Allopurinol-Induced Recurrent DRESS Syndrome: Pathophysiology and Treatment

Abstract

Hyperuricemia is present in approximately 5% of the population. The vast majority is asymptomatic and at no clinical risk. Allopurinol, an analog of hypoxanthine, has been widely used in clinical practice for more than 30 years for the treatment of hyperuricemia and gout. Two percent of patients develop a mild exanthema when on this drug, which usually resolves after withdrawal of the drug. A syndrome characterized by exfoliative dermatitis, hepatitis, interstitial nephritis, and eosinophilia, termed allopurinol hypersensitivity syndrome, has been described, and its etiology related to the accumulation of one of allopurinol's metabolites, oxypurinol, of which clearance is decreased in the setting of renal insufficiency and the use of thiazide diuretics. The term DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) Syndrome has been recently used to describe an entity presenting with similar features.

Keywords:

• allopurinol hypersensitivity
• DRESS syndrome
• allopurinol toxicity
• hyperuricemia
• drug hypersensitivity

INTRODUCTION

Hyperuricemia is a common finding, and its presence has been related to renal calculi, uric acid nephropathy, and gout.[1] Allopurinol was introduced in the mid-1960s, and its administration markedly reduced the severity of this condition.[2] Allopurinol administration has been related to toxic effects, mainly to the skin, kidney, and liver. A sometimes life-threatening condition, named allopurinol hypersensitivity syndrome, that is characterized by fever, eosinophilia, and renal and hepatic toxicity has been described.[2] The term DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome has been recently introduced to describe a disorder characterized by similar features. A patient presenting with this condition is described, and the current approach to this entity is reviewed.

CASE REPORT

A 65-year-old man with psoriasis, mild diabetes mellitus type II treated by diet, mild chronic failure (creatinine: 1.6 mg%), arterial hypertension, and nephrolithiasis was started on allopurinol due to increased serum uric acid. One week later, he developed generalized rash, fever (38.8°C), slight increase in transaminase values, and mild eosinophilia. A hypersensitivity reaction secondary to allopurinol was suspected, and allopurinol was discontinued. A consultant dermatologist prescribed an oral antihistamine and topical corticosteroids, without relief, and the patient was admitted some days later to the Dermatology Ward at our Center. On physical examination, a diffuse exfoliative dermatitis was present over the skin of the thorax, abdomen, and limbs. No other abnormal findings were noted. Laboratory evaluation showed a blood urea of 114 mg/dL, serum creatinine value of 1.71 mg/dL, serum glutamic-oxalacetic transaminase (GOT) value of 55 U/L, glutamic-pyruvate transaminase (GPT) value of 76 U/L, bilirubin level of 0.98 mg/dL, and serum lactic dehydrogenase level of 868 U/L. The leukocyte count on admission was 5,560/mm³ with 13.8% eosinophils (770/mm³). Unexpectedly, his uric acid levels were normal throughout the entire hospitalization (6.30–6.53mg/dL). Later during hospitalization, the leukocyte count increased to 34,000/mm³ with an absolute count of 7,000 eosinophils. He was started on prednisone, 40 mg orally, and topical corticosteroids. After a week of hospitalization, leucocyte and eosinophile number progressively decreased. Glucose values increased on prednisone treatment, and insulin was started. Prednisone administration was gradually stopped, and the patient was discharged.

Four days after discharge, the patient was admitted to our Internal Medicine Ward with a clinical picture of hypoglycemia. Physical examination showed a diffuse rash, which was similar to the exanthema previously described. The next day, he developed a high fever (39°C), and laboratory tests showed severe liver function abnormalities: serum glutamic-oxalacetic transaminase (GOT) value of 807 U/L, glutamic-pyruvate transaminase (GPT) value of 1784 U/L, bilirubin level of 2.61 mg/dL (direct bilirubin: 1.94 mg/dL), serum lactic dehydrogenase level of 1378 U/L, alkaline phosphatase value of 114 U/L, albumin level of 2.88 g/dL, prothrombin time, 23.6 seconds (INR: 1.96), and aPTT, 41.1 seconds. Blood urea was 59 mg/dL, and the creatinine value was 1.81 mg/dL. Uric acid levels about three weeks after allopurinol cessation were within normal limits. The leukocyte count on admission was 14.730/mm³ with 42.4% eosinophils (6.250/mm³). The thrombocyte count was 67.000/mm³.

Prednisone, 40 mg PO, was restarted. The skin rash vanished, and improvement in hepatic function and thrombocyte number followed. Eosinophil number decreased.

The patient was admitted once again to the Dermatology Ward three weeks later when exanthema recurred two days after prednisone treatment was discontinued. This time, the clinical picture consisted of severe exfoliative dermatitis compatible with generalized pustular psoriasis. Mild liver tests dysfunction was present without eosinophilia. A rebound phenomenon on steroid discontinuation was diagnosed and prednisone was restarted at 30 mg/day. Again, improvement was noted. Prednisone was continued for another two months with slow tapering. No recurrence occurred during this time. Blood tests performed one year later showed normal uric acid values without any treatment for uric acid reduction.

DISCUSSION

Hyperuricemia may be defined as a plasma (or serum) urate concentration >7 mg/dL. The complications of hyperuricemia include gouty arthritis, nephrolithiasis, and urate or uric acid nephropathy.[1] Allopurinol, or 4-hydroxypirazolo pyrimidine, an analog of xanthine, is used in the treatment of both primary and secondary hyperuricemia. Allopurinol was introduced in 1963 as a uric acid-lowering agent.[2] Its mechanism of action involves its conversion, after absorbed, to oxypurinol, an analog of xanthine (see Figure 1).[1] Allopurinol is generally well tolerated with few significant adverse effects. Approximately 2% of patients taking the drug develop a mild cutaneous rash. However, a life-threatening toxicity syndrome has been described after its use, which includes some or all of the following: vasculitis, rash, eosinophilia, hepatitis, and progressive renal failure. This condition has been called allopurinol hypersensitivity syndrome (AHS).[2] Criteria for the diagnosis of AHS were suggested by Singer and Wallace[2] and include a documented intake of allopurinol, a lack of exposure to a different drug causing a similar clinical picture, and the presence of at least two major criteria or one major and one minor criterion. Major criteria include worsening renal function, acute hepatocellular injury, and rash, manifested by toxic epidermal necrolysis, erythema multiforme, diffuse maculopapular rash, or exfoliative dermatitis. Minor criteria include fever, leukocytosis, and eosinophilia.[2]

Figure 1. Purine metabolic pathway: conversion of hypoxanthine to xanthine and uric acid, and of allopurinol to oxypurinol.

The etiology of this condition is not entirely understood but seems to be related to the accumulation of oxypurinol, one of allopurinol's metabolites. It is assumed that oxypurinol excess leads to tissue damage, evoking an immunological response with the development of antibodies against tissue components. Cell-mediated immunity has been invoked by others.[3]

The term DRESS syndrome has been recently introduced to describe the association of Drug Rash together with Eosinophilia and Systemic Symptoms.[4] This syndrome, previously named drug hypersentivity syndrome, has been more commonly described after the administration of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine).[4] DRESS syndrome is characterized by skin rash, fever, lymph node enlargement, and single or multiple organ involvement, and starts within eight weeks after the initiation of the therapy. Hematological abnormalities, especially eosinophilia and mononucleosis-like atypical lymphocytosis, are also common.

Patients with chronic renal failure and the simultaneous use of thiazide diuretics are at greatest risk for developing AHS or DRESS syndrome secondary to allopurinol, such as in the present case. There is essentially no renal clearance of oxypurinol when the creatinine clearance has fallen below 10 ml per minute.

In a large series of patients with hypersensitivity to allopurinol, Arellano et al. showed that most of them (76/101) were treated for asymptomatic hyperuricemia—a disturbing finding, as this is not an established indication of the drug.[5] Current indications for treatment of hyperuricemia include symptomatic states, such as nephrolithiasis, uric acid nephropathy, and gouty arthritis or asymptomatic hyperuricemia when cytolytic therapy for neoplastic disease is considered.[1]

Our patient presented with fever, skin rash, marked eosinophilia, and severe liver test abnormalities, and fulfilled all the major and minor criteria for the diagnosis of AHS and DRESS syndrome. He was treated with prednisone, resulting in a prompt improvement of his condition. Withdrawal of steroid treatment resulted in rapid return of symptoms and clinical findings. There is controversy regarding the possible beneficial effects of steroids in this disorder.[6] Tapering steroid dosage is sometimes difficult and may induce symptom rebound,[6] such as in the present case, requiring prolonged administration.

The use of allopurinol for accepted indications and adjusted to renal function is the only way to decrease the incidence of the toxic effects that could be induced by this drug. A remarkable point, one year later, is that his uric acid values were normal, without any uric acid-reducing treatment.

LEARNING POINTS

The use of allopurinol may result in life-threatening toxicity syndrome. An immunological mechanism inducing this syndrome, related to allopurinol metabolite, oxypurinol, has been suggested. Hyperuricemia alone is not an indication for treatment with allopurinol. The use of allopurinol for accepted indications and adjusted to renal function is the only way to decrease the incidence of the toxic effects that could be induced by this drug.

This case shows that the syndrome described can recur after steroid treatment is withdrawn. Therefore, withdrawal from steroid treatment should be done gradually and carefully.