AZA is a thiopurine-derived immunosuppressive drug that is commonly used in several dermatological and rheumatic diseases as a corticosteroid-sparing agent, so recognizing AZA hypersensitivity reactions are important in daily clinical practice. Similar prevalence in men and women, a wide range of age of presentation (16-76 years), and a broad variation in the initial dose of AZA (100 ± 48 mg) have been described previously.[1
] De Fonclare et al
] reported three cases of EN associated with AZA in patients with inflammatory bowel disease. Similarities and differences between those cases and ours can be noted. The time interval between AZA initiation and EN appearance varied from 1 to 2 weeks (a mean of 12 days), similar to our case. However, those patients had fever, rash, and arthralgias in addition to EN. Interestingly, TPMT activity was normal both in de Fonclare's cases and ours. On the other hand, complete remission of all clinical and biochemical abnormalities after discontinuing AZA was noted in all cases, as in our case. Finally, unlike de Fonclaire et al
., we did not re-administer the patient AZA to confirm the diagnosis since life-threatening complications, even with using small doses of AZA or 6-mercaptopurine, have been reported previously.[2
] However, the suspicion of AZA hypersensitivity remained very high because of the following: The chronology of the patient's illness in relation to the initiation of AZA (only 1 week of time between the cause and the suspected effect); the presence of features of hypersensitivity to AZA described previously: Fever and EN; the absence of other causes that could justify the development of fever and EN; and the fast improvement and remission of EN after AZA withdrawal.
The mechanisms involved in AZA hypersensitivity reaction remain unclear. The side effects associated with AZA use have been classified as early or late events. Late adverse reactions are usually dose-dependent and they can be anticipated in part by evaluation of TPMT activity. By contrast, early adverse effects (which normally occur 4 weeks following treatment initiation) are usually idiosyncratic, non-dose-dependent reactions due to hypersensitivity mechanisms and therefore, difficult to predict.[4
] Nevertheless, it has not been yet elucidated whether the drug itself (via its imidazole component) or one of its metabolites (6-mercaptopurine mainly) acts as a hapten that binds to a protein molecule and lastly a type-1 hypersensitivity reaction is elicited.[2
] Finally, genetic polymorphisms in the inositol triphosphate pyrophosphatase gene may also be involved in developing AZA hypersensitivity.[5
To conclude, we want to highlight the interest of this report. On the one hand, this is the first case of EN as a consequence of AZA treatment described in the medical literature in a patient with BP. On the other hand, we want to emphasize that EN may be a clinical sign of hypersensitivity to AZA in patients who have recently started to take this drug. Since hypersensitivity to AZA includes a wide variety of manifestations shared by many rheumatic diseases, this condition should be considered as an alternative diagnosis to the onset or worsening of symptoms secondary to the underlying disease.
What is new?
- This case shows that erythema nodosum (EN) can develop as a consequence of azathioprine (AZA) treatment in patients with bullous pemphigoid (BP).
- This case confirms the need of consideration of hypersensitivity reactions to AZA, such as EN, as potential diagnosis in patients with autoimmune disorders treated with this drug.