Gout Treatment Dosage Affects Risk for Hypersensitivity SyndromeNews Author: Janis C. KellyCME Author: Dsire Lie, MD, MSEdCME Released: 08/07/2012; Valid for credit through 08/07/2013Clinical ContextAccording to the authors, allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. It is characterized by rash (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis), eosinophilia, leukocytosis, fever, hepatitis, and renal failure. The mortality is as high as 27%, there is no cure, and supportive therapy is the main treatment. Dosing guidelines based on creatinine clearance have been proposed, as dosages of more than 300 mg/day may be associated with AHS, especially in patients with renal impairment. The relationship between the allopurinol starting dose and AHS is unknown.This is a retrospective case-control study of patients with gout who developed AHS between 1998 and 2010 to determine the relationship of the starting dose of allopurinol to the occurrence of AHS.Study Synopsis and PerspectiveAllopurinol hypersensitivity syndrome (AHS), a rare but potentially fatal adverse reaction in patients beginning allopurinol therapy for gout, might be largely avoided by keying the starting dose to kidney function and slowly increasing it to therapeutic levels once tolerance is certain, according to a retrospective case-control study.AHS, which is characterized by devastating rash, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, as well as by eosinophilia, leukocytosis, fever, hepatitis, and renal failure, is associated with mortality rates as high as 27% and can be treated only by early diagnosis, prompt allopurinol withdrawal, and supportive care, according to the study, performed by Lisa K. Stamp, MBChB, PhD, FRACP, from the University of Otago, Christchurch, New Zealand, and colleagues and published online July 27 and in the August print issue of Arthritis & Rheumatism.Women, older patients, those with renal impairment, those receiving diuretics, and those who are just beginning allopurinol are at greatest risk.Dr. Stamp's group began the study because of reports that patients receiving "full-dose" allopurinol (300 mg/day) with renal impairment were at risk for AHS and that such patients have reduced excretion of oxypurinol, the active metabolite of allopurinol. Current dosing guidelines do not address starting dose vs maintenance dose issues, and the aim of the study was "to determine the relationship of the starting dose and the dose of allopurinol at the time of the reaction to the occurrence of AHS in patients with gout."The researchers conducted a retrospective case-control study of patients with gout who developed AHS between January 1998 and September 2010. They matched each of the 54 patients with AHS with 3 control patients with gout who were taking allopurinol and did not develop AHS. Control patients were matched for sex, diuretic use when beginning allopurinol, age, and estimated glomerular filtration rate (eGFR). Case patients were identified in the 5 major regions of New Zealand, an area representing about 3 million people.This analysis showed that risk for AHS increased as the allopurinol starting dose corrected for eGFR increased. Patients in the highest quintile of starting dose per eGFR were 23 times more likely to develop ASH, and the starting dose was 1.5 mg/unit or more of eGFR (mg/mL/minute) in 91% of patients with AHS, but in only 36% of patients with gout who did not develop AHS.Dr. Stamp told Medscape Medical News, "We can say that patients who start on or above the creatinine clearancebased dose are more likely to get AHS. The starting dose of 1.5 mg/mL eGFR is based on a receiver operator analysis, using all the data and what is clinically sensible given the tablet sizes."Nearly all of the cases of AHS (90%) occurred within the first 180 days of allopurinol treatment, with a median of 30 days from starting allopurinol.Dr. Stamp said, "We believe the dose should be increased monthly. This is based on the fact that many people with AHS develop it within the first month, there is no rush to increase the dose, and slower increase in allopurinol/reduction in urate may prevent flares of gout when starting allopurinol."Robert Terkeltaub MD, interim chief of the Division of Rheumatology, Allergy, and Immunology at the University of California, San Diego, reviewed the study for Medscape Medical News. "Major allopurinol hypersensitivity, typically termed AHS, is often medically devastating, and typically occurs in the first few months of therapy," Dr. Terkeltaub said."We need better ways of lessening the frequency of AHS, and HLA-B*5801 screening of high-risk individuals is now appreciated to be part of the solution, but we clearly benefit from additional simple, accessible, and economical measures," Dr. Terkeltaub said to Medscape Medical News. "Despite this being a retrospective study, I think it is well done and valuable. The conclusions are in line with standing recommendations from major bodies, specifically the [US Food and Drug Administration] and [the European League Against Rheumatism], with respect to supporting a low starting dose of allopurinol with steady upwards titration to achieve serum urate target. The approach also has putative advantages in likely precipitating fewer early gout flares in the first phase after initiation of urate-lowering drug therapy."Dr. Terkeltaub added, "It should be noted that Rees et al, in a nonrandomized gout education and urate-lowering therapy intervention study, also used a 'start low, go slow' approach for allopurinol, and had very good numbers for both adherence and achievement of serum urate target. In reality, the old renal functionadjusted allopurinol maintenance dosing recommendations of Hande et al from 1984 are obsolete, but those maintenance doses for patients with severe [chronic kidney disease] probably function well as starting doses."The inherent logic of the work by Stamp et al," he continued, "is that starting allopurinol at a low dose, and instructing the patient to be first stopping the drug promptly, and secondly contacting the clinician if pruritus or rash develops, does not avoid mild allopurinol hypersensitivity reactions, but this likely lessens the risk of severe AHS by 'pulling the plug' quickly in the context of a lower drug exposure."One coauthor has received consulting fees, speaking fees, and-or honoraria from Takeda, Ardea, and Novartis and holds a patent for Fonterra milk products for gout. Dr. Stamp and Dr. Terkeltaub have disclosed no relevant financial relationships. Arthritis Rheum. 2012;64:2529-2536. Abstract STUDY HIGHLIGHTS Patients with AHS were identified in 5 major regions of New Zealand (Auckland, Waikato, Wellington, Christchurch, and Dunedin), representing 3 million people. Patients with gout who developed AHS between 1998 and 2010 were identified by physician recall, International Classification of Diseases code searches, and local area database searches, and via the Center for Adverse Reactions Monitoring. Clinical notes were reviewed to identify patients with AHS. Excluded were patients given allopurinol for diagnoses other than gout. Standardized data were collected, including demographics, height, weight, date of gout diagnosis, starting dose of allopurinol, diuretic use and dose at the time of starting allopurinol, time from initiation of allopurinol treatment until AHS, clinical features, treatment, and patient outcome. Laboratory test results were documented, and eGFR was determined using the Modification of Diet in Renal Disease study equation. Cases of AHS were adjudicated by a single blinded investigator using the Gutierrez-Macias criteria: clear history of exposure to allopurinol, lack of exposure to another drug potentially causing the reaction, and 2 of the major criteria (worsening renal function, acute hepatocellular injury, or rash) or 1 of the major criteria and 1 of the minor criteria (fever, eosinophilia, or leukocytosis). For each patient with AHS, 3 control patients who were receiving allopurinol for gout but did not develop AHS were identified and matched for age and risk factors. 54 patients with AHS were confirmed and matched with 157 control patients. For both patients with AHS and control patients, mean age was 64 years, half were men, and almost half were receiving diuretics at the time of allopurinol prescription. Two thirds of the patients with AHS and the control patients alike had an eGFR of less than 60 mL/minute. The presence of tophi was associated with a reduced risk for AHS (odds ratio [OR], 0.29; 95% confidence interval [CI], 0.01 - 0.83; P < .021). Ethnicity was associated with risk for AHS (P < .001). Compared with patients of European descent, there was a decreased risk for AHS in patients of Maori or Pacific Island descent (OR, 0.24; P = .02) and an increased risk for AHS in patients of Chinese descent (OR, 70.8; P = .005). The median time from starting allopurinol to the occurrence of AHS was 30 days. 90% of AHS cases occurred within the first 180 days after starting allopurinol. The median increase in creatinine level in patients who had renal deterioration was 55% from baseline. The median increase in ALT level was 2.4 times the upper limit of normal in patients who had acute hepatocellular injury. Patients with AHS began receiving the drug at a significantly higher dosage than the control patients (mean starting dose, 183.5 mg/day vs 112.2 mg/day). Patients with AHS also were more likely to begin receiving allopurinol at doses higher than the creatinine clearancebased dose than were control patients (OR, 16.7; 95% CI, 5.7 - 47.6; P < .001). The percentage of patients developing AHS increased significantly as the allopurinol dose (corrected for eGFR) increased. There was a significant and strong dose-response relationship between the starting dose of allopurinol (adjusted for eGFR) and the risk for AHS (overall dose effect, P = .001). In patients with AHS, no relationship was found between the allopurinol starting dose and serum urate level. 79% of patients with AHS cases and 53% of control patients started at a dose of 2.0 mg or more of allopurinol per unit of eGFR (mg/mL/minute). A starting dose based on an eGFR of 1.5 mg/mL/minute was selected as a reasonable tradeoff between a clinically practicable dose and the absolute risk for AHS. The authors concluded that the starting dose of allopurinol was an important risk factor for the development of AHS and that a starting dose of 1.5 mg/unit of eGFR was appropriate to minimize the risk for AHS.CLINICAL IMPLICATIONS Risk factors for AHS among patients with gout started on allopurinol include the presence of tophi and ethnicity; clinical features include worsening renal function, acute hepatocellular injury, fever, eosinophilia, and leukocytosis. Starting dose of allopurinol is a risk factor for AHS; a starting dose of 1.5 mg/mL/minute of eGFR is appropriate to minimize the risk for AHS.