FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 359:1524-1526 October 2, 2008 Number 14 Next

PDF PDA Full Text Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

To the Editor: A man in his early 30s presented with an intermittent eczematous eruption over the shaft of his penis and scrotum (Figure 1A). 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.

View larger version (86K): [in this window] [in a new window]   Figure 1. Findings from Examination and Testing of the Patient. Panel A shows the eczematous eruption on the penile shaft. Results of epicutaneous patch testing revealed 2+ and 3+ positive reactions to azathioprine in the 1% and 5% formulations of both the tablet and pure forms only (Panel B, left side) and negative reactions to the vehicle control, 6-mercaptopurine (1% and 5%) and excipients (microstalline sodium, croscamellose sodium, povidone, and propylene glycol). Enzyme-linked immunosorbent spot assays showed few interferon-–producing lymphocytes in the control sample (Panel C) but a significant increase in the number after treatment with 10 µM azathioprine (Panel D).

 
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- 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{at}soton.ac.uk

References

1. Barbaud A, Gonçalo M, Bruynzeel D, Bircher A. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions. Contact Dermatitis 2001;45:321-328. [CrossRef][Web of Science][Medline]
2. Pichler WJ, Tilch J. The lymphocyte transformation test in the diagnosis of drug hypersensitivity. Allergy 2004;59:809-820. [CrossRef][Web of Science][Medline]
3. Czerkinsky C, Nilsson L, Nygren H, Ouchterlony O, Tarkowski A. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods 1983;65:109-121. [CrossRef][Web of Science][Medline]
4. Bergström MA, Ott H, Carlsson A, et al. A skin-like cytochrome P450 cocktail activates prohaptens to contact allergenic metabolites. J Invest Dermatol 2007;127:1145-1153. [CrossRef][Web of Science][Medline]

PDF PDA Full Text Supplementary Material Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation