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We thank Dr Lai for their interest in our study (1). While we did not show a statistically significant link between the use of allopurinol and mortality in people with gout, we agree that Allopurinol Hypersensitivity Syndrome (AHS) is the most serious side-effect of allopurinol, particularly in populations with South East Asian ancestry, leading to the recommendation to screen people of South East Asian descent for the HLA-B*5801 allele prior to starting treatment with allopurinol (2,3).

Background Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain. Methods The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR−), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated. Results In nine population-control studies, HLA-B*5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR−, DOR and AUC were 0.78 (95% CI = 0.71–0.85), 0.96 (95% CI = 0.96–0.97), 14.23 (95% CI = 7.89–25.63), 0.29 (95% CI = 0.16–0.54), 83.5 (95% CI = 50.7–137.4), and 0.97 (95% CI = 0.95–0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3–672.0), Japanese (78.8; 95% CI = 30.4–203.9), and Caucasian (58.4; 95% CI = 16.9–201.5) populations. Overall, HLA-B*5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50–60% sensitivity (pooled sensitivity 56%), compared to the 80–100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations. Conclusions The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B*5801 for detecting allopurinol-induced TEN/SJS is universal. Screening of HLA-B*5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (≥ 5%) risk allele frequency.

Objective Positive HLA-B*5801 carriers are at greater risk of experiencing rare but severe allopurinol hypersensitivity syndrome (AHS) [i.e., Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)]; however, HLA-B*5801 prevalence and AHS risk vary by race/ethnicity. We evaluated the cost-effectiveness of HLA-B*5801 testing according to race/ethnicity in the United States. Methods We determined the cost-effectiveness of universal testing for HLA-B*5801 compared to no testing prior to the initiation of allopurinol per US major race/ethnicity groups. Using US-specific data, SJS/TEN risks and HLA-B*5801 prevalences were modeled per race/ethnicity (i.e., 1/3846 and 0.7% among Caucasians and Hispanics, 1/735 and 3.8% among African Americans, and 1/336 and 7.4% among Asians, respectively). Those who tested positive for HLA-B*5801 received febuxostat. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime. Results Compared to no testing, universal testing for HLA-B*5801 costs more and was more effective for all races/ethnicities. The ICERs varied substantially across racial/ethnic groups, following their HLA-B*5801 prevalences . HLA-B*5801 testing was cost-effective for African Americans (ICER $83,450) and Asians (ICER $64,190), but not for Caucasians or Hispanics (ICER $183,720), using accepted US willingness-to-pay threshold ($109,000/QALY). Results were robust in sensitivity analyses, except that reducing the risk of SJS/TEN by a half made testing not cost-effective for all races/ethnicities. Conclusion Testing for HLA-B*5801 prior to allopurinol initiation is cost-effective for Asians and African Americans, but not for Caucasians or Hispanics in the United States. Reducing AHS risk by other predictive measures could make HLA-B*5801 testing not cost-effective even among Asians and Blacks.

The treatment of gout is based on several principles. Symptom control and termination of the inflammatory process are important early goals, whereas the urate level should be lowered in the long term to prevent further gout attacks and complications. The non-pharmacological approach is based on individually informing the patient on dietary measures and changes of life style. Besides physical measures, such as cold applications on the affected joint, various medications are available for treatment of an acute gout attack. The choice of drug depends on the individual risk profile. If non-steroidal anti-inflammatory drugs (NSAID) and coxibs are chosen it should be taken into account that the use is restricted in patients with renal insufficiency. Moreover, these drugs may have gastrointestinal side effects and are associated with increased cardiovascular morbidity and mortality. Colchicine has gastrointestinal side effects at high dosages but can also be used for differential diagnostics if there is a quick response to treatment. Steroids are an effective alternative and can be given orally or parenterally in patients with dysphagia. Moreover, steroids can be used in cases of renal insufficiency. After symptoms of the acute attack have subsided, urate lowering therapy should be initiated to prevent further attacks. Low-dose urate lowering therapy can be started during an acute gout attack when acute therapy is initiated. Allopurinol is still the medication of choice but its use is restricted in patients with renal insufficiency. A rare but serious side effect is allopurinol hypersensitivity syndrome. Febuxostat can be an alternative in patients who do not tolerate allopurinol. In February 2016, lesinurad, an URAT-1 and OAT-4 inhibitor, was approved in combination with allopurinol or febuxostat. Data on the effectiveness and safety of synthetic uricases and biologicals are still sparse for elderly patients. These substances are reserved for severe cases of gout.

Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life-threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures. Most cases occur within 8-9 weeks of commencing allopurinol, and good patient education at initiation may lead to rapid drug cessation at onset of symptoms. Pretreatment testing for HLA-B*5801 and avoidance of allopurinol when positive reduces the risk of AHS and is cost-effective in some ethnic groups. A low starting allopurinol dose may reduce AHS risk, but the relationship between maintenance dose and AHS is more controversial. Chronic kidney disease increases AHS risk, but slowly increasing the allopurinol dose in chronic kidney disease has not been associated with AHS. Alternative newer treatments are available for patients at risk of AHS, but similar adverse reactions can also occur with these.

Gout is increasingly seen in the elderly population, in large part due to physiological decline in renal function with age, and as a result of therapy for comorbidities, in particular the use of diuretic therapies for hypertension and congestive heart failure. Urate-lowering therapy (ULT) is the cornerstone of successful long-term gout management with the aim of achieving a sustained reduction in urate (

Allopurinol is used to treat hyperuricemia (HU) in a patient of gout. It is also used to prevent HU in a patient of hematological malignancies who are about to undergo chemotherapy. Allopurinol is usually well-tolerated but it occasionally induces hypersensitivity reactions that manifest after few months of therapy. Cutaneous reactions are pruritic, erythematous, or maculopapular eruptions. Rarely fatal toxic epidermal necrolysis or Stevens-Johnson syndrome may occur. Transient leukopenia or leukocytosis, eosinophilia and elevated transaminases may also occur. HU is not a disease in itself. Its level is highly variable in the general population. Uric acid level is influenced by many factors such as dietary intake of proteins, hypertension, and obesity. Only very rarely patients of AHU may progress to gout and renal stones. Not much data is available that support HU alone in an asymptomatic patient in later life shows the diseases which are associated with HU. Sometimes only lifestyle changes, diet restrictions, alcohol restrictions, and treatment of underlying acquired cause may correct HU. Here, we are presenting a rare case of allopurinol hypersensitivity syndrome in an AHU patient. Our aim is to raise awareness among physicians so that they avoid using unnecessarily allopurinol in AHU patients and also titrate the dose of allopurinol in patients of renal failure. Risk-benefit ratio must be considered in these patients before starting allopurinol.

Gout is a common condition which is mainly treated with the hypo-uricemic agent, allopurinol. Although allopurinol is generally a well-tolerated drug, there is a small risk of developing potentially fatal complications, such as allopurinol hypersensitivity syndrome. Recent advances in pharmacogenomics have made possible the identification of genes which confer susceptibility to specific drugs. A recent multi-national case-control study has reported allopurinol as the most common drug associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Several studies have established a strong association between the human leukocyte antigen (HLA)-B*5801 gene and development of Stevens-Johnson syndrome and toxic epidermal necrolysis. The allele frequency of HLA-B*5801 is highest in the South East Asian population.Since other hypo-uricemic agents are available, patients may wish to have HLA-B*5801 testing before being started on allopurinol. As the test for HLA-B*5801 is expensive, time-consuming and only available in selected laboratories, there is a need to evaluate the utility and cost-effectiveness of this test in our region.

Objective The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these "non-gout diseases" has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these "non-gout diseases" and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. Methods Pubmed was searched in January 2016 using the search term "asymptomatic hyperuricaemia". Results and Conclusions Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature.

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.

Objective Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of ≥300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS. Methods A retrospective case–control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (±10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls. Results Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of ≥1.5 mg per unit of estimated GFR (mg/ml/minute). Conclusion Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.

Background. Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLAB*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity. Methods. We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010. Results. Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens–Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLAB58 [18% in HLA-B58 (1) versus 0% in HLA-B58 (� )]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol. Conclusions. In this study, the incidence of allopurinolinduced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.

Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B*5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B*5801 in a Thai population that has a high allelic frequency of this allele.Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B*5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B*5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B*5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B*5801 allele was 1.52 and 100%, respectively.A strong association of allopurinol-induced SJS/TEN with the HLA-B*5801 allele was observed in a Thai population. The results suggest that HLA-B*5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for dosesor = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing toor = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries.The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population.HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam.Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam.At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.

Allopurinol is the mainstay of urate-lowering therapy for patients with gout and impaired renal function. Although rare, a life-threatening hypersensitivity syndrome may occur with this drug. The risk of this allopurinol hypersensitivity syndrome (AHS) is increased in renal impairment. The recognition that AHS may be because of delayed-type hypersensitivity to oxypurinol, the main metabolite of allopurinol, and that oxypurinol concentrations are frequently elevated in patients with renal impairment prescribed standard doses of allopurinol has led to the widespread adoption of allopurinol-dosing guidelines. These guidelines advocate allopurinol dose reduction according to creatinine clearance in patients with renal impairment. However, recent studies have challenged the role of these guidelines, suggesting that AHS may occur even at low doses of allopurinol, and that these guidelines lead to under-treatment of hyperuricemia, a key therapeutic target in gout. Based on current data, we advocate gradual introduction of allopurinol according to current treatment guidelines, with close monitoring of serum uric acid concentrations. In patients with severe disease and persistent hyperuricemia, allopurinol dose escalation above those recommended by the guidelines should be considered, with careful evaluation of the benefits and risks of therapy. Further work is needed to clarify the safety and efficacy of allopurinol dose escalation, particularly in patients with renal impairment.

A human leukocyte antigen haplotype comprising six single-nucleotide polymorphisms (SNPs) confers risk for allopurinol hypersensitivity syndrome in Caucasians. The objective of the current study was to test for association of this haplotype with other, less severe adverse effects (AEs) of allopurinol therapy in a large New Zealand gout cohort. A total of 626 Caucasian and 766 Polynesian patients were genotyped for six SNPs (rs2844665, rs9263715, rs3130931, rs3130501, rs3094188, rs9469003) using TaqMan SNP assays. The CACGAC haplotype occurred at a frequency of 0.018 in Caucasians and 0.009 in Polynesians. The CACGAC haplotype occurred at a significantly higher frequency in Caucasian patients who experienced allopurinol-related AEs (13.3 vs. 1.7%, P=8.9e-06, odds ratio=8.9, 95% confidence interval 2.8-27.9), but it was not associated with overall allopurinol toxicity in Polynesians (P0.05). Our study is the first to demonstrate the potential utility of this six-SNP haplotype as a predictor of milder allopurinol AEs.

Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol–SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol–SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol–SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) ( P < 10 –7 ). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol–SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4–9780.9); corrected P value = 4.7 × 10 –24 ] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23–6665.26); corrected P value = 8.1 × 10 –18 ]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol–SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.

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

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.

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.

We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities.

Objective The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function. Methods We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models. Results Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%). Conclusions There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL.

Background Although uncommon, the most feared adverse event of urate-lowering drugs (ULDs) is allopurinol hypersensitivity syndrome (AHS), primarily manifesting as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). HLA-B*5801 allele carriage (a strong determinant of AHS) varies substantially among races, which may lead to major racial disparities in the risk of SJS/TEN in the context of ULD adverse events (ULDAEs). Such information could immediately help risk stratification to prevent these severe ULDAEs. Objectives To examine potential racial disparities in the risk of SJS/TEN in the context of ULDAEs in a large, racially diverse, and generalizable population. Methods Using the Nationwide Inpatient Sample (NIS, 2009–2013), a database representative of all US hospitalizations, we examined the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes); this combination implicates allopurinol, which is the only ULD established to cause SJS/TEN. Our reference groups were the US Census population, US allopurinol users (from the NHANES), and ULDAE hospitalizations without SJS/TEN (from the NIS). Results We identified 606 patients hospitalized for SJS/TEN as ULDAEs meeting our criteria between 2009–2013 (mean age, 68 years; 44% male). Of these 606 patients, there was a substantial over-representation of Asians (27%) and Blacks (26%), and an under-representation 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 (allopurinol users and ULDAE cases without SJS/TEN). 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% among Asians, Blacks, and Whites, Hispanics, respectively). As no other ULDs available in the US have been established to cause SJS/TEN, these findings support the use of vigilance in these minorities when considering allopurinol. Disclosure of Interest None declared

Allopurinol may induce severe hypersensitivity characterized by hepatitis, interstitial nephritis, and skin rash. The mechanisms for this hypersensitivity syndrome are incompletely elucidated. Immunologic studies were performed on tissue and peripheral blood lymphocytes from a patient with allopurinol hypersensitivity. Immunohistochemistry was performed on sections of the liver biopsy utilizing monoclonal antibodies for T and B lymphocytes. Peripheral blood lymphocyte immunophenotyping by flow cytometry and peripheral blood lymphocyte stimulation studies with either allopurinol or oxypurinol measured as tritiated thymidine uptake were performed in the hypersensitive patient and compared to a group of six patients treated with allopurinol without hypersensitivity and eight normal control patients. Additional single- and dual-color immunophenotyping by flow cytometry of oxypurinol-stimulated lymphocytes was performed in the hypersensitive patient and compared to normal controls. The liver biopsy demonstrated predominantly a T lymphocyte infiltrate. The number of peripheral blood lymphocytes expressing activation antigens was significantly greater in the hypersensitive patient compared to that of both control groups. Lymphocytes from the hypersensitive patient were moderately stimulated by allopurinol and markedly stimulated by oxypurinol compared to both control groups. Oxypurinol-stimulated lymphocytes from the hypersensitive patient demonstrated enhanced expression of activation antigens compared to unstimulated lymphocytes from this patient and normal controls. These studies suggest that cell-mediated immunity directed toward allopurinol and more importantly to its oxypurinol metabolite is involved in the pathogenesis of allopurinol-induced hypersensitivity.

Objective.Allopurinol, a purine base analog inhibitor of xanthine oxidase (XO) activity, remains the standard for pharmacologic urate-lowering management of gout. Allopurinol is efficacious and safe in most patients, but intolerance is estimated to occur in up to 10% of treated patients. Severe or life-threatening allopurinol adverse reactions (AE) occur much less frequently, and include severe cutaneous allopurinol reactions, vasculitis, and/or a multisystem allopurinol hypersensitivity syndrome. During clinical development of febuxostat (FEB), a recently approved non-purine analog inhibitor of XO, subjects with severe allopurinol intolerance were excluded from randomized double-blind FEB/allopurinol comparative trials.Methods.In this retrospective study, safety and urate-lowering efficacy of FEB was assessed in 13 successively encountered gout patients with prior documented severe allopurinol reactions.Results.FEB was well tolerated in 12 of 13 patients, each of whom remains on treatment. One patient previously hospitalized with documented exfoliative erythroderma during allopurinol treatment, developed biopsy-confirmed cutaneous leukocytoclastic vasculitis. None of the other 12 patients treated with FEB showed rash, worsening hepatic function, blood cytopenia or eosinophilia.Conclusion.In 12 of our 13 gout patients with previously documented severe allopurinol AE, FEB treatment was safe. However, the development of a hypersensitivity type cutaneous vasculitis (likely but not definitively FEB-related) early in treatment mandates caution, careful dose escalation, and close monitoring when FEB urate-lowering therapy of allopurinol-intolerant patients is considered.

This is a case series of allopurinol-induced toxic epidermal necrolysis. Revisiting the indications of using allopurinol in asymptomatic hyperuricemia and a critical reappraisal of the safety profile of allopurinol is done in this article. The report is based on case presented at a tertiary hospital in Singapore. The aim of this study is to highlight the fatal consequences of the indiscriminate use of allopurinol. We report four cases of toxic epidermal necrolysis from allopurinol, three of which resulted in death. Our aim is to highlight that allopurinol in all these cases was not indicated and prescribed for asymptomatic hyperuricemia. The incidence and potentially severe and lethal consequences of allopurinol hypersensitivity syndrome and toxic epidermal necrolysis could be kept to a minimum by strictly adhering to the established indications of allopurinol treatment.

This is a case report of a 36-year-old male with tophaceous gout for 16 years. He started therapy with 300 mg/day of allopurinol. He had received variable dexamethasone doses by self-prescription for 16 years. When allopurinol was initiated, he had hyperuricemia and normal renal function. Twenty days after starting allopurinol, he presented diffuse maculopapular rash, conjunctivitis, increase in serum creatinine values, leukocytosis and eosinophilia and the diagnosis of allopurinol hypersensitivity (AH) syndrome was made. He completely recovered from the AH and renal function normalized. However, the gout worsened over the following years in spite of treatment with benzobromarone, low doses of prednisone, and colchicine. Allopurinol desensitization was successful beginning with an oral low dose scheme (6.5 mug/day) until we reached 300mg/day. Today the patient receives allopurinol with no side effects. We believe that this is the first reported example of successful desensitization in full-blown AH with renal involvement. Our cautious regimen might be tried in other such patients.

There is no clear definition of severe gout indeed, several terms refer to severe gout but had not been clearly defined: Severe gout, refractory gout, chronic tophaceous gout, resistant to treatment gout, treatment failure gout. Gout patients frequently have severe associated conditions (metabolic and cardiovascular diseases) that determine its treatment, we will discuss mainly the characteristics and treatment for patients with severe gout per se and gout related renal disease. The scarce proposals for severe gout definition had considered as severe gout:gout arthropathy in >4 joints or ≥1 unstable, complicated, severe articular tophus or tophi; or frequent oligoarticular flares, numerous tophi, joint damage and musculoskeletal disability or ≥5 tophi and/or intradermal tophi. Based in them, we will consider for this presentation severe gout as ≥5 tophi, frequent flares and chronic structural joint damage. Treat to target strategies in rheumatology had considered: Remission, prevention of structural damage and improvement of quality of life. Most rheumatologists agree that these 3 outcomes can be obtained in almost all gout patients if they receive adequate treatment since the onset. In this sense, the most frequent cause of severe gout is longtime inadequate treatment that could prevent irreversible changes. Goals The treatment for severe gout is essentially the same treatment for regular gout, although some characteristics require discussion and alternatives. The objective of the chronic treatment for gout is sUA Allopurinol sub-optimal doses and renal function Many patients with severe gout are the consequence of allopurinol doses strictly adjusted to renal function in order to prevent Allopurinol hypersensitivity syndrome (AHS), in the last decade, several authors coincide that higher doses can be used safely in patients with Gout and this is determinant for improvement in gout and renal variables. AHS is associated in Asia with HLAB*5801, but not in other populations; start low allopurinol doses and careful increase is recommended. High allopurinol doses are reqiired and probenecid can be aggregated to therapy. Also, febuxostat and pegloticase if available, could be used as adjuvant therapy. In some countries benzobromarone is available with good results. Allergy to allopurinol Is observed in around 5% as first chooice, we use probenecid, plus fenofibrate or losartan when needed. If we can not control acute flares and tophus regression, desensitization to allopurinol is indicated. We start with very low doses (50 μg/day) and increase carefully, we need around 3 months to reach 100 mg/day dose. ul in 7/10 treated patients. Other treatment options for them are febuxostat or pegloticase when available. Gout modified by chronic glucocorticoid treatment The inappropriate use of glucocorticoids (either by wrong prescription or by self-prescription) is one of the most important causes of severe gout in many countries.In some countries, glucocorticoids can be obtained without medical prescription, they are very cheap drugs (cheaper than NSAIDs) and patients frequently use them for flares, but without chronic ULT. So, they have frequent and severe flares, require higher doses each time and when they attend to Rheumatologists, frequently have secondary Cushing syndrome with all the metabolic complications. For treatment, we use equivalent doses of prednisone and taper it very slowly until stop (mean time 8 months). At the same time, start with allopurinol and add colchicine, antibiotics when needed; some require hospitalization and surgery. The paper of surgery needs to be stablished, in our experience surgery only should be practiced when tophi complications are associated with infection, tendon, vascular or nerve compressions. Other clinical conditions very important for the treatment of severe gout patients will be presented and discussed. (early age at onset, lithiasis, role of colchicine etc) Severe gout is related with low educational and socio-economic level and limited access to health care, auto-prescribed therapy and the use of alternative treatments. The result is sub-optimal treatment for gout due to multiple causes: physicians frequently do not consider gout important task and prescribe sub-optimal treatment, the patients frequently have evasive coping pattern and in some countries, health authorities frequently do not consider gout as an important health problem. Disclosure of Interest None declared

Background/aims Allopurinol is a urate-lowering agent that is commonly used to prevent chemotherapy-related hyperuricemia. Allopurinol hypersensitivity syndrome (AHS) is a disorder involving multiple organs, which may be accompanied by cutaneous adverse reactions. We identified the characteristics and clinical outcomes of chemotherapy-associated AHS in patients with hematological malignancies. Methods This retrospective single-center study included 26 AHS patients (11 with and 15 without hematological malignancies) admitted to Seoul St. Mary's Hospital. AHS was defined using the criteria of Singer and Wallace. Comparisons were made using the Mann-Whitney U test and Fisher exact test as appropriate. Results In patients with a hematological malignancy and AHS, statistically significant differences were observed in terms of younger age at onset; shorter duration of exposure; higher starting and maintenance doses of allopurinol; lower incidence of eosinophilia, leukocytosis, and underlying renal insufficiency; and more frequent occurrence of fever compared to AHS patients without a hematological malignancy. Two AHS patients with a hematological malignancy were examined for human leukocyte antigen (HLA)-B typing, but neither patient harbored the HLA-B*5801 allele. All of the patients ceased allopurinol treatment, with most patients making a full recovery. Two patients in the study died; however, these deaths were unrelated to AHS. One patient developed serious sequelae of AHS that required hemodialysis. Conclusions Physicians who prescribe allopurinol for the prevention of chemotherapy-related hyperuricemia should be aware of the unique risk of AHS, even in patients with hematological malignancies who do not have known risk factors for AHS. Novel urate-lowering agents should be considered alternative treatments.

Allopurinol is a xanthine oxidase inhibitor widely used to control plasma uric acid levels. Episodes of hypersensitivity to the drug are not rare. A severe form of this with a generalized exanthem, fever and liver involvement has been termed the allopurinol hypersensitivity syndrome (AHS). Patch testing and lymphocyte stimulation testing (LST) are not helpful in confirming this sensitivity. Allopurinol works as a substrate of xanthine oxidase, and is rapidly oxidized into oxypurinol in vivo. Therefore, the biological half-life of oxypurinol is markedly longer than that of allopurinol. In addition, conspicuous pre-existing renal impairment has been noted in many AHS patients. Thus, it is possible that AHS is a manifestation of hypersensitivity to oxy-, not allopurinol. Here, we now report three cases of AHS in which there were significant lymphoproliferative reactions to oxypurinol but not allopurinol.

Allopurinol hypersensitivity syndrome(AHS) is a severe form of cutaneous adverse reaction that is associated with significant morbidity and mortality. We report a case of AHS with the cutaneous manifestation of acute generalised exanthematous pustulosis(AGEP). A 47 year old gentleman, with no previous skin disease, presented with a generalized mildly pruritic erythematous rash on the trunk and all 4 limbs, with patches of superficial non-follicular pustules. Our patient fulfilled both criteria for AGEP and 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

A 43-year-old man developed fever, skin rash, eosinophillia, and severe renal and liver dysfunction following treatment with allopurinol. The patient died after 3 months of hospitalization. Autopsy revealed systemic cytomegalovirus infection and bacteremia.

Allopurinol hypersensitivity syndrome is a severe adverse reaction characterized by rash, fever, and internal organ involvement. We report a case of fatal allopurinol-induced hypersensitivity syndrome associated with acute pancreatitis.A 46-year-old man was treated by allopurinol for asymptomatic hyperuricemia. The patient developed a diffuse erythrodermic maculopapular eruption and fever. Laboratory analysis revealed cytolysis and cholestasis, amylases and lipases were highly elevated. Computed tomography scans revealed pancreatitis Grade C. The treatment of asymptomatic hyperuricemia should only be initiated when there is a clear indication to reduce the incidence and the severe consequences of allopurinol hypersensitivity syndrome.

We investigated the relationship between the toxic effect of allopurinol and pyrimidine metabolism in mice. Allopurinol-induced increases in plasma transaminase levels in dinitrofluorobenzene (DNFB)-sensitized mice were not affected by uridine. In contrast, plasma creatinine and BUN tended to decrease 18 hr after the last injection of uridine. Both plasma and urinary orotidine (OD) were detected in DNFB-sensitized mice after administration of a single dose of allopurinol. In contrast, TEI-6720, a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, caused neither pyrimidine metabolism abnormality nor renal impairment in DNFB-sensitized mice. Also, normal mice administered high doses of allopurinol showed abnormal pyrimidine metabolism together with renal toxicity which could be ameliorated by uridine, indicating that allopurinol essentially causes pyrimidine metabolism abnormality leading to renal impairment. In DNFB-sensitized mice, allopurinol increased urinary OD excretion to an extent similar to that in normal mice administered the same dose of allopurinol. However, renal impairment by allopurinol was more striking in DNFB-sensitized mice than in normal mice. Histopathological observations showed that allopurinol induced calculus formation in the collecting tubules and papillary duct. Calculus formation was increased by DNFB and decreased by uridine. These observations indicate that the enhancement of the renal toxicity of allopurinol by DNFB-sensitization may be due to some biological interactions between DNFB and allopurinol. In humans, it is possible that there are some biological interactions which serve to enhance the toxicity of allopurinol, resulting in the development of allopurinol hypersensitivity syndrome (AHS). In contrast, TEI-6720, had no effect on pyrimidine metabolism and showed no toxic effect.

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.

Background The prevalence of urolithiasis in general Chinese population was 5%>10%. It has been reported as a common complication of gout in many countries (20%>39.5%) but not yet in China. Urolithiasis is one of the contraindications of uricosuric drugs. However, allopurinol, the only other available urate lowering drug in China, has been confirmed high risk of allopurinol hypersensitivity syndrome in Chinese population and those with chronic kidney disease. Objectives To investigate the prevalence of urolithiasis in southern Chinese gout patients and the possible risk factors. Methods 201 hospitalized patients with primary gout were recruited and their clinical data were collected. Current urolithiasis was defined as positive image finding including ultrasound, plain film or computer tomography. Positive history of urolithiasis delivery or urolithiasis surgery but negative image finding was defined as previous urolithiasis. Results (1)Among 201 gout patients, 89.1% were male with mean age 57.5±16.9 years while 10.9% were female with mean age 68.5±11.9 years. The mean disease duration was 7.9±7.4 years with involved joints 6.4±7.4. 30.7% patients presented tophi. The average serum uric acid (sUA) was 8.9±2.7mg/dl with 24h uric acid excretion 451.9±240mg. 91.6% patients excreted uric acid lower than 800mg/24h. Serum creatinine was 133.1±84.6umol/l and estimate glomerular filtration rate (eGFR) 60.0±19.4ml/min. (2) 33.8% patients complicated with urolithiasis, of which 75.0% were current urolithiasis and 33.8% were current urolithiasis without positive urolithiasis history. 84.3% were neprolithiasis and 57.1% were multiple urolithiasis. (3)Table 1 showed significant differences of sUA, hyperuricemia, eGFR, impaired renal function and renal cyst between urolithiasis group and non-urolithaisis group. Current urolithiasis exacerbate eGFR more than previous urolithiasis (51.4±18.3ml/min VS 61.8±17.8ml/min, P=0.045). (4) Urolithiasis was significantly correlated with hyperuricemia (r=0.156, P=0.027), impaired renal function (r=0.27, P Conclusions Our results showed high prevalence of urolithiasis in southern Chinese gout patients. Routine imaging test on urinary system should be performed to detected urolithiasis in all gout patients especially for those with renal impairment. Disclosure of Interest None Declared

OBJECTIVE: To review the pathophysiology, pathology, and clinical findings of allopurinol hypersensitivity syndrome (AHS), an infrequent but life-threatening adverse effect of allopurinol therapy. DATA SOURCES: A MEDLINE search (key terms hepatitis, interstitial nephritis, severe hypersensitivity, severe toxicity, vasculitis, toxic epidermal necrolysis, Lyell's syndrome, erythema multiforme, and Stevens-Johnson syndrome) was used to identify cases reported in the literature through the end of 1990. STUDY SELECTION: All cases evaluated met Singer and Wallace's diagnostic criteria for AHS. DATA EXTRACTION: We extracted data from 101 cases of AHS reported in the literature. The following information, when available, was analyzed: (1) patient data (age, gender, medical history), (2) treatment data (daily dosage of allopurinol, duration of treatment, indications, concomitant medications, and (3) adverse-event data. DATA SYNTHESIS: Patients were mostly middle-aged men with hypertension and/or renal failure receiving excessive doses of allopurinol primarily for asymptomatic hyperuricemia. Cutaneous rash and fever were the most common clinical findings. CONCLUSIONS: Although the pathophysiologic pathway leading to the development of AHS is unknown, it probably involves an immunologic mechanism following allopurinol accumulation in patients with poor renal function. Our findings suggest that the accepted diagnostic criteria for AHS may be too broad, and we recommend the application of more restrictive criteria. There is no effective treatment for AHS. The use of allopurinol only for accepted indications and in dosages adjusted for a patient's renal function may be the only means of minimizing the incidence of AHS.

Keywords: erythema-multiforme-like eruption; amoxycillin; allopurinol hypersensitivity syndrome; systemic contact dermatitis; adverse cutaneous drug reactions; antibiotics; medicaments

Allopurinol, an analogue of hypoxanthine, which inhibits xanthine oxidase, is an effective urate lowering drug that has been the cornerstone in the treatment of hyperuricaemia and gout for decades. In most patients, the drug is well tolerated, however, about 2% of treated patients develop a skin rash. Also, an estimated 0.4%, particularly people with kidney failure or having concomitant thiazide diuretic therapy, may experience a severe idiosyncratic reaction, known as allopurinol hypersensitivity syndrome. This syndrome is characterised by skin reactions, fever, eosinophilia, and multiorgan involvement, with a mortality of 25%.1–3 About 5% of the population and a quarter of hospitalised patients are hyperuricaemic. Most are asymptomatic and will never develop gout. Also, high urate concentrations do not seem to cause cardiovascular disease, as was previously thought.4 Consequently, urate lowering agents are not indicated in the treatment of asymptomatic hyperuricaemia.4 5 We report a case of fatal allopurinol hypersensitivity syndrome after inappropriate treatment of asymptomatic hyperuricaemia. An 80 year old man started treatment with 300 mg allopurinol a day for asymptomatic hyperuricaemia. Uric acid concentration was measured as part of a routine biochemical profile, and was 517 μmol/l. Six weeks later he developed asthenia, anorexia, fever, diarrhoea, jaundice, abdominal pain, and pruritic skin lesions. His past medical history included a duodenal ulcer, high blood pressure, and chronic renal insufficiency. He was taking omeprazole and furosemide. On examination he was feverish. We noticed hepatomegaly, jaundice, and exfoliated skin. The white cell count was 15.4 × 109/l, with 16% eosinophils. Creatinine …