Correspondence

A Case of Conjugal Azathioprine-Induced Contact Hypersensitivity

N Engl J Med 2008; 359:1524-1526October 2, 2008

Article

To the Editor:

A man in his early 30s presented with an intermittent eczematous eruption over the shaft of his penis and scrotum (Figure 1AFigure 1Findings from Examination and Testing of the Patient.). His wife was initially concerned about his fidelity, but a careful history-taking revealed that the rash coincided with his wife's intermittent courses of azathioprine for Crohn's disease. During four courses of such treatment over a 4-year period, her vaginal secretions were yellow, which raised the possibility of secretion of azathioprine or its metabolites that could have led to allergic contact dermatitis in the husband.

Further investigation was undertaken. Both the man and his wife had normal thiopurine methyltransferase levels. Epicutaneous patch testing of petrolatum alone or 1 to 10% of the drug in petrolatum was performed as previously described.1 Azathioprine (pure and tablet forms), its major breakdown product 6-mercaptopurine, and all available tablet excipients were tested on both partners. The husband, but not the wife, reacted to the tablet and pure forms of azathioprine only (Figure 1B).

The presence of drug-specific lymphocytes in the husband's peripheral-blood mononuclear cells was assessed by means of the lymphocyte transformation test,2 but no response was seen, probably reflecting the inherent antilymphocyte activity of azathioprine. However, as shown with the use of an enzyme-linked immunosorbent spot assay,3 both azathioprine and 6-mercaptopurine induced the release of interferon-γ from lymphocytes (50 and 70 positive cells per million, respectively, vs. 4 positive cells per million in the absence of drug) (Figure 1C and 1D). No response was seen in controls (see the Supplementary Appendix, available with the full text of this letter at www.nejm.org). These data, in conjunction with the skin-test results, were interpreted to indicate that the husband had a hypersensitivity to 6-mercaptopurine or a metabolite of 6-mercaptopurine. The negative skin test for 6-mercaptopurine probably reflected its water solubility, causing it to penetrate into the epidermis much less than azathioprine.

Azathioprine is inactive until converted to 6-mercaptopurine and methyl-nitro-thioimidazole by glutathione S-transferase. Then 6-mercaptopurine is converted into the myelotoxic metabolites 6-thioguanine nucleotide and 6-methylmercaptopurine through three competing enzymatic pathways: those involving xanthine oxidase, hypoxanthine guanine phosphoribosyltransferase, and thiopurine methyltransferase. Determination of thiopurine methyltransferase activity has reduced the numbers of adverse reactions due to this pharmacologically predictable toxicity (type A reaction).

However, allergic contact dermatitis is an idiosyncratic T-cell–mediated delayed hypersensitivity (type B reaction). The skin contains considerable amounts of several enzymes, including cytochrome P-450 (CYP) 1A1, CYP1B1, CYP2B6, CYP2E1, and CYP3A5, as well as members of the glutathione S-transferase family. These enzymes may generate allergenic metabolites of various drugs, including azathioprine.4

We have demonstrated, by patch testing and enzyme-linked immunosorbent spot assay, a case of indirect conjugal azathioprine-induced allergic contact dermatitis. The mechanistic basis for the husband's idiosyncratic drug hypersensitivity has not yet been determined, but there may be an aberrant pathway of detoxification within his skin, resulting in the production of an immunogenic compound.

Hywel L. Cooper, B.Med.Sci.
Fethi Louafi, Ph.D.
Peter S. Friedmann, F.Med.Sci.
University of Southampton, Southampton SO16 6YD, United Kingdom
hlc1@soton.ac.uk

4 References

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Citing Articles (3)

Citing Articles

1. 1

   J.K. Aronson. 2011. Drugs that act on the immune system. , 815-839.
   CrossRef

2. 2

   Petra Lehmann, Martin Fleck, Juergen Schoelmerich, Peter Haerle. (2010) Azathioprine-Associated Hypersensitivity Reaction in a Patient With Churg Strauss Vasculitis. JCR: Journal of Clinical Rheumatology 16:5, 242-243
   CrossRef

3. 3

   (2009) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 18:2, i-xiv
   CrossRef