Continuing Medical Education
Azathioprine in dermatology: The past, the present, and the future

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For several decades, dermatologists have utilized azathioprine to treat numerous debilitating skin diseases. This synthetic purine analog is derived from 6-mercaptopurine. It is thought to act by disrupting nucleic acid synthesis and has recently been found to interfere with T-cell activation. The most recognized uses of azathioprine in dermatology are for immunobullous diseases, generalized eczematous disorders, and photodermatoses. In this comprehensive review, the authors present recent advancements in the understanding of azathioprine and address aspects not covered in prior reviews. They (1) summarize the history of azathioprine; (2) discuss metabolism, integrating information from recent publications; (3) review the mechanism of action with attention paid to the activities of azathioprine not mediated by its 6-mercaptopurine metabolites and review new data about inhibition by azathioprine of the CD28 signal transduction pathway; (4) thoroughly examine thiopurine s-methyltransferase genetics, its clinical relevance, and interethnic variations; (5) review prior uses of azathioprine in the field of dermatology and grade the level of evidence; (6) discuss the use of azathioprine in pregnancy and pediatrics; review (7) key drug interactions and (8) adverse effects; (9) suggest a dosing and monitoring approach different from prior recommendations; and (10) explore the future of azathioprine, focusing on laboratory considerations and therapeutic application.

Learning objective

At the conclusion of this learning activity, participants should be familiar with the history and pharmacology of azathioprine; its use in dermatology, including proper dosing; and the potential risks associated with azathioprine administration.

Section snippets

History of azathioprine

During the middle of the twentieth century, the basic concepts of immunology were dynamically evolving. Even though the understanding of immunologic mechanisms was rudimentary, investigators were putting forth remarkably insightful theories of immunologic tolerance8 and were experimentally creating acquired tolerance of skin homografts in rabbits, mice, and chickens.9 Coupled with this novel paradigm in immunology was the postulate that the growth of rapidly dividing cells may be inhibited by

Chemical structure

Unlike many serendipitous discoveries in science, the synthesis of azathioprine resulted from considerable forethought. Knowing that all cells require nucleic acids, Hitchings and Elion postulated that synthetic purine analogs may halt the growth of rapidly dividing cells.12 Thus their laboratory synthesized numerous synthetic purine analogs, including 6-MP. They endeavored to increase the efficacy of 6-MP by protecting it from rapid metabolic catabolism. Utilizing the basic structure of 6-MP,

Important considerations

The dermatologic use of azathioprine in the United States remains completely off-label. Physicians have utilized azathioprine for decades, and it is available in relatively inexpensive, generic formulation. Since it is no longer patented and not as lucrative as newer, more costly medications, the pharmaceutical industry appears to have lost interest in studying azathioprine. Therefore the number of new clinical studies is becoming more limited, and proposals to broaden the official indications

Pregnancy considerations

The official Food and Drug pregnancy category for azathioprine is D; there is evidence of risk to human fetuses, but benefits from use in pregnancy may be acceptable despite the risks. Azathioprine and 6-MP have been shown to cross the human placenta in low concentrations and appear in fetal plasma after 24 hours.191 Although both drugs have been found in the placenta and amniotic fluid of patients taking azathioprine, the inactive metabolite thiouric acid has the greatest concentration.192 The

Drug interactions

Several drugs have been reported to interact with azathioprine. The most obvious interaction is with allopurinol, an XO inhibitor used most often to treat gout. Since azathioprine is catabolized in part by XO, concomitant use may result in severe azathioprine toxicity and hematologic complications. Much has been written about this important interaction and possible deleterious consequences.218, 219, 220, 221, 222, 223 Hematologic complications appear to arise 4 to 6 weeks after combination

Common side effects

Azathioprine is generally well tolerated and has a favorable therapeutic index compared with many other traditional immunosuppressants. Patients who overdosed on massive amounts of azathioprine, 500 mg235 and 7,500 mg,236 were not left with any permanent impairment. The most common symptomatic side effects of azathioprine are gastrointestinal, ranging from nausea to diarrhea. It is not uncommon for patients to experience mild nausea, vomiting, and gastrointestinal discomfort within the first 10

Dosing and monitoring

Azathioprine is available in scored 50 mg tablets and 100 mg vials for intravenous injections. It is relatively inexpensive in the United States, as a month's supply generally costs between $100 and $200.

On the basis of our collective experience of using azathioprine to treat more than 100 patients over the past 20 years (unpublished, open-label use), we propose a new dosing scheme (Table VII). Our dosing strategy is different from prior recommendations in published reports75, 189 and reference

Future considerations

Azathioprine has been utilized for several decades, yet in only 2 studies we reviewed were TPMT levels measured.137, 141 It is possible that many patients found to be unresponsive to azathioprine were underdosed, and those determined to have significant hematologic toxicity had no or low TPMT activity. Therefore future study designs should incorporate TPMT activity for proper dosing. Genotype testing may eventually become routine and may allow for further individualization of therapy on the

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