AUTHOR INFORMATION

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Authored by Diane M Scott, MD, Dermatologist and Dermatopathologist, Palm Beach Dermatology

Coauthored by Daniel Davis, MD, Associate Professor, Departments of Dermatology, Otolaryngology, and Pathology, University of Arkansas for Medical Sciences; Kimberly I Soderberg, MD, Staff Physician, Department of Dermatology, University of Arkansas for Medical Sciences

Diane M Scott, MD, is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Florida Medical Association

Edited by David Woodley, MD, Co-Chair, Professor, Department of Medicine, Division of Dermatology, University of Southern California; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Jeffrey J Miller, MD, Associate Professor, Department of Dermatology, Penn State University, Milton S Hershey Medical Center; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; and Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center

Author's Email:	Diane M Scott, MD
Editor's Email:	David Woodley, MD

eMedicine Journal, February 12 2007, VOLUME 8, Number 2

INTRODUCTION

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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, Lin et al postulate the generation of antibodies to desmoglein 1.

Frequency:

• Internationally: 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

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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

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Pemphigus Erythematosus
Pemphigus Foliaceus
Pemphigus Herpetiformis
Pemphigus Vulgaris
Pemphigus, Paraneoplastic

WORKUP

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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.

TREATMENT

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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

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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 Name	Prednisone (Deltasone) -- 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.
Adult Dose	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 Dose	4-5 mg/m2/d PO or 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; when used with digoxin, digitalis toxicity secondary to hypokalemia may increase; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; adverse effects include weight gain, cushingoid appearance, osteoporosis, avascular necrosis, increase risk of infection, peptic ulcer disease, posterior subcapsular cataract formation, psychosis, agitation, insomnia, depression, hypertension, and skin changes including atrophy, acneiform eruption, striae, poor wound healing, and hirsutism

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.

Drug Name	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.
Adult Dose	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 Dose	Initial dose: 2-5 mg/kg/d PO/IV Maintenance dose: 1-2 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity; low levels of serum TPMT; pregnancy, breastfeeding
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; angiotensin-converting enzyme inhibitors, warfarin, may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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.
Adult Dose	1-2 mg/kg/d PO; alternatively, 2.5-3 mg/kg/d PO qid; intermittent IV pulse also has been used
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function; pregnancy; breastfeeding
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects of cyclophosphamide; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life of cyclophosphamide, while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Hematologic myelosuppression, primarily leukopenia, thrombocytopenia, anemia, gastrointestinal adverse effects, urologic adverse effects, and hemorrhagic cystitis may occur; encourage fluid intake; 45-fold increase in bladder cancer exists; interferes with oogenesis and spermatogenesis; may cause sterility in both sexes but may be irreversible in some patients; may increase risk of malignancy and increased risk of infections

FOLLOW-UP

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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 National Pemphigus 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

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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.

TEST QUESTIONS

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CME Question 1: Thiol drugs are postulated to induce pemphigus via which of the following mechanisms?

A: Interference with keratinocyte transglutaminase
B: Stimulation of proteolytic enzymes
C: Formation of a neoantigen
D: All of the above
E: None of the above

The correct answer is D: Thiol drugs are postulated to induce acantholysis directly by interference with keratinocyte transglutaminase, by activation of proteolytic enzymes, and by interference with the function of the pemphigus antigens. Thiol drugs also may induce antibody production by the formation of neoantigens.

CME Question 2: Pemphigus induced by which of the following drugs is most likely to regress rapidly after the medication is discontinued?

A: Penicillin
B: Cefazolin
C: Levodopa
D: Phenylbutazone
E: Penicillamine

The correct answer is E: Patients with pemphigus induced by thiol drugs (eg, penicillamine) are more likely to experience remission of the disease after withdrawal of the medication.

Pearl Question 1 (T/F): Penicillamine is the most frequently reported cause of drug-induced pemphigus.

The correct answer is True: Penicillamine is the most frequently reported cause. Nearly 100 cases of penicillamine-induced pemphigus have been reported.

Pearl Question 2 (T/F): Clinically, the lesions of non-thiol–induced pemphigus most closely resemble pemphigus vulgaris.

The correct answer is True: They resemble pemphigus vulgaris. Flaccid bullae, skin erosions, and oral erosions usually are seen in pemphigus induced by nonthiol drugs.

Pearl Question 3 (T/F): Direct immunofluorescence findings are negative in patients with drug-induced pemphigus.

The correct answer is False: Direct immunofluorescence findings are positive in 90% of patients with drug-induced pemphigus.

Pearl Question 4 (T/F): A skin biopsy is useful to distinguish drug-induced pemphigus from idiopathic pemphigus.

The correct answer is False: The histologic features of drug-induced pemphigus and idiopathic pemphigus are similar.

BIBLIOGRAPHY

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• Anadolu RY, Birol A, Bostanci S, Boyvatt A: A case of pemphigus vulgaris possibly triggered by quinolones. J Eur Acad Dermatol Venereol 2002 Mar; 16(2): 152-3[Medline].
• Anhalt GJ: Drug-induced pemphigus. Semin Dermatol 1989 Sep; 8(3): 166-72[Medline].
• Brenner S, Wolf R, Ruocco V: Drug-induced pemphigus. I. A survey. Clin Dermatol 1993 Oct-Dec; 11(4): 501-5[Medline].
• Brenner S, Bialy-Golan A, Ruocco V: Drug-induced pemphigus. Clin Dermatol 1998 May-Jun; 16(3): 393-7[Medline].
• Brenner S, Bialy-Golan A, Anhalt GJ: Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 1997 Jun; 36(6 Pt 1): 919-23[Medline].
• Goldberg I, Sasson A, Gat A: Pemphigus vulgaris triggered by glibenclamide and cilazapril. . Acta Dermatovererol Croat. 2005; 13(3): 153-3[Medline].
• Grando SA: Cholinergic control of epidermal cohesion. Exp Dermatol 2006 Apr; 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 2006 Jun; 21(3): 585-7[Medline].
• Landau M, Brenner S: Histopathologic findings in drug-induced pemphigus. Am J Dermatopathol 1997 Aug; 19(4): 411-4[Medline].
• Lin R, Ladd DJ, Powell DJ, Way BV: Localized pemphigus foliaceus induced by topical imiquimod treatment. Arch Dermatol 2004 Jul; 140(7): 889-90[Medline].
• Mutasim DF, Pelc NJ, Anhalt GJ: Drug-induced pemphigus. Dermatol Clin 1993 Jul; 11(3): 463-71[Medline].
• Nagao K, Tankiawa A, Yamamoto N: Decline of anti-desmoglein 1 IgG ELISA scores by withdrawal of D-penicillamine in drug-induced pemphigus foliaceus. Clin Exp Dermatol 2005; 30: 43-5[Medline].
• Nguyen VT, Arredondo J, Chernyavsky AI, et al: Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J Biol Chem 2004 Jan 16; 279(3): 2135-46[Medline].
• Patterson CR, Davies MG: Carbamazepine-induced pemphigus. Clin Exp Dermatol 2003 Jan; 28(1): 98-9[Medline].
• Patterson CR, Davies MG: Pemphigus foliaceus: an adverse reaction to lisinopril. J Dermatolog Treat 2004 Jan; 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 1989 May 15; 63(10): 2005-7[Medline].
• Ruocco V, De Angelis E, Lombardi ML: Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 1993 Oct-Dec; 11(4): 507-13[Medline].
• Uzun S, Durdu M, Akman A, et al: Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol 2006 May; 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].

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