AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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 been described as well. In penicillamine-treated patients, pemphigus foliaceus is more common than pemphigus vulgaris, with an approximate ratio of 4:1.

Pathophysiology

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.

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.

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.

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.

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.

Frequency

International

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/Morbidity

• 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.
• 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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• 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.

Physical

• 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.

Causes

• 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.
• Drugs implicated in drug-induced pemphigus are as follows:
• • Thiols
    • Penicillamine

    • Bucillamine

    • Captopril

    • Lisinopril

    • Pyritinol

    • Thiopronine

    • Piroxicam

    • Thiamazole

    • 5-Thiopyridoxine

    • Gold sodium thiomalate
  • Antibiotics
    • Penicillin and derivatives

    • Cephalosporins

    • Quinolones

    • Rifampicin
  • Pyrazolone derivatives
    • Phenylbutazone

    • Aminopyrine

    • Azapropazone

    • Oxyphenylbutazone
  • Miscellaneous drugs
    • Propanolol

    • Levodopa

    • Heroin

    • Progesterone

    • Carbamazepine

    • Phenobarbital

    • Lysine acetylsalicylate

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Tests

• 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. 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.
• Direct immunofluorescence: Tissue-bound intercellular immunoglobulin G antibodies are diagnostic of pemphigus and are found in most patients (75-90%) with drug-induced pemphigus.

Histologic Findings

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Withdrawal of the offending agent is the first step in treatment. 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.

Consultations

• Burn unit consultation: 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).

Diet

Mucosal lesions may be exacerbated by eating hard or crunchy foods, such as potato chips, crackers, fresh fruits, and uncooked vegetables.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

Drug Category: Corticosteroids

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.

Drug Category: Immunosuppressants

For patients who do not respond to moderate doses of systemic steroids or for patients in whom steroids are contraindicated. Also used as steroid-sparing agents.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Secondary infections may occur because of the disruption of the skin barrier. Extensive erosions may promote entrance of bacteria, resulting in cutaneous infections, bacteremia, or sepsis.

Prognosis

• 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.

Patient Education

• 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure of dermatologists and other providers to be alert to the role of drugs in causing pemphigus. Offending agents must be stopped and the patient treated appropriately.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Anadolu RY, Birol A, Bostanci S, Boyvatt A. A case of pemphigus vulgaris possibly triggered by quinolones. J Eur Acad Dermatol Venereol. Mar 2002;16(2):152-3. [Medline].
• Anhalt GJ. Drug-induced pemphigus. Semin Dermatol. Sep 1989;8(3):166-72. [Medline].
• Brenner S, Bialy-Golan A, Anhalt GJ. Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol. Jun 1997;36(6 Pt 1):919-23. [Medline].
• Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol. May-Jun 1998;16(3):393-7. [Medline].
• Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. I. A survey. Clin Dermatol. Oct-Dec 1993;11(4):501-5. [Medline].
• Goldberg I, Sasson A, Gat A. Pemphigus vulgaris triggered by glibenclamide and cilazapril. Acta Dermatovererol Croat. Oct 1975;13(3):153-3. [Medline].
• Grando SA. Cholinergic control of epidermal cohesion. Exp Dermatol. Apr 2006;15(4):265-82. [Medline].
• Hur JW, Lee CW, Yoo DH. Bucillamine-induced pemphigus vulgaris in a patient with rheumatoid arthritis and polymyositis overlap syndrome. J Korean Med Sci. Jun 2006;21(3):585-7. [Medline].
• Landau M, Brenner S. Histopathologic findings in drug-induced pemphigus. Am J Dermatopathol. Aug 1997;19(4):411-4. [Medline].
• Lin R, Ladd DJ, Powell DJ, Way BV. Localized pemphigus foliaceus induced by topical imiquimod treatment. Arch Dermatol. Jul 2004;140(7):889-90. [Medline].
• Mutasim DF, Pelc NJ, Anhalt GJ. Drug-induced pemphigus. Dermatol Clin. Jul 1993;11(3):463-71. [Medline].
• Nagao K, Tanikawa A, Yamamoto N, Amagai M. Decline of anti-desmoglein 1 IgG ELISA scores by withdrawal of D-penicillamine in drug-induced pemphigus foliaceus. Clin Exp Dermatol. Jan 2005;30(1):43-5. [Medline].
• Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y, Pittelkow M, Grando SA. Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J Biol Chem. Jan 16 2004;279(3):2135-46. [Medline].
• Patterson CR, Davies MG. Carbamazepine-induced pemphigus. Clin Exp Dermatol. Jan 2003;28(1):98-9. [Medline].
• Patterson CR, Davies MG. Pemphigus foliaceus: an adverse reaction to lisinopril. J Dermatolog Treat. Jan 2004;15(1):60-2. [Medline].
• Ramseur WL, Richards F 2nd, Duggan DB. A case of fatal pemphigus vulgaris in association with beta interferon and interleukin-2 therapy. Cancer. May 15 1989;63(10):2005-7. [Medline].
• Ruocco V, De Angelis E, Lombardi ML. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol. Oct-Dec 1993;11(4):507-13. [Medline].
• Uzun S, Durdu M, Akman A, Gunasti S, Uslular C, Memisoglu HR, et al. Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol. May 2006;45(5):523-8. [Medline].
• Wolf R, Brenner S. An active amide group in the molecule of drugs that induce pemphigus: a casual or causal relationship?. Dermatology. 1994;189(1):1-4. [Medline].

Article Last Updated: Jun 11, 2007