Acute generalized exanthematous pustulosis secondary to azathioprine.

Sir,

Azathioprine (AZA) has been widely used as an immunosuppressant for more than 50 years. It is used alone or in combination with other immunosuppressive agents to prevent rejection following organ transplantation and to treat an array of autoimmune diseases and vasculitis. Its steroid-sparing and immunomodulatory effects have been useful for treating Wegener's granulomatosis in remission.[1] AZA hypersensitivity syndrome is a dose-independent allergic reaction that occurs during the first 4 weeks of therapy.[2] Symptoms commonly include fever, malaise, arthralgias, myalgias, nausea, vomiting, diarrhea, and a cutaneous eruption. The most common cutaneous manifestation of AZA hypersensitivity is a neutrophilic dermatosis, and biopsy could be consistent with Sweet's syndrome, erythema nodosum, small-vessel vasculitis, and acute generalized exanthematous pustulosis (AGEP).[2] We report a case of AZA-induced AGEP in a case of Wegener's granulomatosis. AGEP in a case of Wegener's granulomatosis (granulomatosis with polyangiitis).

A 55-year-old man presented at the emergency room with rash, fever, and generalized body ache since 3 days. He had been diagnosed with Wegener's granulomatosis 1 year ago, and was in remission on oral prednisone. He was started on AZA 8 days prior to presentation as a steroid-sparing alternative. Physical examination was significant for temperature of 40.4°C, and tachycardia at 121 beats per minute. There was diffuse nonblanching, erythematous 2-4 mm papulopustules present on his trunk and extremities, most prominently on his hands and distal forearms [Figures 1 and 2]. No mucosal or scalp lesions were noted. Laboratory results showed 90% neutrophils with leukocytosis 14.5 × 109/L, elevated blood urea nitrogen (BUN) 20.3 mmol/L, creatinine 710 mcmol/L, erythrocyte sedimentation rate (ESR) 108 mm/hour, and C-reactive protein (CRP) 307 mg/dL. Chest X-ray did not show any infiltrates. Diagnoses considered on admission were systemic infection with sepsis, flare-up of his underlying vasculitis, and AZA hypersensitivity. He was started on intravenous (IV) methylprednisolone sodium succinate 125 mg every 6 hours, and IV cefepime and vancomycin were added, pending pan culture results. Punch biopsy of a skin lesion showed intracorneal neutrophils and intraepidermal neutrophilic pustules, with prominent subepidermal and dermal neutrophils with lymphocytes, consistent with AGEP [Figures 3 and 4]. Gram and silver stains were negative for any bacteria or fungi. Blood and urine culture results proved negative, and antibiotics were discontinued. His fever and rash improved dramatically within 48 hours of admission along with improvement of his renal functions. He was diagnosed as AZA-induced AGEP. On the Hartwig's Severity Assessment Scale, the patient scored level 4, indicating moderate severity of the drug reaction. The Naranjo Adverse Drug Reaction Probability Scale (Naranjo algorithm) was used to assess the probability whether the adverse drug reaction was due to AZA rather than the result of other factors. As determined by this scale, AZA was the “probable” cause of the adverse drug reaction. The patient was discharged from hospital on oral prednisone.

Figure 1

Erythematous papules on the extensor of forearms

Figure 2

Widespread discreet papules involving the palms and the forearms

Figure 3

Subepidermal and dermal neutrophils with lymphocytes (H and E, ×40)

Figure 4

Intracorneal neutrophils, intraepidermal neutrophilic pustules (H and E, ×100)

AGEP was first described by Baker and Ryan in 1968 as exanthematic pustular psoriasis.[3] This pustular skin eruption, with an incidence of 1-5 per million/year, has an equal age and gender distribution. Commonly used antibiotics reported to induce AGEP include ampicillin, amoxicillin/clavulanic acid, clindamycin, cotrimoxazole, metronidazole, vancomycin, and penicillin.[4] Other implicated drugs are carbamazepine, nystatin, terbinafine, diltiazem, and hydroxychloroquine.[4] Two different temporal patterns of AGEP reaction from the beginning of administration of the offending drug to the onset of the reaction have been identified.[5] Rapid-onset AGEP, evolving in a few hours to 2-3 days after drug intake have been reported with antibiotics.[5] For other drugs, the rash develops after an interval of 1 to 3 weeks (mean: 11 days).[5] The mean duration of the pustules is 9.7 days (4-10 days), followed by a characteristic pinpoint desquamation for a few days.[4] It is a self-limiting disease, with the following clinical features: (1) numerous, small nonfollicular, intraepidermal, or subcorneal pustules (<5 mm) on an erythematous background, (2) typical histopathological changes, (3) fever (>38°C), (4) blood neutrophil count >7 × 109/L, and (5) an acute evolution with spontaneous resolution of pustules in less than 15 days.[5] The typical histopathology of AGEP is characterized by spongiform subcorneal or intraepidermal pustules or both, marked papillary edema (occasionally with the formation of a subepidermal blister), and polymorphous perivascular infiltrates with neutrophils and exocytosis of some eosinophils.[4] be appropriate instead of the comma. In a minority of cases, leukocytoclastic vasculitis with fibrinoid deposition with or without focal necrosis of keratinocytes, is observed.[4]

The diagnosis may be challenging because it may be mistaken for active illness or aggravation of autoimmune disease. Confirming hypersensitivity with rechallenge can produce more severe symptoms. In up to 60% of AZA-hypersensitive patients, 6-MP may be a safe alternative, suggesting that in these individuals, immunological sensitivity is directed against the imidazole rather than the thiopurine moiety of the AZA molecule.[2] It is difficult to predict which patient will develop AZA hypersensitivity, and prescribing the drug should conform to current guidelines.[6] AGEP secondary to AZA has been reported in two patients till date, one with pemphigus foliaceus and the other with ulcerative colitis.[78] The latent period between the administration of AZA and development of the rash in these cases were 20 and 4 days, respectively. Our patient had a latent interval of 8 days, which was close to the mean of 11 days for the development of AGEP.[5] Clinicians need to be aware of this unusual and potentially dangerous reaction to AZA.