Pemphigus is an autoimmune bullous disease characterized by blisters and erosions of the skin and mucous membranes. Several variants of the disease exist, including pemphigus vulgaris, pemphigus foliaceous, and drug-induced pemphigus. Patients with drug-induced pemphigus have autoantibodies that are either circulating or tissue bound.[1] Since the 1950s, evidence has grown that drugs may cause or exacerbate pemphigus. A drug origin should be considered in every new patient with pemphigus. The most common variant of pemphigus associated with drug exposure is pemphigus foliaceus, although pemphigus vulgaris has also been described. In penicillamine-treated patients, pemphigus foliaceus is more common than pemphigus vulgaris, with an approximate ratio of 4:1.
Note the images below.
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Early small blister filled with clear fluid arises on healthy skin.
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Flaccid blister filled with clear fluid arises on healthy skin.
A variety of drugs have been implicated in the onset of drug-induced pemphigus. Some of these drugs induce antibody formation, which results in acantholysis via a mechanism identical to that found in idiopathic pemphigus. Other drugs are postulated to induce acantholysis directly in the absence of antibody formation.[2, 3]
Drugs that induce pemphigus may be categorized into 2 groups: thiol drugs and nonthiol drugs. Thiol drugs are reported most frequently as the culprits of drug-induced pemphigus.[4] They contain a thiol group (-SH) in their chemical structure. Penicillamine, captopril, and enalapril are the thiol drugs most often associated with drug-induced pemphigus.[5, 6]
Thiol drugs are postulated to induce acantholysis through biochemical mechanisms without antibody formation. Experiments with skin explants have demonstrated that thiol drugs can induce acantholysis directly. These investigations have resulted in several hypotheses regarding thiol-induced acantholysis, including the following:
Thiol drugs may interfere with critical enzymes, such as keratinocyte transglutaminase, resulting in loss of epidermal cell cohesion.
Thiol drugs may activate endogenous proteolytic enzymes, such as plasminogen activators, with subsequent cleavage of desmosomal antigens.
Thiol drugs may bind desmoglein 1 or desmoglein 3, creating a neoantigen, which then elicits an immune response.
Binding of the pemphigus antigens by thiol drugs may interfere with their normal function, resulting in acantholysis.
Nonthiol drugs include sulfur-containing drugs and drugs without sulfur in their structure. Sulfur-containing drugs, such as penicillins, cephalosporins, antihypertensive agents, and piroxicam, may undergo hydrolytic breakdown in vivo to form thiols; therefore, they are termed masked thiols.[4] An active amide group is found in the structure of many nonthiol drugs, which has resulted in the speculation that this structure may be responsible for the induction of disease.[7]
Nonthiol drugs are more likely to induce acantholysis via immune mechanisms. Studies of cases of non-thiol–induced pemphigus reveal the presence of autoantibodies that recognize pemphigus antigens, in particular desmoglein 3, which is the pemphigus vulgaris antigen. In fact, this group of patients tends to have clinical, histologic, immunologic, and prognostic features similar to idiopathic pemphigus vulgaris.[8]
One case report describes localized pemphigus foliaceus induced by topical imiquimod treatment. Imiquimod does not contain thiol, sulfur, or amide groups in its structure. The exact mechanism of acantholysis induction from this medication is unknown. Because imiquimod is known to cause a localized immune response at the site of application, the generation of antibodies to desmoglein 1 has been postulated as a mechanism of action.
More than 200 cases of drug-induced pemphigus have been reported, with penicillamine accounting for almost 50%. In patients who take penicillamine for longer than 6 months, it is estimated that 7% develop pemphigus.
Race
Most case series in the literature have not reported the race of patients with drug-induced pemphigus. A number of reports from Israel of drug-induced pemphigus occurring in Jewish persons of Ashkenazi origin suggest an ethnic predominance.
Sex
A recent study evaluating the epidemiology of pemphigus in the Mediterranean region of Turkey found a female predominance (male-to-female ratio, 1:1.4).
Age
Drug-induced pemphigus can occur at any age. In reported cases, patient age has ranged from the third to ninth decade.
Patients with thiol-induced pemphigus and patients lacking cell surface autoantibodies have a more favorable prognosis. Up to 50% of thiol-induced pemphigus cases remit upon withdrawal of the drug.
Patients with pemphigus induced by nonthiol drugs are more likely to have cell surface antibodies and to have a chronic course similar to idiopathic pemphigus vulgaris.
Mortality rates for drug-induced pemphigus have not been published. A fatal case of acute onset pemphigus vulgaris has been reported in a patient treated with interferon beta and recombinant interleukin 2.[9]
Significant morbidity may occur. Patients with extensive cutaneous lesions report significant pain and burning sensations. Oral involvement also causes significant pain and results in decreased oral intake. This may result in dehydration.
Educate patients about their disease and their medications, including adverse effects from therapy.
The International Pemphigus and Pemphigoid Foundation, a nonprofit support group for patients with pemphigus and their families, offers an active web site and a quarterly newsletter, as well as local chapters in many parts of the country.
Most patients develop the eruption a few weeks after starting therapy with the offending agent. In penicillamine use, the eruption may not develop until 6 months after the onset of therapy. Some patients may give a history of a nonspecific eruption prior to the development of pemphigus type lesions.
Clinical manifestations of drug-induced pemphigus depend on the pathomechanism involved.
Disease caused by thiol drugs tends to present with the clinical findings of pemphigus foliaceus. Erythematous, scaly, crusted plaques occur primarily on the trunk. Occasional superficial vesicles and bullae may be seen, but usually, they are ruptured. Oral lesions do not occur.
Nonthiol drug-induced pemphigus presents predominantly as pemphigus vulgaris. Flaccid bullae and erosions occur on normal-appearing skin and, also, on the oral mucosa.[17]
Speculation exists that genetic predisposition may be important in non-thiol–triggered pemphigus. Human leukocyte antigen DR4 (HLA-DR4) is associated with idiopathic pemphigus; however, few studies have provided data concerning HLA typing in cases of drug-induced pemphigus.
Thiols implicated in drug-induced pemphigus are as follows:
Penicillamine[10]
Bucillamine[11]
Captopril
Lisinopril[12]
Pyritinol
Thiopronine
Piroxicam
Thiamazole
5-Thiopyridoxine
Gold sodium thiomalat
Antibiotics implicated in drug-induced pemphigus are as follows:
Penicillin and derivatives
Cephalosporins
Quinolones[13]
Rifampicin
Pyrazolone derivatives implicated in drug-induced pemphigus are as follows:
Phenylbutazone
Aminopyrine
Azapropazone
Oxyphenylbutazone
Miscellaneous drugs implicated in drug-induced pemphigus are as follows:
Secondary infections may occur in drug-induced pemphigus because of the disruption of the skin barrier. Extensive erosions may promote entrance of bacteria, resulting in cutaneous infections, bacteremia, or sepsis.
The interferon-gamma release test has been used in the diagnosis of drug-induced pemphigus. Initially, the patient is either exposed or not exposed to the drug; following exposure, the release of interferon-gamma from the patient’s lymphocytes is assessed with the use of an enzyme-linked immunosorbent assay (ELISA). The interferon-gamma release test allows for the identification of the specific drug that may be inducing pemphigus in the patient. The culprit drug is identified and can then be discontinued.[18]
Indirect immunofluorescence
Circulating autoantibodies are present in approximately 70% of patients with drug-induced pemphigus. When positive, indirect immunofluorescence findings usually reveal low titers of antibodies, which do not correlate with the severity of the disease. These antibodies recognize the pemphigus foliaceus antigen (desmoglein 1), pemphigus vulgaris antigen (desmoglein 3), or both. In drug-induced pemphigus, the presence of antibodies to desmoglein are diagnostic and allow prediction of outcome.[1] Circulating autoantibodies have been demonstrated to be more likely to occur in patients with non–thiol-induced pemphigus. In this group, the immunologic pattern and clinical course are similar to that of idiopathic pemphigus vulgaris.[19]
Direct immunofluorescence
Tissue-bound intercellular immunoglobulin G antibodies are diagnostic of pemphigus and are found in most patients (75-90%) with drug-induced pemphigus. A normal staining pattern of antidesmoglein 32-2B is an indicator for a good prognosis in drug-induced pemphigus. This can be used as a diagnostic tool in which studies have shown to have a 70.3% sensitivity and 83.9% specificity in confirming a diagnosis of drug-induced pemphigus.[20]
Histologic features of established lesions correlate with the clinical appearance. Lesions resembling pemphigus foliaceus reveal superficial epidermal acantholysis, while those resembling pemphigus vulgaris reveal suprabasal acantholysis. Eosinophilic spongiosis may be present. It is not possible to distinguish between idiopathic and drug-induced pemphigus based on histologic features.[21]
Withdrawal of the offending agent is the first step in treatment. In addition, use of steroids (prednisolone) has shown to be an effective treatment for drug-induced pemphigus.[18] Most, but not all, patients go into remission once the offending agent is stopped. Some patients may follow a chronic course identical to that of idiopathic pemphigus vulgaris. These patients require systemic corticosteroids and/or immunosuppressive therapy.[22]
For patients who have erosions involving a significant portion of the body surface area, the burn unit is helpful in providing wound care (cleansing, application of topical antibiotics, and bandaging).
Mucosal lesions may be exacerbated by eating hard or crunchy foods, such as potato chips, crackers, fresh fruits, and uncooked vegetables.
Certain foods that contain thiols and phenols should also be considered as inducers of pemphigus. Thiol-containing foods include garlic, chives, and onion; phenol-containing foods include mango, cashew, and black pepper. Foods containing these chemical properties are heavily consumed in India, thus suggesting an explanation for the higher prevalence and earlier onset of pemphigus in that country.[23]
For patients in whom the disease does not resolve upon withdrawal of the offending agent, medical therapy is necessary. Generally, systemic corticosteroids or other immunosuppressants are required. Anecdotal reports support the use of alternate immunomodulating agents (eg, antimalarial drugs, rituximab, intravenous immunoglobulin, mycophenolate mofetil). Recent reports suggest targeting cholinergic drugs as antiacantholytic therapy for idiopathic pemphigus.
Clinical Context:
Prednisone is the initial drug of choice for severe or recalcitrant cases of drug-induced pemphigus. It is an immunosuppressant for the treatment of autoimmune disorders, and it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. It up-regulates keratinocyte adhesion molecules desmoglein 1 and 3.
Systemic corticosteroids (eg, prednisone) should be initiated in patients with disease that persists after the implicated agent has been discontinued. Since most cases of drug-induced pemphigus involve an immune mechanism, the anti-inflammatory and immune modulating properties of corticosteroids are beneficial. In idiopathic pemphigus vulgaris and pemphigus foliaceus, high doses of systemic corticosteroids may be needed. This also may be necessary for cases of drug-induced pemphigus.
Clinical Context:
Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity. Azathioprine is useful in steroid-resistant patients. It is less toxic than some other immunosuppressants. Generally, it is used in conjunction with low doses of systemic corticosteroids.
Prior measurement of thiopurine methyltransferase (TPMT) levels can be useful in guiding the initial dose.
Clinical Context:
Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Cyclophosphamide is effective in treating pemphigus; however, this drug also is very toxic.
Immunosuppressants are for patients who do not respond to moderate doses of systemic steroids or for patients in whom steroids are contraindicated. They also are used as steroid-sparing agents.
Chris G Adigun, MD, FAAD, Director and Physician, Dermatology and Laser Center of Chapel Hill; Senior Medical Advisor, Klara
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Celgene; Cipher; Sciton; Lumenis.
Coauthor(s)
Omobola Onikoyi, DO, MSc, American Osteopathic Association (AOA) Internship, Manchester Memorial Hospital, Eastern Connecticut Health Network
Disclosure: Nothing to disclose.
Specialty Editors
Michael J Wells, MD, FAAD, Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD, Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Daniel Davis, MD, Associate Professor, Departments of Dermatology, Otolaryngology, and Pathology, University of Arkansas for Medical Science
Disclosure: Nothing to disclose.
David Timothy Woodley, MD, Professor and Chair, Department of Dermatology, Keck School of Medicine of the University of Southern California
Disclosure: Received consulting fee from Shire Pharmaceuticals for consulting.
Diane M Scott, MD, Dermatologist, Arch Health Partners
Disclosure: Nothing to disclose.
Acknowledgements
Kimberly I Soderberg, MD Consulting Staff, Oyster Point Dermatology
Kimberly I Soderberg, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Arkansas Medical Society, and Women's Dermatologic Society
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