DINESH KHANNA, JOHN D. FITZGERALD, PUJA P. KHANNA, SANGMEE BAE, MANJIT K. SINGH, TUHINA NEOGI, MICHAEL H. PILLINGER, JOAN MERILL, SUSAN LEE, SHRADDHA PRAKASH, MARIAN KALDAS, MANEESH GOGIA, FERNANDO PEREZ-RUIZ, WILL TAYLOR, FREDERIC LIOTE, HYON CHOI, JASVINDER A. SINGH, NICOLA DALBETH, SANFORD KAPLAN, VANDANA NIYYAR, DANIELLE JONES, STEVEN A. YAROWS, BLAKE ROESSLER, GAIL KERR, CHARLES KING, GERALD LEVY, DANIEL E. FURST, N. LAWRENCE EDWARDS, BRIAN MANDELL, H. RALPH SCHUMACHER, MARK ROBBINS, NEIL WENGER, AND ROBERT TERKELTAUB

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2012 American College of Rheumatology guidelines for management of gout. Part 1: Systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia

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.

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HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol

Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations.

Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach.

Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L ) and <5 mg/dL (300 µmol/L ) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended.

Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

https://ard.bmj.com/content/annrheumdis/76/1/29.full.pdf

2016 updated EULAR evidence-based recommendations for the management of gout

Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study

Background Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS–TEN) in the Han Chinese and other Asian populations but not in European populations. Methods We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. Results The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Nor...

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HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

BackgroundStevens–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 s

A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.

OBJECTIVE To draw attention to the many cases of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) related to nevirapine detected in a multinational case-control study of SJS and TEN. METHODS Actively detected cases and matched hospital controls were interviewed for exposure to drugs and other risk factors. Data were analysed with case-control and case-crossover methods. RESULTS Between May 1997 and November 1999, a diagnosis of SJS or TEN was established in 246 patients. Eighteen were known to be infected by HIV-1 (7.3%), 15 out of these 18 had been exposed to nevirapine. The reaction began 10-240 days after the introduction of nevirapine (median, 12 days) and all patients had received escalating doses. In 10 patients the reaction occurred with the initial dosage. All but one patients received simultaneously a variety of other antiretroviral agents but no specific drug combination emerged, and nevirapine was the only drug significantly associated with an increased risk of SJS or TEN in HIV-infected persons [odds ratio, 62 (10.4; +infinity) in the case-control analysis; odds ratio, +infinity (2.8; +infinity) in the case-crossover analysis]. CONCLUSIONS In European countries the risk of SJS or TEN in the context of HIV infection appears to be associated with nevirapine. The respect of a lead-in period does not appear to prevent SJS or TEN. Because of the severity of these reactions and the long elimination half-life of nevirapine, we suggest discontinuation of the drug as soon as any eruption occurs.

Jan-Nico Bouwes-Bavinck

Papers

A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.

Nevirapine and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis.