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Drug-induced pemphigus
Drug-induced pemphigus
Clinical features Pemphigus may be related to a wide range of drugs, either directly as a causative factor or indirectly as a precipitating or triggering factor.1โ15 The range of drugs is quite wide but many belong to the thiol group of compounds (characterized by the presence of an -SH group) including penicillamine, captopril, bucillamine, and thiopronine.1,4,15 Thiol-induced acantholysis is mediated by both immune and direct biochemical mechanisms.5 Penicillamine most often induces pemphigus in the setting of rheumatoid arthritis.6 Although foliaceus is most commonly encountered, vulgaris, erythematosus, and herpetiform variants may occur.2,6โ8,15 Other drugs that contain sulfur, which can also form -SH groups, include gold compounds, penicillins, rifampicin, and cephalosporins.4 Topical application of imiquimod has been reported to cause pemphigus foliaceus and vegetans.16โ18 Additionally, both pemphigus foliaceus and vulgaris lesions have been described as a consequence of radiotherapy.19โ22 Clinically, drug-induced pemphigus can resemble vulgaris, foliaceus, erythematosus, and vegetans variants, the first being most often encountered.4 In the older literature, foliaceus variants were typical but with a change in prescribing habits to non-thiol-related drugs, vulgaris-type cases are more frequently seen.4 In most cases of imiquimod-induced pemphigus foliaceus, disease is localized to the sites of application, although there is one report of both localized and distant lesions.17 In the setting of radiotherapy, all patients developed pemphigus at the site of radiation.19โ24 One patient also had distant lesions.25
penicillins, phenacetin, sulfasalazine, spironolactone, enoxaparin, dipeptidyl peptidase IV inhibitors, metronidazole, mammalian target of rapamycin (mTOR) inhibitors, and levofloxacin have been incriminated in alleged drug-induced bullous and mucosal pemphigoid.1โ19 Of these, antirheumatics, cardiovascular drugs, and antimicrobial drugs are the most important.6 Penicillamine is among the most commonly incriminated (mucosal more than bullous), usually in rheumatoid arthritis patients.6,20โ21 Furosemide (frusemide) is believed to be an important cause of drug-induced bullous pemphigoid, although recently this has been challenged, with the author suggesting that diagnoses of pseudoporphyria or epidermolysis bullosa acquisita may be more appropriate.6,22,23 The ACE inhibitors, captopril and enalapril, have both been associated with immunologically proven bullous pemphigoid.2,8
The penicillins including amoxicillin and procaine penicillin G are the most frequently implicated antibiotics.6
Clinically, drug-induced bullous pemphigoid is similar to idiopathic disease although the lesions are often polymorphic, mimicking other drug-induced bullous dermatoses such as EM, eczematous dermatitis, and porphyria cutanea tarda.6 In drug-induced disease, mucous membranes are often involved, thereby blurring the distinction between bullous and mucosal variants of pemphigoid. In some patients, there appears to be overlap between bullous pemphigoid and pemphigus vulgaris.6
Histologic features Drug-induced variants are characterized by linear IgG and C3 along the basement membrane region on direct immunofluorescence.7,8 By indirect immunofluorescence, the antibodies bind to the epidermal side (roof) of split skin.2,5,6 Western immunoblotting has demonstrated that the antibodies react with both the 230- and 180-kD bullous pemphigoid antigens.2,3
Pathogenesis and histologic features Histologically, drug-induced and idiopathic variants are indistinguishable.26 Intercellular IgG and circulating antibodies are variable in drug-induced pemphigus, although in a series of 10 patients all had positive direct immunofluorescence and 80% had circulating antibodies.4 Such antibodies may recognize desmoglein 3 and/or 1.1,25