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.
To the Editor:
Azathioprine (AZA) hypersensitivity is an immunologically mediated reaction that presents within 1 to 4 weeks of drug initiation.1 Its cutaneous manifestations include Sweet syndrome, erythema nodosum (EN), and acute generalized exanthematous pustulosis, with 88% of cases presenting as neutrophilic dermatoses.2 Confirmation with cutaneous biopsy and cessation of medication is essential to prevent life-threatening anaphylactoid reactions.
A 58-year-old man with a history of Crohn disease was admitted with high fevers (>38.9°C); abdominal pain; diarrhea; and a nonpruritic “pimplelike” rash on the face, chest, and back with a tender nodule on the right leg of 5 days’ duration. Eight days prior to admission, he had started AZA for treatment of Crohn disease. In the hospital he received intravenous metronidazole for a presumed bowel infection; however, the lesions and symptoms did not resolve. Other medical history included psoriatic arthritis for which he was taking oral prednisone 50 mg daily; prednisone was continued during hospitalization.
Physical examination showed that the patient was alert and well appearing. On the face, upper chest and back (Figure 1), shoulders, and knees were fewer than 20 sparsely distributed, nontender, 3- to 4-mm pustules. The patient’s scalp, lower back, abdomen, arms, and feet were spared. There also was a solitary 3.5-cm, tender, erythematous nodule on the right lower leg (Figure 2). Blood tests revealed leukocytosis (15,000/mm3 [reference range, 4300–10,300/mm3]) with neutrophilia (90%) and an elevated C-reactive protein level of 173 mg/L (reference range, <10 mg/L). Liver function tests were normal. Thiopurine methyltransferase (TPMT) was on the low end of the reference range. Tissue culture of a shoulder pustule grew only Staphylococcus non-aureus. Blood cultures were negative. A 4-mm punch biopsy specimen from the right leg nodule revealed septal panniculitis with neutrophilic and granulomatous infiltrate consistent with EN.
A clinical diagnosis of AZA hypersensitivity was made. Antibiotics and AZA were discontinued and the patient’s lesions resolved within 6 days. Medication rechallenge was not attempted and the patient is now managed with infliximab.
Azathioprine is a well-known and commonly used drug for inflammatory bowel diseases, rheumatoid arthritis, and prevention of transplant rejection. Hypersensitivity is a lesser-known complication of AZA therapy, with most reactions occurring within 4 weeks of treatment initiation. A PubMed search of articles indexed for MEDLINE using the search terms azathioprine and hypersensitivity found only 67 documented cases of AZA hypersensitivity between 1986 and 2009.2 Common findings include fever, malaise, arthralgia, nausea, vomiting, diarrhea, headache, and neutrophilic dermatoses.
