Azathioprine-induced maculopapular rash in a pemphigus vulgaris patient

Dear Sir,

Pemphigus vulgaris (PV) is a chronic, potentially life-threatening autoimmune blistering disorder characterized by the formation of flaccid blisters and erosions on the skin and mucous membranes. Systemic corticosteroids and immunosuppressive drugs like azathioprine are typically used in treatment. Hepatotoxicity, bone marrow suppression, and gastrointestinal adverse effects are commonly encountered side effects of azathioprine. Azathioprine-induced skin rash is extremely uncommon.^[1] The present case illustrates the importance of identification of the causal drug and timely diagnosis of azathioprine-induced skin rash, an extremely uncommon occurrence in itself.

A 45-year-old female, a known case of PV with no prior comorbidities, who had been treated with prednisolone, was recently prescribed azathioprine (1 mg/kg/day as a starting dose) as a steroid-sparing agent. The patient started to develop an erythematous, pruritic rash on the abdomen a week after starting azathioprine, followed by involvement of the back and limbs that quickly progressed to involve other areas of the body. There was no fever or systemic symptoms. On examination, ill-defined erythematous maculopapular to plaque lesions were seen symmetrically distributed on the upper back, chest, belly, and both upper and lower limbs [Figure 1]. The maculopapular rash was coalescing to form plaques with a geographic configuration on the flexor aspect of the arms and the bathing trunk area. A complete blood count, liver function tests, and renal function tests were within normal limits. Skin biopsy was performed in view of a suspected drug-induced rash. There was interface dermatitis in the form of lymphocytic exocytosis, basal cell vacuolization, apoptotic keratinocytes, and pigment incontinence. The upper dermis showed moderate lymphomononuclear inflammatory infiltrate in the perivascular region. Features were consistent with drug-induced dermatitis [Figure 2]. Owing to the temporal correlation of starting azathioprine and the onset of her rash and biopsy findings, a drug-induced maculopapular rash due to azathioprine was considered as the possible diagnosis. The Naranjo scale was applied for causality assessment. The total score was 6, suggestive of a “probable” adverse drug reaction. A “probable” reaction on the scale means that the reaction (1) followed a reasonable temporal sequence after a drug, (2) followed a recognized response to the suspected drug, (3) was confirmed by withdrawal but not by exposure to the drug, and (4) could not be reasonably explained by the known characteristics of the patient’s clinical state. Azathioprine was stopped immediately, and the patient’s symptoms gradually resolved after discontinuation of the medication, starting from 48 hours after withdrawal, and the rash completely resolved within a week’s time [Supplementary figure].

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Figure 1 (a-b): Index case with ill-defined erythematous maculopapular lesions symmetrically distributed on the chest, abdomen, upper limbs, and back, coalescing to form plaques with geographic configuration on the flexor aspect of the arms and bathing the trunk area

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Figure 2: Skin biopsy showed interface dermatitis in the form of lymphocytic exocytosis, basal cell vacuolization (black arrows), apoptotic keratinocytes (blue arrows), and pigment incontinence (black circles). The upper dermis showed moderate lymphomononuclear inflammatory infiltrate in the perivascular region (black stars) (a) (H&E, 40x) (b) and (H&E, 100x). H&E: Hematoxylin and eosin.

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Supplementary figure (A&B): Complete resolution of rash within 1 week after discontinuing azathioprine

For management of PV, the patient was continued on oral prednisolone. Throughout the follow-up period, the patient’s PV stayed under control and did not have any notable flare-ups. We did not reintroduce the drug for rechallenge, given the potential for a severe shock-like syndrome.

Azathioprine is a purine analog that is commonly used in the management of autoimmune conditions, including PV. It is useful in the management of disease activity, but it can also have some unusual side effects. Acute onset of fever, arthralgias, abdominal pain, nausea, and skin eruptions, the most common of which are neutrophilic dermatoses^[1], are the hallmarks of azathioprine hypersensitivity syndrome. This is an uncommon adverse event that happens within weeks after starting azathioprine. Even though stopping azathioprine usually reverses the hypersensitivity syndrome, it is important to avoid taking azathioprine again because it can cause anaphylaxis.^[1,2] Erythema nodosum, small-vessel vasculitis, nonspecific dermatitis, and more serious disorders, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, are some of the cutaneous reactions to azathioprine.^[1,3-5] These reactions are unrelated to the thiopurine methyltransferase levels and are idiosyncratic.

The present situation emphasizes the need to take into account drug-induced skin responses in patients receiving immunosuppressives that are often used to manage drug-induced rash. After stopping the implicated drug, maculopapular rashes can be reversed.