Efficacy of the HLA-B∗58:01 Screening Test in Preventing Allopurinol-Induced Severe Cutaneous Adverse Reactions in Patients with Chronic Renal Insufficiency-A Prospective Study.

BACKGROUND: Thus far, human leukocyte antigen (HLA)-B∗58:01 has been recognized as the most important risk factor for allopurinol induced severe cutaneous adverse reactions (SCARs). OBJECTIVE: To determine the usefulness of prospective screening for the HLA-B∗58:01 allele to identify Korean individuals at risk for SCARs induced by allopurinol treatment. METHODS: We prospectively enrolled 542 patients with chronic renal insufficiency (CRI) from 10 hospitals nationwide and performed DNA genotyping to determine whether they carried the HLA-B∗58:01 allele. Of these, 503 HLA-B∗58:01-negative patients (92.8% of total) were treated with allopurinol, and 39 HLA-B∗58:01-positive patients (7.2%) were treated with febuxostat, an alternative drug. The patients then were followed up biweekly for 90 days using a telephone survey to monitor symptoms of adverse drug reactions, including SCARs. As a control, we used the historical incidence rate of allopurinol-induced SCARs in 4002 patients with CRI from the same hospitals who were enrolled retrospectively. RESULTS: Nineteen patients in the prospective cohort developed mild and transient adverse reactions but none showed allopurinol-induced SCARs. By contrast, we identified 38 patients with allopurinol-induced SCARs (0.95%) in the historical control. The difference in the incidence of allopurinol-induced SCARs between the prospective cohort and historical control was statistically significant (0% vs 0.95%, respectively; P = .029). CONCLUSIONS: The present study demonstrated the clinical usefulness of the HLA-B∗58:01 screening test before allopurinol administration to prevent allopurinol-induced SCARs in patients with CRI.

The Presence of HLA-B75, DR13 Homozygosity, or DR14 Additionally Increases the Risk of Allopurinol-Induced Severe Cutaneous Adverse Reactions in HLA-B*58:01 Carriers.

BACKGROUND: Although HLA-B*58:01 is a well-known risk factor for the development of allopurinol-induced severe cutaneous adverse reactions (SCARs), most of the HLA-B*58:01 carriers do not suffer from SCARs despite a long-term use of allopurinol. This suggests that there are other risk factors that determine the fate of HLA-B*58:01 carriers. OBJECTIVE: The aim of this study was to investigate the additional genetic factors that increase the risk of allopurinol-induced SCARs in HLA-B*58:01 carriers. METHODS: The incidence of allopurinol-induced SCARs was investigated according to coexisting HLA alleles in all subjects with HLA-B*58:01 who took allopurinol between 2003 and 2017. The allopurinol tolerant group was defined as a group who took allopurinol for more than 60 days without developing hypersensitivity and was compared with the allopurinol-induced SCAR group. RESULTS: Among the retrospective cohort consisting of 367 HLA-B*58:01 carriers treated with allopurinol, 11 (3.0%) were diagnosed with allopurinol-induced SCARs. When HLA-B75, DR13 homozygosity, or DR14 was present, the incidence of SCARs increased up to 22.2% (odds ratio [OR], 19.568; P = .015), 20.0% (OR, 38.458; P = .001), and 10.7% (OR, 19.355; P = .004), respectively. Among the 153 HLA-B*58:01 carriers with chronic renal insufficiency (CRI), the incidence of SCARs doubled to 6.5% and further increased to 40%, 30%, and 37.5% in the presence of HLA-B75, DR13 homozygosity, or DR14, respectively. CONCLUSIONS: Secondary screening with HLA-B75, DR13 homozygosity, and DR14 in addition to primary screening with HLA-B*58:01 would enable a more accurate prediction of SCAR occurrence, especially in patients with CRI.

NEW STRATEGIES TO PREDICT AND PREVENT SERIOUS IMMUNOLOGICALLY MEDIATED ADVERSE DRUG REACTIONS.

Preventive efforts for serious immunologically mediated adverse drug reactions (IM-ADRs) have been fueled by discovery of strong class I human leukocyte antigen (HLA) associations; however, the low positive predictive value of HLA for IM-ADRs has limited translation. Studies were undertaken to explain why most patients carrying an HLA risk allele do not develop IM-ADR on exposure to the risk drug. Tissue-specific approaches defined the T-cell receptor (TCR) repertoire and phenotype of the pathogenic T cells found in the skin and blister fluid of IM-ADRs. Dominant CD8+ T cell clonotypes representing >50% of total TCRαß sequences among CD8+ CD137+ T cells were identified in tissue to identify the pathogenic activated T cells. Identification of the specific molecular and cellular signatures of the antigen-driven pathogenic T cells will facilitate more specific mechanisms to determine the small percentage of individuals carrying an HLA risk allele who are likely to develop an IM-ADR before drug exposure.

Immunopathogenesis and risk factors for allopurinol severe cutaneous adverse reactions.

PURPOSE OF REVIEW: The article reviews the immunopathogenesis and risk factors related to allopurinol-induced severe cutaneous adverse reactions (SCARs). RECENT FINDINGS: For years, allopurinol remains one of the leading cause for SCARs worldwide. The pathogenesis of allopurinol-induced SCARs have been discovered in recent years. HLA-B58 : 01 has been found to be strongly associated with allopurinol-SCARs with functional interactions between allopurinol/its metabolite-oxypurinol and the T-cell receptor (TCR). However, the genetic strength of HLA-B58 : 01 may vary among different ethnic populations. In addition to HLA-B58 : 01, specific T cells with preferential TCR clonotypes, which have no cross-reactivity with new xanthine oxidase inhibitors structurally different from allopurinol, are found to play a crucial role for allopurinol-induced SCARs. Furthermore, other nongenetic factors such as renal impairment are also found to be an important factor resulting in allopurinol-induced SCARs of greater severity and poorer prognosis. SUMMARY: There are multiple risk factors for allopurinol-induced SCARs, including genetic and nongenetic factors. Activation of specific T cells with preferential TCR and its functional interaction of HLA-B58 : 01 molecule and allopurinol/oxypurinol are involved in the immune mechanism of allopurinol-induced SCAR. Patients with allopurinol-induced SCARs with renal impairment have significantly higher risk of mortality. A structurally different new generation xanthine oxidase inhibitor can provide a safer alternative for patients intolerant to allopurinol.

Allopurinol hypersensitivity: investigating the cause and minimizing the risk.

Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B(*)58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B(*)58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide-oxypurinol-HLA-B(*)58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.

Research on Susceptible Genes and Immunological Pathogenesis of Cutaneous Adverse Drug Reactions in Chinese Hans.

Cutaneous adverse drug reactions (cADRs) include mild maculopapular exanthems (MPE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). We used HLA high-resolution genotyping and genome wide association analysis (GWAS) to identify the genetic markers for cADRs induced by common culprit drugs in Han Chinese population. To further understand the immunopathogenesis of cADRs, and with the goal of developing treatment strategies, we compared the expression of cytoxic cytokines between the patients with cADRs and normal controls. Our data suggested that the carbamazepine induced SJS/TEN, allopurinol induced CADRs, methazolamide induced SJS/TEN and SASP induced DRESS were respectively strongly associated with HLA-B*15:02, HLA-B*58:01, HLA-B*59:01 and HLA-B*13:01. In addition, increased expression of cytotoxic cytokines in sera and tissues of cADRs patients were found, compared with healthy controls. Our findings may shed light on prediction and prevention of cADRs, provide clues to pathogenesis, and guide treatment strategies of these reactions.

Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01.

Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell-reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01(+) and HLA-B*58:01(-) donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the "pharmacological interaction with immune receptors" (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01(+) donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vß repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

Allopurinol hypersensitivity is primarily mediated by dose-dependent oxypurinol-specific T cell response.

BACKGROUND: Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken. OBJECTIVE: Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells. METHODS: Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naïve HLA-B*58:01(+) and HLA-B*58:01(-) individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and (51) Cr release assay. RESULTS: Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status. CONCLUSIONS AND CLINICAL RELEVANCE: This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele.

Pharmacogenetics of allopurinol--making an old drug safer.

Allopurinol is a drug that has been used for decades to lower serum urate levels in patients with gout or chronic renal failure and in cancer patients undergoing chemotherapy at risk of tumor lysis syndrome. Patients may develop cutaneous hypersensitivity reactions, ranging from mild rashes to potentially fatal severe cutaneous adverse reactions (SCARs) namely drug hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Recent studies have demonstrated the association between human leukocyte antigen (HLA) B*58:01 allele and allopurinol-induced SCARs, which might explain ethnic differences in their incidences. Genotyping is now required before starting abacavir and carbamazepine so as to identify individuals susceptible to SJS. However, no genetic screening is advocated before commencement of allopurinol. The lack of availability of a rapid and inexpensive screening test for the HLA-B*58:01 allele is one of the obstacles to such screening. Development of a test that is quick, accurate, and cost-effective is warranted.

HLA alleles and drug hypersensitivity reactions.

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions.

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

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 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 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.

Intravenous desensitization to allopurinol in a heart transplant patient with gout.

BACKGROUND: Oral desensitization with allopurinol presents a problem for patients with allopurinol hypersensitivity and gout that needs to be controlled rapidly. To our knowledge, only 1 case report of intravenous (i.v.) desensitization has been previously published. OBJECTIVE: To present a case report of a patient with cutaneous reactions to allopurinol who underwent i.v. allopurinol desensitization. METHODS: Intravenous infusion of allopurinol was performed using an escalating, 19-dose protocol. RESULTS: No adverse reactions were precipitated by 2 i.v., escalating dose procedures, allowing continuation of effective treatment of the patient's hyperuricemia. CONCLUSIONS: This case of safe and effective desensitization with allopurinol by the i.v. route should emphasize the need for a trial of this protocol in additional patients in whom rapid desensitization would be advantageous.

Allopurinol hypersensitivity syndrome and acute myocardial infarction--two case reports.

INTRODUCTION: Allopurinol hypersensitivity syndrome is an idiosyncratic drug reaction characterised by an acute and severe multiorgan disease. It usually begins 2 to 6 weeks after starting allopurinol. The most important and critical characteristics are the presence of visceral involvement and haematological abnormalities; hepatitis, interstitial nephritis and eosinophilia are most frequently seen. However, cardiac involvement has not been previously reported. CLINICAL PICTURE: Two previously well young Chinese men presented with fever, rash and hepatitis 3 weeks after taking allopurinol. The clinicopathological presentation was typical of allopurinol hypersensitivity syndrome. TREATMENT AND OUTCOME: Both men received systemic corticosteroid therapy and had full recovery. A few months later, they each had an acute myocardial infarction with a fatal outcome, despite minimal cardiac risk factors and no family history of coronary artery disease. CONCLUSION: The immunologic process in allopurinol hypersensitivity syndrome may have caused coronary vasculitis and subsequent myocardial infarct. Alternatively, the idiosyncratic reaction may have damaged myocardium, with the resultant myocarditis masquerading as coronary artery disease. Patients with allopurinol hypersensitivity syndrome should be followed up for cardiac involvement.

Efficacy and safety of desensitization to allopurinol following cutaneous reactions.

OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.

Role of UW solution and sodium nitroprusside in reperfusion of liver xenografts from guinea-pig to rat.

Guinea-pig livers are poorly reperfused when transplanted into rats. We have observed that, in contrast to that of the rat, the guinea-pig intrahepatic portal vein (PV) has a thick layer of smooth muscle. It is possible that, after perfusion of the liver with ice-cold saline, this could go into spasm, resulting in poor reperfusion. To test this hypothesis, guinea-pig livers were perfused with different solutions stored at varying temperatures and transplanted into LEW rats. To prevent xenograft hyperacute rejection, all xenograft recipients were treated with 80 U/kg cobra venom factor (CVF) i.v. on days -1 and 0. In addition to the percentage reperfusion, PV resistance and recipient survival were also monitored. In group I, liver xenografts perfused with ice-cold saline (4 degrees C) reperfused poorly (20-30%), resulting in the development of portal hypertension (16.5 cmH2O vs. 12 cmH2O in naive LEW rats) and shortened mean survival time (11.7 +/- 4.2 h). In contrast, group II livers perfused with saline at room temperature (23 degrees C) underwent homogeneous reperfusion (98-100%) with no increase in portal vein resistance, indicating that low temperature was the main trigger for the spasm of the PV. Moreover, recipient survival in this group was significantly prolonged to a mean of 22 + 2.6 h (P < 0.01). Although UW solution (group III) and the vasodilator sodium nitroprusside (NP) (group IV) when used alone improved the degree of hepatic reperfusion, it was still not optimal. The supplementation, however, of UW solution with NP in group V animals resulted in homogeneous reperfusion (98%) with no portal hypertension and consistent prolonged graft survival of 21.0 +/- 1.7 h. Therefore, this study has determined that the riddle of the abnormal reperfusion of guinea-pig liver xenografts by rat blood is nonimmune mediated and is due to the spasm of the strong smooth muscle in the PV tree produced by cold perfusates.

[Fatal outcome in allopurinol hypersensitivity syndrome]. / Letalt forløbende allopurinolhypersensitivitetssyndrom.

A 76 year-old otherwise healthy man was treated with allopurinol after a single episode of gout. He developed allopurinol hypersensitivity syndrome with epidermal necrolysis, dermal vasculitis, impaired renal function, fever, gastrointestinal bleeding, and possibly pulmonary vasculitis. The outcome was lethal. Controlling allopurinol therapy according to renal function is emphasized.