eMedicine Specialties > Dermatology > Bullous Diseases

Pemphigus, Drug-Induced

Diane M Scott, MD, Dermatologist and Dermatopathologist, Palm Beach Dermatology
Daniel Davis, MD, Associate Professor, Departments of Dermatology, Otolaryngology, and Pathology, University of Arkansas for Medical Sciences; Kimberly I Soderberg, MD, Consulting Staff, Oyster Point Dermatology

Updated: Nov 13, 2009

Introduction

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 also been described. 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.

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 2.³
• 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

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
    • Penicillamine⁴
    • Bucillamine⁵
    • Captopril
    • Lisinopril⁶
    • Pyritinol
    • Thiopronine
    • Piroxicam
    • Thiamazole
    • 5-Thiopyridoxine
    • Gold sodium thiomalate
  • Antibiotics
    • Penicillin and derivatives
    • Cephalosporins
    • Quinolones⁷
    • Rifampicin
  • Pyrazolone derivatives
    • Phenylbutazone
    • Aminopyrine
    • Azapropazone
    • Oxyphenylbutazone
  • Miscellaneous drugs
    • Propanolol
    • Levodopa
    • Heroin
    • Progesterone
    • Carbamazepine⁸
    • Phenobarbital
    • Lysine acetylsalicylate
    • Imiquimod⁹
    • Glibenclamide¹⁰
    • Cilazapril¹⁰

Differential Diagnoses

Pemphigus Erythematosus
Pemphigus Foliaceus
Pemphigus Herpetiformis
Pemphigus Vulgaris
Pemphigus, Paraneoplastic

Workup

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.¹¹
• 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.¹²

Treatment

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

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.

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.

Prednisone (Deltasone, Orasone, Sterapred)

Initial DOC for severe or recalcitrant cases of drug-induced pemphigus. Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Up-regulates keratinocyte adhesion molecules desmoglein 1 and 3.

Dosing

Adult

0.5-2 mg/kg/d PO; high doses (eg, 150-200 mg/d PO) may be needed; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect

Pediatric

4-5 mg/m²/d PO or 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; coadministration with ritonavir may significantly increase serum concentrations of prednisone; concomitant therapy with montelukast may result in severe peripheral edema; clarithromycin may increase risk of psychotic symptoms
Postmarketing surveillance reports indicate that risk of tendon rupture may be increased in patients receiving concomitant fluoroquinolones and corticosteroids, especially elderly patients; administration of asparaginase concurrently with or before prednisone therapy may result in increased toxicity

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May unmask hypertension or diabetes or exacerbate peptic ulcer disease and tuberculosis; long-term sequelae associated with long-term steroid use include osteoporosis, cataracts, and pituitary-hypothalamic axis suppression; with high doses, patients may develop a steroid psychosis and are at increased risk of infections, particularly when oral steroids are used in conjunction with other immunosuppressants; frequently monitor patient's blood sugar level, blood pressure, and weight; monitor for Cushing syndrome

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.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Useful in steroid-resistant patients. Less toxic than some other immunosuppressants. Generally, used in conjunction with low doses of systemic corticosteroids.
Prior measurement of thiopurine methyltransferase (TPMT) levels can be useful in guiding initial dose.

Dosing

Adult

1-3 mg/kg/d PO/IV; alternatively, 1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d

Pediatric

Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine; coadministration with mycophenolate may increase toxicity; alfalfa, black Cohosh, and echinacea may reduce immunosuppressive drug effectiveness

Contraindications

Documented hypersensitivity; deficiency of thiopurine methyltransferase (can result in severe myelosuppression and leukopenia); history of treatment with alkylating agents

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause leukopenia, thrombocytopenia, hemorrhagic cystitis, liver toxicity, nausea and vomiting, and increased risk of infection; increases risk of neoplasia; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated; hepatotoxicity and pancreatitis may occur; hepatotoxicity and pancreatitis reported

Cyclophosphamide (Cytoxan, Neosar)

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. Effective in treating pemphigus; however, this drug also is very toxic.

Dosing

Adult

1-2 mg/kg/d PO; alternatively, 2.5-3 mg/kg/d PO qid; intermittent IV pulse also has been used

Pediatric

Administer as in adults

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; concurrent use of NSAIDs has resulted in increases in cyclosporine levels, nephrotoxicity, and increased plasma creatinine concentrations
Concomitant use of ACE inhibitors may decrease renal function; coadministration with nevirapine and St. John's wort may reduce immunosuppressive drug effectiveness
Increased risk of infection by live vaccine; coadministration with trastuzumab may increase cardiac toxicity; coadministration with tamoxifen may increase risk of thromboembolism

Contraindications

Documented hypersensitivity; severely depressed bone marrow function; pregnancy; breastfeeding

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; adverse effects include oligospermia or azoospermia, cardiomyopathy, infectious disease, interstitial pneumonia, increase risk of malignancy, possibility of increased toxicity in adrenalectomized patients

Follow-up

Complications

• 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.

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

Medicolegal 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

1. 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].

2. 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].

3. 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].

4. 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].

5. 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].

6. Patterson CR, Davies MG. Pemphigus foliaceus: an adverse reaction to lisinopril. J Dermatolog Treat. Jan 2004;15(1):60-2. [Medline].

7. 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].

8. Patterson CR, Davies MG. Carbamazepine-induced pemphigus. Clin Exp Dermatol. Jan 2003;28(1):98-9. [Medline].

9. Lin R, Ladd DJ Jr, Powell DJ, Way BV. Localized pemphigus foliaceus induced by topical imiquimod treatment. Arch Dermatol. Jul 2004;140(7):889-90. [Medline].

10. Azad Khan AK, Johnston HH, Truelove SC. Proceedings: Bacterial breakdown of sulphasalazine (salazopyrin). Gut. Oct 1975;16(10):832. [Medline].

11. Maruani A, Machet MC, Carlotti A, Giraudeau B, Vaillant L, Machet L. Immunostaining with antibodies to desmoglein provides the diagnosis of drug-induced pemphigus and allows prediction of outcome. Am J Clin Pathol. Sep 2008;130(3):369-74. [Medline].

12. Landau M, Brenner S. Histopathologic findings in drug-induced pemphigus. Am J Dermatopathol. Aug 1997;19(4):411-4. [Medline].

13. Anhalt GJ. Drug-induced pemphigus. Semin Dermatol. Sep 1989;8(3):166-72. [Medline].

14. Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol. May-Jun 1998;16(3):393-7. [Medline].

15. Brenner S, Wolf R, Ruocco V. Drug-induced pemphigus. I. A survey. Clin Dermatol. Oct-Dec 1993;11(4):501-5. [Medline].

16. Grando SA. Cholinergic control of epidermal cohesion. Exp Dermatol. Apr 2006;15(4):265-82. [Medline].

17. Mutasim DF, Pelc NJ, Anhalt GJ. Drug-induced pemphigus. Dermatol Clin. Jul 1993;11(3):463-71. [Medline].

18. 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].

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Keywords

pemphigus, drug-induced pemphigus, antibiotic-induced pemphigus, medication-induced pemphigus, thiol-induced pemphigus, pyrazolone-induced pemphigus

Contributor Information and Disclosures

Author

Diane M Scott, MD, Dermatologist and Dermatopathologist, Palm Beach Dermatology
Diane M Scott, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Coauthor(s)

Daniel Davis, MD, Associate Professor, Departments of Dermatology, Otolaryngology, and Pathology, University of Arkansas for Medical Sciences
Disclosure: Nothing to disclose.

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.

Medical Editor

David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California
David 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, and Southern Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn 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, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

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