Drug-Induced Pemphigus

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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.

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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. ^{[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.

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.

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.

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Feng S, Zhou W, Zhang J, Jin P. Analysis of 6 cases of drug-induced pemphigus. Eur J Dermatol. 2011 Sep-Oct. 21(5):696-9. [Medline].

Brenner S, Goldberg I. Drug-induced pemphigus. Clin Dermatol. 2011 Jul-Aug. 29(4):455-7. [Medline].

Pietkiewicz P, Gornowicz-Porowska J, Bowszyc-Dmochowska M, Dmochowski M. A retrospective study of antihypertensives in pemphigus: a still unchartered odyssey particularly between thiols, amides and phenols. Arch Med Sci. 2015 Oct 12. 11 (5):1021-7. [Medline].

Yoshimura K, Ishii N, Hamada T, Abe T, Ono F, Hashikawa K, et al. Clinical and immunological profiles in 17 Japanese patients with drug-induced pemphigus studied at Kurume University. Br J Dermatol. 2014 Sep. 171(3):544-53. [Medline].

Khashoggi M, Machet L, Perrinaud A, Brive D, Machet MC, Maruani A, et al. [D-penicillamine-induced pemphigus: changes in anti-32-2B immunostaining patterns]. Ann Dermatol Venereol. 2013 Aug-Sep. 140(8-9):531-4. [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].

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].

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].

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. 2005 Jan. 30(1):43-5. [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]. [Full Text].

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

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].

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

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

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

Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Dermatol Clin. 2011 Jul. 29(3):373-80, vii. [Medline].

Brenner S, Goldberg I. Drug-induced pemphigus. Clin Dermatol. 2011 Jul-Aug. 29 (4):455-7. [Medline].

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. 2008 Sep. 130(3):369-74. [Medline].

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. 2008 Sep. 130 (3):369-74. [Medline].

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

Quaresma MV, Bernardes Filho F, Hezel J, Peretti MC, Kac BK, Azulay-Abulafia L. Dapsone in the treatment of pemphigus vulgaris: adverse effects and its importance as a corticosteroid sparing agent. An Bras Dermatol. 2015 May-Jun. 90 (3 Suppl 1):51-4. [Medline].

Brenner S, Srebrnik A, Goldberg I. Pemphigus can be induced by topical phenol as well as by foods and drugs that contain phenols or thiols. J Cosmet Dermatol. 2003 Jul. 2 (3-4):161-5. [Medline].

Chris G Adigun, MD, FAAD Director and Physician, Dermatology and Laser Center of Chapel Hill; Senior Medical Advisor, Klara

Chris G Adigun, MD, FAAD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, Council for Nail Disorders, North Carolina Dermatology Association, North Carolina Medical Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Valeant; Sandos; Cipher; Klara; Miramar<br/>Serve(d) as a speaker or a member of a speakers bureau for: Celgene; Cipher; Klara.

Omobola Onikoyi, MS Touro University College of Osteopathic Medicine

Omobola Onikoyi, MS is a member of the following medical societies: American Vitiligo Research Foundation, Medical Dermatology Society, National Psoriasis Foundation, North American Hair Research Society, Wound Healing Society

Disclosure: Nothing to disclose.

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

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.

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.

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.

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.

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

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.

Drug-Induced Pemphigus

Research & References of Drug-Induced Pemphigus|A&C Accounting And Tax Services
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