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Drug-Induced Pemphigus

  • Author: Diane M Scott, MD; Chief Editor: Dirk M Elston, MD  more...
Updated: Oct 30, 2014


Drug-induced pemphigus is a well-established variant of pemphigus. 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.

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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.[1, 2]

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. 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.[3, 4]

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, and piroxicam, may undergo hydrolytic breakdown in vivo to form thiols; therefore, they are termed masked thiols. 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.[5]

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.[6]

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.


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.[7]

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.


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.


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).


Drug-induced pemphigus can occur at any age. In reported cases, patient age has ranged from the third to ninth decade.

Contributor Information and Disclosures

Diane M Scott, MD Dermatologist, Arch Health Partners

Diane M Scott, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.


Daniel Davis, MD Associate Professor, Departments of Dermatology, Otolaryngology, and Pathology, University of Arkansas for Medical Science

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

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

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

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

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

David Timothy Woodley, MD Professor and Chair, Department of Dermatology, Keck School of Medicine of the University of Southern California

David Timothy Woodley, MD is a member of the following medical societies: American Academy of Dermatology, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Physicians, American Federation for Medical Research, American Society for Clinical Investigation, New York Academy of Medicine, Society for Investigative Dermatology, Southern Medical Association

Disclosure: Received consulting fee from Shire Pharmaceuticals for consulting.


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

Disclosure: Nothing to disclose.

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Early small blister filled with clear fluid arises on healthy skin.
Flaccid blister filled with clear fluid arises on healthy skin.
An erosion.
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