Case Report
Dermatology 2010;221:201–205
Autoimmune Bullous Skin Diseases Occurring
under Anti-Tumor Necrosis Factor Therapy:
Two Case Reports
L. Boussemart a S. Jacobelli a F. Batteux b C. Goulvestre b P. Grange a A. Carlotti a
J.P. Morini a I. Gorin a J.M. Ziza c M.F. Avril a N. Dupin a
Departments of a Dermatology and Venereology and b Immunology, Hôpital Cochin, and c Department of
Rheumatology, Groupe Hospitalier Diaconesses-Croix Saint-Simon, Paris, France
Key Words
Anti-TNF therapy ⴢ Bullous pemphigoid ⴢ
Pemphigus foliaceus
Abstract
Background: Anti-tumor necrosis factor
(TNF) agents are increasingly being used for
a rapidly expanding number of rheumatic
and systemic diseases. As a result of this use,
and of the longer follow-up periods of treat-
ment, there are a growing number of reports
of the development of autoimmune pro-
cesses related to anti-TNF agents. The use of
anti-TNF agents has been associated with
more and more cases of autoimmune diseas-
es, principally cutaneous vasculitis, lupus-
like syndrome, systemic lupus erythema-
tosus and interstitial lung disease. Obser-
vations: We report 2 cases of autoimmune
bullous skin disease occurring in patients
undergoing TNF-targeted therapy: a bul-
lous pemphigoid and a pemphigus foliace-
us. Both patients were treated by anti-TNF
agents for rheumatoid arthritis and showed
improvement following interruption of that
treatment. Here, we discuss the relationship
between anti-TNF therapy and the occur-
rence of autoimmune bullous disease. Con-
clusion: Anti-TNF agents should be consid-
ered as a potential cause of drug-induced
autoimmune bullous skin disease.
Copyright © 2010 S. Karger AG, Basel
© 2010 S. Karger AG, Basel
1018–8665/10/2213–0201$26.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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Received: April 8, 2010
DOI: 10.1159/000318008
Introduction
Pemphigus and the pemphigoid group
of diseases are distinct autoimmune con-
ditions in which autoantibodies with dif-
ferent specificities cause skin blistering by
different mechanisms [1]. Their classifica-
tion is based on the location of the blister:
intraepidermal and subepidermal.
Pemphigus is characterized by kerati-
nocyte detachment that leads to the devel-
opment of intraepidermal blisters and ero-
sions, which can become life-threatening.
The pathogenic autoantibodies recognize
desmogleins, which are members of the
desmosomal cadherin family of cell adhe-
sion molecules. Desmoglein 3 is targeted
in pemphigus vulgaris, while desmoglein
1 is targeted in pemphigus foliaceus. The
large majority of patients with pemphigus
develop the disease spontaneously; how-
ever, there is a small group of patients who
develop pemphigus after treatment with
certain medications, of which penicilla-
mine and captopril are the best document-
ed [2].
Bullous pemphigoid (BP) is a chron-
ic, autoimmune, subepidermal, blistering
skin disease that involves the mucous
membranes in about 20% of patients. Bul-
lous pemphigoid is characterized by the
presence of immunoglobulin G (IgG) au-
toantibodies specific for the hemidesmo-
Prof. Nicolas Dupin
Service de Dermatologie, Hôpital Cochin
APHP and UPRES EA 1833, Université René Descartes, Paris
89 rue D’Assas, FR–75006 Paris (France)
Tel. +33 158 411 813, Fax +33 158 411 765, E-Mail nicolas.dupin @ cch.aphp.fr
Accepted after revision: June 23, 2010
Published online: August 19, 2010
somal bullous pemphigoid antigens BP230
and collagen type XVII, previously called
BP180. The etiology for bullous pemphi-
goid is mostly idiopathic with the highest
occurrence in elderly patients; however,
some cases of bullous pemphigoid have
also been associated with drug therapy [3].
The occurrence of autoimmune bul-
lous skin disease in patients undergoing
tumor necrosis factor (TNF)-targeted
therapy has never been described. TNF- ␣
is a cytokine that plays a crucial role in
causing inflammation by means of pre-
dominantly T-cell-mediated tissue dam-
age. Inhibition of TNF- ␣ has recently
emerged as an effective therapy for treat-
ing rheumatoid arthritis (RA) [4, 5].
More than 1 million patients with this
disease have been treated with anti-TNF
agents. In 2009, Ramos-Casals et al. [6] re-
viewed 379 cases of autoimmune diseases
secondary to anti-TNF agents through a
baseline Medline search of articles pub-
lished between January 1990 and May
2008. Among those cases, there were no
reports of autoimmune bullous skin dis-
ease.
In this paper, we describe 2 cases of au-
toimmune bullous skin disease occurring
during anti-TNF therapy: one case of bul-
lous pemphigoid under adalimumab treat-
ment and one case of pemphigus foliaceus
under infliximab treatment.
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Fig. 1. Patient 1: a tense blister located on
the upper gingival mucosa.
Fig. 2. Patient 1: a crusty eroded blister on
the back, with a delicate remnant of the
blister roof at its rim.
Case Reports
Patient 1
A 71-year-old woman followed up since
2001 for erosive RA had been treated with
corticosteroids in combination with leflu-
nomide from 2001 to 2004. Then she re-
ported an important flare up that led to the
initiation of anti-TNF therapy – etaner-
cept from February to June 2005, inflix-
imab from June 2005 to April 2006 (both
discontinued due to lack of efficacy), and
then adalimumab (40 mg every 2 weeks)
from May 2006 to July 2009. Together with
anti-TNF therapy, patient 1 was also treat-
ed with azathioprine 50 mg/day from Feb-
ruary 2005 to November 2006 (discontin-
ued because of low RA activity under
adalimumab). Her history before anti-
TNF therapy did not disclose any features
of skin disorders.
In April 2009, she developed an urti-
carial eruption, which over several weeks
developed into blisters. These lesions were
pruritic. Discrete blisters arose on ery-
thematous skin and were scattered
throughout the body, including the back,
neckline, flexor forearms and lower legs
(fig.  1, 2). At this time, besides adalimu-
mab, her treatment consisted of hydroxy-
chloroquine, venlafaxine, bisoprolol, hy-
drochlorothiazide, risedronate, calcium
carbonate-vitamin D3, acetylsalicylic acid
and paracetamol.
Within a month, the oral mucous mem-
brane was also affected by irregular gingi-
val erosions. Other areas – including the
conjunctiva, labia, vagina and anus – were
not affected. Histological examination of
gingival and skin biopsies revealed a super-
ficial dermal inflammation consisting of
lymphocytes, with deposition of IgG, C3
and discrete IgA along the basement mem-
brane by direct immunofluorescence. In-
202 Dermatology 2010;221:201–205
1 2
Color version available online
Color version available online
direct immunofluorescence was per-
Color version available online
formed using the patient’s serum, docu-
menting the presence of IgG circulating
autoantibodies that target the skin base- 230 kDa
ment membrane, as deposits of IgG were
found on the epidermal side of sodium-
chloride-treated skin. Serum levels of auto- 180 kDa
antibodies against collagen type XVII were
positive by ELISA. Furthermore, immu- 160 kDa
noblotting demonstrated reactivity with
BP230 and collagen type XVII, according
to the method of Batteux et al. [7]. This
method used an extract of keratinocytes
cultured according to the method of Green
et al. [8]. No band related to the presence of
anti-laminin 332 autoantibodies (a reliable 1 2
marker for patients with antiepiligrin cica- Patient No.
tricial pemphigoid) [9]. More precisely, no
bands corresponding to the unprocessed
and the processed (200 and 165 kDa, re- Fig. 3. Detection of anti-BP Ag1, anti-BP
spectively) ␣3 subunits, the unprocessed Ag2 and anti-Dsg1 antibodies in patients’
and the processed ␥2 subunits (150 and 105 sera by Western blot analysis on keratino-
kDa, respectively) and the ␤3 subunit (140 cyte extracts.
kDa) of laminin 332 were detected (fig. 3).
In the absence of another known cause,
we suspected bullous pemphigoid, possi-
bly induced by anti-TNF treatment. Curi-
ously for bullous pemphigoid, the periph- Patient 2
eral blood smear did not find hypereosino- A 62-year-old man, who had had RA
philia. The diagnosis appeared to us, more since 1991, was treated by corticosteroids
exactly, as an intermediate form between in combination with Allochrysine from
bullous pemphigoid and cicatricial pem- 1991 to 1992 (discontinued because of pro-
phigoid, showing some clinical and bio- teinuria), methotrexate from 1992 to 1996
logical features from both diseases. (discontinued because of adverse effects
The initiation of treatment with topical such as nausea and somnolence), and sala-
corticosteroids, together with the inter- zopyrine together with leflunomide from
ruption of adalimumab treatment in July 1996 to 2003. Because of an important
2009, led to rapid blister healing on the flare-up occurring in April 2003, the dose
skin, with erythematous atrophic scars of corticosteroids was increased. Salazo-
and milia. However, because of the persis- pyrine and leflunomide were replaced by
tence of gingival erosions which resembled azathioprine (150 mg/day) in combination
those found in cicatricial pemphigoid, she with anti-TNF therapy such as infliximab
was treated with dapsone 75 mg/day in within conventional doses (3 mg/kg) in
September 2009. July 2003. Similarly to patient 1, before
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Fig. 4. Patient 2: widespread blisters, ero-
sions and crusts on the upper trunk.
Fig. 5. Patient 2: closer view of an eroded
blister of the trunk located on an erythem-
atous base.
anti-TNF therapy, the medical history of
patient 2 failed to disclose any features of
skin disorders.
Patient 2 was diagnosed with pemphi-
gus foliaceus in June 2004, after 7 inflix-
imab infusions, on the basis of the fol-
lowing data: presence of recurrent blis-
ter formation, erosions and crust on the
trunk and legs since April 2004 (fig. 4, 5);
presence of the Nikolsky sign; histologi-
cal detection of intraepidermal blister-
ing; positive direct immunofluorescence
and indirect immunofluorescence. Direct
immunofluorescence demonstrated inter-
cellular substance deposition of IgG in
combination with C3 and C1q. Serum lev-
els of autoantibodies against desmoglein 1
were positive by ELISA. A Western blot as-
say was also performed using the same
method as described in patient 1 (fig. 3) [9].
At the time of diagnosis, the serum of pa-
tient 2 only demonstrated binding to a
160-kDa protein (desmoglein 1). This is
typically observed in pemphigus foliaceus.
At this time, besides infliximab and aza-
thioprine, his treatment consisted of pred-
nisone (9 mg/day), calcium carbonate-vi-
tamin D3, omeprazole, fluindione (for a
mechanical prosthetic heart valve), ginkgo
biloba and loratadine.
The use of topical corticosteroids such
as clobetasol propionate 0.5%, together
with infliximab treatment interruption af-
ter the last infusion in April 2004, led to a
dramatic reduction in the severity of the
pemphigus. Serum levels of autoantibodies
against desmoglein 1, measured by ELISA,
decreased from 30 RU/ml in June 2004 to
11 RU/ml in November 2004 (normal ! 20
RU/ml). The patient still experienced some
mild flare-ups (1 or 2 blisters) on his chest
until November 2008, when the pemphi-
gus definitely faded, i.e. 4 years after dis-
continuation of infliximab treatment. To
Autoimmune Bullous Skin Diseases
under Anti-TNF Therapy
4 5
Color version available online
Color version available online
treat the RA, the azathioprine alone (150 An increasing number of publications
mg/day) was replaced by rituximab infu- report altered expression of numerous cy-
sions as a second-line biological treatment tokines, including TNF- ␣, in autoimmune
in April 2009. To date, since November bullous skin diseases such as bullous pem-
2008, the patient has achieved a complete phigoid [13]. Abnormal TNF- ␣ levels have
clinical remission of his pemphigus. been found in both blister fluid and serum
In the absence of another known cause, of bullous pemphigoid patients and TNF-
the diagnosis was pemphigus foliaceus ␣ serum levels correlate with disease activ-
possibly induced by anti-TNF treatment. ity in bullous pemphigoid patients [14].
Based on these data, TNF- ␣ seems to play
an important pathogenic role, at least in
Discussion bullous pemphigoid.
Autoimmune skin disease has not to
We report 2 patients who developed an our knowledge been described as a side ef-
autoimmune bullous skin disease during fect of TNF-targeted therapies and a caus-
TNF-targeted therapies for RA: patient 1 al relationship cannot formally be estab-
developed bullous pemphigoid 3 years af- lished in our case report. However, there
ter the initiation of adalimumab treat- are a growing number of reports of the de-
ment, and patient 2 was diagnosed with velopment of autoimmune processes relat-
pemphigus foliaceus occurring 9 months ed to anti-TNF agents.
after the initiation of infliximab treat- Such an immunological mechanism is
ment. Both autoimmune bullous skin dis- different from the other drug-induced
eases improved after the interruption of mechanisms known to trigger pemphigus
the anti-TNF treatment. or bullous pemphigoid [15, 16]. In 2004,
However, there are two confounding Baroni et al. [17] demonstrated that capto-
factors that might have helped obtaining pril and pemphigus serum, acting by a bio-
such clinical improvement: First, both of chemical and immunological mechanism,
our patients were treated with potent topi- respectively, trigger apoptosis in keratino-
cal corticosteroids in addition to stopping cytes, with induction of the iNOS gene and
anti-TNF-therapy. In bullous pemphigoid, hsp70 in the cascade of events leading to
the French study group on autoimmune programmed cell death. Anti-TNF agents
bullous disorders showed that treatment may trigger autoimmune bullous diseases
with topical steroids is sufficient to induce in a different manner, probably using the
clinical remission [10, 11]. Therefore, it is same pathway that is involved in other
not possible to rule out that topical treat- types of autoimmune diseases secondary
ment was crucial for the induction of clin- to anti-TNF agents, such as lupus-like syn-
ical remission at least in patient 1. Second, drome, interstitial lung disease, anti-phos-
the long-term remission in patient 2 might pholipid syndrome, inflammatory myopa-
not only be explained by the termination thies, autoimmune hepatitis and thyroid-
of anti-TNF-therapy, as in April 2009 the itis [6].
patient received anti-CD20 antibody treat- The mechanism of this effect of TNF-
ment, which has been demonstrated to be blocking agents is not well understood, but
a very potent therapy in recalcitrant pem- modulation of the homing of Th1 and Th2
phigus [12]. cells may explain the induction of autoim-
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mune disease [18]. The inhibitory proper-
ties of TNF-targeted therapies suggest that
the immunological state of the treated pa-
tients shifts from Th1 to Th2 dominance,
which is known to be involved in autoim-
mune bullous skin disease such as bullous
pemphigoid [19, 20] or pemphigus [21].
Interestingly, several case reports have
shown that anti-TNF agents can also be an
effective treatment for recalcitrant bullous
pemphigoid [22], pemphigus [21] and even
atopic dermatitis [23], which are all con-
sidered as mainly Th2-driven. Anti-TNF
therapy is also currently employed in a
controlled prospective trial for autoim-
mune pemphigus.
As a matter of fact, anti-TNF agents do
not always act as a simple Th1 inhibitor. In
2007, Liu et al. [24] reported that TNF-
alpha has a critical role in the Th1/Th2
switch mediated by eosinophils. Eosino-
phils cultured with TNF- ␣ plus IL-4 had
increased mRNA expression and protein
secretion of Th2 chemokines, CCL17 (thy-
mus and activation-regulated chemokine)
and CCL22 (macrophage-derived chemo-
kine). Conversely, the Th1 chemokines,
CXCL9 (monokine induced by IFN-␥)
and CXCL10 (IFN-␥-inducible protein-
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