Review
The cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome

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Background

Azathioprine (AZA) hypersensitivity syndrome is a rare side effect that typically occurs early in the initiation of therapy and may include a cutaneous eruption. It is often under-recognized because it mimics infection or disease exacerbation. Until recently, the cutaneous findings associated with AZA hypersensitivity have been reported using nonspecific, descriptive terms without a supportive diagnostic biopsy.

Objective

To characterize the cutaneous and histologic findings associated with AZA hypersensitivity syndrome.

Methods

We conducted a retrospective analysis of two cases of AZA hypersensitivity syndrome and describe the cutaneous manifestations and histological findings of each case. A review of the English literature for cases of AZA hypersensitivity or allergic or adverse reactions associated with AZA was performed.

Results

Sixty-seven cases of AZA hypersensitivity were reviewed; 49% (33/67) had cutaneous manifestations. Of those cases presenting with cutaneous findings, 76% (25/33) had biopsy results or clinical features consistent with a neutrophilic dermatosis, whereas the other 24% (8/33) were reported as a nonspecific cutaneous eruption.

Limitations

Only case reports in which the skin findings could be classified were reviewed.

Conclusions

The predominant cutaneous reaction reported in the literature and observed in the present case series is a neutrophilic dermatosis. Hypersensitivity to AZA can manifest along a wide clinical spectrum from local neutrophilic disease to a systemic syndrome. Skin findings may be an important early clue to the diagnosis of AZA hypersensitivity and aid in prompt recognition and treatment of this potentially life-threatening adverse drug effect.

Introduction

Azathioprine (AZA) (Imuran, Azasan), the nitroimidazole of 6-mercaptopurine (6-MP), was first used in 1961 as an immunosuppressant for kidney transplantation. Since then it has become an effective corticosteroid-sparing agent in a variety of autoimmune inflammatory diseases to include rheumatoid arthritis, systemic lupus erythematosus, vasculitis, inflammatory bowel disease (IBD), bullous pemphigoid, pemphigus, and others. Dose-dependent toxic side effects (myelosuppression, gastrointestinal side effects, hepatotoxicity) have been well recognized. Less well-characterized is AZA hypersensitivity syndrome and its cutaneous manifestations.

We present two cases of the skin manifestations of AZA hypersensitivity syndrome and review the literature to better characterize the skin findings in this under-recognized but important entity.

Section snippets

Material and methods

From July 2007 through March 2009, the Department of Dermatology at Wilford Hall Medical Center (Lackland AFB, Texas) was consulted on two cases of a “rash” thought to be caused by AZA. The clinical records and photographs of these cases were reviewed. A thorough review of the English-language literature was performed comparing the results of previous case reports with our two patients. The PubMed database was searched using the following terms: azathioprine, hypersensitivity, allergic

Case 1

A 39-year-old Caucasian woman with Crohn's disease presented with vomiting, diarrhea, fever, and arthralgias 4 weeks after starting AZA therapy. Before she started AZA, her thiopurine methyltransferase (TPMT) levels were in the normal range. Her AZA dose at presentation was 100 mg daily. She was also taking prednisone, 30 mg daily. Her AZA was discontinued, and she was admitted to the hospital for work-up and treatment of sepsis and exacerbation of Crohn's disease. Her white blood cell count on

Discussion

AZA is an effective and well-tolerated immunosuppressive agent. While approved by the Food and Drug Administration in the United States for severe rheumatoid arthritis and prevention of rejection in renal transplantation, it has numerous off-label uses. AZA continues to be a useful steroid-sparing medication in the treatment of many systemic autoimmune conditions such as IBD, systemic lupus erythematosus, myasthenia gravis, and others.38 The most common dermatologic conditions treated with AZA

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    Funding sources: None.

    Conflicts of interest: None declared.

    The opinions expressed in this article are that of the authors and do not represent official policy of the United States government, the Department of Defense, the U.S. Air Force or the U.S. Army.

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