Azathioprine Hypersensitivity Syndrome: Two Cases of Febrile Neutrophilic Dermatosis Induced by Azathioprine

Abstract

Background: Azathioprine is an immunosuppressive agent used in the treatment of immune-mediated diseases. Azathioprine hypersensitivity syndrome is a rare adverse reaction occurring a few days to weeks after the administration of azathioprine. Case 1: A 36-year-old male with ulcerative colitis presented with erythematous plaques, pustules and erosions on the lower back, buttocks and thighs associated with high fever (39°C) 2 weeks after the initiation of azathioprine 100 mg/day. Additional findings included leukocytosis (18.6 g/L) with neutrophilia (11.1 g/L) and elevated C-reactive protein (128 mg/L). Histopathology showed a dense infiltrate of neutrophils in the hair follicles. We increased the dose of prednisone to 1 mg/kg/day (60 mg/day) and azathioprine was discontinued. He had marked improvement within 3 weeks and did not have any relapse with a 1-year follow-up. Case 2: A 57-year-old male with ulcerative colitis presented with erythematous plaques and pustules on the lower limbs associated with high fever (40°C) 1 week after the initiation of azathioprine 75 mg/day. Leukocytosis with neutrophilia (13.6 g/L) and elevated C-reactive protein (344 mg/L) were among the laboratory findings. Histopathology showed a dense infiltrate of neutrophils in the hair follicles. The dose of prednisone was increased to 20 mg/day and azathioprine was discontinued, which led to complete remission within 7 days. He did not have any relapse with a 6-month follow-up. Conclusion: The development of acute neutrophilic dermatitis 2 weeks after the initiation of azathioprine and the complete resolution after its withdrawal were in favor of azathioprine hypersensitivity syndrome. It should not be confused with Sweet syndrome associated with inflammatory bowel disease, as maintenance of azathioprine treatment may lead to life-threatening reactions.

Azathioprine hypersensitivity syndrome: report of two cases with cutaneous manifestations

“…The most frequently reported cutaneous manifestations include maculopapular, vesicular or pustular lesions, while purpura or erythema nodosum are less frequently observed. 1,2,4,5 One of our cases had the histopathological features of leucocytoclastic vasculitis on skin biopsy, and the other one developed palpable purpura on his limbs. In the literature, there are few cases of AHS presenting with leucocytoclastic vasculitis, 6,7 but this feature does not seem to be related to a higher incidence of severe symptoms such as renal symptoms, cardiac failure or severe hypotension.…”

“…1,2,5 In addition, clinical presentation usually differed somewhat from SS, as AHS skin lesions are often painless, with many being located on the legs. 1,4,5 Despite the difficulty as to whether the condition is AHS with SS-like presentation or AZA-induced SS, the most important issue is knowing that in patients with AHS, continuance or reintroduction of the drug can lead to multiorgan failure, including liver or kidney dysfunction, severe hypotension, congestive heart failure and cardiogenic shock syndrome. [9][10][11] These potentially life-threatening reactions associated with AHS can be completely reversed when AZA is discontinued and appropriate haemodynamic support started.…”

“…A clear improvement in both cutaneous and systemic symptoms is seen in a few days after discontinuing AZA. 1,[3][4][5]13 Epicutaneous patch tests can be performed to confirm the diagnosis, as there are published cases with positive results with 1% and 5% AZA patch tests. 14 This suggests a type IV hypersensitivity reaction similar to that of AGEP.…”

Drug Hypersensitivity due to Azathioprine with Elevated Procalcitonin

“…It is a purine antagonist that is metabolized by thiopurine methyltransferase (TPMT) to the active compound, 6-mercaptopurine; however this metabolism seems to be unrelated to the incidence of hypersensitivity [ 10 ]. Furthermore, azathioprine has an inactive metabolite, methyl nitroimidazole, which may be responsible for the hypersensitivity reactions due to the generation of a hapten during metabolism [ 4 , 9 , 11 , 12 ]. Although rare, there have been about 70 cases of azathioprine-induced hypersensitivity reported in the literature thus far, with concurrent corticosteroids at presentation being present in 39% of patients [ 9 ].…”

Vesiculobullous eruption in neutropenic patient with Crohn's disease

“…Although druginduced SS is more common with G-CSF than with azathioprine, azathioprine-associated SS has been reported. 4 This patient had hypoplastic bone marrow consistent with azathioprine (6-MP) toxicity, which may have induced SS.…”