Azathioprine Hypersensitivity Presenting as Neutrophilic Dermatosis and Erythema Nodosum
Practice Points
- Azathioprine is a well-known immunosuppressant for renal transplant recipients and inflammatory bowel disease with several off-label uses in dermatology including immunobullous dermatoses, neutrophilic dermatoses, and autoimmune connective tissue diseases.
- Azathioprine hypersensitivity is rare and can present with systemic symptoms of fever and a neutrophilic dermatosis, which is usually self-limited but can progress to an anaphylactoid reaction with multiorgan failure.
- If a more mild hypersensitivity reaction is appreciated, then a rechallenge is not recommended and should be avoided.
Previously reported cases of AZA hypersensitivity with cutaneous manifestations include Sweet syndrome (17.9%), small vessel vasculitis (10.4%), EN (4.4%), acute generalized exanthematous pustulosis (4.4%), and nonspecific cutaneous findings (11.9%).2 One other case reported AZA hypersensitivity presenting as EN with a neutrophilic pustular dermatosis.3 Although Sweet syndrome–like lesions, EN, and acute generalized exanthematous pustulosis have been reported in the context of inflammatory bowel disease, in this case the appearance of these symptoms within 1 week of AZA initiation and resolution after AZA discontinuation is highly suggestive of AZA hypersensitivity. Also, several reports have documented rapid (within a few hours) recurrence of symptoms on rechallenge with AZA.4-6 Moreover, cases of cutaneous AZA hypersensitivity reactions in patients with no history of inflammatory bowel diseases have been reported.6-8
As in this case, cutaneous AZA hypersensitivity can occur even in the setting of normal TPMT levels, suggesting that this phenomenon is a dose-independent reaction.2 Abnormal metabolism of AZA does not appear to be related to previously reported neutrophilic pustular dermatosis3,4 or EN.4 Although the mechanism of hypersensitivity is unclear, there is a report of a patient who developed AZA hypersensitivity but was able to tolerate 6-mercaptopurine, a metabolite of AZA. The authors suggested that the imidazole component of AZA might be responsible for hypersensitivity reactions.9
The differential diagnosis of a patient with these findings includes infectious, rheumatologic, neurologic, or autoimmune diseases, as well as septic shock. Hence, negative cultures and a failure to respond to antibiotics make infection less likely. An appropriate time course of AZA initiation, the development of rash, and a cutaneous biopsy can lead to prompt diagnosis and cessation of AZA.
Once AZA hypersensitivity is suspected, the drug should be discontinued and the reaction should resolve within 2 to 3 days2 and the skin lesions within 5 to 6 days.2,10 Medication rechallenge is contraindicated because AZA rarely has been associated with shock syndrome and hypotension.11-19
Azathioprine hypersensitivity is a serious yet still underrecognized condition in the dermatologic community. In our case, symptoms appeared rapidly and resolved quickly after AZA was discontinued. Azathioprine-induced neutrophilic dermatosis presenting with EN should be recognized as a potential dermatologic manifestation of AZA hypersensitivity, which is a dose-dependent reaction even with normal TPMT levels. Rechallenge with AZA is not recommended due to the risk of a life-threatening anaphylactoid reaction.
