Allopurinol Hypersensitivity Syndrome Research Articles

Allopurinol hypersensitivity syndrome Raising awareness of an uncommon but potentially serious adverse event among kidney stone patients.

Allopurinol is a commonly prescribed agent in the urologic population for the prevention of urinary stones. Although generally well-tolerated, several serious potential side effects can occur with its use. Allopurinol hypersensitivity syndrome (AHS), in particular, is a relatively rare but potentially life-threatening complication. With the observed increase in urinary stone disease, especially those of uric acid composition, it is likely that the use of allopurinol will increase. Urologists play an important role in the assessment and medical management of patients with urinary stones, thus a greater awareness of the potential adverse events associated with allopurinol use, especially AHS, is important, as well as strategies that can minimize such risks. Herein, we review the potential adverse effects of allopurinol. In addition, the results of a comprehensive review of the current literature on AHS will be presented, highlighting those patients at highest risk, reviewing the genetic susceptibility testing currently available, and providing guidance on best practices when allopurinol therapy is being considered.

Allopurinol hypersensitivity syndrome.

Allopurinol hypersensitivity syndrome includes Stevens–Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms. It affects about 1 in 1000 patients prescribed allopurinol, and reported mortality is between 20% and 25%.[1][1] Patients typically present

Pharmacological overview for therapy of gout and hyperuricemia

Hyperuricemia & gout are disease conditions marked by over production and reduced excretion of uric acid. These conditions are linked with unhealthy lifestyle, Hypertension, Diabetes Mellitus, Metabolic syndrome, Cardiovascular & Chronic renal disease. Thus controlling & monitoring uric acid level becomes important. Development in the technology have led to greater insights into the pathophysiology of gout & hyperuricemia. Now we have a better understanding of involvement of interleukin 1β in inflammatory process of gout. Thus with better understanding newer therapeutic targets are being explored for treatment of gout & hyperuricemia. The armamentarium of drugs being used in therapy of acute gout here been expanded with recent addition by interleukin-1 inhibitors especially for refractory patients and patients with comorbidities. As these new therapies are evolving we need to focus on improving the use of Allopurinol through patient education and training of physicians in order to minimize development of Allopurinol hypersensitivity syndrome (AHS). Further pretesting of Human leukocyte Antigen- B ( HLA-B*5801*) should be considered in Asian population. Febuxostat being critically new drug needs cautious approach, proper education of patients and Adverse Drug Reaction (ADR) reporting. With entry of Pegloticase there is a new class of drug added for treating hyperuricemia.

What’s new on the front-line of gout pharmacotherapy?

ABSTRACT Introduction Gout is the most common form of inflammatory arthritis affecting millions of persons around the world. Painful flares and tophaceous deposits are debilitating, reduce quality of life and put strain on health-care systems. Areas Covered This review provides an overview of the treatment of gout flares and lowering serum urate. First line agents are discussed with emphasis on emerging evidence. Novel therapies are also covered. Expert opinion Lifestyle modifications form a part of gout prevention. NSAIDs, colchicine, and glucocorticoids are first line agents for gout flares. The IL-1β antagonists are highly effective for arresting flares but their cost-effectiveness render them salvage therapies. Allopurinol is an agent of first choice for urate lowering therapy. In Southeast Asian and Black populations, screening for HLA*B58:01 mutation is a cost-effective approach to decrease the occurrence of allopurinol hypersensitivity syndrome. Febuxostat is another efficacious urate lowering therapy, but has received a U.S. FDA black box warning for cardiovascular safety. Novel uricosurics are a class for continued drug development; verinurad and arhalofenate are agents with future promise. For patients with recalcitrant gout, pegloticase is effective. Its immunogenicity significantly threatens the achievement of sustained urate lowering responses. Abrogating pegloticase’s immunogenicity with immunomodulatory co-therapy may lend to sustained efficacy.

Update on gout management: what is old and what is new.

The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality and societal costs. In this review, we discuss recent advances in epidemiology and treatment strategies for gout. Genetic factors and obesity are prominent contributors to hyperuricemia and gout, while dietary factors contribute to less variance in serum urate, though can still have some contribution to population attributable risk. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network outlined appropriate terminology regarding gout, which will aid in communication about various aspects of the disease. The 2020 American College of Rheumatology gout guideline offers comprehensive evidence-based recommendations for the management of hyperuricemia using urate-lowering therapy, prophylaxis when initiating urate-lowering therapy, treatment of gout flare and adjunctive management strategies. There is improved understanding of risk factors for allopurinol hypersensitivity syndrome and well tolerated use of allopurinol in chronic kidney disease. Trial data have provided new insights regarding cardiovascular risk with febuxostat. Several new drug therapies are being tested for both urate-lowering efficacy and gout flare management. Although there have been significant advances in understanding of risk factors and treatment approaches, gout remains suboptimally managed. There is substantial need for improving gout management efforts and gout education among patients and clinicians.

Flavones scaffold of Chromolaena odorata as a potential xanthine oxidase inhibitor: Induced Fit Docking and ADME studies.

Introduction: Gout is a type of painful inflammation initiated by the interactions between monosodium urate crystals and connective tissue. Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine, then to uric acid. The primary treatments for gout include XO inhibitors. At present, allopurinol is the most used XO inhibitor for the treatment of gout. However, it can cause adverse effects commonly known as allopurinol hypersensitivity syndrome, thereby limiting its usage. Consequently, it is necessary to develop potent and less toxic inhibitors of XO. Chromolaena odorata is one of such plants under investigation for its diverse health benefits. Methods: Phytochemicals of C. odorata were screened against XO receptor, using molecular docking. The top five hit compounds of glide docking yield flavones scaffold which were subjected to induced fit docking (IFD) and absorption, distribution, metabolism, and excretion (ADME) studies. Results: The result showed that flavones scaffold of C. odorata can bind with higher affinity and lower free energy values when compared to that of the standard, allopurinol. The IFD scores of the flavones scaffold range from -1525.25 to -1527.99 kcal/mol. Conclusion: Our results have shown that flavones scaffold might have the potential to act as an effective drug candidate when compared to allopurinol in treating and/or preventing gout and some inflammatory condition.

Clinical evaluation of a substitute of HLA-B*58:01 in different Chinese ethnic groups.

The goal of this research was to investigate the linkage disequilibrium between rs9263726 and HLA-B*58:01 in different Chinese ethnic groups (Han, Tibet, and Hui) and to study the feasibility of rs9263726 replacing HLA-B*58:01 as an efficient indicator of potential allopurinol hypersensitivity syndrome. In this study, rs9263726 and HLA-B*58:01 were detected in all samples. For samples of individuals whose rs9263726 genotypes were not consistent with HLA-B*58:01, we did high-resolution typing of HLA-B gene to further confirm the correlation of rs9263726 genotype and special HLA-B alleles. We confirmed that the linkage disequilibrium between rs9263726 and HLA-B*58:01 was more significant in the Han ethnic group (r2=0.886, D’=1.0) than in the Tibet and Hui ethnic groups (for Tibetan, r2=0.606, D’=0.866; for Hui, r2=0.622, D’=0.924). For Han Chinese, samples with the GG genotype of rs9263726 did not carry HLA-B*58:01, while AA genotype samples were homozygous carriers of HLA-B*58:01. However, GA genotype samples of rs9263726 required a more sophisticated HLA-B genotyping assay before it was possible to identify whether they were HLA-B*58:01 carriers or not. For Tibetan and Hui, the linkage disequilibrium between rs9263726 and HLA-B*58:01 was not significant. Therefore, rs9263726 cannot replace HLA-B*58:01 in these two groups.

How to prevent allopurinol hypersensitivity reactions?

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.

Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis.

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. 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. 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. 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.

Crystal arthritides - gout and calcium pyrophosphate arthritis : Part3: Treatment.

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 aquick 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. Arare 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.

The cost-effectiveness of HLA-B*5801 screening to guide initial urate-lowering therapy for gout in the United States.

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. 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. 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. 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.

Racial disparities in the risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the United States.

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. 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. 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%). 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.

A human leukocyte antigen locus haplotype confers risk for allopurinol-related adverse effects in Caucasian patients with gout.

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 (P>0.05). Our study is the first to demonstrate the potential utility of this six-SNP haplotype as a predictor of milder allopurinol AEs.

An open-label, 6-month study of allopurinol safety in gout: The LASSO study

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 14.4%, 300mg in 65.4%, and >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-, 300-, and >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 <300, 300, and >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.

Allopurinol hypersensitivity syndrome in patients with hematological malignancies: characteristics and clinical outcomes.

Background/AimsAllopurinol 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.MethodsThis 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.ResultsIn 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.ConclusionsPhysicians 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 inappropriate use in case of asymptomatic hyperuricemic patient causes fatal Allopurinol hypersensitive syndrome: lesson to all

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.

Urate-Lowering Therapy: Current Options and Future Prospects for Elderly Patients with Gout

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 (<0.36 mmol/L, or lower [<0.30 mmol/L] in those with tophi). After decades during which there has been relatively little interest in developing new agents to treat gout, the last 5-10 years has seen a plethora of new agents with several now used in routine clinical practice. There has also been a renewed focus on the optimal use of established ULT, specifically allopurinol, which remains the first-line therapy for most patients. There is emerging data on its use in patients with renal impairment and better recognition of risk factors of the rare but potentially lethal allopurinol hypersensitivity syndrome (AHS). Febuxostat, a new xanthine oxidase inhibitor, is now established in everyday practice. Uricosuric agents may be indicated in certain patient groups, whilst a new class of recombinant uricases (pegloticase) given by intravenous infusion may achieve dramatic and rapid urate-lowering effects. Cost and other factors have thus far limited its use to the very severe cases. Furthermore, increased understanding of urate metabolism has led to the development of a number of drugs currently under clinical evaluation. Common therapeutic targets are the urate transporters in the kidney and alternative xanthine oxidase inhibition pathways. These advances bode well for the better management of gout and hyperuricaemia in our elderly patients.

Safety profile of anti-gout agents

Recent interest in gout has led to development of new drugs for acute gout and long-term urate-lowering, as well as interest in improving the use of older drugs. The patients' comorbidities and concomitant medications may contribute to the risk of adverse drug reactions with anti-gout therapies. This review will highlight recent data on the safety of drugs used in gout. Colchicine has a narrow therapeutic index, and low doses are effective with less gastrointestinal toxicity. There are significant interactions between colchicine and CYP3A4 and P-glycoprotein inhibitors, and the colchicine dose must be reduced. Allopurinol and febuxostat have similar adverse effect profiles. Recent data have highlighted the risk association of HLA-B5801 in some ethnic groups and of allopurinol starting dose in allopurinol hypersensitivity syndrome. Further long-term cardiovascular safety data in patients with cardiovascular disease or cardiovascular risk factors receiving febuxostat and allopurinol are pending. Infusion reactions are common in patients receiving pegloticase, particularly in patients with pre-infusion serum urate above 0.36mmol/l (6 mg/dl). In general, treatments for gout are well tolerated, although clinicians must keep in mind the potential for drug interactions and the contribution of comorbidities to the potential for adverse effects with gout therapies.

Safety and Efficacy of Allopurinol in Chronic Kidney Disease

To review the evidence surrounding the use of allopurinol in chronic kidney disease (CKD) and discuss safety and efficacy considerations of such use. A literature search was conducted through MEDLINE (1950-July 2013), PubMed (1965-July 2013), and International Pharmaceutical Abstracts (1970-July 2013) using the search terms allopurinol and kidney or renal. In addition, reference citations from publications identified were reviewed. All articles in English identified from the data sources were evaluated for inclusion. Gout management with allopurinol in patients with CKD can be challenging because of the risk of adverse events and uncertain efficacy. Not all gout treatment guidelines provide recommendations for allopurinol use specifically in patients with CKD. Literature regarding the safety and efficacy of dosing allopurinol in CKD has shown inconsistent results and is based primarily on retrospective, case cohort or observational data. Some trials have demonstrated an increased risk of allopurinol-induced adverse reactions in patients with CKD, whereas others have not confirmed renal insufficiency as a risk factor. More CKD patients achieved a target uric acid level in studies where the allopurinol dose was titrated to effect as compared with those studies in which patients were given renally adjusted or untitrated allopurinol doses. Studies evaluating allopurinol use in patients with CKD have reported inconsistent findings relative to safety and efficacy. Providers should be aware of the potential risk of allopurinol hypersensitivity syndrome as well as the need for reducing the initiation dose and gradual titration of allopurinol to safely achieve a target serum urate level in this population.

Association Between Adverse Reactions to Allopurinol and Exposures to High Maintenance Doses

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. 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. 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%). 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.