000;292:384-90.
21. Buechner SA, Winkelmann RK, Banks PM. Identification of
T-cell subpopulations in granuloma annulare. Arch Dermatol 1983;119:125-8.
22. Umbert P, Winkelmann RK. Histologic, ultrastructural and
histochemical studies of granuloma annulare. Arch Dermatol 1977;113:1681-6.
23. Hanna WM, Moreno-Merlo F, Andrighetti L. Granuloma annulare: an elastic tissue disease? Case report and literature review.
Ultrastruct Pathol 1999;23:33-8.
24. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J
Dermatol 1997;36:326-33.
25. Stewart LR, George S Hamacher K L, Hsu S. Granuloma annulare
of the palms. Dermatol Online J 2011;17:5.
26. Hawryluk EB, Izikson L. English JC 3rd. Non-infectious granulo-
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THALIDOMIDE INDUCED GRANULOMA ANNULARE
matous diseases of the skin and their associated systemic diseases:
an evidence-based update to important clinical questions. Am J
Clin Dermatol 2010;11:171-81.
27. Dahl MV Granuloma annulare: long-term follow-up. Arch Dermatol 2007;143:946-7.
28. Saripalli YV, Gaspari AA. Focus on: biologics that affect therapeutic agents in dermatology. J Drugs Dermatol 2005;4:233-45.
29. Deng A, Harvey V, Sina B, Strobel D, Badros A, Junkins-Hopkins
JM et al. Interstitial granulomatous dermatitis associated with
the use of tumor necrosis factor alpha inhibitors. Arch Dermatol
2006;142:198-202.
30. Klausner JD, Freedman VH, Kaplan G. Thalidomide as an AntiTNF-a Inhibitor: Implications for Clinical Use Clin Immunol and
Immunopathol 1996;81:219-23.
31. Tomasini C, Pippione M. Interstitial granulomatous dermatitis
with plaques. J Am Acad Dermatol 2002;46:892-9.
32. Gordon K, Miteva M, Torchia D, Romanelli P. Allopurinol-induced palisaded neutrophilic and granulomatous dermatitis. Cutan
Ocul Toxicol 2012;31:338-40.
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33. Hernández N, Peñate Y, Borrego L. Generalized erythematousviolaceous plaques in a patient with a history of dyslipidemia.
Interstitial granulomatous drug reaction (IGDR). Int J Dermatol
2013;52:393-4.
34. Thornsberry LA, English JC 3rd. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J Clin
Dermatol 2013;14:279-90.
35. Wendling D, Prati C. Paradoxical effects of anti-TNF-α agents in
inflammatory diseases. Expert Rev Clin Immunol 2014;10:15969.
36. Yazganoğlu KD, Tambay E, Mete O, Ozkaya E. Interstitial granulomatous drug reaction due to thalidomide. J Eur Acad Dermatol
Venereol 2009;23:490-3.
Presented at the 88th SIDeMaST National Congress.
Conflicts of interest.—The authors certify that there is no conflict
of interest with any financial organization regarding the material discussed in the manuscript.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
333

ORIGINAL ARTICLES
G ITAL DERMATOL VENEREOL 2014;149:335-40
Topical lactoferrin can improve stable psoriatic plaque
R. SARACENO 1, T. GRAMICCIA 1, S. CHIMENTI 1, P. VALENTI 1, M. PIETROPAOLI 2, L. BIANCHI 1
Aim. Lactoferrin (LF), a non-haem iron binding glycoprotein, shares antimicrobial properties with innate immune
system components influencing proinflammatory release of
cytokines involved in psoriatic plaque development. The objective of the study was to verify if LF could provide a therapeutic application in psoriasis.
Methods. An open-label, two arms, 4-week trial was designed
on 30 subjects affected by mild to moderate plaque psoriasis.
All patients received oral bovine LF 100 mg. Fifteen patients
(group A) were topically treated with 10% LF ointment, 15
patients (group B) with 20% LF ointment. All patients applied only ointment vehicle on contra lateral target lesion as
intra-patient side to side control. Efficacy was assessed by
Target Lesion Score.
Results. Twenty-two patients completed the study. Improvement in elevation, redness and scaling was observed on LF
treated psoriatic target lesions comparing to the controlateral controls (P<0.05). There was no additional efficacy for
20% versus 10% topical applications. Oral drug alone did
not exert any improvement on the control plaques receiving
topical placebo.
Conclusion. Our clinical results suggest that LF could be
included as a possible safe topical therapeutic option in the
treatment of psoriatic plaque.
Key words: Lactoferrin - Immune system - Interleukin-6 - Psoriasis.
P
soriasis is a chronic inflammatory skin disease
affecting 1% to 3% of the Italian population.1
It ranges in severity from mild to severe, and patients experience significant deterioration in quality
of life.2-4 Topical therapies represent the first line
treatment for patients with mild to moderate stable
Corresponding author: R. Saraceno, MD, Department of Dermatology, Policlinico Tor Vergata, viale Oxford 81, 00133 Rome, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1Department of Dermatology
Tor Vergata University, Rome, Italy
2Biotechnology Society, Rome, Italy
and localized plaque psoriasis affecting less than
10% of the body’s surface.5 Interactions among keratinocytes and components of innate and acquired
immune system are considered main steps in the
pathogenesis of psoriasis.6 Innate immune cells
produce key cytokines (tumour necrosis factor-α
[TNF-α], interferon-α [IFN-α], interferon-γ [IFN-γ],
interleukin-1β [IL-1β], and interleukin-6 [IL-6]) that
activate myeloid dendritic cells.7 Activated myeloid
dendritic cells lead to T cell differentiation, keratinocytes activation and production of antimicrobial peptides (i.e., cathelicidin, psoriasin and β-defensins).8
Lactoferrin (LF), a non haem iron binding glycoprotein belonging to transferrin family, has been reported to possess both antibacterial and immune modulatory properties.9 LF is the second most abundant
protein in human milk and is found in most exocrine
secretions including tears, nasal secretions, saliva, intestinal mucus and genital secretions.10, 11 Moreover,
LF is a key element in the host defense system involved in several physiological functions including a
direct antimicrobial role by limiting the proliferation
and adhesion of microbes and/or by killing them.12
These properties are mainly related to the ability to
sequester iron in biological fluids or to destabilize
the membranes of microorganisms.13 In addition to
the antimicrobial properties, both in vitro and in vivo
studies, suggest that LF may have a direct effect on
regulation of cytokine production including TNF-α,
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
335
SARACENO
Topical lactoferrin and psorias
IFN-γ, IL-6 and IL-1β.14, 15 TNF-α and IL-6 play an
important pathogenetic role in psoriasis.7 The role of
TNF-α is clinically validated by the effect of antiTNF-α targeted therapies. IL-6 is raised in psoriasis
and the pleiotropic effects include stimulation of epidermal keratinocyte hyperplasia as well as promoting the differentiation of IL-17-producing T lymphocytes.15 According to these findings, we designed
a clinical and investigative study in order to evaluate
the therapeutic properties of bovine LF (bLF) topically applied and the possible additional effect of low
doses of bLF orally administered in patients affected
by mild to moderate stable plaque-type psoriasis.
Materials and methods
A four-week, prospective, bilateral-paired controlled study of bLF in subjects with mild to moderate
psoriasis showing stable localized symmetrical lesions was disegned. Patients were randomized (1:1)
according to the CONSORT criteria.16 The study
protocol and consent form were approved by the local health authority and all subjects provided written
informed consent prior to study enrollment. Inclusion
criteria were: 1) clinical diagnosis of stable and symmetrical plaque psoriasis for at least one month and
involving <10% body surface area; 2) age 18 years or
above; 3) psoriasis area and severity index (PASI) 17
score ≤10. Paired target lesions were considered when
in similar anatomic locations and with equal baseline
severity score for erythema, scaling and infiltration.
Subjects who were pregnant or nursing were not included in the study. Patients were also ineligible if
they had used topical agents within 4 weeks from the
enrollment or received systemic antipsoriatic drugs
within 8 weeks from the entry date. Symmetrical lesions localized on the knees or elbows with similar
TLS (±1) were selected by a dermatologist not directly involved in the study using photos and masked
as to the date of when the photos were taken. Patients
were treated for 4 weeks according to the mean duration of most of the psoriatic topical treatments, as
follows: 1) bLF ointment on the target lesion; 2) only
ointment vehicle on a contra lateral target lesion as
intra-patient side to side control. Thirty out-patients
(15 women and 15 men, mean age 49.2, range 1867 years) with stable bilateral symmetrical psoriasis
were enrolled in this study. Fifteen patients were included in group A and 15 in group B. Only psoriatic
336
target lesions were treated with bLF 10% ointment
BID (group A) or bLF 20% ointment OD (group B).
bLF ointment was provided by Giellepi Chemicals
S.p.a. (Seregno, Milan, Italy). The ointment composition was 10 or 20% of bLF in a mixture of liquid
paraffin and polyethylene, as hydrophobic gel base
vehicle. Oral bLF, 100 mg (Lattoglobina® 100 mg
capsules, Grünenthal-Formenti, Achen, Germany),
was fasting administered BID in both groups. Because of the preliminary design of the study, oral placebo treated groups with and without drug or placebo
ointment were not included. Visits were scheduled
at baseline, at week 2 and at week 4. The follow-up
period was 4 weeks. Evaluation was performed by
PASI score (for the inclusion criteria) and by assessing erythema, scaling, and infiltration according TLS,
using a four point scale for each parameter (0=none;
1=mild; 2=moderate, 3=severe). The clinical evaluation was assessed by a blinded independent dermatologist. VAS from 0 to 10 was also proposed to assess patient pruritic symptoms. Safety was evaluated
by recording any adverse event occurring during the
study period. Routine bloods tests, serum ferritin,
iron and transferrin levels were performed at baseline, at week 4 and at the end of the study.
Biochemical assay
Plasma concentrations of TNF-α and IL-6 were
determined in duplicate using a high sensitivity commercial sandwich enzyme-linked immunosorbent
assay (ELISA) kit (Mabtech, Italy). All assay procedures were performed as described by the manufacturer. The lower limit of cytokine’s detection was
0.02 pg/mL for IL-6, and 0.06 pg/mL for TNF-α.
Statistical analysis
The minimal level of significance of the differences was fixed at P≤0.05 for all the procedures. The statistical analysis was carried out by using SPSS11.01
Software. The study was designed to reach a power
of 0.80 with a type 1 error of 0.05, using the “POWER and PRECISION 3.2” program, SPSS.
Results
A total of 22 (12 women and 10 men, mean age
51.6, range 18-67 years) out of 30 patients with bi-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Topical lactoferrin and psorias
SARACENO
Table I.—Baseline characteristics of the study population.
Group A
Total number of patients
Male/Female
Mean age (range)
Mean age of onset (years)±SD
Psoriatic arthritis
Mean PASI T0 (range)
Mean TLS T0 (range)
Group B
15
7/8
49.5 (18-67)
35.0±13
1/15
3.1 (1.2-6.8)
4.9 (2-6)
A
15
5/10
49.0 (18-66)
31.8±15
2/15
3.4 (1.2-7.4)
5.0 (3-6)
B
Figure 1.—Group A: Clinical response of the target lesion (A) after 4 weeks (B) of treatment with bLF 10% applied BID.
lateral symmetrical psoriasis completed the study.
Ten patients were counted in group A (4 women and
6 men) and 12 patients in group B (8 women and 4
men). Eight patients discontinued the study due to
lack of efficacy (2 patients of group A and 1 patient
of group B), worsening of the treated lesion (1 patient of group B) and lack of compliance (4 patients
of group B). Lesions were localized on knees and
elbows. The study population was homogeneous for
demographics and disease features (Table I). Over
the treatment period, both bLF 10% and bLF 20%
ointments improved the target lesions: reduction of
plaques’ elevation, redness and scaling were noted
after 4 weeks of treatment, slightly more evident in
group B patients (Figures 1, 2).
The mean TLS improved by 23.5% at week 2 and
by 37.3% at week 4 in group A, and by 25.8% at
week 2 and by 35.5% at week 4 in group B (Figure 3).
These changes were statistically significant (P<0.05
Wilcoxon two sample test). In both groups, over the
4-week treatment period, a substantial improvement
Vol. 149 - No. 3
of itch from baseline to week 4 (VAS score: from 5.8
to 3.2) was noticed in the target bLF treated lesions,
compared to the control lesions (VAS score at week
4 was 5.1). At 4 week of follow-up, these results
were not maintained. Adverse events were observed
in 3 subjects in group B and these included burning
sensation at the site of drug application (these subjects did not withdraw from the study). No serious
adverse events were reported during the study and
the follow-up period. No significant changes in routine laboratory values were observed in any of the
patients. In group A, serum TNF-α and IL-6 mean
levels at week 0 and week 4 showed no significant
variations (Table II).
Discussion
LF is a member of the transferrin family of nonhaem iron binding proteins with several physiological functions including protection against microbial
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
337
SARACENO
Topical lactoferrin and psorias
A
B
Figure 2.—Group B: Clinical response of the target lesion (A) after 4 weeks (B) of treatment with bLf 20% applied OD.
static effect related to the high iron binding affinity
of the protein that deprives iron-requiring bacteria of
this essential growth nutrient.18-20 The second antibacterial property of LF is due to a direct bactericidal
effect against gram negative and gram positive bacteria that cannot be attributed to simple iron deprivation.12 Moreover, in vitro and in vivo studies suggest
that LF plays an anti-inflammatory effect by inhibiting the production of several cytokines including
TNF-α,13 IL-6 14 and by influencing dendritic cells,21
that are key mediators of the inflammatory response
in psoriasis.7 Psoriasis is a chronic inflammatory disorder mediated by elements of the innate and adaptive
immune systems.7 Innate immunity is non-specific
and protects the body against the constant risks of
pathogens.8 Thus the epidermis constitutes a major
barrier to the environment and provide the first line
of defense against invading microbes. Even though
our study was conducted in a small series of cases,
we could observe a clinical effect of bLF ointment
in the local treatment of stable localized psoriatic
plaques. Both the concentrations proposed achieved
similar improvement. In contrast, the clinical com-
Figure 3.—The chart shows the efficacy of lactoferrin on the target lesion score (TLS) in both groups of treatment. In contrast the
same PASI at baseline and at week 4 highlights that no changes
in the controlateral side were induced by lactoferrin orally administered. *Changes statistically significant (P<0.05 Wilcoxon two
sample tests).
infection, regulation of myelopoiesis and systemic
immune responses.9-12 The antibacterial functions of
LF have been substantiated by both in vitro 13 and in
vivo 14 evidences. The first mechanism is a bacterio-
Table II.—Serum IL-6 and TNF-α levels at baseline and 4 weeks after therapy.
Serum cytokines
IL-6 (pg/mL)
TNF-α (pg/mL)
T0
2.112 (±3.820)
25.233 (±6.425)
T4
3.446 (±8.758)
23.073 (±3.283)
These parameters were detected in order to evaluate the immunomodulatory effects of bovine lactoferrin orally administered on the release of two key
cytokines in psoriasis. A slight increase in IL-6 and a slight decrease in TNF-α serum concentrations were observed at the end of treatment (T4). Both
variations were not statistically significant.
338
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Topical lactoferrin and psorias
parable contralateral plaques who only received the
systemic oral bLF or those treated with placebo ointment vehicle, did not show any clinical improvement
suggesting that oral bLF at the dosage proposed did
not reach the skin or was too low or ineffective or
administrated for a too short period of time. The antimicrobial effects of bLF and the aforementioned opposite results, suggest that the topical application of
bLF locally may modulate the expression and functions of epidermal barrier components such as corneocytes and specialized cells of epidermis namely
Langerhans’ cells. According with this hypothesis,
it has been demonstrated that the topical administration of the iron-binding protein, human LF, inhibits
Langerhans’ cells migration and TNF-α release.13, 21
By these experiments, LF appeared as a potent
inhibitor of Langerhans’ cells migration and TNF-α
production. These properties could explain and justify its role in treating chronic skin inflammation such
as psoriasis in which TNF-α is an important mediator. Furthermore, since LF exists as a constituent of
normal skin, raises the possibility that in psoriasis LF
could be reduced and that LF may act as endogenous
regulator of skin immune functions influencing local cytokines production. We were not able to correlate the slight variations detected in the serum levels
of TNF-α and IL-6 in our patients at the end of the
protocol with the anti-inflammatory effect mediated
by the oral Lf in other subjects.22 Moreover, patients
reported a significant reduction in pruritic symptoms
in both sides. This effect could be mediated by the
aforementioned cytokines or through more specific
pathways (i.e., substance P, histamine).
One of the key mechanism of innate immune
responses are the existence of receptors to recognize pathogens and the production of factors that
kill pathogens such as the antimicrobial peptides
(AMPs).23 AMPs are emerging as participants in the
defense system of the epithelial barriers and they represent a primary system for protection in response to
microbial invasion. AMPs dysfunction emerges as a
central factor in the pathogenesis of several cutaneous diseases including psoriasis.24 Evidence of this
comes from the observation that psoriatic keratinocytes are a rich source of AMPs, including LL-37,
β-defensins, and S100A7.25 It has been recently
demonstrated that the aforementioned AMPs bind
self-DNA and self-RNA to form structures that gain
access to endosomal Toll-like receptors, leading to
an aberrant activation of plasmacytoid dendritic cells
Vol. 149 - No. 3
SARACENO
(pDCs) to produce IFN-γ.26 pDC-derived IFN-γ may
initiate the autoimmune-inflammatory cascade in
psoriasis, a process characterized by the activation
of myeloid DCs and their maturation into DCs that
stimulate pathogenic autoimmune T cells.26 According with the antimicrobial properties of both Lf and
AMPs, LF may compete with AMPs, down-regulate
their expressions and the development of autoimmunity. This mechanism could further explain the antiinflammatory effects of LF in psoriasis.
Limitations of the study
Main limitations are represented by the small size
samples of the cases enrolled, the absence of a control
group not taking oral bLF, the short period of the study,
and the low doses of oral LF. The study design did not
include a control group only treated with topical LF
because previous studies showed that only high doses
(800 mg to 5 g) of oral LF are effective in the treatment
of psoriasis.27, 28 For this reason we administered low
doses of oral LF in order to evaluate a possible synergistic effect with topical LF ointment. Since oral LF did
not show synergistic or positive effects, the absence of
a control group could not be considered a major limitation. Finally, since several topical and available treatments are effective in the short period, we decided to
evaluate the efficacy of a new formulation in a 4-week
period.29 Further investigations could evaluate possible
synergistic effect of topical bLF associated with corticosteroid as most of the therapeutic experiences either
as fixed combination 30 or as separate daily application.31
The clinical results observed in our study suggest
that LF could become a new therapeutic option in the
treatment of mild and localized psoriasis. LF was well
tolerated and transient site burning reported from three
patients occurs during the first few days and resolves
within 1 week of therapy. According with these results
and to the limited adverse events observed, the once
daily application (20% formulation) could be considered more suitable for psoriatic patients and possibly
increase compliance to the treatment.
References
  1. Saraceno R, Mannheimer R, Chimenti S. Regional Distribution of
psoriasis in Italy. J Eur Acad Dermatol Venereol 2008;22:324-9.
  2. Krueger GG, Feldman SR, Camisa C, Duvic M, Elder JT, Gottlieb
AB et al. Two considerations for patients with psoriasis and their
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Topical lactoferrin and psorias
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constitutes a clinically significant improvement when treating psoriasis? J Am Acad Dermatol 2000;43:281-5.
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  4. Linder D, Sampogna F, Torreggiani A, Balato N, Bianchi L, Cassano N et al. Psodisk, a new visual method for assessing the burden of
psoriasis on patients. J Eur Acad Dermatol Venereol 2012;26:11635.
  5. Lebwohl M, Ali S. Treatment of psoriasis. Part 1. Topical therapy
and phototherapy. J Am Acad Dermatol 2001;45:487-98; 499-502.
  6. Chiricozzi A, Zhang S, Dattola A, Gabellini M, Chimenti S, Nistico
SP. Role of Th17 in the pathogenesis of cutaneous inflammatory
diseases. J Biol Regul Homeost Agents 2012;26:313-8.
  7. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med
2009;361:496-509.
  8. Schauber J, Gallo RL. Antimicrobial peptides and the skin immune
defense system. J Allergy Clin Immunol 2009;124:R13-8.
  9. Legrand D, Pierce A, Elass E, Carpentier M, Mariller C, Mazurier J. Lactoferrin structure and functions. Adv Exp Med Biol
2008;606:163-94.
10. Rodríguez-Franco DA, Vázquez-Moreno L, Ramos-Clamont Montfort G. Antimicrobial mechanisms and potential clinical application of lactoferrin. Rev Latinoam Microbiol 2005;47:102-11.
11. Valenti P, Antonini G. Lactoferrin: an important host defence against
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12. Ward PP, Conneely OM. Lactoferrin: role in iron homeostasis and
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13. Machnicki M, Zimecki M, Zagulski T. Lactoferrin regulates the release of tumour necrosis factor alpha and interleukin 6 in vivo. Int J
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14. Crouch SP, Slater KJ, Fletcher J. Regulation of cytokine release
from mononuclear cells by the iron-binding protein lactoferrin.
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15. Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent
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16. Schultz KF, Altman DG, Moher D. The CONSORT Group. CONSORT 2010 Statement: Updated Guidelines for Reporting ParallelGroup Randomized Trials. Trials 2010;11:32.
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18. Bullen JJ, Rogers HJ, Leigh L. Iron-binding proteins in milk and resistance to Escherichia coli infection in infants. Br Med J 1972;1:69.
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21. Cumberbatch M, Bhushan M, Dearman RJ, Kimber I, Griffiths CE.
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2003;132:352-9.
22. Paesano R, Pietropaoli M, Gessani S, Valenti P. The influence of
lactoferrin, orally administered, on systemic iron homeostasis in
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23. Gilliet M, Lande R. Antimicrobial peptides and self-DNA in autoimmune skin inflammation. Curr Opin Immunol 2008;20:401-7.
24. Büchau AS, Gallo RL. Innate immunity and antimicrobial defense
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25. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey
B et al. Plasmacytoid dendritic cells sense self-DNA coupled with
antimicrobial peptide. Nature 2007;449:564-9.
26. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman
O et al. Plasmacytoid predendritic cells initiate psoriasis through
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27. Drouin R, Moroni O, Cantin K, Juneau C. A double-blind, placebocontrolled, randomized trial of XP-828L (800 mg) on the quality of
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28. Poulin Y, Bissonnette R, Juneau C, Cantin K, Drouin R, Poubelle
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29. Kamili QU, Menter A. Topical treatment of psoriasis. Curr Probl
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betamethasone dipropionate in the treatment of plaque psoriasis. G
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31. Calzavara-Pinton P, Rossi MT, Sala R, Venturini M. The separate
daily application of tacalcitol 4 µg/g ointment and budesonide
0.25 mg/g cream is more effective than the single daily application
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Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
Received on October 30, 2013.
Accepted for publication on November 20, 2013.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

G ITAL DERMATOL VENEREOL 2014;149:341-6
Clinically and/or histologically
pigmented poromas in Caucasian patients
R. BETTI 1, C. BOMBONATO 1, A. CERRI 1, L. MONEGHINI 2, P. ABRAMO 1, S. MENNI 1
Aim. Pigmented poromas are rarely reported and considered
to be more common in non-white people and on non-acral
sites. Objective of the present study was to report our cases of
pigmented poromas with particular attention to the presence
of clinical and/or microscopic evidence of pigmentation, their
characteristics and the diagnostic pitfall with other pathologies.
Methods. All the histologically confirmed poromas observed
from January 1994 to July 2012 were considered. Clinicepidemiological data were collected. The presence of clinical
pigmentation was recorded as well as the presence of melanin
pigmentation or melanocytes in the histologic specimens.
Results. One hundred and one patients with poromas were
collected. All the patients were Caucasians. All the lesions
were solitary. Only three patients had a clinically visible
pigmented poromas. In eight cases the presence of melanin
and melanocytes did not produce a clinically visible pigmentation. All the poromas with pigmentation did not occur on
palmo-plantar surfaces.
Conclusion. Pigmented poromas may be observed even in
Caucasian patients and their clinical aspect mimic basal
cell carcinoma and/or melanoma. The presence of pigment
visible at the histology may not be observed in the clinical
expression. The absence of pigmentation on palmo-plantar
location is confirmed in all the reported cases.
Key
words:
1Dermatologic Clinic,
Department of Health Sciences
University of Milan, San Paolo Hospital, Milan, Italy
2Department of Health Sciences, Division of Pathology
University of Milan, San Paolo Hospital, Milan, Italy patients.2 They are usually non-pigmented even if
the pigmented variant can be occasionally found.3-12
This variant seems to be more frequent in non-white
people and on non-acral sites 12 although recently a
pigmented palmar case has been reported.13
This study describes three additional cases of clinically pigmented poromas (PP) in white patients and
briefly discusses their frequency, their characteristics, the diagnostic pitfall with other pathologies, the
problem of the supposed pigmentation mechanism
and other cases in which the presence of melanin
and/or melanocytes in the histologic specimens did
not involve an evident clinical pigmentation.
Materials and methods
Poroma - Pigmentation - Foot.
Subject populations
P
oromas are benign adnexal tumors derived from
cells of the outer layer of acrosyringium and the
sweat duct ridge.1 They often appear as flesh-colored
to reddish solitary nodules, papules or plaques, frequently present on the palmo-plantar area of aged
Corresponding author: R. Betti, Department of Health Sciences, Division of Dermatology, University of Milan, San Paolo Hospital, via di
Rudinì 8, 20142 Milan, Italy. E-mail: [email protected]
Vol. 149 - No. 3
All the cases of histologically confirmed poromas
observed in our institution from January 1994 to July
2012 were collected. Clinic-epidemiological data recorded were age at diagnosis, gender, location, size,
symptoms, color, preoperative diagnosis. Pathological diagnosis according to the four accepted poromas
subtypes was made: these are classically based on
the difference of their tumor cells location.2 Classic
poromas (EP) exhibit a lobular growth pattern and
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
341
BETTI
Pigmented poromas
A
B
C
D
Figure 1.—Patient 1. A) A 1 cm in diameter uniformly brownish nodular lesion over the left retroauricular region of a 67-year-old
white man; B) anastomosing cords of small monomorphous polygonal, epithelial poroid cells extending from the epidermis onto the
subjacent dermis with sporadic cystic spaces delimitated by cuticolar cells (HE x2.5); diffuse areas with melanin pigmented poroid
cells were present (HE x10); C) the presence of intracellular melanin in the poroid cells is diffuse; D) MART-1 immunohistochemical
stain show the presence of dendritic melanocytes dispersed throughout the lesion (MART-1 x40).
broad connection to the overlying epidermis, Hidroacanthomas simplex (HS) are essentially located within the epidermis, whereas dermal duct tumors (DDT)
are intradermal neoplasms mostly composed of small
lobular aggregations of cells, with little or no connection to the epidermis. Poroid hidroadenoma (PH)
were described by Abenoza and Ackerman as dermal
neoplasms consisting of single or few large aggregations of “poroid” and “cuticular” cells, with cystic
areas.2 The presence of clinical pigmentation was recorded as well as the presence of melanin pigmentation or melanocytes in the histologic specimens.
342
Results
A total of 101 patients with poromas participated into the study. Among them, 33 were EPs,
6 HSs, 3PHs. No DDTs were observed. Microscopic and/or clinical presence of pigmentation
was observed in eleven cases. The clinical data
of pigmented poromas are summarized in Table
I. Only three patients had a clinically visible pigmentation. In the other eight patients the presence of melanin deposition in the poroid cells
(five patients) and melanocytes (three patients) or
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Pigmented poromas
BETTI
A
B
C
D
Figure 2.—Patient 2. Flesh to brownish dome shaped nodule 12x10 mm in diameter on the back of a 69-year-old Caucasian man (A).
The pigmentation is uniform but more visible in the emilateral portion of the nodule. The majority of tumor cells consisted of small,
dark, homogeneous poroid cells and cuticular cells. Melanin filled poroid cells and dispersed MART-1 dendritic melanocytes were also
seen (B) (HE, original magnification x40). Patient 3. Irregularly pigmented nodular lesion on the inner surface of right subauricular
region of a 64-year-old white man (C). Anastomosing cords and lobules of small monomorphous cuboidal epithelial cells extending
from the epidermis into the subjacent dermis. At the basal level, in a scattered manner, an increased number of melanin poroid cells
and basal melanocytes were visible (D) (HE, original magnification x10).
both (five patients) slight scattered in the dermis
do not produce a clinically visible pigmentation.
Poromas on the feet (Table I, patients 4, 8, 11)
were never located on the soles but on the dorsal
surface. The presurgical clinical diagnosis of the
three pigmented poromas was: Patient 1 (Figure
1): suspected melanoma; Patient 2 (Figures 2A,
B): suspected basal cell carcinoma or possibly
melanoma; Patient 3 (Figures 2C, D): basal cell
carcinoma.
Vol. 149 - No. 3
Case reports
Patient 1.—A 67-year-old white man had a 1-cm brownish nodule with smooth surface of 8-months duration on
his left retro auricular region (Figure 1A). On palpation, a
firm and freely movable lesion was felt. Hematoxylin and
eosin-stained sections after an excisional biopsy revealed a
dermal nodule composed of anastomosing cords of small
monomorphic polygonal, epithelial poroid cells extending from the epidermis to the subjacent dermis with sporadic cystic spaces delimitated by cuticular cells (Figure
1B). Areas with diffuse intracellular presence of melanin
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
343
BETTI
Pigmented poromas
Table I.—Patients with histologic and/or clinically evident pigmented poromas.
Patient
Age
Sex
Site
Clinical pigmentation
Histologic Diagnosis
1
2
3
4
5
6
7
8
9
10
11
67
64
69
58
55
83
72
68
43
51
69
M
M
M
M
F
M
F
M
F
M
M
Retroauricular
Subauricular
Back
Foot
Face
Buttock
Hand (finger)
Foot
Trunk
Armpit
Foot
+ (Figure 1)
+ (Figure 2C)
+ (Figure 2A)
-
Poroma
Poroma
Poroma
Poroma
Poroma
Poroma
Poroma
Poroma
Hidroacanthoma simplex
Poroma
Poroma
All the samples showed the presence of pigmentation at the histology.
in the pigmented poroid cells were present (Figure 1C).
MART-1 immunohistochemical stain showed the presence
of dendritic melanocytes dispersed throughout the neoplasia (Figure 1D).
Patient 2.—A 69-year-old white man presented with a
14-months history of a dome shaped nodular lesion on his
back. The nodule showed a uniform pigmentation mainly
located in its emilateral portion. The nodule felt elastic
hard and presented flesh to brownish, well circumscribed,
12x10 mm in diameter (Figure 2A). On histological examination the majority of tumor cells consisted of small,
dark, homogeneous poroid and cuticular cells. The poroid
cells were melanin filled and dispersed MART-1 dendritic
melanocytes were observed (Figure 2B).
Patient 3.—A 64-year-old white man presented with
a 1-year history of enlarging, soft, irregularly pigmented
nodular lesion on the inner surface of his right subauricular
region. On physical examination, a 12 mm in size, nontender lesion, with both pigmented and non-pigmented areas clearly distinct in location, was observed (Figure 2C).
Microscopic examination revealed anastomosing cords
and lobules of small monomorphic cuboidal epithelial cells
extending from the epidermis to the subjacent dermis. At
the basal level, an increased number of melanocytes and
melanin filled basal cells was visible in a scattered manner (Figure 2D), moreover a slight number of melanin pigmented poroid cells in the epidermis was also present.
Discussion
Pigmented poromas are rare, a general total of 50
cases including ours 4-16 being reported in literature.
Their anatomical locations were determined as follows: head and neck 17 cases (including ours), trunk
including buttocks 13 cases (including ours), arms 19
cases. All the described cases do not include lesions
344
on palms and soles, so certainly PPs have a predilection for non acral sites, in contrast with the more
prevalent non pigmented variant.3, 4 Although most
of the literature reports affected Japanese, oriental
or non-white patients, some reports (including ours)
certainly have interested white patients.10, 16 In a few
reports patient race is not specified.12, 15 All the reports describe PPs as rare. However, Battistella et al.
analyzed the clinical characteristics of 266 patients
with poromas and reported a 17% of pigmented
cases,1 questioning the real rarity of pigmented poromas. In absence of any further specification, probably some confusion exists when one considering the
clinical expression of pigmentation and the histologic
presence of melanin and/or melanocytes within the
tumoral lobules. In our clinical records of 101 poromas, eleven cases showed the histologic presence of
pigmentation within the tumoral lobules (Table I), but
only three patients showed the clinical expression of
pigmentation (Figures 1, 2). Another report 4 documented three clinically pigmented cases out of 25 patients and seven cases with the microscopic presence
of melanin deposits. The report of Moore et al. does
not clearly indicate the clinical presence of pigmentation 14 although the authors tend to equalize the histologic presence of pigment with the clinical expression in five patients. Anyway, Minagawa and Koga
stressed the fact that PPs contain variable amounts of
melanin 11 and this causes the tumors to vary in color.
The poroma variations based on the amounts of melanin within the lesion and the different histopathological features 2 may cause problems in differential
diagnosis with a variety of benign and malignant
conditions above all basal cell carcinoma, seborrheic
keratosis and melanoma.5, 10, 11 Dermatoscopy may be
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Pigmented poromas
BETTI
useful in narrowing the diagnosis.11 The absence of
pigment network, the presence of branched streaks
or aggregated pigment globules, varying dark-brown
and blue-grey colors in variable sized ovoid nests,
blue-gray dots and arborizing vessels, but not maple
leaf-like structures and spoke-wheel areas share common features with basal cell carcinoma. Atypical pigment network, dots or globules, streaks, irregular and
polymorphous blood vessels, regression structures
and a blue-white veil share features with melanomas.
For these reasons a precautionary narrow- margin excision or excisional surgery is recommended.5, 10 It
has been hypothesized that melanocytes colonization
of a poroma may be an indicator of malignant transformation to porocarcinoma.6 Moreover, it has been
observed that porocarcinoma develops from or is associated with a pre-existing poroma in nearly half
of the cases.17, 18 However, porocarcinoma arising in
pre-existing pigmented poroma is extremely rare and
this finding is at best speculative and has not been
validated by larger studies.12 We have not observed
the presence of malignant transformation in our 101
poromas, nor we have had the opportunity to observe
the suggested transformation of long-standing poromas.19 About the mechanism/s of pigmentation of the
tumoral lobules several hypothesis have been proposed to explain this phenomenon present in a range
of skin tumors including poromas. Endothelin-1 (ET1), a peptide known to trigger melanocyte activation
and to act as a potent mitogen and melanogen for
melanocytes has been implicated to participate in the
pigmentation process in seborrheic keratosis, actinic
keratosis and basal cell carcinomas.20 Hu et al. indicated the possibility that the up-regulation of Endothelin-1 (ET-1) or other melanocytic-stimulating
factors may be associated with the colonization (migration and proliferation) of melanocytes from the
adjacent epidermis to the poroma at non acral sites
only.3 In order to explain the lack of pigmentation at
acral sites, the same authors hypothesized that certain
characteristics of acral (palmo-plantar) skin inhibit
melanocytic colonization. Ueo et al. proposed that for
intraepidermal lesion (i.e., hidroacanthoma simplex)
the melanin may be transferred to the tumor directly
from adjacent normal basal melanocytes.18 Another
possibility 21 may be the activation by the tumor of
melanocytes persistently present within the eccrine
acrosyringium, but even this hypothesis is inconsistent with the lack of reports of palmo-plantar PPs. The
lack of response of vitiligo palmo-plantar lesions to
Vol. 149 - No. 3
UVB therapy suggest that melanocytes poorly colonize these areas.3 The sum of findings seem to indicate
that other factors may play a role in the melanocytic
colonization of poromas. These factors may depend
on signals derived from the tumors lobules as well
as from the surrounding dermal stroma. Further studies are obviously necessary to elucidate this mechanism. Based on these referred literature reports about
the pigmentation mechanisms, to discuss the different features of pigmentation seen in our cases may
be only speculative. We have different conditions.
The diffuse, uniform clinical pigmentation present
in patient 1 and the uniformly diffused but emilaterally localized in patient 2 can reflect the uniform
presence of melanin filled poroid cells and dendritic
mrlanocytes scattered throughout the dermis. The
scattered slight pigmentation of the third case can reflect the slight scattered presence of pigment in the
basal layer. The absence of clinically relevant or evident pigmentation despite the histological presence
of melanocytes, melanin or melanophages in the tumor may be explained by the low density of pigment
and the different depth of the tumor lobules interested
by the pigmentation. As suggested, differences in the
density of melanocytes in the surrounding epidermis
may be partially explain the lack of pigment.3 In summary our cases suggest that PPs may be observed in
white patients and their clinical aspect mimicks basal cell carcinoma and/or melanoma. Moreover, the
presence of histological pigment may not to produce
a clinical pigmented expression. The absence of pigmentation on palmo-plantar location is confirmed in
all our reported cases and no malignant transformation was observed.
References
  1. Battistella M, Langbein L, Peltre Band Cribier B. From hidroacanthoma simplex to poroid hidroadenoma: clinicopathologic and
immunohistochemic study of poroid neoplasms and reappraisal of
their histogenesis. Am J Dermatopathol 2010;32:459-68.
  2. Abenoza P, Ackerman AB. Neoplasms with eccrine differentiation.
In: Abenoza P, Ackerman AB, editors. Ackerman’s histologic diagnosis of neoplastic skin diseases. Philadelphia: Lea and Febiger eds;
1990. p. 113-85.
  3. Hu SC, Chen GS, Wu CS, Chai CY, Chen WT, Lan CC. Pigmented
eccrine poromas: expression of melanocyte stimulating cytokines
by tumour cells does not always result in melanocyte colonization.
J Eur Acad Dermatol Venereol 2008;22:303-10.
  4. Chen CC, Chang YT, Liu HN. Clinical and histological characteristics of poroid neoplasms: a study of 25 cases in Taiwan. Int J Dermatol 2006;45:722-7.
  5. Nicolino R, Zalaudek I, Ferrara G, Annese P, Giorgio CM, Mo-
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Pigmented poromas
scarella E et al. Dermoscopy of eccrine poroma. Dermatology
2007;215:160-3.
  6. Wang SH, Tsai TF. Congenital polypoid pigmented eccrine poroma
of a young woman. J Eur Acad Dermatol Venereol 2008;22:366-8.
  7. Chiu HH, Chen PH, Wu CS, Chen GS, Chen GS, Tsai KB, Wen CH
et al. Origin of poroid hidradenoma and pigmentation mechanism
of eccrine poroma: critical analysis of an unique presentation. J Eur
Acad Dermatol Venereol 2009;23:597-59.
  8. Allende I, Gardeazabal J, Acebo E, Díaz-Pérez JL. Pigmented eccrine poroma. Actas Dermosifiliogr 2008;99:496.
  9. Ishida M, Hotta M, Kushima R, Okabe H. A case of porocarcinoma
arising in pigmented hidroacanthoma simplex with multiple lymph
node, liver and bone metastases. J Cutan Pathol 2011;38:227-31.
10. Smith EV, Madan V, Joshi A, May K, Motley RJ. A pigmented lesion on the foot. Clin Exp Dermatol 2012;37:84-6.
11. Minagawa A, Koga I. Dermoscopy of pigmented poroma. Dermatology 2010;221:78-83.
12. Phelps A, Murphy MJ. Pigmented classic poroma: a tumor with a
predilection for nonacral sites?. J Cutan Pathol 2010;37:1121-2.
13. Nishikawa Y, Kaneko T, Takiyoshi N, Aizu T, Nakajima K, Matsuzaki Y et al. Dermoscopy of eccrine poroma with calcification. J
Dermatol Case Rep 2009;28:38-40.
14. Elloumi-Jellouli A, Marrrak H, Ben Ammar S, Ben Ayed M, Mokhtar
I. Porome eccrine pigmentè. Ann Dermatol Venereol 2004;131:1023.
15. Moore TO, Orman HL, Orman SK, Helm KF. Poromas of the head
and neck. J Am Acad Dermatol 2001;44:48-52.
346
16. Zina AM, Bundino S, Pippione MG. Pigmented hidroacanthoma
simplex with porocarcinoma. Light and electron microscopic study
of a case. J Cutan Pathol 1982;9:104-12.
17. Nakanishi Y, Matsuno Y, Shimoda T, Wada T, Yamazaki N, Yamamoto A et al. Eccrine porocarcinoma with melanocyte colonization.
Br J Dermatol 1998;138:519-21.
18. Ueo T, Kashima K, Daa T, Kondoh Y, Yanagi T, Yokoyama S. Porocarcinoma arising in pigmented hidroacanthoma simplex. Am J
Dermatopathol 2005;27:500-3.
19. Manaka I, Kadono S, Kawashima M, Kobayashi T, Imokawa G.
The mechanism of hyperpigmentation in seborrheic keratosis involves the high expression of endothelin-converting enzyme-1a and
TNF-a, which stimulate secretion of endothelin-1. Br J Dermatol
2001;145:895-903.
20. Vural P, Erzengin D, Canbaz M, Selcuki D. Nitric oxide and endothelin-1,2 in actinic keratosis and basal cell carcinoma: changes
in nitric oxide/endothelin ratio. Int J Dermatol 2001;40:704-8.
21. Robson A, Greene J, Ansari N, Kim B. Eccrine porocarcinoma (malignant eccrine poroma): a clinicopathologic study of 69 cases. Am
J Surg Pathol 2001;25:710-20.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
Received on September 6, 2013.
Accepted for publication on October 15, 2013.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

G ITAL DERMATOL VENEREOL 2014;149:347-53
In vivo and in vitro evaluation of topical formulations
containing physiological lipid mixture
for replacement of skin barrier function
C. BARBA 1, J. L. PARRA 1, L. CODERCH 1, A. SEMENZATO
Aim. The aim of the study was to describe a new in vivo and
in vitro approach of the efficacy evaluation of cosmetic emollients to better understand the link between the formulation
and the activity of cosmetic products.
Methods. Two long term in vivo studies were carried out on
nine healthy Caucasian volunteers mean age 40±12 years to
evaluate the protecting and repairing effects of the two different barrier repair cosmetic formulations. The application of
the formulations was repeated once a day during 7 days and
biophysical parameters (TEWL and Skin Hydration) were
measured before and after Sodium laureth sulphate exposure
The in vitro study was carried out by freeze substitution transmission electron microscopy (FSTEM) on stratum corneum
samples obtained by sections of fresh skin from young pigs, depleted with a solvent mixture and treated with the two products
Results. The in vivo results demonstrated that daily product
application provided a reinforcement of the skin barrier with
protecting and repairing effects from chemical injuries the
extent of which was dependent on the formulation features
(product A>product B) The role of the technical form on the
lipid availability was confirmed by the in vitro evaluation tests.
Conclusion. The results point out that a daily application of
physiological lipid mixture containing emulsion can protect
healthy skin and promote the reparing effect on unpaired
barrier skin, reducing TEWL and maintaining hydration of
the stratum corneum. The efficacy degree is higher when the
cosmetic form promotes the availability of active ingredients
increasing the product performance.
Key words: Emollients - Cosmetics - Ceramides - Dermatitis,
Atopic.
C
osmetic emollients are widely used for the management of atopic dermatitis since many years,
as adjuvant of pharmacological therapies.1
Corresponding author: A. Semenzato, Department of Pharmaceutical
and Pharmacological Sciences, Via F. Marzolo 5, 35131 Padua, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1IQAC-CSIC,
2
Barcelona, Spain
2Department of Pharmaceutical
and Pharmacological Sciences
University of Padua, Padua, Italy
According to the “bricks and mortar model” proposed in nineties by P.M. Elias,2, 3 the stratum corneum, the first line of defense within the epidermal
barrier,4 is a multicellular vertically stacked layer of
cells embedded within a hydrophobic extracellular
matrix, predominantly composed of 50% ceramides,
20-25% cholesterol, and 10-20% free fatty acids.5
This peculiar structure provides fundamental roles
in maintaining protection from the environment as
well as preventing water loss.6 A significant decrease
in all three key lipids, especially ceramides, has been
well established in atopic skin, characterized by an
increased TEWL and enhanced barrier permeability, because the lipid imbalance and the inadequate
amounts of ceramides contribute to defective formation of the corneocyte lipid envelope and lipid mortar.7, 8
The topical application of ointments or creams,
containing high lipid concentrations, can provide
positive effects to dry skin and impaired epidermal
barrier by means of occlusive effects, as a consequence of lipids deposition on the external skin surface.1, 8
Cosmetic emollients available on the market are
numerous and very different in composition and
in the functional effects they can deliver. Most of
them, the so called traditional emollients, contain
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high concentrations of highly hydrophobic mineral
oils which can create an occlusive film on the skin
surface that powerfully decreases the water loss
through epidermis and improves the dryness symptoms. These products are normally characterized by
a lower compliance by the patients, since they are
not easy to spread and leave an oily feeling on the
skin surface. Apolar lipids, even though they are
very effective in reducing water loss on the short
time, are not able to repair the functional deficiency
of atopic skin, in terms of lipid synthesis, in particular as regards the diminished amount of ceramides.5, 9
The most innovative formulations on the market
focus their activity on the so called “physiologic lipid replacement therapy”. They contain epidermal
lipid mixtures (ceramide/cholesterol/fatty acid) as
active ingredients to restore normal balance of the
epidermal barrier.10, 11
In contrast to traditional emollients that form
an external occlusive barrier due to the presence
of petrolatum or other mineral oils, physiological lipid-based topical emulsions are supposed to
permeate the stratum corneum and stimulate the
endogenous lipid synthesis, particularly of ceramides, leading, in a long period, to an increase of
the total amount of epidermal “mortar”. Because of
this peculiar mechanism of action these cosmetic
emollients are usually called barrier repair topical
emulsions.12, 13
The maximal efficacy can be reached using all the
three components (ceramides, cholesterol, fatty acids) in a proper physiological ratios.8
The helpfulness of cosmetic emollients in the management of pathological skin is commonly evaluated
in vivo using non-invasive biophysical techniques
(transepidermal water loss [TEWL] and skin hydration, in terms of water-holding capacity of stratum
corneum), before and after treatment.14-16 These in
vivo tests allow to quantify the clinical effects of
emollients. However, they are not able to discriminate the effects of the different ingredients (i.e., active molecules and vehicle components).
The purpose of this study is to describe a new approach to the efficacy evaluation of cosmetic emollients carried out both in vivo and in vitro to better
understand the link between formulation and efficacy of products, in the perspective to provide to dermatologists some key elements in the product choice
within the wide market offer.
348
Materials and methods
We studied two oil in water emulsions, named
Product A and Product B, containing hydrocarbons
and triglycerides as oily phase and a physiological
lipid mixture (ceramide, cholesterol, fatty acid) as
barrier repair ingredients.
The two products are different in that:
—— Product A is a cream based on a non-ionic
emulsifier that possesses high affinity and compatibility with skin that contains an amount of ceramide
3 times greater than Product B and an amount of occlusive lipids 1.5 times greater than Product B.
—— Product B is a gel-emulsion based on a polymeric emulsifier, belonging to the acrylates family.
In vivo studies
Subjects
Nine healthy Caucasian volunteers (all females)
phototype III–IV, mean age 40±12 years (range 2957 years), participated in the studies. The subjects
were advised to avoid topical drugs or moisturisers
on the tested areas for 48h before the experiments.
To obtain reliable measurements, the volunteers
were acclimatised for 15 min in a conditioned room
(22.5°C, 50% RH) before the experiments.
Biophysical measurements
TEWL, which indicates the barrier function of
skin, was measured using a Tewameter TM 210
(Courage and Khazaka). Skin hydration was determined using a Corneometer CM 85 (Courage &
Khazaka), which measures skin capacitance in arbitrary units (AU). All parameters were recorded in accordance with established guidelines.17, 18
Protection study
A long-term study was performed to test the protective effect of the two cosmetic emollients applied
to normal skin, followed by SLS exposure. Baseline
measurements of TEWL and skin capacitance were
obtained in three marked zones of the right volar forearm before topical application: two areas for topical
treatment (Product A and B) and one untreated area
(control). Samples were randomly applied (20 µL)
onto the marked areas of 4 cm2 using a micropipette
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Microman® M25 (Gilson, France). After 24 h (day 1)
both parameters, TEWL and skin capacitance, were
evaluated and then 20 µL of solutions were applied
again. The application of the two products was repeated once a day during 7 days with a total of 7
applications, and parameters were measured on days
1, 4, 7 and 9. Next, the three areas were exposed to
2% sodium laureth sulphate (SLS) aqueous solution
for 2 h (see below) and the resultant irritant reaction
was assessed 2 h 30 min by measuring TEWL and
skin capacitance.
Statistical analysis
SLS Exposure.—Twenty-five µL of an aqueous
solution of 2% SLS were applied on a filter paper placed in each of several aluminium chambers
(d=8 mm, Finn Chambers, Epitest Oy, Finland).
The chambers were fixed to the skin for 2h with
adhesive tape. Upon removal of the patch, the skin
was gently rinsed with water and allowed to dry.
Sample preparation
Repairing study
A long-term study was done to test the reparative
effect of the two cosmetic emollients on disturbed
skin. Baseline measurements of TEWL and skin
capacitance were obtained in three marked areas
of the left volar forearm before topical application:
two areas for topical treatment (Product A and B)
and one untreated area (control). Next, the three areas were exposed to 0.5% SLS aqueous solution for
24 h (see below) and the resultant irritant reaction
was assessed 24 h after SLS exposure by measuring
TEWL and skin capacitance (day 1). Then Product
A and Product B were randomly applied (20 µL)
onto the marked areas of 4 cm2 using micropipette
Microman® M25 (Gilson, France). After 24 h (day
2) parameters, TEWL and skin capacitance were
evaluated. The application of the two products was
repeated once a day during 7 days with a total of 7
applications, and TEWL and skin capacitance were
measured on days 1, 2, 4, 7 and 10.
SLS Exposure.—Twenty-five µL of an aqueous solution 0.5% SLS were applied on a filter paper placed
in each of several aluminium chambers (d=8 mm,
Finn Chambers, Epitest Oy, Finland). The chambers
were fixed to the skin for 24 hours with adhesive
tape. Upon removal of the patch, the skin was gently
rinsed with water and allowed to dry.
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The mean values and standard deviations (SD)
were calculated. Dixon’s test was used for detecting
outliers, which were excluded from the data. Oneway analysis of variance, with the Kruskal–Wallis
test, was used to determine significant differences
between the values obtained from the different treatments (significance level accepted: P<0.05).
In vitro studies
Sections of fresh skin from young pigs, weighing
20-30 kg, were placed in water at 70°C for 3-4 min
and the epidermis was scraped off in sheets. To isolate stratum corneum (SC), the epidermal sheets
were incubated for 2 h at 37ºC with the epidermal
side in contact with a solution of 0.5% Trypsin in
PBS at pH 7.4. Trypsin is used to remove adherent
cells from epidermis. After the 2h, the Trypsin was
removed by several washes of the SC with Milli-Q
water.19 SC samples were then treated with chloroform/methanol (2:1) during 2 h, obtaining lipid depleted SC (Ld SC).
SC treatments
Lipid depleted SC samples were treated with
100mg of Product A or Product B, incubated at
25°C for 48 h, then removed, immediately washed
with water, for 15 minutes, at constant agitation and
stored at dryness.
Freeze-substitution transmission
microscopy experiments
electron
The SC samples were fixed in 5% glutaraldehyde
in 0.1M sodium cacodylate buffer, pH 7.3, and postfixed in 0.25% RuO4 in 0.1 M sodium cacodylate, pH
6.8, with 0.25% potassium ferrocyanide (K4Fe(CN)6).
After 1h the RuO4 solution was replaced by fresh
RuO4 in order to establish an optimal fixation. After
rising in buffer, the SC samples were cryofixed, by
rapid freezing on a liquid nitrogen cooled metal mirror (Cryo-vacublock, Leica) at -196°C prior to freezesubstitution, as described elsewhere.20, 21 Finally the
samples were transferred to a mold containing Lowicryl, and were incubated for 8 h at -50°C under
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Figure 1.—Variation of TEWL and skin capacitance after sample application. Changes were evaluated vs. both basal and placebo
values (*P<0.05).
UVA-radiation, to allow polymerization. Ultrathin
sections were cut (Ultracut UCT, Leica), transferred
to Formvar-coated grids and examined in a Hitachi
600 transmission electron microscope.
Results
In vivo studies
Figure 1 displays the variation of the two parameters (skin TEWL and the skin capacitance) after sample application during the treatment period. Changes
were evaluated vs. both the basal and the control values. TEWL values were slightly decreased on day 4
and 7, but the baseline levels were re-established on
day 9. Skin capacitance values showed a statistically
significant increase after topical application of both
the formulations, at all the control times.
Figure 2 shows the effects induced by SLS on the
biophysical parameters of the skin areas treated with
the two products and untreated (control).
At 2 h 30 min an increase of TEWL values of all
the treated areas was found, but the skin areas previously treated for one week with Product A and B show
statistically significant lower values than the control
area.
In Figure 3 the reparative effect of the two products on disturbed skin is shown. Both the emulsions
induced a higher repairing effect of the barrier function and promoted a repairing of the skin hydration,
being the Product A the most effective one.
In vitro studies
Figure 2.—Variation of TEWL at different intervals following
SLS exposure. Changes evaluated vs. basal values (*P<0.05).
350
In Figure 4, the freeze-substitution transmission
electron microscopy (FSTEM) micrographs of SC
before and after lipid depletion are shown. The in
vitro protocol used allows a good visualization of lipid bilayers in the untreated stratum corneum sample
(Figure 4A) and a clear absence of lipid bilayers in
the SC sample extracted with solvents (Figure 4B).
In Figure 5 the effects of Product A and B appli-
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Figure 3.—Variation of TEWL and skin capacitance on the reparation study. Changes were evaluated vs. both basal and placebo values
(*P<0.05).
A
B
Figure 4.—FSTEM micrographs for SC untreated (A), lipid extracted (B).
A
B
Figure 5.—FSTEM micrographs for lipid extracted SC treated with product A (on the left) and product B (on the right).
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cation on lipid depleted SC samples are shown The
FSTEM micrographs point out the different ability to
permeate the stratum corneum and fill up the intercellular spaces of the two products. A partial bilayer
reconstitution has been found on the lipid depleted
SC samples treated with the Product A, but not in
those on which Product B was applied.
Discussion
The objects of this study were two commercial
products, specifically formulated for a physiologic
lipid replacement therapy. In a clinical perspective
the two products would have been classified as comparable or similar.
As a matter of fact, both are water in oil systems,
easy to spread, with a good skin feeling, containing
a physiological lipid mixture (ceramide, cholesterol,
fatty acid) together with some apolar lipids (hydrocarbons and triglycerides) as active ingredients.
However, the two products, seen in a technological formulation perspective, show some significant
differences, that could justify a different skin performance.
The first difference is the topical delivery vehicle
used: Product A is an cream based on a non-ionic
emulsifier that possesses high affinity and compatibility with skin, whereas Product B is a gel-emulsion based on a polymeric emulsifier, belonging to
the acrylates family.
The second difference is the amount of the active
ingredients in each formulation: Product A contains
an amount of ceramides three times greater than
Product B and an amount of lipids 1.5 times greater
than Product B.
The in vivo/in vitro testing protocol used in this
study, point out some peculiar skin behaviour of the
two products, strictly related to their formulation
compositions.
The in vivo results carried out on normal skin,
showed an increase of skin hydration (Product
A>Product B), but no marked effects on TEWL after
products application. As expected, the barrier function of normal skin, measured by TEWL values, was
slightly modified by the application of the two emollients, since both the formulations did not present a
marked occlusive character. However, skin hydration
is statistically significant increased, being the Product A more markedly effective, suggesting that both
352
Product A and B moisturized the stratum corneum
with a non-occlusive mechanism.
A one week treatment with product A and B promoted a reinforcement of the skin barrier, that was
demonstrated by a lower increase of the TEWL values in respect to untreated skin, after SLS (Product
A>Product B) This protective effect on normal skin
can be related to the lipid barrier replacement mechanism of the active ingredients.
The ability of the two formulations on repairing
the damaged skin was confirmed by the in vivo study
carried out on pre-treated skin. The two products induced a high repairing effect of the barrier function,
both in terms of TEWL values and skin water-holding capacity (Product A> Product B)
A reinforcement of the skin barrier due to the application of these ceramide containing formulations,
led to a protecting effect from chemical injuries.
Once again, the protective effect was more pronounced for the cream (Product A), than for the gelemulsion (Product B).
This is not surprising considering the formulation
differences between of the two emulsions. As a matter of fact, the non-ionic emulsifier system used in
Product A supported and promoted the bioavailability of the active ingredients, in a more effective way,
than the acrylate polymers used in Product B.
The influence of the formulation on the bioavailability of lipids was confirmed by the in vitro evaluation tests. Only Product A, formulated with a nonionic emulsifier, with high skin affinity, was effective
in the stratum corneum permeation and able to fill up
the intercellular spaces. This was not so for the gel
emulsion based on acrylate polymers (Product B).
Conclusions
To maintain skin hydration and reinforce its barrier function, with a daily regular moisturizer use,
is an essential part of the atopic dermatitis and dry
skin management and every day dermatologists are
requested to select for their patients the appropriate
product among a broad market offer.
The classification commonly used in: traditional
emollients (i.e., with a relevant external occlusive effects), and innovative formulations based on the barrier repair activity of the ceramide dominant physiological lipid-based mixtures seems inadequate, from
a technological point of view, to justify and explain
the different clinical effects.
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The performance of cosmetic emollients and their
mechanism of interaction with healthy and impaired
skin can be very different depending on their composition, not only as regards the active ingredients but
also the technical form.
A daily application of the two products, that are
both physiological lipid mixture containing emulsions, can moisturize normal skin and promote the
repairing effect on unpaired barrier skin reducing
TEWL and maintaining hydration of the stratum
corneum. The extent of this effect is higher when the
cosmetic form of the product promotes the bioavailability of active ingredients leading to a more effective skin performance on dry and atopic skin. A better understanding of the most advantageous product
compositions can be obtained using in vivo/in vitro
methodologies.
References
  1. Mack Correa MC, Nebus J. Management of patients with atopic
dermatitis: the role of emollient therapy. Dermatol Res Practice
2012:836931.
  2. Elias PM. Lipids and the epidermal permeability barrier. Arch Dermatol Res 1981;270:95-117.
  3. Elias PM, Menon GK. Structural and lipid biochemical correlates
of the epidermal permeability barrier. Adv Lipid Res 1991;24:1-26.
  4. Elias PM. Stratum corneum defensive functions: an integrated view.
J Invest Dermatol 2005;25:183-200.
  5. Sugarman JL. The epidermal barrier in atopic dermatitis. Semin Cutan Med Surg 2008;27:108-14.
  6. Elias PM, Wakefield JS. Therapeutic implications of a barrierbased pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol
2011;41:282-95.
  7. Danby S, Cork MJ. A new understanding of atopic dermatitis: the
role of epidermal barrier dysfunction and subclinical inflammation.
J Clin Dermatol 2010;1:33-46.
  8. Sajiæ D, Asiniwasis R, Skotnicki-Grant S. A look at epidermal barrier function in atopic dermatitis: physiologic lipid replacement and
the role of ceramides. Skin therapy letter 2012;17:6-9.
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  9. Anderson PC, Dinulos JG. Are the new moisturizers more effective? Curr Opin Pediatr 2009;21:486-90.
10. Mao-Qiang M, Brown BE, Wu-Pong S, Feingold KR, Elias PM.
Exogenous nonphysiologic vs physiologic lipids. Divergent mechanisms for correction of permeability barrier dysfunction. Arch Dermatol 1995;131:809-16.
11. Man MQ M, Feingold KR, Thornfeldt CR, Elias PM, Optimization
of physiological lipid mixtures for barrier repair, J Invest Dermatol
1996;106:1096-101
12. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis. J Drugs
Dermatol 2009;8:1106-11.
13. Draelos ZD. The effect of ceramide-containing skin care products
on eczema resolution duration. Cutis 2008;81:87-91.
14. Coderch L, Fonollosa J, De Pera M, De la Maza A, Parra JL. Efficacy of stratum corneum lipid supplementation on human skin.
Contact Dermatitis 2002;47:139-46.
15. Coderch L, López O, de la Maza A, Parra JL. Ceramides and skin
function. Am J Clin Dermatol 2003;4:107-9.
16. Ramírez R, Martí M, Barba C, Méndez S, Parra JL, Coderch L.
Skin efficacy of liposomes composed of internal wool lipids rich in
ceramides. Int J Cosmet Sci 2010;61:235-45.
17. Rogier V, EEMCO Group. EEMCO guidance for the assessment
of transepidermal water loss in cosmetic sciences Skin Pharmacol
Appl Skin Physiol 2001;14:117-28.
18. Berardesca E. EEMCO Group. EEMCO Guidance for the assessment of stratum corneum hydration: electrical methods. Skin Res
Technol 197;3:126-32.
19. López O, Cócera M, Wertz PW, López-Iglesias C, de la Maza A.
New arrangement of proteins and lipids in the stratum corneum
cornified envelope. Biophys Biochem Acta 2007;1768:521-9.
20. Van den Bergh BAI, Bouwstra JA, Junginger HE, Wertz PW. Elasticity of vesicles affects hairless mouse skin structure and permeability. J Controlled Rel 1999;62:367-79.
21. Lopez O, Cocera M, Coderch L, Parra JL, de la Maza A. Reconstitution of liposomes inside the intercellular lipid domain of the
stratum corneum. Langmuir 2002;18:7002-8.
Funding.—This work was partly funded by Unifarco S.p.A. The authors wish to thank Carmen López-Iglesias for her expert assistance with
the FSTEM study performed in the Scientific and Technological CenterUniversity of Barcelona (CCIT-UB).
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
Received on July 19, 2013.
Accepted for publication on September 24, 2013.
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G ITAL DERMATOL VENEREOL 2014;149:355-61
Psychopathology and eating disorders in patients with psoriasis
M. L. CROSTA 1, G. CALDAROLA 2, S. FRAIETTA 1, A. CRABA 1
C. BENEDETTI 2, V. COCO 2, L. JANIRI 1, L. RINALDI 1, C. DE SIMONE 2
Aim. Psoriasis is a multifactorial chronic inflammatory skin
disease that often occurs in patients who are overweight or
obese. In literature the connections between obesity and eating disorders are well known, but few studies have investigated the link between eating disorders and psoriasis.
We hypothesized that Eating Disorders (ED) can be considered a psychogenic cofactors, which contribute to the development of obesity and metabolic syndrome in psoriatic patients, who are frequently prone to psychiatric comorbidity.
Methods. From January to April 2011 we enrolled 100 consecutive psoriatic outpatients and a control group of 100 selected non-psoriatic outpatients, matched by age, gender, and
BMI to the study group. The assessment battery was composed by the Psoriasis Area Severity Index (PASI) score, the
Eating Disorder Inventory (EDI) and the Symptom Checklist-90 Revised (SCL-90-R®).
Results. Our data showed that most of EDI and SCL-90R
subscales was mostly altered in psoriatic population compared to patients without psoriasis. Moreover, we noticed in
patients with psoriasis an association between the progressive
weight increase and an impairment on most of EDI subscales.
Conclusion. Psoriasis is associated with psychopathological traits, which are frequently found in EDs. Since obesity
makes psoriasis less susceptible to therapy and weight loss
improves drug response, dermatologists should be alert to
suspect the presence of this condition.
Key words: Psoriasis - Eating disorders – Psychopathology Obesity.
P
soriasis is a multifactorial chronic inflammatory
skin disease. This condition is known to be associated with serious comorbidities, and, among
them, has been shown that the most frequent is PsoCorresponding author: G. Caldarola, Department of Dermatology,
Sacro Cuore Catholic University, L.go F. Vito 8, 00168 Rome, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1Institute of Psychiatry
Catholic University of the Sacred Heart, Rome, Italy
2Institute of Dermatology
Catholic University of the Sacred Heart, Rome, Italy
riatic Arthritis.1 Furthermore, prevalence of obesity,
metabolic syndrome and cardiovascular disease have
been found to be higher among patients with psoriasis compared with the general population.2-7
It is known from the literature, that psoriasis often
occurs in patients who are overweight or obese.8, 9
There are also many studies showing the relation
between obesity and eating disorders (ED).10-12
EDs are conditions defined by abnormal eating
habits, which may involve either insufficient or excessive food intake. Anorexia nervosa and Bulimia
nervosa are the most common specific form. Other
types include binge eating disorder (BED) and ED
not otherwise specified. BED, as defined by the diagnostic and statistical manual of mental disorders,
fourth edition (DSM-IV TR), is characterized by
recurrent episodes of binge eating (e.g., eating an
unusually large amount of food accompanied by a
sense of lack of control) in the absence of significant
compensatory behaviours (e.g., self-induced vomiting, excessive exercise).12 Moreover, it is associated
with significant medical complications related to
obesity, psychiatric comorbidity and reduced quality
of life.13, 14
BED can be considered among the psychopathological cofactors that may contribute to the development of obesity and metabolic syndrome in pa-
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tients with psoriasis, which are also prone to several
psychiatric comorbidities, including depression and
anxiety.15-23
From this evidence, few studies have investigated
the relation between EDs and psoriasis, showing in
particular the possible influence of BED on obesity
and metabolic syndrome related to psoriasis.24, 25 The
purpose of our research was to evaluate the presence
of a disturbance of eating behavior and psychopathological traits in patients suffering from psoriasis, in
comparison with a population not affected and correlate data with the severity of the skin disorder and
the Body Mass Index (BMI).
Materials and methods
This was an observational study carried out at the
Department of Dermatology of the Catholic University of Sacred Heart in collaboration with the Institute of Psychiatry.
One hundred consecutive and unselected patients
affected by psoriasis were enrolled into the study
from January to April 2011. During the same period,
we selected a group of 100 non-psoriatic patients attending the videodermoscopy outpatient clinic of the
same Department. We matched the two groups by
age, gender and BMI. In fact, major confounding factors are gender and age, as eating disorders are significantly more common among women and younger
age groups. Moreover, we matched the two groups
by BMI to avoid the influence of obesity on EDs.
Patients with and without psoriasis had to be at
least 18 year old and they had to fill in two psychiatric questionnaire: Eating Disorder Inventory (EDI)
and Symptom Checklist 90 Revised (SCL-90-R®).
All patients were evaluated in different clinical
aspects, which included gender, weight, height and
morbidity (diabetes, hypertension, dyslipidemia,
metabolic syndrome, cardiovascular diseases, liver
disease, cancer).
BMI was calculated as weight and height ratio
(kg/m2). On BMI basis, the two populations were
divided into 3 groups: normal weight (BMI<25 kg/
m2), overweight (BMI 25-29.9 kg/m2) and obese
(BMI≥30 kg/m2).
Moreover we collected data about psoriasis type
and severity, duration of disease, and current treatments. We evaluated the severity of psoriasis using
PASI (Psoriasis Area Severity Index).26
356
To determine the PASI score, a score is assigned
from 0 to 4 to the psoriatic lesions on the basis of
erythema, infiltration and desquamation. Four anatomic regions (head, trunk, arms and legs) are evaluated separately and a score from 0 to 6 is assigned to
each region, depending on the surface rate involved.
Scores are multiplied by a coefficient and then added
together. Total score ranges from 0 (absence of disease) to 72 (high severity psoriasis). Using the PASI
score we divided our population into 3 groups: remission (PASI 0), mild disease (0<PASI<10), moderate-severe disease (PASI>10).
EDs were analysed using EDI. The EDI 27, 28 is a
widely used self-report measure of EDs, developed
by Garner et al. in 1983 to measure symptoms of
anorexia nervosa, bulimia and BED, although it does
not allow a specific diagnosis. It is made up of 64
items grouped into 8 subscales. Three of them measure attitudes and behaviours related to eating, weight
and body imaging: drive for thinness (DT), bulimia
(B) and body dissatisfaction (BD). The other 5 subscales explore general clinically relevant psychological traits: ineffectiveness (IN), perfectionism (PE),
interpersonal distrust (ID), interoceptive awareness
(IA) and maturity fears (MF).
The SCL-90-R 29 is used as a screening measure of general psychiatric symptomatology. It is a
self-report format made up of 90 items validated
by Derogatis et al. in 1977. It includes dimensions
measuring somatization (SOM), obsessive-compulsive (OC), depression (DEP), anxiety (ANX), phobic
anxiety (PHOB), hostility (HOS), interpersonal sensitivity (IS), paranoid ideation (PAR), psychoticism
(PSY), and sleep disease (SLEEP). We have used the
suggested cut-off scores (psychopathological traits
>1). We also calculated a Global Severity Index
(GSI). It represents the sum of the scores divided by
the number of items and it is designed to measure
overall psychological distress; the cut-off score for
the GSI used in this study is 0.57, as indicated by the
existing literature:30, 31 scores equal to or above 0.57
are considered to be indicative of “dysfunctional”
subjects, who have a high probability of psychiatric
disorders.
Statistical analysis
Data collection and statistical analyses were performed by an independent investigator. Categorical
variables were described as numbers and percent-
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CROSTA
ages; continuous variables were described as mean
± standard deviation (SD) or median ± range. Categorical variables were analysed using multivariable
analysis or chi square tests. To compare continuous
variables we used the Pearson correlation and the
ANalysis Of VAriance (ANOVA) in a model that
included an independent predictor on univariate
analyses. P values inferior to 0.05 were considered
statistically significant. When multiple T test were
performed, Bonferroni style correction was used.
Statistical analyses were performed using the statistical software IBM-SPSS version 19.0.
Results
A total of 200 subjects were enrolled in the study:
100 patients with psoriasis and 100 without it. The
demographic and clinical characteristics were similar in the two study groups (Table I). It is worthy of
note that 65% of the patients with psoriasis had a
BMI higher than 25: 46% of them were overweight
(BMI 25-30) and 19% were obese (BMI≥30).
Table II reports the results of the EDI questionnaire at multivariable analysis by psoriasis with
BMI, age and gender. The cut-offs vary in the different subscales. In the table we reported, the number of
patients with above threshold scores at each subscale
and the mean score for the two sample groups.
There were no significant differences between the
psoriasis group and the group without psoriasis in
the EDI subscales, except for the BD (P=0.03) and
ID (P=0.006) subscales. showing more pathological
scores in patients with psoriasis.
Table III shows, instead, the results of the SCL90-R questionnaire at multivariable analysis by psoriasis with BMI, age and gender, which indirectly
assesses the presence of psychopathological traits. A
score ≥1 was considered pathological.
Interestingly, the SCL-90-R questionnaire was
globally more impaired in patients with psoriasis
than in patients not affected, as indicated by higher
score on the GSI. In addition, this difference was
statistically significant in 4 of 10 subscales (PAR,
ANX, DEP and SOM).
On the basis of the BMI, we divided patients with
psoriasis into 3 groups: 35 patients with BMI<25
(35%), 46 patients with BMI 25-30 (46%), 19 patients with BMI≥30 (19%).
Table IV summarizes EDI results in the 3 different BMI classes of psoriatic patients. The ANOVA
analyses showed significant differences in some
EDI subscales as B (P=0.007), BD (P=0.001) and
IA (P=0.064) in the obese group compared to the
other two groups. Moreover, there was a strong
trend towards significance in some other SCL-90-R
subscales (ANX (P=0.08), HOS (P=0.08), PAR
(P=0.09), SI (P=0.09).
Table I.—Baseline clinical characteristics.
Subjects (%)
Age (mean±SD)
(range)
Gender: male/female
BMI (mean±SD)
Morbidity
Diabetes (%)
Hypertension (%)
Dyslipidemia (%)
Liver diseases (%)
Metabolic syndrome (%)
Cardiovascular disesase (%)
Cancer
PASI (mean±SD).
Disease duration (mean±SD)
Psoriatic Arthritis (%)
Treatment
Topic (%)
Sistemic (%)
Biological (%)
With psoriasis
Without psoriasis
P
100 (50%)
47.7±12.9
20-73
51/49
27.2±4.3
100 (50%)
50.8±15.2
19-80
61/39
27.8±4.4
0.12
0.16
0.34
14
26
7
2
12
2
0
4±5.6
13.8±12.7
44
18
25
6
0
14
3
0
-
0.44
0.87
0.77
0.48
0.67
0.65
0
-
19
17
55
-
-
BMI: Body Mass Index; PASI: Psoriasis Area Severity Index
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Table II.—EDI subscales at multivariable analysis.
Subscale
DT (n.v.<14.5)
Number of patients (%)
mean±SD
B (n.v.<7.5)
Number of patients (%)
mean±SD
BD (n.v.<15.8)
Number of patients (%)
mean±SD
IN (n.v.<15.8)
Number of patients (%)
mean±SD
P (n.v.<9)
Number of patients (%)
mean±SD
ID (n.v.<8)
Number of patients (%)
mean±SD
IA (n.v. <13.8)
Number of patients (%)
mean±SD
MF (n.v.<9.5)
Number of patients (%)
mean±SD
Number of patients with at least
one altered subscale (%)
With psoriasis
Without psoriasis
P
4 (4%)
3.76±4.3
6 (6%)
2.96±4.71
0.56
2 (2%)
0.72±2.42
2 (2%)
0.78±1.81
0.17
8 (8%)
7.47±5.49
13 (13%)
7.19±6.31
0.03
4 (4%)
3.44±3.99
0 (0%)
2.68±3.09
0.08
5 (5%)
2.64±2.86
8 (8%)
2.82±3.19
0.85
22 (22%)
4.42±3.66
4 (4%)
2.95±2.68
0.006
4 (4%)
2.76±3.46
1 (1%)
1.78±2.73
0.07
17 (17%)
5.7±4.54
43 (43%)
14 (14%)
5.06±3.78
31 (31%)
0.64
0.08
DT: drive for thinness; B: bulimia; BD: body dissatisfaction; IN: ineffectiveness; P: perfectionism; ID: interpersonal distrust; IA: interoceptive awareness; MF: maturity fears.
The Pearson correlation was used to highlight
the association between the progressive increase
in weight and the worsening of the EDI scores: the
increase in BMI led to an increase in the scores of
five EDI subscales. In particular, BMI had a significant association with DT (P=0.01), B (P<0.001),
BD (P=0.006), IN (P=0.014) and IA (P=0.001), in
the psoriasis group, but no correlation was observed
between the increasing in BMI and the SCL-90-R
scores Conversely, the Pearson correlation showed
an association between the increase in BMI and
only two EDI subscales in the control group: BD
(P=0.02) and ID (P=0.008); but there was an important correlation between the increase in BMI
and several SCL-90-R subscales: SOM (P=0.017),
OC (P=0.004), ANX (P=0.05), HOS (P=0.04), PAR
(P=0.009), PSY (P=0.047), SLEEP (P=0.013).
Moreover, for a better understanding of the psychological traits in the psoriasis group, we divided
the population into 3 sub-groups on the basis of
PASI score: 30 patients (30%) with disease remission (PASI 0), 56 patients (56%) with low-grade
disease (0<PASI<10) and 14 patients (14%) with
moderate-to-severe skin disease (PASI>10).
358
There was no significant association between disease severity and psychopathological traits, probably
due to the non-homogeneous sample.
Nevertheless, using the Pearson correlation, we
observed a significantly worsening in the scores
of two SCL-90-R subscales (HOS [P=0.026] and
PHOB [P=0.034]) associated with an increase in the
PASI score while there were no significant correlations between EDI subscales and PASI.
We also investigated two other independent variables as “psoriasis duration” and “previous treatments”, but no correlation was found with psychological traits.
Discussion
Psoriasis is an autoimmune disease with a strong
psychosomatic component whose onset and recurrence often follow trauma or stressful life events.32 If
it is difficult to establish a cause-effect relationship
between psychological factors and psoriasis, it is
rather certain that the disease has a significant impact
on the psychological state and quality of life.33-35
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EATING DISORDERS IN PSORIASIS
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Table III.—SCL-90-R subscales at multivariable analysis.
Subscale
SOM
Number of patients (%)
mean±SD
OC
Number of patients (%)
mean±SD
IS
Number of patients (%)
mean±SD
DEP
Number of patients (%)
mean±SD
ANX
Number of patients (%)
mean±SD
HOS
Number of patients (%)
mean±SD
PHOB
Number of patients (%)
mean±SD
PAR
Number of patients (%)
mean±SD
PSY
Number of patients (%)
mean±SD
SLEEP
Number of patients (%)
mean±SD
GSI
Number of patients (%)
mean±SD
With psoriasis
Without psoriasis
P
39 (39%)
0.90±0.70
23 (23%)
0.67±0.56
<0.001
38 (38%)
0.89±0.69
32 (32%)
0.70±0.60
0.12
23 (23%)
0.71±0.66
19 (19%)
0.60±0.55
0.32
37 (37%)
0.91±0.73
25 (25%)
0.64±0.57
0.002
35 (35%)
0.78±0.66
15 (15%)
0.53±0.52
0.003
20 (20%)
0.67±0.62
20 (20%)
0.56±0.57
0.64
9 (9%)
0.27±0.45
6 (6%)
0.24±0.42
0.49
35 (35%)
0.89±0.77
22 (22%)
0.56±0.65
0.02
14 (14%)
0.43±0.49
8 (8%)
0.28±0.40
0.07
51 (51%)
1.07±1.06
36 (36%)
0.80±0.83
0.31
23 (23%)
0.75±0.56
14 (14%)
0.57±0.48
0.02
SOM: somatisation; OC: obsessive-compulsive; DEP: depression; ANX: anxiety; PHOB: phobic anxiety; HOS: hostility; IS interpersonal sensitivity;
PAR: paranoid ideation; PSY: psychoticism; SLEEP: sleep disease; GSI: Global Severity Index.
Table IV.—EDI results in the 3 BMI classes analysed by ANOVA.
Subscale
DT (n.v.<14.5) mean±SD
B (n.v.<7.5) mean±SD
BD (n.v.<15.8) mean±SD
IN (n.v.<15.8) mean±SD
P (n.v.<9) mean±SD
ID (n.v.<8) mean±SD
IA (n.v.<13.8) mean±SD
MF (n.v.<9.5) mean±SD
BMI<25
BMI 25-30
BMI>30
P
2.91±3.89
0.11±0.40
7±6.26
3.57±4.15
2.89±2.88
3.57±3.48
2.63±3.15
6.26±5.36
3.83±4.30
0.57±1.50
6.74±3.91
2.76±2.94
2.22±2.75
4.91±3.62
1.83±2.32
5.04±3.67
5.16±4.84
2.21±4.42
10.11±6.66
4.84±5.49
3.21±3.07
4.79±3.97
5.26±4.95
6.26±4.82
0.186
0.007
0.064
0.156
0.367
0.235
0.001
0.414
DT: drive for thinness, B: bulimia, BD: body dissatisfaction, IN: ineffectiveness, P: perfectionism, ID: interpersonal distrust, IA: interoceptive awareness,
MF: maturity fears.
Many psoriatic people have common psychopathological traits, among which are: the difficulty of
experiencing and verbalizing their emotions (alexithymia); dysfunctional emotional responses, which
includes the use of neurotic defenses (avoidance, de-
Vol. 149 - No. 3
nial, repression, feeling isolations), and indications
of a fear of intimate contact.36
The objective of this study was to assess concomitant ED and psychopathological traits in patients
with psoriasis, trying to correlate data with different
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features of cutaneous disease (duration, severity) and
BMI. This is the first prospective study evaluating
the presence of these conditions in two groups of patients, with and without psoriasis. In fact, the previous studies about this argument are a cross-sectional,
randomized, and controlled trial who evaluated it
only in 100 psoriatic patients and a retrospective, observational study of medical claims data in pediatric
population.24, 25
Our data showed a higher prevalence of psychopathological traits and symptoms indicating an eating disorder in patients with psoriasis compared to
those without psoriasis. Regarding the EDI, BD and
ID subscales showed a statistically significant alteration in patients with psoriasis. The first scale evaluates the belief that some parts of the body (especially
those associated with typical changes of puberty) are
too big or too fat. The fat body, grotesque and so distant from the standard, induces shame and discomfort feelings.
ID represents a sense of alienation and reluctance
to establish close relationships and can be considered a useful indicator of quality of life. These data
disagree with the abovementioned retrospective
study in the pediatric population, which missed in
finding any association between the presence of psoriasis and EDI.23
Moreover, we found that psoriatic patients had a
greater symptom severity of psychological distress
as shown by General Severity Index (GSI) total score
on the SCL-90-R. In addition they reported more somatization, depression, anxiety and paranoid ideation symptoms as showed on the relative subscales
of SCL-90-R.
These data are in accordance with literature. In
particular, several studies reported the association
between depression and psoriasis, with different
opinions regarding the cause-effect relationship. In
particular, recent studies define the major depressive disorder such as an inflammatory condition with
elevated levels of pro-inflammatory cytokines,37 as
well various autoimmune diseases, such as psoriasis.
An interesting consideration that emerged from
our study was the relationship between BMI and results of EDI in psoriatic people. In fact an association
between the increasing weight and the worsening
of EDI subscales was more frequent in the psoriasis
group than in controls, through the Pearson correlation. With increasing BMI, the two groups showed an
opposite trend in the two test scores. In particular, the
360
psoriatic group showed a worsening of eating disorder symptoms, assessed by the EDI subscales without
deterioration of the psychopathological traits, detected by SCL-90-R. On the contrary, weight increase in
the control group worsened the general psychological
state. We may deduce that, in psoriatic patients, overweight/obesity is more frequently associated with an
eating disorder than in general population. This hypothesis was also confirmed in our study by the comparison of patient and control obese subgroups, which
showed, in patients with psoriasis, a higher prevalence
of altered subscales in both questionnaires. However,
these data have been not reported because referring to
a very small sample of subjects. Moreover, this result
is in accordance with a previous cross-sectional, randomized, and controlled trial, which evaluated the eating behaviors in 100 psoriatic patients, by the Eating
Attitude Test, Beck Depression Inventory and Beck
Anxiety Inventory, and a psychiatric interview. The
authors found an higher prevalence of ED in patients
with psoriasis and metabolic syndrome compared to
the group of patients with psoriasis and without metabolic syndrome. Finally, our data indicates that there
is not a correlation between the severity of somatic
disease, assessed by PASI, and the patient psychological distress, indicated by GSI. It means that the
impact of the psychological experience may not correlate with objective disease severity: in fact, even a
mild-to-moderate involvement may have heavy psychological consequences.
Limitations
Because of some limitations, our study should
be acknowledged as mainly hypothesis generating. First, our study population is relatively small.
Second, patients were not evaluated by a psychiatrist, but they were only assessed by two self-rating
scales. In fact, with these instruments, we may find
the presence of symptoms related to an altered eating behavior. Then, further studies should include
a psychiatric clinical interview in order to confirm
a full diagnosis of BED according to the criteria of
DSM-IV TR.
Conclusions
Our data show different associations between eating disorders and psoriasis, but they are not sufficient
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
EATING DISORDERS IN PSORIASIS
to make a specific diagnosis. In patients with psoriasis, EDs seem to be associated with overweight/
obesity more frequently than in general population. This suggests the importance of suspecting by
dermatologist the presence of an eating disorder in
overweight/obese patients with psoriasis. When this
comorbidity is found, a psychological approach to
improve food control may help to lose weight and to
increase response to therapy.
References
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  2. Sommer DM, Jenisch S, Suchan M, Christophers E, Weichenthal
M. Increased prevalence of the metabolic syndrome in patients with
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  6. Armstrong AW, Harskamp CT, Armstrong EJ. The association between psoriasis and obesity: a systematic review and meta-analysis
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  8. Sterry W, Strober BE, Menter A. Obesity in psoriasis: the metabolic,
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Acad Dermatol 2010;63:1058-69.
10. Stunkard AJ. Eating disorders and obesity. Psychiatr Clin North
Am 2011;34:765-71.
11. Villarejo C, Fernández-Aranda F, et al. Lifetime obesity in patients
with eating disorders: increasing prevalence, clinical and personality correlates. Eur Eat Disord Rev 2012;20:250-4.
12. American Psychiatric Association, Ed., Diagnostic and Statistical
Manual of Mental Disorders. 5th edition, Washington, DC, USA;
2012.
13. Rieger E, Wilfley DE, Stein RI, Marino V, Crow SJ. A comparison
of quality of life in obese individuals with and without binge eating
disorder. Int J Eat Disord 2005;37:234-40.
14. Wilfley DE, Wilson GT, Agras WS. The clinical significance of
binge eating disorder. Int J Eat Disord 2003;34:S96-S106.
15. Haves J, Koo J. Psoriasis: depression, anxiety, smoking and drinking habits. Dermatol Ther. 2010;23:174-80.
16. Kurd SK, Troxel AB, Crits-Christoph P. The risk of depression, anxiety and suicidality in patients with psoriasis: a population-based
cohort study. Arch Dermatol 2010;146:891-5.
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17. Russo PA, Ilchef R, Cooper AJ. Psychiatric morbidity in psoriasis:
a review. Australas J Dermatol 2004;45:155-9.
18. Van Voorhees AS, Fried R. Depression and quality of life in psoriasis. Postgrad Med 2009;121:154-61.
19. Misery L. Depression and psoriasis. Ann Dermatol Venereol
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20. Kieć-Swierczyńska M, Dudek B, Krecisz B, SwierczyńskaMachura D, Dudek W, Garnczarek A et al. The role of psychological factors and psychiatric disorders in skin diseases. Med Pr. 2006;
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21. Parafianowicz K, Sicińska J, Moran A, Szumański J, Staniszewski
K, Rudnicka L et al. Psychiatric comorbidities of psoriasis: pilot
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22. Gupta MA, Gupta AK. Psychiatric and psychological co-morbidity
in patients with dermatologic disorders: epidemiology and management. Am J Clin Dermatol 2003;4:833-42.
23. G Savron, R Montanaro, G Landi, G Bartolucci. Psychological
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24. Altunay I, Demirci GT, Ates B, Kucukunal A, Aydın C,
Karamustafalıoglu O et al. Do eating disorders accompany metabolic syndrome in psoriasis patients? Results of a preliminary study.
Clin Cosmet Investig Dermatol 2011;4:139-43.
25. Kimball AB, Wu EQ, Guérin A, Yu AP, Tsaneva M, Gupta SR et al.
Risks of developing psychiatric disorders in pediatric patients with
psoriasis. J Am Acad Dermatol 2012;67:651-7.e1-2.
26. Fredriksson T, Pettersson U. Severe psoriasis--oral therapy with a
new retinoid. Dermatologica 1978;157:238-44.
27. Garner DM, Olmsted MP, Polivy J. Development and validation of
a multidimensional Eating Disorder Inventory for anorexia nervosa
and bulimia. Int J Eating Dis 1983;2:15-34.
28. Milos G, Spindler A, Schnyder U. Psychiatric comorbidity and Eating Disorder Inventory (EDI) profiles in eating disorder patients.
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29. Derogatis LR. SCL-90-R, administration, scoring and procedures
manual for the Revised version. Baltimore. Johns Hopkins University, School of Medicine; 1977.
30. Schauenburg H, Strack M. Die Symptom-Checklist-90-R zur darstellung von statistischen und klinisch signifikanten psychotherapieergebnissen. Psychother Psychosom Med Psychol 1998;48:257-64.
31. Schauenburg H, Strack M. Measuring psychotherapeutic change
with the symptom checklist SCL-90-R. Psychother Psychosom
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32. Rieder E, Tausk F. Psoriasis, a model of dermatologic psychosomatic disease: psychiatric implications and treatments. Int J Dermatol
2012;51:12-26.
33. Anzieu D. L’Io-pelle. Rome: Borla; 1987.
34. Anzieu D. L’epidermide nomade e la pelle psichica. Milan: Cortina;
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35. Anzieu D. Il pensare. Dall’Io-pelle all’Io pensante, Borla, Roma
1996;
36. Anzieu D. Gli involucri psichici. Milan: Masson; 1997.
37. Elomaa AP, Niskanen L, Herzig KH, Viinamäki H, Hintikka J,
Koivumaa-Honkanen H et al. Elevated levels of serum IL-5 are associated with an increased likelihood of major depressive disorder.
BMC Psychiatry 2012;9:12:22.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
Received on May 8, 2013.
Accepted for publication on September 20, 2013.
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CASE REPORTS
G ITAL DERMATOL VENEREOL 2014;149:363-6
Periungual pyogenic granulomas
due to topical tazarotene for nail psoriasis
B. M. PIRACCINI, M. VENTURI, A. PATRIZI
Tazarotene is a topically-applied, receptor-selective retinoid
that has been shown to modulate several major pathogenic
factors of psoriasis. Adverse effects are those of topical application of retinoids, the most common being mild to moderate
burning, itching, stinging, and erythema, due to mild to moderate local skin irritation. While pyogenic granuloma–like lesions are a well recognized side effects of systemic retinoids,
to our knowledge in the literature there is only one reported
case of pyogenic granuloma (PG) following topical application of tazarotene for scalp psoriasis. In this paper we report
2 cases of periungual PGs following application of topical
tazarotene and we present a review of the literature.
Key words: Granuloma, pyogenic - Tazarotene - Nails - Psoriasis - Retinoids, adverse effects.
T
azarotene is a topically-applied, receptor-selective retinoid that has been shown to modulate several major pathogenic factors of psoriasis.1
Adverse effects are those of topical application of
retinoids, the most common being mild to moderate
burning, itching, stinging, and erythema, due to mild
to moderate local skin irritation.2 While pyogenic
granuloma-like lesions are a well recognized side
effects of systemic retinoids,3-5 to our knowledge in
the literature there is only one reported case of pyogenic granuloma (PG) following topical application
of tazarotene for scalp psoriasis.3 In this paper we
report 2 cases of periungual PGs following application of topical tazarotene and we present a review of
the literature.
Corresponding author: B. M. Piraccini, Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Via Massarenti 1, 40138 Bologna, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
Division of Dermatology, Department of Experimental,
Diagnostic and Specialty Medicine
University of Bologna, Bologna, Italy
Case series
Case 1.—A 77-year-old woman presented with nail
psoriasis involving all the nails of both hands. She had
been treated with calcipotriol+betamethasone ointment
once daily for six months with no benefit, so the patient
was commenced on tazarotene 0.1% gel once daily.
Three months after the beginning of this therapy, numerous periungual PG-like lesions appeared in the areas
treated with the topical retinoid (Figure 1). The lesions
had a diameter ranging from 0.5 to 1.5 cm and were very
painful. The diagnosis of PGs was clinical. It was decided to stop the tazarotene and to start a topical treatment with clobetasol propionate ointment twice daily
applied under occlusion in the evening. Two weeks later
the lesions regressed. She was advised to continue her
treatment regimen only with calcipotriol betamethasone
ointment.
Case 2.—A 39-year-old man presented with nail psoriasis, developed one year before in the hands. The patient was treated with tazarotene 0.1% gel once daily.
Two months after the beginning of the topical retinoid,
a PG appeared in the II digit of left hand (Figure 2). The
lesion was mildly painful, had a diameter of no more
than 0.5 cm, but with a tendency to enlarge. A skin biopsy was not performed because clinical features were
already suggestive of PG. The patient was recommended
to stop tazarotene. Two weeks later, the lesion was still
present but was improving. PG healed over the next 4
weeks.
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PIRACCINI
PERIUNGUAL PYOGENIC GRANULOMAS DUE TO TOPICAL TAZAROTENE FOR NAIL PSORIASIS
Figure 1.—Numerous periungual PGs in the areas treated with tazarotene.
Figure 2.—A PG appeared in the II digit of left hand treated with
the topical retinoid.
Discussion
Nail PG is a relatively common acquired benign
vascular tumour often seen as an emergency because
364
of its tendency to bleed.6 Nail PGs are due to different
causes and, according to the pathogenesis, they have
been classified by Piraccini et al.6 in PGs due to drugs,
local mechanical trauma, peripheral nerve injury and
inflammatory systemic diseases. Histopathology
shows similar features in every type of PGs, irrespective of cause and location, but, when PG is single, especially if the nail bed is involved, histological examination is necessary to rule out malignant melanoma.6
Treatment must be chosen according to the etiology,
but a first line approach involves the application of
topical steroids and antibiotics or curettage.6 If PGs
are due to drugs, topical medication or curettage may
be effective, but, usually, a decrease in the dose or a
suspension of the drug is required.6 The drugs that
mostly induce periungual and subungual PGs are
retinoids (systemic isotretinoin, systemic etretinate,
systemic acitretin), antiretrovirals (indinavir, lamivudine), antineoplastic and immunosuppressive drugs
(epidermal growth factor receptor inhibitors, capecitabine, cyclosporin, docetaxel, mitoxantrone).6
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
PERIUNGUAL PYOGENIC GRANULOMAS DUE TO TOPICAL TAZAROTENE FOR NAIL PSORIASIS
In this paper we present 2 cases of PGs linked to
topical tazarotene. An association between oral retinoids and the development of PG-like lesions is well
known and substantiated by recurrence of the lesions
with rechallenge of the suspected agent.3-6 On the
other hand, cases of PGs after topical retinoids are
only published as single case reports. The first case
of PGs as a side effect of topical tretinoin for acne
was published in 1979,7, 8 and 10 years later multiple
PGs on a patient’s scalp treated with a combination
of topical minoxidil and retinoic acid 5, 9 were reported. Another patient developed a PG-like reaction
during treatment with oral isotretinoin for acne, and
later PGs appeared on his chest after the use of topical tretinoin.4, 5 Therefore, the autohors 4 suggested
that care should be taken if a topical retinoid is considered for maintenance therapy, because it can lead
again to development of new PG-like lesions.4 In addition, care should be used to avoid application of
tretinoin cream to open oozing skin, because of the
possible onset of PG-like reaction.4
In the literature only one case of PG has been associated to topical tazarotene treatment during a controlled clinical trial of tazarotene 0.1% gel for scalp
psoriasis.3
Tazarotene is a third-generation acetylenic, retinoid prodrug.1, 2 It focuses its activity on the predominant retinoic acid receptor (RAR) subtypes in the
skin, RAR γ and RAR β, and has little or no interaction with other ubiquitous retinoid receptor types
expressed elsewhere in the body.1 Adverse effects
are typical of topical retinoids, the most common being mild to moderate local irritation with burning or
itching and erythema.1, 2 Local irritation after tazarotene application for nail psoriasis (of the lateral
folds or of the distal pulp) 11, 12 is usually manageable and transient and clearly dose-related.1, 2 Other
side effects reported are peeling of the proximal nail
fold,10, 11 desquamation 11 and paronychia.10, 11
The use of tazarotene for nail psoriasis was fist
suggested by Scher et al.10 in 2001. Later, several papers have confirmed its efficacy on nail psoriasis and
its good tolerability, even in children.11-14 Finally, in
2012, the therapeutic value and safety of tazarotene
in a hydrophilic ointment formulation for the management of nail psoriasis have been proved in an
open observational study.14
Our 2 patients with nail psoriasis improved after
topical application of tazarotene gel, but they developed periungual PGs after 2 and 3 months of therapy.
Vol. 149 - No. 3
PIRACCINI
These are the first 2 cases of PGs due to tazarotene localized to the nail tissues, and this is also the first report
of periungual PGs following tazarotene therapy for
nail psoriasis. Although 2 cases do not permit to draw
conclusions about the latency of onset of PGs after the
beginning of cure, it is important to point out that our
patients developed periungual PGs later than the other
cases due to topical retinoids reported in the literature.
The latency before onset of tazarotene-induced PG in
the case presented by Dawkins et al.3 was 2 weeks,
as was that of PGs in patients treated with a different
topical retinoid (tretinoin cream).4, 7, 8 PGs due to systemic retinoids appear after about 3 months of treatment (ranging from 3 to 12 weeks),3, 6 so Teknetzis et
al.8 suggested that PGs due to topical retinoids seem to
develop earlier than those in the case of oral isotretinoin treatment. Consequently, it was suggested that caution in the topical use of these drugs may be warranted
particularly during the first 2-3 weeks of treatment.8
Conclusions
PGs in our patients occurred after 2 and 3 months
of tazarotene application. So it is likely that Dermatologists will encounter similar side effects associated to topical retinoids also after a long period of
treatment. Therefore they should continue a particular surveillance during the whole treatment time and
not only in the first weeks.
References
  1. Marks R. Clinical safety of tazarotene in the treatment of plaque
psoriasis. J Am Acad Dermatol 1997;37(2 Pt 3):S25-32.
  2. Krueger GG, Drake LA, Elias PM, Lowe NJ, Guzzo C, Weinstein GD, et al. The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis. Arch Dermatol
1998;134:57-60.
  3. Dawkins MA, Clark AR, Feldman SR. Pyogenic granuloma-like lesion associated with topical tazarotene therapy. J Am Acad Dermatol 2000;43:154-5.
  4. MacKenzie-Wood AR, Wood G. Pyogenic granuloma-like lesions in a
patient using topical tretinoin. Australas J Dermatol 1998;39:248-50.
  5. Pierson JC, Owens NM. Pyogenic granuloma-like lesions associated
with topical retinoid therapy. J Am Acad Dermatol.2001;45:967-8.
  6. Piraccini BM, Bellavista S, Misciali C, Tosti A, De Berker D, Richert B. Periungual and subungual pyogenic granuloma. Br J Dermatol 2010;163:941-53.
  7. Hegeborn M, Kirechner S. Multiple granulomata pyogenica bei
acne vulgaris. Dermatologica 1979;158:93-8.
  8. Teknetzis A, Ioannides VD, Vakali G, Lefaki I, Minas A. Pyogenic
granulomas following topical application of tretinoin. J Eur Acad
Dermatol Venereol 2004;18:337-9.
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PIRACCINI
PERIUNGUAL PYOGENIC GRANULOMAS DUE TO TOPICAL TAZAROTENE FOR NAIL PSORIASIS
  9. Baran R. Explosive eruption of pyogenic granuloma of the scalp
due to topical combination therapy of minoxidil and retinoic acid.
Dermatologica 1989;179:76-8.
10. Scher RK, Stiller M, Zhu YI. Tazaroteno 0 1% gel in the treatment
of fingernail psoriasis: a double-blind, randomized, vehiclecontrolled study. Cutis. 2001;68:355-8.
11. Bianchi L, Soda R, Diluvio L, Chimenti S. Tazarotene 0.1% gel for
psoriasis of the fingernails and toenails: an open, prospective study.
Br J Dermatol. 2003;149:207-9.
12. Rigopoulos D, Gregoriou S, Katsambas A. Treatment of psoriatic
nails with tazarotene cream 0.1% vs clobetasol propionate 0.05%
cream: a double bind study. Acta Derm Venereol. 2007;87:167-8.
13. Diluvio L, Campione E, Paternò EJ, Mordenti C, El Hachem M,
366
Chimenti S. Childhood nail psoriasis: a useful treatment with tazarotene 0.05%. Pediatr Dermatol. 2007;24:332-3.
14. Fischer-Levancini C, Sánchez-Regaña M, Llambí F, Collgros H,
Expósito-Serrano V, Umbert-Millet P. Nail psoriasis: treatment
with tazarotene 0.1% hydrophilic ointment. Actas Dermosifiliogr
2012;103:725-8.
Conflicts of interest.—The authors certify that there is no conflict of
interest with any financial organization regarding the material discussed
in the manuscript.
Received on December 11, 2012.
Accepted for publication on March 11, 2013.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

G ITAL DERMATOL VENEREOL 2014;149:367-70
Multiple skin ulcers due to Serratia marcescens
in an immunocompetent patient
M. CARLESIMO 1, A. PENNICA 2, M. MUSCIANESE 1, U. BOTTONI 3, C. ABRUZZESE 1, M. GIUBETTINI 1,
G. PRANTEDA 4, G. PRANTEDA 1
Serratia marcescens is a species of gram negative bacillus,
classified as a member of the Enterobacteriaceae, mainly involved in opportunistic infections, particulary in the hospital
environment. Cutaneous infections have rarely reported in
literature and are predominantly observed in elderly or in
immunocompromised patients. The clinical manifestations of
skin infections include granulomatous lesions, necrotizing fasciitis, nodules, cellulitis, ulcers, dermal abscesses. Infections
caused by S. marcescens may be difficult to treat because of
resistance to a variety of antibiotics, including ampicillin and
first and second generation cephalosporins. Aminoglycosides
have good activity against S. marcescens, but resistant strains
have also been described. We report a very intriguing case of
S. marcescens infection, in an immunocompetent 18-year-old
man, causing multiple rounded ulcers of varying sizes, along
with few pustular lesions that both clinically and histopathologically mimic a pyoderma gangrenosum (PG). This is a non
infectious neutrophilic skin disorder, characterized by painful and rapidly progressing skin ulceration. According to our
experience, we would strongly recommend to perform cultures of multiple skin ulcers resembling PG, even in young
healthy patients, to ensure correct diagnosis and treatment,
since resistant to conventional antibiotics bacteria such as S.
marcescens may be the cause of these lesions, like in the case
here reported.
Key words: Pyoderma gangrenosum - Immunocompetence Serratia marcescens.
S
erratia marcescens was originally considered
to be an innocuous saprophytic organism. Since
the first reported S. marcescens infection in 1951,1
Corresponding author: G. Pranteda, MD, Operative Unit of Dermatology, NESMOS Department, Faculty of Medicine, La Sapienza University of Rome, Via di Grottarossa 1039, 00189 Rome, Italy.
E-mail: [email protected]
Vol. 149 - No. 3
1Operative
Unit of Dermatology, NESMOS Department
Faculty of Medicine and Psychology, “Sapienza”
Sant’Andrea Hospital, Rome, Italy
2Operative Unit of Infective Diseases
Faculty of Medicine and Psychology
“Sapienza” Sant’Andrea Hospital, Rome, Italy
3Department of Health Sciences
“Magna Graecia” University, Catanzaro, Italy
4Operative Unit of Dermatology
Faculty of Medicine and Dentistry
“Sapienza”, Umberto I Hospital, Rome, Italy
similar cases have been reported with increasing frequency. S. marcescens is mainly involved in nosocomial infections, particularly urinary and lower respiratory tracts infections, as well as surgical wounds.
Cutaneous infections are predominantly observed in
immunocompromised patients or in patients affected
by chronic debilitating disorders.2 We report a very
rare case of multiple skin ulcers (MSU) caused by
S. marcescens in an immunocompetent 18-year-old
male.
Case report
A 18-year-old romanian student was admitted to our
Department because of multiple rounded ulcers in absence of systemic symptoms. The current lesions began
one year before as a small pustule and ruptured rapidly to
form deep and painful ulcers. In Romania, he underwent
a histological examination, which showed a diagnosis of
pyoderma gangrenosum (PG), thus the patient underwent
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
367
CARLESIMO
Skin ulcers due to S. marcescens in an immunocompetent patient
Figure 1.—A) Multiple ulcerative lesions, some of which are fused together, on the right leg. These oozing and crusting ulcers were
characterized by well-defined erythematous to violaceous borders. Pieces of necrotic epidermidis are attached on borders and in the
center of lesions; B) close up of some fused lesions in which necrotic and crusting aspects are evident.
prednisone (35 mg daily) and dapsone (75 mg daily for
six days a week) for three months. Despite treatment was
replaced with sulfamethoxazole-trimethoprim and minocyclin when relapses recurred, no healing was obtained.
Worsening of lesions prompted admission to our Departement six months later. He was apyrexial and physical
exhamination showed multiple painful and deep ulcers
with well-defined erythematous to violaceous borders on
the lower legs, the trunk and the upper limbs with an inguinal and axillary associated lymphadenopathy (Figure
1). Mucous membranes were not involved. His past medical hystory was unremarkable. Result of routine laboratory examinations were within normal range, except for
a slight normochromic normocytic anemia (hemogobin:
11.6 g/dL) increased C-reactive protein (C-RP 6.36 mg/
dL) and erythrocyte sedimentation rate (ESR 67 mm/h)
values. All the other laboratory tests were within normal
ranges or negative. All instrumental investigations were
normal. We performed a cultural and histological examination that showed chronic inflammatory infiltrates in the
superficial dermis with acanthosis and pseudoepitheliomatous hyperplasia of epidermidis, focal abscessual areas
surrounded by a zone of granulomatous inflammation, and
features of leucocytoclastic vasculitis (Figure 2). The microbiology report indicated growth of the bacterium S. marcescens
sensitive to ciprofloxacin, gentamicin and cefotaxime. Thus, the
patient was treated with eradication therapy with intravenous ciprofloxacin (800 mg daily for five days), then oral
ciprofloxacin (1000 mg daily for 30 days) with a significant improvement. At 3-month follow up, the ulcers had
reduced in size and active healing and atrophic scar were
present. The normalization of inflammatory markers was
observed too. There was no evidence of recurrence during
12 months of follow-up however a long-term follow-up is
recommended in order to detect an underlying immunodepression.
368
Discussion
In the last decades S. marcescens has become of
interest since its ability to cause serious infections.
It is a facultative anaerobe with good survival abilities even in hostile conditions. Consequently, it can
act as a nosocomial agent. It is often involved in
urinary and lower respiratory tract infections, and
surgical wounds infections. The incidence of cutaneous infections caused by S. marcescens is extremely low and in most such istances are observed
in immunodepressed patients. Clinical manifestations include granulomatous lesions, fasciitis, nodules, cellulitis, ulcers and dermal abscesses.2 This
case is intriguing since it is a case of S. marcescens infection, in an immunocompetent 18-yearold man, causing ulcerative lesions in which histopathological examination was consistent with
PG-like lesion. In our case the patient presented lesions both clinically and histopathologically similar to PG, a non infectious neutrophilic skin disorder3. Nevertheless, a culture examination revealed
an infection by S. marscences. Absence of underlying diseases commonly associated to PG (inflammatory bowel disease, polyarthritis, immune deficiency
status and hematologic disorders), and healing of
lesions after antibiotic therapy are both elements
that support a non-secondary infection. Thus, in the
case here reported, S. marcescens is the etiologic
agent of these lesions. To the best of our knowledge
this is one of the few reported cases of PG-like le-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
Skin ulcers due to S. marcescens in an immunocompetent patient
CARLESIMO
Figure 2.—A) Zoned acute and chronic inflammatory infiltrates in the superficial dermis with acanthosis and pseudoepitheliomatous
hyperplasia of epidermidis (Haematoxylin and eosin, original magnification 30x); B) visible focal abscessual areas surrounded by a
zone of granulomatous inflammation bordered by a rim of lymphocytes and plasma cells (Haematoxylin and eosin, original magnification 160x); C) features of leucocytoclastic vasculitis probable of secondary meaning (Haematoxylin and eosin, original magnification
400x).
sions linked to S. marcescens infection in a young
immunocompetent patient, who is probably genetically predisposed. In literature, cutaneous lesions
similar to those in our patient have been linked to
Helicobacter Cinaedi in a patient affected by a primary immunodeficiency.4 We strongly recommend
the early consideration of infection by uncommon
Vol. 149 - No. 3
bacteria such as S. marcescens also in immunocompetent young patients, since its recognition and
treatment with a prolonged antibiotic therapy can
lead to clinical improvement. Therefore it is always
advisable to perform an easily obtainable cultural
examination of MSU since this finding can modulate the therapy. GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
369
CARLESIMO
Skin ulcers due to S. marcescens in an immunocompetent patient
References
  1. Wheat, RP, Zuckerman, A, Rantz, LA. Infection due to Chromobacteria: report of eleven cases. Arch Intern Med 1951;88:461-6.
  2. Marzano AV, Gasparini G, Caputo R. Cutaneous infection caused
by Serratia marcescens. Cutis 2000;66:461-3.
  3. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34:395-409;
  4. Dua J, Elliot E, Bright P, Grigoriadou S, Bull R, Millar M, Wijesu-
370
riya N, Longhurst HJ. Pyoderma gangrenosum-like ulcer caused by
Helicobacter cinaedi in a patient with x-linked agammaglobulinaemia. Clin Exp Dermatol 2012;37:642-5
Presented at the 87th SIDeMaST Congress, 21-24 November
2012.
Conflicts of interest.—The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014
CORRESPONDENCE
A case of superimposed segmental giant melanocytic nevus
TO THE EDITOR: Giant congenital melanocytic nevi
(CMN) are congenital pigmented lesions affecting 1 in
20,000 live births, defined by surface diameter measuring
20 cm or more.1 Giant CMN show a high risk of developing malignant melanomas and are often associated with
leptomeningeal melanocytosis.2
A full-term neonate was referred to our outpatient clinic
for the evaluation of an extensive congenital skin pigmentation. Physical examination showed the presence of a
main segmental nevus affecting the right lower limb associated with diffuse smaller round-to-oval nevi variable in
diameter affecting scalp, face, trunk, and limbs (Figure 1).
A diagnosis of superimposed segmental giant CMN was
made on the basis of clinical findings and confirmed by
histopathology. Magnetic resonance imaging (MRI) of the
brain and spine was negative for melanosis or thickening
of the leptomeninges.
Several polygenic skin disorders, including psoriasis, atopic dermatitis, vitiligo, etc, are known to present in a pronounced segmental or linear arrangement often associated
with a less severe non-segmental involvement.3 This pattern
of clinical presentation has been defined as “superimposed
segmental manifestation of a polygenic skin disorder”.3
In analogy to mendelian skin disorders, it may be explained by the concept of loss of heterozygosity (LOH),3, 4
i.e., a genetic mechanism by which a somatic cell becomes
heterozygous if one allele is lost or homozygous if both alleles of the same gene or both chromosomal loci are lost.4
The etiology of giant CMN is still unknown, even if
molecular studies, regarding both congenital and acquired
melanocytic nevi, have recently identified common polygenic mutations involving loci of BRAF, N-ras, MC1R,
and p53.5
In analogy to what mentioned above, our case can be
considered a clear example of superimposed segmental manifestation of a polygenic skin disorder. Both giant CMN and smaller melanocytic nevi rise from a postzygotic mutational event, which happens earlier in giant
CMN and later in nevi. In fact, while the main segmental
nevus affecting the right lower limb would be the result of
a LOH occurring in a precocious phase of a heterozygous
embryo development, scattered smaller melanocytic nevi
Figure 1.—A) Main segmental nevus affecting the right lower limb associated with diffuse smaller round-to-oval nevi; B) particular
of the scalp.
Vol. 149 - No. 3
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
371
CORRESPONDENCE
would represent the result of the background heterozygous
mutation probably occurring in a post-zygotic phase of the
development of an otherwise healthy embryo.
Recently, Happle has reviewed several historical cases
of giant CMN associated with small disseminated nevi and
has hypothesized that they could be categorized as “superimposed patchy manifestations of a polygenic disorder”,
because the term “segmental” was not always appropriate
to define the revised cases.5 Conversely, in our case, “segmental” is the best adequate adjective to describe the particular pattern of presentation of the giant CMN.
To the best of our knowledge, excluding the historical
cases revised by Happle,5 this is the first original case of
giant CMN presenting as a superimposed segmental manifestation of a polygenic skin disorder, again confirming
the geniality and the originality of the theory on ‘superimposed skin disorders’ proposed by Happle to explain these
diseases.
V. PICCOLO
Department of Dermatology and Venereology, Second
University of Naples, Naples, Italy
[email protected]
T. RUSSO
Department of Dermatology and Venereology, Second
University of Naples, Naples, Italy
R. PICCIOCCHI
Pediatric Dermatology Unit, A.O.R.N. Santobono-Pausillipon,
Naples, Italy
O. AMETRANO
Pediatric Dermatology Unit, A.O.R.N. Santobono-Pausillipon,
Naples, Italy
E. MOSCARELLA
Skin Cancer Unit, Arcispedale S. Maria Nuova, IRCCS Reggio
Emilia, Italy
G ITAL DERMATOL VENEREOL 2014;149:371-2
References
  1. Kopf AW, Bart RS, Hennessey P. Congenital nevocytic nevi and malignant melanomas. J Am Acad Dermatol 1979;1:123-30.
  2. Danarti R, König A, Happle R. Large congenital melanocytic nevi
may reflect paradominant inheritance implying allelic loss. Eur J
Dermatol 2003;13:430-2.
  3. Happle R. Superimposed segmental manifestation of polygenic skin
disorders. J Am Acad Dermatol 2007;57:690-9.
  4. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol 1999;41:143-61.
  5. Happle R. Giant melanocytic nevus may be explained as a superimposed patchy manifestation of a polygenic trait. Dermatology
2010;221:30-3.
Lymphangiomas arising on lymphedema:
first step of malignant development
TO THE EDITOR: A 45-year-old woman presented to our
department with a crop of papular lesions that had appeared
on her left limb over the last 2 months, at first on the thigh
and then on the leg. The lesions were light brown, slightly
prominent and translucid, smooth, rounded, with regular
edges and painless. The same limb was markedly lymphedematous due to primary lymphedema precox, which
had been diagnosed through lymphoscintigraphy about 6
years before. This investigation had disclosed, on the left,
a failed flow of the radiocolloid, a congenital lack of iliac
and lumbar-aortic lymph nodes as well as a great “dermal back flow”. The clinical diagnosis of lymphangioma
arisen on lymphedema was suspected (Figure 1). A punch
biopsy showed normal epidermis lying on a degenerated
collagen tissue, vascular cavities coated by lymphatic endothelium and stuffed of lymphoid cells along with spots
of amorphous material. No mitotic figures and cellular
pleomorphism were seen (Figure 2). The structural pattern
was compatible with the diagnosis of fibrolymphangioma.
This case is of interest because it is a clear example of
the three steps theory postulated by McConnel and Haslam
372
in 1956.1 They described 3 cases of angiosarcoma and 2 of
lymphangiomatosis arisen on lymphedematous arms (due
to radical mastectomy) and reviewed of the literature, thus
finding cases where angiosarcomas had arisen in lymphedematous extremities also in the absence of any previous
history of malignancies. On this basis, they recognized the
long-standing lymphedema (rather than a malignant diathesis) as the main etiological factor and then, from the histological study, they drew the typical development of the
lesions in three phases. The first stage is lymphedema accompanied by widespread degeneration of subcutaneous
and dermal collagen and, to a lesser extent, degeneration of
fatty tissue, as well as lymphocytic cuffing of small blood
vessels, particularly those at the lower edge of the dermis.
The second stage is that of premalignant angiomatosis, i.e., a
multifocal proliferation of endothelial cells in the lower dermis and subcutaneous tissue, which in the larger and more
superficial areas appear on the surface as bruises or vesicles.
Many of these proliferating vessels seem to be arisen from
lymphatics and often they form anastomosing plexus or
cavernous spaces filled with lymphocytes. In our patient we
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

CORRESPONDENCE
Figure 2.—Normal epidermis lying on a degenerated collagen tissue, lymph spaces and ectasic lymph vessels (Hematoxylin and
eosin stain, 200X).
Figure 1.—Multiples lymphangiomas on the markedly lympheodematous left limb.
found a perfect matching of all these features, as described
above. The third stage described by McConnell and Haslam
is frankly malignant angiosarcoma; therefore, considering the high risk of the patient, we scheduled an intensive
follow-up. Although the authors defined the relationship
between edema and malignancy as obscure, to date, with
the collection of new cases and the increased knowledge,
we might recognize the cause of malignancy in the reduced
antineoplastic immune surveillance due to the hampering
of the regular lymph flow including the normal trafficking
of immune cells. There is laboratory evidence confirming
the presence of impaired lymphocytes and Langerhans cells
trafficking in patients with obstructive lymphedema of the
lower extremities, which makes the lymphedematous region
an immunologically vulnerable site for the development of
neoplasms.2, 3 In fact, the impossibility to scavenge potential neoplastic cells has a role in the growth of malignancies
even more important of the degeneration of the connective
tissue resulting from the severe lymphedema. This could
explain also the unique but significant case of a squamous
cell carcinoma (SCC) arisen within lymphangioma circumsciptum.4 SCC comes from a different precursor cell that
should not be involved in the degeneration process caused
by lymphostasis. In this light, we can add this case to the
Vol. 149 - No. 3
expanding chapter of the immunocompromised district: a
cutaneous site that has been damaged and immunologically
“marked” by a variety of clinical events, such as chronic
lymphedema, herpetic infections, vaccination, ionizing or
UV radiation, thermal burns, or trauma.4 After the cause of
event has disappeared, the affected district may either appear clinically normal or show cutaneous changes, but its
immune behaviour is often compromised forever. An immunocompromised district becomes a site that is particularly
susceptible to subsequent outbreaks of opportunistic infections, tumours and immunity-related disorders, often confined to the district itself. The reason for the anomaly of the
local immune control may reside in locally hampered lymph
drainage (as typically occurs in chronic lymphedema), or in
locally altered neuromediator signalling (as it typically occurs in herpes zoster infection) or in the concomitant two
condition (as it typically occurs in amputation stumps and
radiation dermatitis).5 The case we present here fits this novel concept perfectly, since the appearance of premalignant
lymphangioma affects the lymphedematous limb only.
A. LO SCHIAVO
Department of Dermatology, Second University of Naples,
Naples, Italy
G. BRANCACCIO
Department of Dermatology, Second University of Naples,
Naples, Italy
[email protected]
F. ROMANO
Department of Dermatology, Second University of Naples,
Naples, Italy
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CORRESPONDENCE
S. CACCAVALE
Department of Dermatology, Second University of Naples,
Naples, Italy
G ITAL DERMATOL VENEREOL 2014;149:372-4
References
  1. McConnell EM, Haslam P. Angiosarcoma in post-mastectomy lymphoedema; a report of 5 cases and a review of the literature. Br J
Surg 1959;46:322-32.
  2. Mallon E, Powell S, Mortimer P, Ryan TJ. Evidence for altered cellmediated immunity in postmastectomy lymphoedema. Br J Dermatol 1997;137:928-33.
  3. Ruocco V, Schwartz RA, Ruocco E. Lymphedema: an immunologically vulnerable site for development of neoplasms. J Am Acad Dermatol 2002;47:124-7.
  4. Wilson GR, Cox NH, McLean NR, Scott D. Squamous cell carcinoma arising within congenital lymphangioma circumscriptum. Br
J Dermatol 1993;129:337-9.
  5. Ruocco V, Brunetti G, Puca RV, Ruocco E. The immunocompromised district: a unifying concept for lymphoedematous, herpes-infected and otherwise damaged sites. J Eur Acad Dermatol Venereol
2009;23:1364-73.
A rare association between neurofibromatosis
type 1 and vulvar sarcoma
TO THE EDITOR: Neurofibromatosis type 1 (NF1) is a
rare genetic disorder sporadic or genetically transmitted in
autosomal dominant fashion with an estimated incidence of
1:3000-4000 live births.
Clinical diagnostic criteria are well established, with patients needing two or more of the following: six or more
café-au-lait spots, two neurofibromas or one plexiform
neurofibroma, axillary or groin freckling, optic glioma, two
Lisch nodules, bone dysplasia and first-degree relative with
NF1.
Susceptibility to neoplastic transformation is the main
feature of the disease with a probability from 3 to 4 times
greater than the general population to develop both benign
and malignant tumors, supporting the classification of NF1
as a tumor predisposition syndrome.
In addition to neurofibromas, optic pathway glioma,
pheochromocytoma and leukemia, certain sarcomas are
more frequent in NF1 patients than in the general population, most commonly malignant peripheral nerve sheath
tumour (MPNST) and rhabdomyosarcoma.1
Sarcomas rarely involve the female genital tract; the uterus is primarily involved (90% of cases). The vulva is a rare
site of presentation for primary malignant tumours; more
commonly it is a site of metastasis or direct extension from
tumours originating in other genital sites such as the cervix
or endometrium, or from extragenital sites, including the
rectum and bladder. Vulvar sarcomas are uncommon, comprising only approximately 2% of all vulvar malignancies.2
We report the first occurrence of a malignant, high grade,
non differentiated vulvar sarcoma in a patient with NF1.
A 44-year-old female with a previous diagnosis of NF1
was referred to our Department for the presence of a large
vulvar mass, rapidly increasing in size over the last two
years.
Clinical examination revealed a large, nodular and exophytic mass, easily bleeding, painful, partially necrotic and
374
friable, involving the right side of the vulva (Figure 1). The
surrounding skin appeared intensely erythematous and the
inguinal lymph nodes were palpable bilaterally.
Pelvic MRI revealed a large parenchymatous mass,
(12×10×10 cm), localized in the median and paramedian
vulva, with extra-vulvar development, showing inhomogeneous structure and containing cystic necrotic areas. The
patient underwent a right hemivulvectomy. Histopathologic
examination revealed a highly cellular, malignant tumor invading the skin and the subcutaneous tissue, composed of
sheets of spindle-shaped cells provided with ovalar nuclei
and weakly eosinophilic cytoplasm. In places the tumor
cells were arranged in a herringbone pattern, though most
part of the tumor showed no definite cell arrangement. A
minor proportion of the tumor included small, rounded cell
elements with abundant deeply eosinophilic cytoplasm and
polar nuclei, reminiscent of rhabdomyosarcoma. Scarce fibrillary stroma was interspersed among the tumor cells. Extensive intratumoural necrosis and high mitotic index (30
mitoses/HPF) were observed (Figure 2). The tumor cells
immunoreacted only with vimentin, showing no staining
with a large panel of antibodies, including S-100 protein,
cytokeratin 5/6 and 7, EMA, desmin, CD117, thrombomodulin, smooth muscle actin, myoglobin, neurofilaments, striated muscle actin, HMB45, Melan A, calretinin and CD34.
Based on the morphologic and immunohistochemical results, a diagnosis of malignant, high grade non differentiated sarcoma, with fibrosarcoma-like areas was rendered.
Postoperatively, the patient received adjuvant chemotherapy and she died three months later because of lung
metastases’ presence.
More than fifty histologic adult soft tissue sarcoma subtypes exist and they display a wide spectrum of clinical
activities ranging from relatively slow-growing lesions to
aggressive locally and regionally destructive lesions with
potential for systemic metastasis. Furthermore, many of
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CORRESPONDENCE
Figure 2.—Histological appearance of the para-vulvar sarcoma
in this NF1 patient. Tumour cells are arranged in a herringbone
pattern, resembling a fibrosarcoma (Hematoxylin-eosin, 100x).
Figure 1.—A large, nodular and exophytic mass, easily bleeding,
painful, partially necrotic and friable, involving the right side of
the vulva.
these subtypes can occur at any age and in every part of
the body.3
As to the vulva, Davos published a series of 16 vulvar
sarcomas in non NF1 patients. Five were leiomyosarcoma;
other sarcomas were malignant fibrous histiocytomas, one
of which represented a dermatofibrosarcoma protuberans,
and one each of fibrosarcoma, hemangiosarcoma, malignant hemangiopericytoma, epithelioid sarcoma, malignant
schwannoma, malignant mesothelioma, and embrional
rhabdomyosarcoma.2 The commonest site of origin was the
labium majus (64%), followed by the posterior fourchette
and by the deep vulvar tissues adjacent to Bartholin’s gland.
In our case, the histological examination pointed to an
undifferentiated pleomorphic sarcoma (UPS). This term is
used for the classification of sarcomas that show no definable line of differentiation by histological, immunohistochemical, ultrastructural or molecular criteria.
Overall 5-year survival of patients with UPS has been
roughly 50%. Local surgical resection is the treatment of
choice and negative margins are particularly important.
The role of adjuvant chemotherapy and radiation is also
unclear.
The differential microscopical diagnosis in the present
case was mainly with a MPNST, also referred to as malignant schwannoma, malignant neurilemmoma or neurofibrosarcoma, which resembles routine fibrosarcoma in its
overall organization. However, comma-shaped Schwann
Vol. 149 - No. 3
cells were not demonstrable by both light microscopy
examination and using S-100 antibody. In addition, there
was no evidence of nuclear palisading. Despite morphological hints of focal rhabdomyoblastic differentiation in
the tumour, such those characteristically observed in Triton tumour, no immunoreactivity for striated muscle actin
antibody was present. Nevertheless, MPNST cannot be entirely ruled out as this malignancy is known to be “one of
the most difficult and elusive diagnoses in soft tissue diseases”. However, the occurrence of a MPNST in the vulvar
area in extremely uncommon as the lesion is usually found
in the lower extremities and head and neck region.
Three cases of endocervical fibroblastic MPNST have recently been described in non-NF1 patients. However, these
tumours differed from the present case in that they showed
fibrocyte-like differentiation, as demonstrated ultrastructurally and by positive immunoreaction of tumour cells with
both S-100 and CD 34.4
The association of non neurogenic sarcomas and NF1 is
rarely described in literature.
Zöller found two cases of leiomyosarcoma among 70
patients with NF1. Synovial sarcoma and gastrointestinal
stromal tumour are also becoming increasingly recognized
in association with NF1, and sporadic cases of malignant
fibrous histiocytoma have been described in these patients.5
We describe a NF1 patient affected by a vulvar pleomorphic high grade undifferentiated sarcoma to underline the
uncommon association and the presence of a rare sarcoma
in an atypical setting such as the vulva. As NF1 patient may
die at a young age after the onset an associated malignancy,
it is important to examine routinely these patients in order
to have an early diagnosis and treatment for a better outcome.
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375
CORRESPONDENCE
E. MIRAGLIA
Department of Dermatology, La Sapienza University of
Rome, Policlinico Umberto I, Rome, Italy
[email protected]
I. PECORELLA
Department of Experimental Medicine and Pathology,
La Sapienza University of Rome, Policlinico Umberto I,
Rome, Italy
F. PERSECHINO
Department of Dermatology, La Sapienza University of
Rome, Policlinico Umberto I, Rome, Italy
B. VISCONTI
Department of Dermatology, La Sapienza University of
Rome, Policlinico Umberto I, Rome, Italy
S. CALVIERI
Department of Dermatology, La Sapienza University of
Rome, Policlinico Umberto I, Rome, Italy
S. GIUSTINI
Department of Dermatology, La Sapienza University of
Rome, Policlinico Umberto I, Rome, Italy
G ITAL DERMATOL VENEREOL 2014;149:374-6
References
  1. de Oliveira MG, Pozatti Moure S, Sérgio Batista P, Moraes Chaves
AC, Rados PV, Sant’Ana Filho M. NF1 diagnosis criteria and associated sarcomatous tumor review of the literature and case report. Oral
Maxillofac Surg 2008;12:231-5.
  2. Davos I, Abell MR. Soft tissue sarcomas of vulva. Gynecol Oncol
1976;4:70-86.
  3. Dei Tos AP Classification of pleomorphic sarcomas: where are we
now? Histopathology 2006;48:51-62.
  4. Mills AM, Karamchandani JR, Vogel H, Longacre TA. Endocervical
fibroblastic malignant peripheral nerve sheath tumor (neurofibrosarcoma): report of a novel entity possibly related to endocervical
CD34 fibrocytes. Am J Surg Pathol 2011;35:404-12.
  5. Zöller ME, Rembeck B, Oden A, Samuelsson M, Angervall L. Malignant an benign tumors in patients with neurofibromatosis type 1
in a defined Swedish population. Cancer 1997;79:2125-31.
A clinical case of cutaneous silica granuloma
TO THE EDITOR: Silica granuloma occurs as a consequence of the introduction in the skin of silicon dioxide,
usually after injury. It was first described by Shattock in
1916 as a pseudotuberculoma silicoticum and later by
Faulds in 1935 and Eden Ed Herbert in 1936.1-3 There is
usually a long latency period from the moment of silicon penetration in the skin and the clinical appearance
of the granuloma. This latency period varies from 1 year
to more than 50 years, with an average interval of 10
years.
Silica granulomas have a clinical appearance of single
or multiple nodules along the scar line of a previous injury.
The pathogenesis of silica granuloma is not clear. According to Rank et al. it is likely that silica granulomas represent a reaction due to immune mediated hypersensibility
after a period of latency of many years after the injury in
subjects with a predisposition.4
The histopathological picture reminds us of the sarcoidosis granuloma.2 The medium and deep dermis, sometimes
even the hypodermis, are occupied by nodular infiltrates
with a distinct peripheral boundary made up of epithelioid cells and some giant multinucleate cells type Langhans or external body type and few lymphocyte cells at the
boundaries of the epithelioid nodules.2 The most typical
finding is the presence in the cytoplasm of some giant cells
of birefringent, brilliant, polygonal and elongated crystals, observable only under polarised light. Without these
mineral inclusions it is not possible to distinguish a silica
granuloma from a cutaneous sarcoidosis.2 The apparently
low incidence of the silica granuloma is partly due to the
376
lack of routine exams under polarized light. Energy-dispersive X-ray analysis allows definitive diagnosis of silica
granuloma. In this process a characteristic X-ray emission
spectrum is evoked, it is recorded in graphic form, with
characteristic peaks identifiable with an element’s atomic
number.3 Some researchers have reported cases of systemic sarcoidosis associated with cutaneous manifestations
where polarized crystals were evidently associated with
the formation of the skin granuloma. As it is well known,
Figure 1.—The lesion on the forehead before treatment.
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Figure 2.—Foreign-body granulomatous inflammation, sarcoid
type. “Bare” granulomas adjacent to each other with no lymphocytes and plasma cells interposition can be observed. (Hematoxylin and eosin; magnification 2.5X).
sarcoidosis has a particular tropism for scars and for areas
previously exposed to injury. The foreign body could serve
as a substrate stimulating the formation of the granuloma
and in some cases of sarcoidosis. Surgical excision is the
best treatment. Alternative treatments are intralesional injections of steroids with the risk of recurrence, once the
treatment is suspended. Other systemic treatments with
steroids, antibiotics and radiotherapy have been described.
In some cases a spontaneous solution of the lesions is possible, so an observation period of 6-12 months is advis-
able.5 The authors describe a case of silica granuloma in a
65-year-old patient after a latency period of 30 years and
on a previous scar.
A 65-year-old man presented to our facility with nodular lesions in the area of post-trauma scar lesions in the
left frontal region (trauma occurred 30 years before). The
patient had cranial trauma due to a car accident causing the
breakage of the windscreen, which had in turn caused a cut
injury in the left frontal region, that was surgically sutured.
After about 30 years from the previous trauma and along
the scar line, multiple painless nodules appeared. At the
objective exam a linear scar about 10 cm long and parallel to the line of the left eyebrow and of a red-purple color
standing out on the cutaneous level was observed. Multiple
nodules distributed in an irregular manner could be felt at
touch. They were along the line of the scar and of a painless fibrous thick consistency (Figure 1).
A biopsy of a nodular lesion was performed and the
histopathological exam showed an area of chronic, granulomatous tissue, with giant cells and no necrosis inflammation composed by multiple granulomas of epithelioid
cells and giant multinucleate cells, surrounded by little
inflammatory infiltration, as can be observed in sarcoid
type granulomatous reactions. Rare fragments of foreign
non-pigmented birefringent crystal material were present
in some granulomas. The Ziehl-Nielsen coloration performed to search alchol-acid resistant bacilli was negative.
The histopathological samples showed chronic granulomatous inflammation of the skin with sarcoid similar aspects,
as can be observed in foreign bodies containing siliconates
(Figures 2-4). Clinical and instrumental exams were performed in order to exclude a systemic sarcoidosis, and the
results were negative. The diagnosis was silica granuloma
and surgical revision of the scar was the treatment proposed.
Figure 3.—Birefringent foreign body in the cytoplasm of a giant cell (Hematoxylin and eosin; magnification 20X).
Vol. 149 - No. 3
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377
CORRESPONDENCE
P. FINO
Department of Plastic, Reconstructive and Esthetic
Surgery, University of Rome “Sapienza”, Policlinico
Umberto I, Rome, Italy
[email protected]
V. AMOROSI
Department of Plastic, Reconstructive and
Esthetic Surgery, University of Rome “Sapienza”,
Policlinico Umberto I, Rome, Italy
F. PIRO
Department of Pathology,
San Giovanni-Addolorata Hospital, Rome, Italy
D. PEDACE
Dermatology and Venereology, Free Practioner
Figure 4.—The Ziehl-Nielsen stain was negative for alchol-acid
resistent bacilli.
Histologically, cutaneous silica granulomas are significant for their resemblance with cutaneous sarcoidosis. Furthermore, the non-specific clinical presentation
makes the diagnosis more difficult and cutaneous silica
granuloma might be a lesion that is often underdiagnosed. Thus, a thorough clinical history, histopathological examination and observation under polarized light
microscopy are essential in achieving an accurate diagnosis and for implementing appropriate management.
We suggest to any doctor and dermatologists who observe a lesion with the characteristics described above
to consider this diagnostic hypothesis. Previous trauma
information and silica exposure must be asked for in the
clinical anamnesis.
M. G. ONESTI
Department of Plastic, Reconstructive and
Esthetic Surgery, University of Rome “Sapienza”,
Policlinico Umberto I, Rome, Italy
S. CARELLA
Department of Plastic, Reconstructive and Esthetic
Surgery, University of Rome “Sapienza”, Policlinico
Umberto I, Rome, Italy
C. LATINI
Department of Maxillofacial and Plastic, Reconstructive
Surgery, San Giovanni-Addolorata Hospital, Rome, Italy
G ITAL DERMATOL VENEREOL 2014;149:376-8
References
  1. Shattock SG. Pseudotuberculoma silicoticum of the lip. Proc R Soc
Med 1916;10:19-21.
  2. Fernandez-Flores A, Montero MG. Does cutaneous silica granuloma develop mainly in predisposed patients? Eur J Dermatol
2006;16:321-2.
  3. Bovenmyer DA, Landas SK, Bovenmyer JA. Spontaneous resolution of silica granuloma. J Am Acad Dermatol 1990;23:322-4.
  4. Rank BK, Hicks JD, Lovie M. Pseudotuberculoma granulosum silicoticum. Br J Plast Surg 1972;25:42-8.
  5. Fernandez-Flores A. Birefringent particles in granulomatous dermatitis, sarcoidal-type as well as in other non-granulomatous
skin disorders in patients without sarcoidosis. Bratisl Lek Listy
2009;110:328-31.
Merkel cell carcinoma of the lower limb
TO THE EDITOR: A 83-year-old woman presented with
a dome-shaped, deep, bluish- red nodule on her left thigh,
measuring 2.0 cm in diameter (Figure 1). After informed
consent and local anesthesia, the lesion was widely excised with a 3 cm border. Histopathological examination
revealed a small cell undifferentiated carcinoma/Merkel’s
cells carcinoma (MCC), infiltrating the dermis, the sub-
378
cutaneous tissue and the vascular spaces with aggregates
of small round blue cells showing hyper-chromatic nuclei,
scant cytoplasm and mitoses (Figures 2, 3). Immunohistochemistry was positive for both citokeratin 20 (CK-20) and
chromogranin A, but negative for S100, CK-7 and common
leukocyte antigens. Sentinel lymphnode biopsy (SLNB),
physical examination and imaging studies, including total-
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
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CORRESPONDENCE
Figure 1.—Our patient showing a dome-shaped, deep, bluish-red
nodule on her left thigh.
body computer tomography (CT-SCAN), were negative,
hence disease stage was I. The patient was treated with adjuvant external beam radiotherapy (EBRT) (6000 cGy) to
the surgical area. A 7-year-follow-up did not show evidence
of recurrence or metastasis. We have decided to examine
retrospectively the presence of Merkel cell polyomavirus
(MCV) in 2 formalin-fixed paraffin-embedded sections.
Sections of 10 μm were obtained from formalin-fixed paraffin-embedded tissue biopsy specimens from the patient
and were extracted with xylene to remove the paraffin, followed by two washes with absolute ethanol to remove the
xylene. The presence of MCV was searched by primer-directed amplification with PCR. Specific primer pairs were
designed to detect the viral large T protein (LT1 and LT3)
and the viral capsid protein (VP1). For PCR amplification,
a sensitive GoTaq® Flexi DNA polymerase system (Promega, Madison, WI, USA) was used with 0.5 μg 10 μL−1
genomic DNA, and 20 pmol of each primer. To demonstrate
that the quality and quantity of the DNA samples isolated
from the formalin-fixed paraffin-embedded tissue biopsies
were acceptable, a 268-bp segment of the human β-globin
gene was also amplified. Amplification products were separated by electrophoresis in 1.5% agarose gel stained with
GelRed™ (Biotium Inc., Hayward, CA, USA). For the
DNA sequence analysis, the PCR products were excised
and purified with the Cycle-Pure mini kit (Omega Bio-Tek
Inc., Norcross, GA, USA). The purified PCR products were
Vol. 149 - No. 3
Figure 2.—Small cell undifferentiated Merkel’s cells carcinoma,
infiltrating the dermis, the subcutaneous tissue and the vascular
spaces (hematossilin-eosin 25X).
Figure 3.—MCC showing vesicular, basophilic nuclei with prominent nucleoli and multiple mitoses (hematossilin-eosin 200X).
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
379
CORRESPONDENCE
subjected to direct sequencing. In both sections, PCR was
negative. MCC, first described by Toker as “trabecular carcinoma” of the skin in 1972 is a rare, highly malignant tumor of the skin which displays features of neuroendocrine
differentiation. Often initially misdiagnosed due to its nondistinctive appearance, MCC usually occurs as a painless,
dome-shaped, deep red nodule on sun-exposed skin with
predominance in older patients. The acronym AEIOU has
recently been proposed to describe the classical clinical
characteristics of MCC: asymptomatic, expanding rapidly,
immune suppression, older than 50 years of age, UV-exposed site on fair skin.1 The incidence of MCC has risen
substantially over time, with an estimated three time increase annually between 1986 and 2001.1 The etiology of
MCC is unknown. However, many patients with MCC have
had a history of other synchronous or metachronous sunassociated skin cancers, implicating excessive sun exposure
as a common risk factor for developing MCC. There may
be an increased reciprocal risk of MCC with haematologic
diseases and malignant melanoma, suggesting that MCC
may share etiologic influences with other malignancies.1
Immunosuppressed patients are also at a higher risk for
developing MCC.1 Although the MCV may explain the increased incidence of MCC in immunosuppressed patients,
in our case, MCV research performed on formalin-fixed and
paraffin-embedded tissue specimens with quantitative PCR
was negative.2, 3 Frozen tissues from MCC patients seem to
have higher percentages of PCR positivity.3 Patients with
MCC should be rigorously staged. The primary site should
be evaluated for satellite lesions and dermal seeding. To
date, there seems to be no optimal imaging algorithm and
fluorodeoxyglucose positron emission tomography (PET
imaging), not performed in our case, has been reported
useful.4 Although the contribution of sentinel lymphnode
biopsy to accurate staging of patients with MCC is generally accepted, its potential significance in terms of predicting patient prognosis remains controversial. Depending on
the stage of disease and patient’s health status, the primary
treatment of MCC involves wide surgical excision with at
least 2 to 3 cm margins. However, many clinicians believe
that even in stage I MCC, surgery should be combined with
adjuvant EBRT to the primary site and primary nodal chains
because of a high loco-regional recurrence.5 Although most
MCC cell lines are more radio-resistant than other small
cell carcinomas, most clinical studies, as our case, demonstrated better local control rates with adjuvant EBRT after
surgery.5 Combined EBRT and chemotherapy (doxorubicin
in particular) have been suggested for patients with more
advanced disease while, in disseminated diseases, the effect of EBRT is questionable and systemic chemotherapy
induces considerable toxicity and treatment-related deaths.
Recently, few studies have been published on the combination of chemotherapy with peptide receptor radionuclide
therapy (PRRNT) in advanced stages of MCC. Male sex,
tumor size, advanced clinical stage, small cell size, high
mitotic index, diffuse pattern, as well as p53, have all been
reported as poor prognostic factors, while better survival
380
was associated with limb localization, early stage disease,
younger age and female sex.1 In our patient, age did not
influence the prognosis. In conclusion, MCC is rare and
almost always misdiagnosed during physical examination. Research has improved the accuracy of diagnosis of
MCC through immunohistochemical staining, but the exact
pathogenesis of MCC is still uncertain and the role of adjuvant radiation therapy continues to be debated. Although
we know that only multi-institutional prospective clinical
trials will explain the pathogenesis and define the exact role
of radiation therapy of MCC, we reported our single case
to underline that it is necessary to maintain a high index of
suspicion for MCC in every skin lesion that presents as a
solitary dome-shaped nodule, even in uncommon locations
such as the thigh.
M. DE PAOLA
Section of Dermatology, Department of Clinical
Medicine and Immunological Sciences, University of
Siena, Santa Maria alle Scotte Hospital, Siena, Italy
[email protected]
S. POGGIALI
Section of Dermatology, Department of Clinical
Medicine and Immunological Sciences, University of
Siena, Santa Maria alle Scotte Hospital, Siena, Italy
C. MIRACCO
Department of Human Pathology and Oncology,
University of Siena, Santa Maria alle Scotte Hospital,
Siena, Italy
C. PISANI
Section of Dermatology, Department of Clinical
Medicine and Immunological Sciences, University of
Siena, Santa Maria alle Scotte Hospital, Siena, Italy
A. BATSIKOSTA
Section of Dermatology, Department of Clinical
Medicine and Immunological Sciences, University of
Siena, Santa Maria alle Scotte Hospital, Siena, Italy
R. BILENCHI
Section of Dermatology, Department of Clinical
Medicine and Immunological Sciences, University of
Siena, Santa Maria alle Scotte Hospital, Siena, Italy
G ITAL DERMATOL VENEREOL 2014;149:378-81
References
  1. Heath M , Jaimes N, Lemos B, Mostaghimi A, Wang LC, Peñas
PF et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol
2008;58:375-81.
  2. Varga E, Kiss M, Szabó K, Kemény L Detection of Merkel cell
polyomavirus DNA in Merkel cell carcinomas. Br J Dermatol
2009;161:930-2.
  3. Touzé A, Gaitan J, Maruani A, Le Bidre E, Doussinaud A, Clavel C
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
June 2014

CORRESPONDENCE
et al. Merkel cell polyomavirus strains in patients with Merkel cell
carcinoma. Emerg Infect Dis 2009;15:960-2.
  4. Iagaru A, Quon A, McDougall IR, Gambhir SS. Merkel cell carcinoma: is there a role for 2-deoxy-2-[f-18]fluoro-d-glucose-positron
emission tomography/computed tomography? Mol Imaging Biol
2006;8:212-7.
  5. Eng TY, Boersma MG, Fuller CD, Cavanaugh SX, Valenzuela F,
Herman TS. Treatment of Merkel cell carcinoma. Am J Clin Oncol
2004;27:510-5.
  6. Salavati A, Prasad V, Schneider CP, Herbst R, Baum RP. Peptide
receptor radionuclide therapy of Merkel cell carcinoma using
(177)lutetium-labeled somatostatin analogs in combination with
radiosensitizing chemotherapy: a potential novel treatment based
on molecular pathology. Ann Nucl Med 2012;26:365-9.
Yellow urticaria in a patient with hepatic cirrhosis
TO THE EDITOR: Most urticarial reactions were
previously thought to occur as a result of immunological
or inflammatory mechanisms. The lesions of urticaria are
usually observed as erythematous plaques. However, we
present the case of a 56-year-old man with acute urticaria
that appeared yellow because of hyperbilirubinemia.
A 56-year-old Japanese man was admitted to our hospital, presenting with clouding of consciousness and a
high-grade continuous fever with chills. General physical
examination revealed jaundice and a body temperature
of 38.5 °C, with marked neck stiffness with a positive
Kernig’s sign. His medical history included chronic hepatitis C and alcoholic cirrhosis, for which he had received
treatment with lansoprazole, ursodeoxycholic acid, furosemide, and spironolactone for 5 years prior to presentation. He had also been undergoing endoscopic injection
sclerotherapy for recurrent gastrointestinal bleeding. A
cerebrospinal fluid (CSF) analysis revealed leukocytosis,
a high protein concentration, and low glucose levels, with
a decreased CSF-to-serum glucose ratio. Because cerebral meningitis was suspected, blood and cerebrospinal
fluid samples were examined. The cultures of both these
samples tested positive for hemolytic streptococcus. On
the basis of a hemolytic streptococcus meningitis diagnosis, the patient intravenously received vancomycin and
ampicillin. Approximately 24 h after receiving the antibiotics, he developed multiple well-defined, yellowish, edematous plaques that disseminated into the buttocks and
anterior region of his knees (Figure 1). He was unable to
describe any symptoms because he was comatose. Hematological examination revealed hyperbilirubinemia (direct
bilirubin level, 5.2 mg/dL [reference range, 0-0.4 mg/dL];
total bilirubin level, 8.1 mg/dL [reference range, 0.3-1.2
mg/dL]), and thrombopenia (platelet count, 24,000/mm3).
Liver enzyme levels were mildly elevated (aspartate aminotransferase level, 48 U/L [reference range, 13-33 U/L]).
A half day later, the swelling subsided, but some of the
yellowish macules persisted. On day 4, the patient died
from progressive multiple-organ failure while comatose.
Yellowish changes in skin color are usually evident in
xanthoma, during ingestion of antimalarial drugs, in carotenemia, and in yellow urticaria.1, 2 The present patient’s
dietary history ruled out food-induced skin discoloration.
Although vancomycin and ampicillin were administered
Vol. 149 - No. 3
before the appearance of the rash, there had been no report
of yellowish skin eruptions by these drugs. Based on the
clinical course of the eruption, we diagnosed the patient
with yellow urticaria secondary to an elevated bilirubin
level. We believe that the yellowish skin color was a consequence of the increased permeability of the blood vessels in
the wheal and the deposition of excess bilirubin in the surrounding dermis. Previous reports have failed to show the
existence of bilirubin in biopsy tissue by Gmelin staining.3
According to us a minimal bilirubin level must be present
in a tissue section to be detected by Gmelin staining.
In our previous report and that of Imanishi et al.,3 it is
interesting to note that yellowish wheal had appeared after
an increase in blood bilirubin levels within a few days. Bilirubin, a breakdown product of normal heme catabolism,
A
B
Figure 1.—Yellowish edematous plaques located around the right
knee (A) and on the buttocks (B).
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CORRESPONDENCE
is now thought to be biologically active and hence may
trigger urticarial reaction. Bilirubin has been shown to induce a dose-dependent decrease in transepithelial electrical resistance and an increase in paracellular permeability
of the intestinal epithelium to fluorescent dextran.4 Moreover, increased intestinal permeability has been observed
not only in vitro but in vivo as well.5 Given the severity of
the infection, it might have been possible to easily increase
vascular permeability. However, these results indicate that
the elevation of serum bilirubin levels may have caused the
increased permeability of blood vessels. Thus, we propose
that hyperbilirubinemia may be a causative factor for urticaria, though further evidences are needed to support this
hypothesis.
T. CHIBA
Department of Dermatology, Iizuka Hospital, Fukuoka, Japan
[email protected]
F. HAYASHI
Department of Neurology, Iizuka Hospital, Fukuoka, Japan
M. SHINMURA
Department of Neurology, Iizuka Hospital, Fukuoka, Japan
M. KIYOMATSU
Department of Dermatology, Iizuka Hospital, Fukuoka, Japan
382
S. TATEMATSU
Department of Dermatology, Iizuka Hospital, Fukuoka, Japan
M. NAKAO
Department of Dermatology, Iizuka Hospital, Fukuoka, Japan
M. FURUE
Department of Dermatology, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan
G ITAL DERMATOL VENEREOL 2014;149:381-2
References
  1. Narváez-Moreno B, Pereyra-Rodríguez JJ. Yellow urticaria. N Engl
J Med 20; 2; 367.
  2. Patel SB, Mutasim DF. Yellow urticaria secondary to hyperbilirubinemia in a patient with end-stage liver disease. Cutis 20;; 0: 41-4.
  3. Imanishi H, Tsuruta D, Kobayashi H, Ishii M. Yellow urticaria associated with hepatitis type-C liver cirrhosTh of Dermaogy 206;33:
823-4.
  4. Raimondi F, Crivaro V, Capasso L, Maiuri L, Santoro P, Tuci M, et
al. Unconjugated bilirubin modulates the intestinal epithelial barrier function in a human-derived in vitro model. Pediatric Research
206;60: 30-3.
  5. Welsh FK, Ramsden CW, MacLennan K, Sheridan MB, Barclay
GR, Guillu PJ, et al. Increased intestinal permeability and altered
mucosal immunity in cholestatic jaundice. Annals of surgery
998;227:205-12.
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June 2014