Introduction
Up to 20% of cases of bullous pemphigoid (BP) show an atypical presentation, exhibiting
localized distribution or non-bullous lesions, such as eczematous, urticarial, prurigolike,
and erythema multiformelike papules and plaques.
1
These atypical presentations can be associated with a delay in diagnosis and thus
require a high degree of suspicion. We present a case of recalcitrant BP localized
to the anogenital region with subsequent generalization after administration of etanercept,
a tumor necrosis factor–alpha (TNF-α) inhibitor. Our review of bibliographic databases
did not find any cases with similar distribution and course. TNF-α inhibitors are
used in the treatment of pemphigus and pemphigoid. With expanding use of TNF-α inhibitors
and longer follow-up periods, there are increasing reports of autoimmune diseases
associated with these therapies, including autoimmune bullous disease and systemic
lupus erythematosus.
2
This case highlights that caution should be exercised when considering anti–TNF-α
therapy for autoimmune bullous diseases.
Case report
A 79-year-old white woman with a history of psoriasis and diabetes type 2 presented
with recalcitrant, perianal/perineal, and perivaginal inflammatory erosions that were
unresponsive to potent topical corticosteroids (Fig 1). Biopsy found lichenoid interface
dermatitis with eosinophils and a subepidermal cleft. Direct immunofluorescence results
(DIF) were negative. The histopathologic differential diagnosis included a lichenoid
hypersensitivity reaction, lichenoid contact dermatitis, and a primary immunobullous
disorder, likely BP. Laboratory testing found normal serology findings, with the exception
of mild eosinophilia (0.67 K/μL; normal, <0.45 K/μL), and a normal urinalysis result. The
eruption did not respond to courses of hydroxychloroquine, mycophenolate mofetil,
and oral antibiotics or narrowband ultraviolet light B and aminolevulinic acid photodynamic
therapy. Oral corticosteroid tapers provided only temporary benefit, and diabetes
was a contraindication to longer systemic steroid treatment.
Lesions remained relatively stable for 16 months, and at that time etanercept was
administered for a psoriasis flare. Within 3 days of starting etanercept, the patient
had generalized, pruritic, urticarial, and bullous lesions (Fig 2). Biopsy of a bullous
lesion on the left upper thigh found a subepidermal blister with eosinophils (Fig
3). DIF of perilesional skin of both the right arm and perianal area found linear
C3 and IgG at the dermal–epidermal junction (Fig 4). There was no IgA or IgM deposition.
A salt-split skin immunofluorescence study on the perianal specimen found IgG and
C3 localized to the blister roof, confirming the diagnosis of BP and ruling out epidermolysis
bullosa acquisita. The patient was treated successfully with dapsone, with new bulla
formation ceasing 3 weeks into dapsone treatment at 100 mg/d. The lesions and pruritus
further improved at a dapsone dose of 150 mg/d.
Discussion
Localized BP is uncommon and requires a high index of suspicion.
1
There are rare reports of pediatric genital BP and 1 report of perineal/perianal BP
in an adult.3, 4 Adult BP localized to both perianal/perineal and perivaginal areas,
such as that seen in our patient, is an exceedingly rare presentation. The differential
diagnosis of BP localized to the genital and perianal area includes lichen sclerosus
et atrophicus, irritant dermatitis, intertrigo, bullous lichen planus, and immunobullous
diseases, such as pemphigus vulgaris and epidermolysis bullosa acquisita. The clinical
course, histology, and immunofluorescence studies help differentiate among these entities.
In this case, the original DIF result of the perianal eruption was negative, possibly
because of concomitant use of topical corticosteroids. Repeat DIF after a period of
nonsteroid use is indicated if BP is suspected and the initial DIF result is negative.
TNF-α inhibitors have been used for the treatment of autoimmune bullous diseases;
however, there are rare reports of paradoxical development of pemphigus and BP during
anti–TNF-α therapy.5, 6, 7, 8, 9, 10 In each of these cases, BP developed months to
years after initiation of TNF-α inhibitor treatment, in contrast to this case in which
localized BP generalized immediately after administration of an anti–TNF-α agent.
In our case, a causal relationship between etanercept and generalized BP is supported
by the onset of generalization immediately after etanercept administration and improvement
of the eruption after discontinuation of the drug. Furthermore, this finding is supported
by similar reports in the literature.5, 10 Case reports of pemphigus and BP induced
by TNF-α inhibitors indicate that patients achieved both clinical and serologic remission
after cessation of the TNF-α inhibitor. In a case of etanercept-induced BP, the presence
of circulating autoantibodies against the BP180 antigen decreased into the normal
range after removal of the offending biologic drug.
10
Similarly, Boussemart et al
8
reported a case of infliximab-associated pemphigus foliaceus with normalization of
antidesmoglein 1 autoantibodies after cessation of infliximab therapy. Rechallenge
in select patients resulted in re-emergence of pemphigus/pemphigoid.6, 10
The pathogenetic mechanism of TNF-α inhibitor–induced BP has yet to be deciphered,
although several hypotheses exist. TNF-α appears to play an important role in BP,
as abnormal levels of TNF-α have been identified in the serum and blister fluid of
patients, and serum TNF-α levels correlate with disease severity.
8
Liu et al
11
found that TNF-α can drive eosinophils to secrete either helper T cell (Th)1 or Th2
cytokines, depending on the chemokine profile of the microenvironment.
11
Thus, an individual's unique inflammatory state may affect the downstream consequences
of TNF-α inhibition and can explain the ability of anti-TNF agents to both treat and
promote BP. TNF-α inhibitors may also alter the regulatory T-cell function, leading
to loss of B-cell suppression and promotion of autoantibody production. Another theory
is that TNF-α inhibitors may act as haptens that alter basement membrane proteins
and render them susceptible to immune attack.
12
In this case, it is possible that exposure of the BP180 antigen or the inflammatory
microenvironment in the eroded anogenital plaques may have hastened the immune response
generated by etanercept, resulting in almost immediate generalization. Further studies
are needed to better elucidate the mechanism of action of TNF-α inhibitors and to
determine how the cytokine milieu may affect TNF-induced alterations in Th1/Th2 balance.
This case highlights that treatment with TNF-α inhibitors can be associated with generalization
of localized BP. Caution should be exercised when contemplating anti–TNF-α therapy
for the treatment of autoimmune bullous disorders. Additionally, TNF-α inhibitors
should be considered in the etiologies of autoimmune bullous disease.