Linear Immunoglobulin A Bullous Dermatosis Induced by Gemcitabine

Abstract

To report a case of linear immunoglobulin (Ig) A bullous dermatosis (LABD) induced by gemcitabine.
A 59-year-old man was diagnosed with squamous-cell carcinoma of the lung in T4N2M0 stage and treated with cisplatin, vinorelbine, and gemcitabine. Twenty-four hours after the administration of gemcitabine, a symmetric, bullous, herpetiform eruption appeared on his trunk and upper limbs. Histopathologic examination and direct immunofluorescence test were consistent with IgA bullous dermatosis. Cutaneous lesions resolved two weeks after the drug was withdrawn and topical steroid treatment was instituted.
Drug-induced LABD is a variant of classic or idiopathic LABD. Vancomycin is the most frequently implicated drug, but other agents have been reported to cause LABD. According to the Naranjo probability scale, the relationship of gemcitabine treatment with cutaneous eruption in our patient is possible.
We report the first case of gemcitabine-induced LABD. Clinicians should monitor patients receiving this drug for signs of LABD.

Full text

The Annals of Pharmacotherapy ■2001 July/August, Volume 35 ■891
www.theannals.com
Linear immunoglobulin (Ig) A bullous dermatosis (LABD)
is a heterogeneous disease that includes several der-
matoses characterized by linear deposition of IgA along
the basal membrane zone. LABD induced by drugs was
characterized by Baden et al.1in 1988, but other cases of
LABD related to drugs were previously described.
The main clinical, histopathologic, immunofluores-
cence, immunoelectron microscopy, and immunopatholog-
ic features of drug-induced LABD are similar to those of
classic or idiopathic LABD, but some differences usually
occur. Mucous-membrane lesions have been described in
drug-induced LABD,1,2 but develop less frequently than in
the classic LABD form of the disease. Spontaneous remis-
sion usually occurs once the offending agent is withdrawn
and immune deposits disappear from the skin.
The most frequently implicated drug in LABD is vanco-
mycin.1-12 Other drugs that have been described as causal
agents of LABD include lithium13; cefamandole and capto-
pril14; diclofenac15,16; piroxicam and somatostatin2; gliben-
clamide17; iodine18; penicillin G, ampicillin, amiodarone,
rifampin, trimethoprim/sulfamethoxazole and sulfisoxa-
zole19; phenytoin, gamma interferon, interleukin-2, and
polychemotherapy20; ceftriaxone and metronidazole21; and
furosemide, and granulocyte colony–stimulating factor.
We describe a case of LABD caused by a cytotoxic drug,
gemcitabine, which has not been previously described as a
cause of this disease.
CASE REPORT
A 59-year-old man with advanced diabetes mellitus and arte-
riosclerotic peripheral arteriopathy was diagnosed in August
1999, with bronchoscopy, of squamous-cell carcinoma of the
lung in T4N2M0 stage. The patient had smoked until two years
prior to diagnosis and has no known drug allergies. At the time of
chemotherapy initiation, he was taking the following chronic
medications: NPH insulin, pentoxifylline, and bromazepam.
Chemotherapy treatment with cisplatin, vinorelbine, and gem-
citabine was initiated. The last drug started was gemcitabine
1000 mg/m2(1840 mg) dissolved in 250 mL of NaCl 0.9% and
infused over 30 minutes. Twenty-four hours after the administra-
tion of gemcitabine, a symmetric vesiculo-bullous eruption with
herpetiform features appeared on his scapular areas, neck, and
thighs (Figure 1).
The clinical differential diagnosis prior to histopathologic ex-
amination included herpetiform dermatitis, LABD, and paraneo-
plastic pemphigus. A cutaneous biopsy showed focal necrosis of
keratinocytes in the epidermis, without multinucleated cells or vi-
ral inclusions. Focal dermo-epidermal detachment initiating a
subepidermal blister with hydropic changes in the basal mem-
brane was observed. The dermis showed a diffuse inflammatory
infiltrate composed of eosinophils, some neutrophils, and perivas-
cular lymphocytes, which affected the papillary dermis (Figure 2).
Direct immunofluorescence examination showed slightly linear
IgA deposits on the basal membrane (Figure 3), and was negative
for IgG, IgM, C3, C4, and C1Q.
Linear Immunoglobulin A Bullous Dermatosis
Induced by Gemcitabine
Jesús del Pozo, Walter Martínez, María T Yebra-Pimentel, Manuel Almagro,
Carmen Peña-Penabad, and Eduardo Fonseca
OBJECTIVE:To report a case of linear immunoglobulin (Ig) A bullous dermatosis (LABD) induced by gemcitabine.
CASE SUMMARY:A 59-year-old man was diagnosed with squamous-cell carcinoma of the lung in T4N2M0 stage and treated with
cisplatin, vinorelbine, and gemcitabine. Twenty-four hours after the administration of gemcitabine, a symmetric, bullous, herpetiform
eruption appeared on his trunk and upper limbs. Histopathologic examination and direct immunofluorescence test were consistent
with IgA bullous dermatosis. Cutaneous lesions resolved two weeks after the drug was withdrawn and topical steroid treatment was
instituted.
DISCUSSION:Drug-induced LABD is a variant of classic or idiopathic LABD. Vancomycin is the most frequently implicated drug, but
other agents have been reported to cause LABD. According to the Naranjo probability scale, the relationship of gemcitabine
treatment with cutaneous eruption in our patient is possible.
CONCLUSIONS:We report the first case of gemcitabine-induced LABD. Clinicians should monitor patients receiving this drug for
signs of LABD.
KEY WORDS:gemcitabine, linear IgA bullous dermatosis.
Ann Pharmacother 2001;35:891-3.
Author information provided at the end of the text.
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Gemcitabine treatment was stopped, and cutaneous lesions re-
solved in two weeks with daily treatment with topical methyl-
prednisolone. The steroid was applied until clearance of cuta-
neous lesions. Six days after gemcitabine was discontinued, a
new treatment cycle with cisplatin and vinorelbine was adminis-
tered. The existing cutaneous lesions disappeared and no new
ones appeared.
Discussion
Drug-induced LABD is a clinically heterogeneous dis-
ease. Urticariform lesions similar to those seen with ery-
thema multiforme-like,14 bullous pemphigoid-like, der-
matitis herpetiformis-like,19 and toxic epidermal necroly-
sis-like lesions have been described. The lesions usually
appear a few days after administration of the drug, and
slowly decrease after the medication is withdrawn. The
temporal sequence is the most important clinical data used
to determine the causal drug, but occasionally it is very
difficult to identify that agent because of the polypharmacy
received by the patient. Other factors may be implicated in
LABD, such as neoplasia or infections. In our case, the
temporal sequence is adequate in determination of drug-in-
duced LABD, as the eruption first appeared after adminis-
tration of gemcitabine.
The histopathologic findings in LABD, according to the
clinical features, are very diverse.8,11 Skin biopsies usually
show subepidermal blisters with papillary abscesses con-
taining inflammatory cells, mainly neutrophils and, occa-
sionally, eosinophils. In other cases, the histopathologic
findings are similar to those with dermatitis herpetiformis,
bullous pemphigoid, erythema multiforme, or toxic epider-
mal necrolysis. For this reason, immunopathologic studies
are necessary to diagnose drug-induced LABD. Our case
showed the typical histopathologic features of this disease.
Treatment of LABD usually includes reduction or with-
drawal of the possible causal drug and use of topical thera-
py, as was performed in our patient. Nevertheless, sys-
temic treatments are necessary in some cases, dapsone and
steroids being the drugs used the most.
Gemcitabine is a specific S-phase cytotoxic drug mainly
used in treatment of non-small-cell lung and pancreas neo-
plasias.22 Hematologic toxicity, gastrointestinal intolerance,
and renal alterations are the more frequent secondary effects
of this drug, but cutaneous alterations have also been de-
scribed. Mild cutaneous eruptions in 25% of patients,23 as
well as occasional blister formation and ulceration at sites of
injection, peripheral and facial edema, and aphtous stomati-
tis have been reported in patients treated with gemcitabine.24
The Naranjo probability scale25 indicates a possible rela-
tionship between LABD and gemcitabine in this patient.
892 ■The Annals of Pharmacotherapy ■2001 July/August, Volume 35 www.theannals.com
J del Pozo et al.
Figure 3. Direct immunofluorescence test with linear immunoglobulin A de-
posits at dermo-epidermal junction.
Figure 2. Focal areas of dermo-epidermal detachment and a diffuse inflam-
matory infiltrate composed of eosinophils, some neutrophils and perivascu-
lar lymphocytes in papillary dermis.
Figure 1. Bullous eruption with herpetiform features localized on the trunk.

Summary
To our knowledge, gemcitabine-induced LABD has not
been previously described; however, it should be consid-
ered a potential adverse effect of gemcitabine.
Jesús del Pozo MD, Clinical Specialist, Department of Dermatol-
ogy, Hospital Juan Canalejo, La Coruña, Spain
Walter Martínez MD, Clinical Specialist, Department of Dermatol-
ogy, Hospital Juan Canalejo
María T Yebra-Pimentel MD, Specialist, Department of Pathology,
Hospital Juan Canalejo
Manuel Almagro MD, Clinical Specialist, Department of Derma-
tology, Hospital Juan Canalejo
Carmen Peña-Penabad MD, Clinical Specialist, Department of
Dermatology, Hospital Juan Canalejo
Eduardo Fonseca MD, Director, Department of Dermatology, Hos-
pital Juan Canalejo
Reprints: Jesús del Pozo MD, Servicio de Dermatología, Hospital
Juan Canalejo, Xubias de Arriba, 84, 15006 La Coruña, Spain, FAX
981/205375, E-mail der@canalejo.org
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EXTRACTO
OBJETIVO:Presentamos un caso de dermatosis ampollosa IgA lineal
inducida tras un tratamiento con gemcitabina.
CASO CLÍNICA:Un enfermo varón de 59 años fue diagnosticado de un
carcinoma epidermoide de pulmón en estadio T4N2M0 y tratado con
cisplatino, vinorelbina, y gemcitabina. Cuarenta y ocho horas tras la
administración de gemcitabina, le apareció en el tronco y las
extremidades superiores una erupción ampollosa y simétrica de aspecto
herpetiforme. El estudio histopatológico de una biopsia cutánea y el test
de inmunofluorescencia directa fueron compatibles con una dermatitis
ampollosa IgA lineal. Las lesiones ampollosas curaron, dos semanas tras
la suspensión del fármaco, con tratamiento esteroideo tópico.
DISCUSIÓN:La dermatosis ampollosa IgA lineal inducida es una variante
de la dermatosis ampollosa IgA lineal clásica o idiopática producida por
fármacos. El fármaco que más frecuentemente está implicado en estas
reacciones es la vancomicina, pero se han descrito casos producidos por
otros muchos fármacos. En nuestro caso la relación entre el tratamiento
con gemcitabina y la erupción cutánea según la escala de probabilidad
ADR de Naranjo fue posible.
CONCLUSIONES:Presentamos un nuevo caso de dermatosis ampollosa
IgA lineal relacionada con un tratamiento con gemcitabina, un fármaco
que previamente no había sido implicado en esta entidad.
Eduardo Fonseca
RÉSUMÉ
OBJECTIF:Rapporter un cas de dermatose bulleuse linéaire à IgA
(DBLIgA) causé par un traitement à la gemcitabine.
RÉSUMÉ DU CAS:Un diagnostic de carcinome des cellules squameuses du
poumon, stade T4N2M0, a été posé chez un homme de 59 ans. Un
traitement à base de cisplatine, de vinorelbine, et de gemcitabine a été
entrepris. Vingt-quatre heures après l’administration de la gemcitabine,
une éruption herpétiforme, symétrique et bulleuse est apparue au niveau
du tronc et des membres supérieurs. Les résultats de l’analyse histopatho-
logique et d’un test d’immunofluorescence étaient compatibles avec le
diagnostic de DBLIgA. Deux semaines après l’arrêt de la gemcitabine et
suite à l’utilisation de stéroïdes topiques, les lésions étaient disparues.
DISCUSSION:La DBLIgA d’origine médicamenteuse est une variante de
la DBLIgA classique ou idiopathique. Parmi les médicaments ayant
causé une DBLIgA, la vancomycine a été la plus fréquemment
impliquée. Selon l’algorithme de Naranjo, le lien entre la réaction
cutanée observée et la gemcitabine est possible.
CONCLUSIONS:Ce rapport de cas de DBLIgA est le premier associé à
l’utilisation de la gemcitabine.
Alain Marcotte
Case Reports
The Annals of Pharmacotherapy ■2001 July/August, Volume 35 ■893
www.theannals.com