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Objectives HLA-B * 5801 allele carriage (a strong determinant of allopurinol hypersensitivity syndrome) varies substantially among races, which may lead to racial disparities in the risk of Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in the context of urate-lowering drug adverse events (ULDAEs). We examined this hypothesis in a large, racially diverse, and generalizable setting. Methods Using a database representative of US hospitalizations (2009–2013), we investigated the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes). Our reference groups included the US Census population, US allopurinol users, and ULDAE hospitalizations without SJS/TEN. Results We identified 606 cases hospitalized for SJS/TEN as ULDAEs (mean age=68 years; 44% male), among which there was an overrepresentation of Asians (27%) and Blacks (26%), and an underrepresentation of Whites (29%) and Hispanics (% too-low-to-report), compared with the US Census population (5%, 12%, 67%, and 15%, respectively). The hospitalization rate ratios for SJS/TEN among Asians, Blacks, and Whites were 11.9, 5.0, and 1.0 (referent), respectively. These associations persisted using other national referents. According to the NHANES 2009–2012, allopurinol constituted 96.8% of urate-lowering drug use, followed by probenecid (2.1%). Conclusions These national data indicate that Asians and Blacks have a substantially higher risk of SJS/TEN as ULDAEs than Whites (or Hispanics), correlating well with corresponding frequencies of HLA-B * 5801 in the US population (i.e., 7.4%, 4%, 1%, and 1%, respectively). Given its market dominance and established association with SJS/TEN, our findings support the use of vigilance in these minorities when considering allopurinol.

Background The term chronic kidney disease (CKD) is used to describe abnormal kidney function (or structure). People with CKD have an increased prevalence of cardiovascular disease (CVD). Evidence is emerging that allopurinol may have a role to play in slowing down the progression of CKD and reducing the risk of CVD. Objectives This systematic review addresses the research question: does allopurinol reduce mortality, the progression of chronic kidney disease or cardiovascular risk in people with CKD? Data sources The following databases were searched on 7 January 2013: MEDLINE (1946 to 7 January 2013), EMBASE (1974 to 28 December 2012), The Cochrane Library (Issue 1, 2013) and ClinicalTrials.gov. Bibliographies of retrieved citations were also examined and two manufacturers of allopurinol were approached for data. Review methods Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. Summary statistics were extracted for each outcome and, where possible, data were pooled. Meta-analysis was carried out using fixed-effects models. Results Efficacy evidence was derived solely from four randomised controlled trials (RCTs). Adverse event (AE) data were derived from the RCTs and 21 observational studies. Progression of CKD was measured by estimated glomerular filtration rate (eGFR) in three trials and by changes in serum creatinine in the other. No significant differences in eGFR over time were reported. The only significant difference between groups was reported in one trial at 24 months favouring allopurinol [eGFR: 42.2 ml/minute/1.73 m2, standard deviation (SD) 13.2 vs. 35.9 ml/minute/1.73 m2, SD 12.3 ml/minute/1.73 m2; p

Allopurinol hypersensitivity syndrome (AHS) is a severe drug reaction. It is characterized by rash, fever, and internal organ involvement. It may present in different clinical forms. We present a case of acute generalized exanthematous pustulosis occurring as a manifestation of AHS.

BACKGROUND—Because serious adverse reactions to allopurinol have been related to a reduce creatinine clearance rate and prolonged half life of oxypurinol, it has been recommended that the dose should be adjusted according to the rate of creatinine clearance. However, in some patients with gout the dose is not sufficient to reduce serum levels of uric acid (⩽390 µmol/l) and to halt disease progression. OBJECTIVE—To determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate. METHODS—Data on 120 patients with gout receiving allopurinol, in whom the starting dose was adjusted according to creatinine clearance rate and later increased in some patients to control the disease, were retrospectively reviewed. Two groups were compared: group A, 52 patients receiving creatinine clearance adjusted maintenance doses of allopurinol and group B, 68 patients receiving non-adjusted higher maintenance doses of allopurinol. RESULTS—During follow up 57% required higher allopurinol doses than those recommended according to their creatinine clearance rate. Only five (4%) of 120 consecutive patients developed allopurinol related adverse reactions: four minor skin reactions and one allopurinol hypersensitivity syndrome (AHS). Three of these (including the case of AHS) occurred in group A and two in group B (p=NS). The duration of allopurinol treatment was the same in both groups (group A: 2.3 (3.3) years; group B: 3.7 (4.8) years). No patient in group A, but 44% in group B had a creatinine clearance rate of

Sir, A relationship between allopurinol hypersensitivity syndrome (AHS) and viral infections, especially with human herpes virus (HHV)-6, has been suspected since the first report of AHS in 1970 [1]. Although participation of other opportunistic viral infections has also been reported, the mechanisms by which any of these contribute to AHS are still unknown. We report a case of a 39-year-old woman receiving peritoneal dialysis due to lupus nephritis who developed severe AHS, which may have resulted from influenza virus infection. She experienced a systemic skin rash with high fever just after administration of allopurinol. Both hypereosinophilia and high titre influenza virus type A-specific antibody were present before admission and at hospital day 6. Because antibody titres for HHV-6 IgG, Epstein-Barr virus, measles and rubella were positive but within the normal range, we suspected that the AHS may have been induced by influenza virus infection. Her symptoms diminished following withdrawal of allopurinol and administration of predonisolone. Current hypotheses for mechanisms of the AHS onset include two pathways Fig. ​Fig.1.1. First, storage of allopurinol and its metabolite, oxypurinol, may directly inflict cell damage, especially in patients with renal dysfunction. A second possible pathway suggests that a type III allergic reaction caused by allopurinol may induce the re-activation of HHV-6, or activation of other opportunistic viruses, such as cytomegalovirus [2] and Epstein-Barr virus [3], through the activation of T-lymphocytes. Recently, CD46 was identified as a receptor for HHV-6, and it was therefore suggested that this reactivated virus damages cells, including epidermal cells and lymphocytes, via CD46 binding [4]. In the present case, the influenza virus titre was elevated in parallel with the clinical symptoms of AHS, and it is possible that this virus exacerbated the cascade reaction in the same way as do other viruses. We suggest that such community-acquired bacterial and viral infections may also accelerate these cascade reactions and that genetic factors may interact with these events. Fig. 1 Possible mechanism for the onset of allopurinol hypersensitivity syndrome. In addition to established pathways (direct cellular injury and inactivation of viruses), community infection may accelerate the cascade. Conflict of interest statement. None declared.

ObjectivesAllopurinol is the most widely prescribed serum uric acid-lowering therapy (ULT) in gout. To achieve serum uric acid (sUA) concentrations associated with clinical benefit, allopurinol is serially uptitrated with sUA monitoring. Suboptimal dosing is a key contributor to poor clinical outcomes, but few data are available on the safety and efficacy of dose-titrated allopurinol, particularly at doses >300mg/d. The objective of this open-label study was to investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses.MethodsLong-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) was a large, 6-month, multicenter study of allopurinol (NCT01391325). Adults meeting American Rheumatism Association Criteria for Classification of Acute Arthritis of Primary Gout and ≥2 gout flares in the previous year were eligible. Investigators were encouraged (but not required) to titrate allopurinol doses to achieve target sUA < 6.0mg/dL. The primary objective was evaluation of the safety of dose-titrated allopurinol by clinical and laboratory examinations at monthly visits. Secondary objectives included sUA-lowering efficacy and gout flare frequency.ResultsOf 1735 patients enrolled, 1732 received ≥1 allopurinol doses. The maximal daily allopurinol dose during study was 300mg in 20.2% of patients; dosing duration was 115.5, 152.0, and 159.7 days, respectively. Overall, baseline demographic characteristics and comorbidity rates were similar across these three categories, but patients receiving >300-mg maximal dose had more severe gout. Treatment-emergent adverse events possibly related to allopurinol occurred in 15.2%, 9.5%, and 11.4% of patients in the 300-mg categories, respectively. Rash incidence was low (1.5%) and allopurinol hypersensitivity syndrome was not reported. No clinically meaningful changes occurred in laboratory values. sUA < 6.0mg/dL at month 6 was achieved by 35.9% of patients overall: 22.4%, 35.0%, and 48.3% in dosing categories 300mg, respectively.ConclusionsThis large multicenter study found that the allopurinol dose-titration strategy was well tolerated, without new safety signals emerging over 6 months. However, despite encouragement to treat to target, significant proportions of patients did not achieve target sUA.