How to prevent allopurinol hypersensitivity reactions?

How to prevent allopurinol hypersensitivity reactions? Abstract 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, allopurinol, allopurinol hypersensitivity, chronic kidney disease Rheumatology key messages The severity of allopurinol hypersensitivity syndrome warrants consideration of preventative measures. Screening for HLA-B*5801 in people with gout at high risk of allopurinol hypersensitivity syndrome is recommended. Low allopurinol starting dose may reduce risk; the relationship with maintenance dose in kidney disease is controversial. Introduction Allopurinol has been associated with severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis, Stevens–Johnson syndrome and allopurinol hypersensitivity syndrome (AHS). These syndromes have similar clinical features, including fever, eosinophilia, hepatic and renal dysfunction and rash. Although the terms AHS and SCAR have been used interchangeably and globally to describe severe allopurinol allergic reactions, there are some differences, especially with respect to DRESS and Stevens–Johnson syndrome/toxic epidermal necrolysis (Table 1 and Fig. 1). The incidence of allopurinol-induced SCAR has been reported to be 0.69 (95% CI: 0.52, 0.92) per 1000 person-years [1]. Although rare, these adverse reactions may be associated with significant morbidity and mortality. The ability to predict and minimize these rare adverse events has been recognized as an important research gap by the Agency for Healthcare Research and Quality [2]. Table 1 Clinical features of severe allopurinol adverse events Type of reaction  Rash  Liver dysfunction  Renal dysfunction  Fever  Eosinophilia  Leucocytosis  Other  AHS  TEN, erythema multiforme, exfoliative dermatitis, diffuse maculopapular rash  Yes  Yes  Yes  Yes  Yes    DRESS  Various, including maculopapular, urticarial, exfoliative, lichenoid, pustular, bullous, target-like or eczema-like rashes  Yes  Yes  Yes  Yes  Atypical lymphocytosis  Inflammation of internal organs, including interstitial pneumonitis, pleuritis and acute respiratory distress syndrome, lymphadenopathy  TEN/SJS  Bullous mucocutaneous disease with epidermal necrosis, extensive detachment of the epidermis and erosions of mucous membranes    Yes  Yes  No  Atypical lymphocytes do not generally occur  Sore throat, conjunctivitis, arthralgia; other mucosal membranes in gastrointestinal or respiratory tract may be involved  Type of reaction  Rash  Liver dysfunction  Renal dysfunction  Fever  Eosinophilia  Leucocytosis  Other  AHS  TEN, erythema multiforme, exfoliative dermatitis, diffuse maculopapular rash  Yes  Yes  Yes  Yes  Yes    DRESS  Various, including maculopapular, urticarial, exfoliative, lichenoid, pustular, bullous, target-like or eczema-like rashes  Yes  Yes  Yes  Yes  Atypical lymphocytosis  Inflammation of internal organs, including interstitial pneumonitis, pleuritis and acute respiratory distress syndrome, lymphadenopathy  TEN/SJS  Bullous mucocutaneous disease with epidermal necrosis, extensive detachment of the epidermis and erosions of mucous membranes    Yes  Yes  No  Atypical lymphocytes do not generally occur  Sore throat, conjunctivitis, arthralgia; other mucosal membranes in gastrointestinal or respiratory tract may be involved  AHS: allopurinol hypersensitivity syndrome; DRESS: drug reaction with eosinophilia and systemic symptoms; SJS: Stevens Johnson Syndrome; TEN: toxic epidermal necrolysis. Fig. 1 View largeDownload slide Overlap between different clinical presentations of allopurinol-related adverse reactions The sizes of the circles in this figure in no way relate to the frequency of these adverse reactions. Reproduced from Stamp L, Day R, Yun J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 2016;12:235–42 [3] with permission. Fig. 1 View largeDownload slide Overlap between different clinical presentations of allopurinol-related adverse reactions The sizes of the circles in this figure in no way relate to the frequency of these adverse reactions. Reproduced from Stamp L, Day R, Yun J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 2016;12:235–42 [3] with permission. A number of risk factors for AHS have been identified and can be grouped into the following three broad categories: time-related factors, genetic factors and drug concentration factors (Fig. 2). Currently, the only mechanism for predicting and minimizing the risk of severe allopurinol-related adverse reactions is via screening for and modification of these known risk factors. However, it is important to recognize that a combination of these risk factors may be more likely to result in severe adverse events rather than the presence of a single risk factor. This review outlines the evidence for these risk factors and how they might be modified to reduce risk. Fig. 2 View largeDownload slide Risk factors for allopurinol hypersensitivity reactions Fig. 2 View largeDownload slide Risk factors for allopurinol hypersensitivity reactions Time-related factors AHS typically occurs within the first few weeks to months after starting allopurinol. In the largest review to date, of 901 published cases of AHS, the median time to onset of AHS was 3 weeks, and 90% of cases occurred within the first 8–9 weeks after commencing allopurinol [4]. Whether there is an increase in risk after each allopurinol dose increase is unknown, but in a recent randomized controlled trial of dose escalation in people on allopurinol at creatinine clearance-based dose but with serum urate above target there were no cases of AHS, although there were some rashes with dose increase [5]. Although this study was not powered to detect AHS, it provides some data on the issue. The ultimate way to prevent AHS is not to use allopurinol. In this regard, there should be a clear and appropriate indication for allopurinol therapy. Treatment of asymptomatic hyperuricaemia with allopurinol is not routinely recommended. The incidence of allopurinol hypersensitivity has been reported to be significantly higher and to have worse outcomes in people treated with allopurinol for asymptomatic hyperuricaemia, particularly in those who also have concomitant renal or cardiovascular disease [6]. With respect to the management of gout, the indications for urate-lowering therapy include recurrent flares, tophi and gout arthropathy [7, 8]. There are a number of alternative urate-lowering therapies available and new agents under development, so avoiding allopurinol is now a realistic option [9]. However, every drug has its own potential adverse effects, some of which may also be severe. Febuxostat, a relatively new urate-lowering therapy, is frequently considered after failure to reach target serum urate with allopurinol or if allopurinol is not tolerated. Like allopurinol, febuxostat is a xanthine oxidase inhibitor. Cases of febuxostat-associated minor skin reactions, hypersensitivity and DRESS are emerging in those who have previously received allopurinol and in allopurinol-naive individuals [10–13]. Given the rarity of this adverse event, it is not surprising that such reports are being noted only in the post-marketing surveillance phase. With the emergence of these reports, the European Medicines Agency and the Health Canada have released warnings [14, 15]. Patient and health-care practitioner education about allopurinol-related SCAR is important. The mainstay of treatment of these severe reactions is withdrawal of allopurinol. Patients should be educated about the time course and symptoms of these severe reactions. Patients should be advised to cease allopurinol and seek medical attention if rash or itch appears, especially if they occur within weeks to months after starting allopurinol or after a dose increase. Likewise, health-care practitioners should be cognisant of the need to consider allopurinol as a cause of rash and hypersensitivity reactions and determine whether there is associated bone marrow suppression, kidney or liver impairment, as failure to cease allopurinol quickly may result in poorer outcomes. Genetic factors HLA-B*5801 Pharmacogenetics is becoming an increasingly recognized method for determining the risk of medication-related adverse events. In 2005, an association between HLA-B*5801 and increased risk of allopurinol-related SCAR in Han Chinese was identified [16]. Subsequently, this association has been observed in a number of other ethnic populations [17]. A gene dosage effect has also been reported recently, with those who have two HLA-B*5801 alleles having an increased risk of allopurinol-related cutaneous adverse reactions compared with the risk in carriers of a single HLA-B*5801 allele in a Han Chinese population (odds ratio = 81.47, 95% CI 19.51, 568.95) [18]. The allele frequency of HLA-B*5801 varies across different ethnic populations. The allele is most common in East Asian populations, including those of Han Chinese (13.3–20.4%) [16, 19], Korean (12.2%) and Thai (8.1%) [20] descent and found much less frequently in those of Japanese (0.6%) [21] and European descent (1.5–5.2%) [22, 23]. Although genetic factors are not currently modifiable, rapid tests to identify the presence of HLA-B*5801 are becoming available, which enable screening before commencement of therapy with allopurinol [24]. The approximate cost of genotyping varies in different countries (e.g. USA ∼$75USD, Korea ∼$63USD), and screening for HLA-B*5801 has been reported to be cost-effective in those of Korean descent with renal insufficiency [25], Thai descent [26], Asian and African American descent but not for those of Caucasian or Hispanic descent in the USA [27]. The 2012 ACR Guidelines for the management of gout recommend screening for the presence of HLA-B*5801 before commencing allopurinol in those at high risk of AHS, namely all those of Han Chinese or Thai descent and those of Korean descent with ⩾stage 3 chronic kidney disease (CKD), and avoiding use of allopurinol in those who are HLA-B*5801 positive [7]. This strategy of prospective screening and allopurinol avoidance in positive individuals has been trialled in Taiwan, and none of 2339 HLA-B*5801-negative participants who received allopurinol developed SCAR, a significant reduction from the 0.3% or seven expected cases estimated from historical incidence data [28]. It is important to note in this study that the indication in 24% of those treated with allopurinol was asymptomatic hyperuricaemia. Avoidance of allopurinol in those individuals who are positive for HLA-B*5801 is currently recommended by the Clinical Pharmacogenomics Implementation Consortium [29]. However, a recent study has reported that none of 30 HLA-B*5801-positive individuals with CKD who commenced allopurinol according to a 28 day tolerance induction protocol developed SCAR over a 90-day period [30]. Cutaneous adverse reactions can also occur in individuals negative for HLA-B*5801 [18]. Taken together, these data suggest that additional factors must be involved in development of allopurinol-related SCAR in at least some individuals, and that allopurinol may not need to be avoided in certain HLA-B*5801-positive individuals. The minor allele of ABCG2 single nucleotide polymorphism rs2231142 has also been reported to be associated with poor response to allopurinol defined as serum urate ⩾6 mg/dl despite allopurinol >300 mg/day [odds ratio = 2.71, (95%CI 1.70, 4.48), P = 6.0 × 10−5] [31]. This association remained significant after adjustment for age, sex, BMI, ethnicity, estimated glomerular filtration rate (eGFR), diuretic use and serum urate off urate-lowering therapy. Studies to determine the accuracy of dose-prediction models are required. However, the decision to avoid allopurinol based on unwillingness to use higher than creatinine clearance-based doses may also be influenced by local regulatory controls on prescribing, as well as availability and funding arrangements for alternative urate-lowering therapies. Drug concentration factors A number of variables influence the drug concentration in the blood, mainly via effects on drug clearance. Some variables are related to the drug itself, for example, dose, route of administration and metabolism/excretion mechanisms, whereas others are related to patient factors, for example, BMI, age, kidney function and concomitant medications. Allopurinol is rapidly converted to the active metabolite oxypurinol, which can be measured in plasma. Oxypurinol is primarily excreted via the kidneys, and plasma oxypurinol concentrations are inversely correlated with creatinine clearance [32]. There is a wide range of plasma oxypurinol concentrations with any given allopurinol dose in a group of patients, but within individuals there is a good correlation between allopurinol dose and plasma oxypurinol concentration [32]. In addition, concomitant furosemide therapy is associated with higher plasma oxypurinol concentrations for any given allopurinol dose [32]. Despite the evidence that the AHS risk factors, dose, kidney function and diuretic therapy, are associated with increased plasma oxypurinol concentrations, the relationship between oxypurinol concentration and AHS is less clear. Many individuals tolerate very high oxypurinol concentrations with no adverse effects or SCAR, whereas some cases of AHS have been reported in individuals with low oxypurinol concentrations [32–35]. However, in individuals who do develop SCAR, those with higher plasma oxypurinol concentrations have worse outcomes [36]. It seems that additional risk factors are required beyond plasma oxypurinol concentration alone, and the interaction or additive effect of the individual risk factors may be most important. Dose In the seminal paper on AHS by Hande et al. [37] in 1984, the dose of allopurinol, kidney function and diuretics were identified as important risk factors. However, the relationship between allopurinol dose and allopurinol-related SCAR remains controversial. When considering dose, it is important to distinguish between the starting dose of allopurinol and the dose required to achieve target serum urate; that is, the maintenance dose. In the case series by Hande et al. [37], which included 24/78 cases with asymptomatic hyperuricaemia, allopurinol was commenced at 200–400 mg daily for the majority of those who developed AHS [37]. In a retrospective case-controlled study, we have shown that a higher allopurinol starting dose was associated with an increased risk of AHS; in those who developed AHS, the mean (s.e.m.) starting dose of allopurinol was 183.5 (14.0) mg/day compared with 112.2 (6.3) mg/day (P < 0.001) in the allopurinol-tolerant controls matched on age, gender, kidney function and use of diuretics [38]. Receiver operating characteristic curve analysis indicated that the starting dose of allopurinol in 91% of AHS cases and 36% of controls was ⩾1.5 mg/U of eGFR (in milligrams per millilitre per minute). In comparison, 79% of AHS cases and 53% of controls started at a dose of ⩾2.0 mg of allopurinol per unit of eGFR. Thus, a starting dose based on an eGFR of 1.5 mg/ml/min seems a reasonable trade-off between a clinically practicable dose and the absolute risk of AHS [38]. This association with starting dose has not been observed in another study [36]. Whether this start low and slow dose-escalation strategy reduces the incidence of AHS has not been formally examined, and given the rarity of AHS it is unlikely that any clinical trial of sufficient size is going to be undertaken. However, commencing allopurinol at lower doses is a practical and simple strategy that may reduce the risk of AHS, and the ACR 2012 gout recommendations advocate a starting dose of no more than 100 mg daily for any person with gout, with a lower dose of 50 mg daily in those with ⩾stage 4 CKD [7]. The 2016 EULAR gout recommendations advocate a starting dose of 100 mg daily in those with normal renal function, and although no specific starting dose is proposed for those with CKD, it is stated that all urate-lowering therapies should be started at low dose and titrated up [8]. More controversial than the starting dose is the maintenance dose of allopurinol, particularly in those with impaired kidney function. This is evidenced by differences in allopurinol dosing recommendations from the ACR and EULAR. The ACR 2012 gout guidelines advocate a gradual allopurinol dose escalation to achieve target serum urate and state that the dose can be increased above 300 mg daily even in those with impaired kidney function with appropriate patient education and monitoring [7]. In contrast, the 2016 EULAR recommendations for the management of gout advocate limiting the dose of allopurinol based on creatinine clearance and using an alternate agent if this restricted dose fails to lower urate to the treatment target [8]. It is widely recognized that the creatinine clearance-based allopurinol dosing as outlined by Hande et al. [37] results in the majority of people not achieving target urate. For example, in a study of 250 individuals, only 19% of those on the creatinine clearance-based dose of allopurinol achieved a serum urate <0.36 mmol/l [39]. In the 12-month febuxostat compared with allopurinol in patients with hyperuricaemia and gout (FACT) study, in which eGFR had to be >50 ml/min/1.73 m2, only 88/242 (36%) of those who received fixed dose allopurinol 300 mg daily achieved urate <0.36 mmol/l at the final visit [40]. Thus, limiting the dose of allopurinol to that based on creatinine clearance is not usually effective in achieving the target urate concentration and exposes the individual to the risk of potential adverse effects during the early phase of treatment without the therapeutic benefit offered by using higher than creatinine clearance-based doses in those who tolerate the drug. There are increasing data indicating that the use of allopurinol at higher than the creatinine clearance-based dose is effective in achieving target serum urate, even in those with renal impairment [41–43]. The safety of this dose-escalation strategy has been questioned, particularly in regard to allopurinol-related SCAR. It is important to recognize that there is no evidence that restricting the maintenance dose of allopurinol reduces the risk of SCAR, and indeed, in those who tolerate the creatinine clearance-based dose and have passed through the early risk period, dose escalation may be tolerated. Although the limited number of dose-escalation studies have not shown an increase in SCAR, they have, however, not been adequately powered to detect these rare events [39, 41, 43]. It is unlikely that a clinical trial of sufficient size to answer this question will ever be undertaken. Chronic kidney disease CKD is one of the most common co-morbidities in people with gout, with data from NHANES reporting that 71% have ⩾stage 2 CKD [44]. The association between CKD and AHS is well recognized [18, 36]. In the large series of 901 AHS cases, CKD was the most common co-morbidity, occurring in 48% [4]. In most cases, kidney function is not readily modifiable; thus, when considering how to minimize the risk or prevent adverse effects, avoidance of allopurinol may be the only option. The ability to predict the dose of allopurinol required to achieve target urate would be a significant advantage. Modelling studies have not identified kidney function as an important covariate in the relationship between allopurinol dose and serum urate [45, 46]. Graham et al. [45] have, however, shown that pretreatment plasma urate is important in determining the dose of allopurinol required to achieve target urate (Table 2). Table 2 Dose of allopurinol required to achieve target urate based on pretreatment serum urate concentration Pretreatment plasma urate (mmol/l)  Predicted allopurinol dose (mg/day) to achieve urate 0.36 mmol/l  Predicted allopurinol dose (mg/day) to achieve urate 0.30 mmol/l  0.65  405  775  0.6  335  665  0.55  265  554  0.5  195  443  0.45  126  332  Pretreatment plasma urate (mmol/l)  Predicted allopurinol dose (mg/day) to achieve urate 0.36 mmol/l  Predicted allopurinol dose (mg/day) to achieve urate 0.30 mmol/l  0.65  405  775  0.6  335  665  0.55  265  554  0.5  195  443  0.45  126  332  Adapted with permission from John Wiley and Sons from Graham et al. Understanding the dose–response relationship of allopurinol: predicting the optimal dosage. Br J Clin Pharmacol 2013;76:932–8 [45]. One potential way to stratify the risk of SCAR in individuals with CKD is by the presence or absence of the HLA-B*5801 risk allele. Ng et al. [18] reported a significant increase in risk of allopurinol-related cutaneous adverse reactions in Han Chinese, including SCAR in those with HLA-B*5801 and CKD, with the highest risk in those homozygous for HLA-B*5801 and with eGFR <30 ml/min/1.73 m2 (odds ratio = 1269.45; 95% CI: 192.3, 15 260.1). Thus, using the combination of gene dose and eGFR may be better than using either risk factor alone in predicting adverse events. Avoiding the use of allopurinol in those at the highest risk, that is eGFR <30 ml/min/1.73 m2 and HLA-B*5801, may be reasonable, whereas the usual start low, go slow allopurinol dose-escalation strategy may be reasonable for those with only one of these two risk factors. Concomitant agents: diuretics The use of diuretics in patients with gout is common, because many have co-morbidities, such as hypertension and ischaemic heart disease. Concomitant therapy with diuretics poses several issues. Firstly, diuretics are associated with an increased risk of SCAR/AHS [37]. Secondly, they increase serum urate. Thirdly, at least in the case of furosemide, there is an increase in plasma oxypurinol concentration but, despite this, those receiving furosemide require higher doses of allopurinol to achieve target urate compared with those not receiving furosemide [47]. With regard to minimizing the risk of SCAR, clinicians should consider the indications for ongoing diuretic use and whether alternative agents could be used. Hence, consideration should be given to those agents which have not been associated with an increase in serum urate, such as losartan [48] and calcium channel blockers [49]. Summary Gout and allopurinol treatment are common, and although AHS is considered rare, a large number of cases have occurred, and preventative measures should be considered when patients are about to commence therapy. Patient education regarding the possibility of AHS and the need to stop allopurinol may reduce severity when it occurs. Pre-testing for HLA-B*5801 should be considered when available in at least some subgroups of Asian and African ethnicity, could also be considered in those with CKD, and may be considered more widely depending on cost. Low starting allopurinol dose, that is, 100 mg daily, or 50 mg in those with severe CKD, is likely to reduce the risk of AHS. However, the relationship of plasma drug concentration and maintenance dose to AHS risk is less clear. The risk of AHS in severe CKD patients, and the additional risk with diuretics and need for higher allopurinol doses in these patients, may be sufficient to warrant consideration of alternative therapies in some cases. Supplement: This supplement was funded by Grunenthal. 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Plasma oxypurinol concentration in a patient with allopurinol hypersensitivity. J Rheumatol  1989; 16: 842– 4. Google Scholar PubMed  35 Casas E, Puig J, Mateos F, Jiménez M, Michán A, Ramoz T. The allopurinol hypersensitivity syndrome: its relation to plasma oxypurinol levels. Adv Exp Med Biol  1989; 253A: 257– 60. Google Scholar CrossRef Search ADS PubMed  36 Chung W-H, Chang W-C, Stocker S et al.   Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin. Ann Rheum Dis  2015; 74: 2157– 64. http://dx.doi.org/10.1136/annrheumdis-2014-205577 Google Scholar CrossRef Search ADS PubMed  37 Hande K, Noone R, Stone W. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med  1984; 76: 47– 56. 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Google Scholar CrossRef Search ADS PubMed  49 Chanard J, Toupance O, Lavaud S et al.   Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients. Nephrol Dial Transplant  2003; 18: 2147– 53. http://dx.doi.org/10.1093/ndt/gfg341 Google Scholar CrossRef Search ADS PubMed  © The Author 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

How to prevent allopurinol hypersensitivity reactions?

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Abstract

Abstract 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, allopurinol, allopurinol hypersensitivity, chronic kidney disease Rheumatology key messages The severity of allopurinol hypersensitivity syndrome warrants consideration of preventative measures. Screening for HLA-B*5801 in people with gout at high risk of allopurinol hypersensitivity syndrome is recommended. Low allopurinol starting dose may reduce risk; the relationship with maintenance dose in kidney disease is controversial. Introduction Allopurinol has been associated with severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis, Stevens–Johnson syndrome and allopurinol hypersensitivity syndrome (AHS). These syndromes have similar clinical features, including fever, eosinophilia, hepatic and renal dysfunction and rash. Although the terms AHS and SCAR have been used interchangeably and globally to describe severe allopurinol allergic reactions, there are some differences, especially with respect to DRESS and Stevens–Johnson syndrome/toxic epidermal necrolysis (Table 1 and Fig. 1). The incidence of allopurinol-induced SCAR has been reported to be 0.69 (95% CI: 0.52, 0.92) per 1000 person-years [1]. Although rare, these adverse reactions may be associated with significant morbidity and mortality. The ability to predict and minimize these rare adverse events has been recognized as an important research gap by the Agency for Healthcare Research and Quality [2]. Table 1 Clinical features of severe allopurinol adverse events Type of reaction  Rash  Liver dysfunction  Renal dysfunction  Fever  Eosinophilia  Leucocytosis  Other  AHS  TEN, erythema multiforme, exfoliative dermatitis, diffuse maculopapular rash  Yes  Yes  Yes  Yes  Yes    DRESS  Various, including maculopapular, urticarial, exfoliative, lichenoid, pustular, bullous, target-like or eczema-like rashes  Yes  Yes  Yes  Yes  Atypical lymphocytosis  Inflammation of internal organs, including interstitial pneumonitis, pleuritis and acute respiratory distress syndrome, lymphadenopathy  TEN/SJS  Bullous mucocutaneous disease with epidermal necrosis, extensive detachment of the epidermis and erosions of mucous membranes    Yes  Yes  No  Atypical lymphocytes do not generally occur  Sore throat, conjunctivitis, arthralgia; other mucosal membranes in gastrointestinal or respiratory tract may be involved  Type of reaction  Rash  Liver dysfunction  Renal dysfunction  Fever  Eosinophilia  Leucocytosis  Other  AHS  TEN, erythema multiforme, exfoliative dermatitis, diffuse maculopapular rash  Yes  Yes  Yes  Yes  Yes    DRESS  Various, including maculopapular, urticarial, exfoliative, lichenoid, pustular, bullous, target-like or eczema-like rashes  Yes  Yes  Yes  Yes  Atypical lymphocytosis  Inflammation of internal organs, including interstitial pneumonitis, pleuritis and acute respiratory distress syndrome, lymphadenopathy  TEN/SJS  Bullous mucocutaneous disease with epidermal necrosis, extensive detachment of the epidermis and erosions of mucous membranes    Yes  Yes  No  Atypical lymphocytes do not generally occur  Sore throat, conjunctivitis, arthralgia; other mucosal membranes in gastrointestinal or respiratory tract may be involved  AHS: allopurinol hypersensitivity syndrome; DRESS: drug reaction with eosinophilia and systemic symptoms; SJS: Stevens Johnson Syndrome; TEN: toxic epidermal necrolysis. Fig. 1 View largeDownload slide Overlap between different clinical presentations of allopurinol-related adverse reactions The sizes of the circles in this figure in no way relate to the frequency of these adverse reactions. Reproduced from Stamp L, Day R, Yun J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 2016;12:235–42 [3] with permission. Fig. 1 View largeDownload slide Overlap between different clinical presentations of allopurinol-related adverse reactions The sizes of the circles in this figure in no way relate to the frequency of these adverse reactions. Reproduced from Stamp L, Day R, Yun J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 2016;12:235–42 [3] with permission. A number of risk factors for AHS have been identified and can be grouped into the following three broad categories: time-related factors, genetic factors and drug concentration factors (Fig. 2). Currently, the only mechanism for predicting and minimizing the risk of severe allopurinol-related adverse reactions is via screening for and modification of these known risk factors. However, it is important to recognize that a combination of these risk factors may be more likely to result in severe adverse events rather than the presence of a single risk factor. This review outlines the evidence for these risk factors and how they might be modified to reduce risk. Fig. 2 View largeDownload slide Risk factors for allopurinol hypersensitivity reactions Fig. 2 View largeDownload slide Risk factors for allopurinol hypersensitivity reactions Time-related factors AHS typically occurs within the first few weeks to months after starting allopurinol. In the largest review to date, of 901 published cases of AHS, the median time to onset of AHS was 3 weeks, and 90% of cases occurred within the first 8–9 weeks after commencing allopurinol [4]. Whether there is an increase in risk after each allopurinol dose increase is unknown, but in a recent randomized controlled trial of dose escalation in people on allopurinol at creatinine clearance-based dose but with serum urate above target there were no cases of AHS, although there were some rashes with dose increase [5]. Although this study was not powered to detect AHS, it provides some data on the issue. The ultimate way to prevent AHS is not to use allopurinol. In this regard, there should be a clear and appropriate indication for allopurinol therapy. Treatment of asymptomatic hyperuricaemia with allopurinol is not routinely recommended. The incidence of allopurinol hypersensitivity has been reported to be significantly higher and to have worse outcomes in people treated with allopurinol for asymptomatic hyperuricaemia, particularly in those who also have concomitant renal or cardiovascular disease [6]. With respect to the management of gout, the indications for urate-lowering therapy include recurrent flares, tophi and gout arthropathy [7, 8]. There are a number of alternative urate-lowering therapies available and new agents under development, so avoiding allopurinol is now a realistic option [9]. However, every drug has its own potential adverse effects, some of which may also be severe. Febuxostat, a relatively new urate-lowering therapy, is frequently considered after failure to reach target serum urate with allopurinol or if allopurinol is not tolerated. Like allopurinol, febuxostat is a xanthine oxidase inhibitor. Cases of febuxostat-associated minor skin reactions, hypersensitivity and DRESS are emerging in those who have previously received allopurinol and in allopurinol-naive individuals [10–13]. Given the rarity of this adverse event, it is not surprising that such reports are being noted only in the post-marketing surveillance phase. With the emergence of these reports, the European Medicines Agency and the Health Canada have released warnings [14, 15]. Patient and health-care practitioner education about allopurinol-related SCAR is important. The mainstay of treatment of these severe reactions is withdrawal of allopurinol. Patients should be educated about the time course and symptoms of these severe reactions. Patients should be advised to cease allopurinol and seek medical attention if rash or itch appears, especially if they occur within weeks to months after starting allopurinol or after a dose increase. Likewise, health-care practitioners should be cognisant of the need to consider allopurinol as a cause of rash and hypersensitivity reactions and determine whether there is associated bone marrow suppression, kidney or liver impairment, as failure to cease allopurinol quickly may result in poorer outcomes. Genetic factors HLA-B*5801 Pharmacogenetics is becoming an increasingly recognized method for determining the risk of medication-related adverse events. In 2005, an association between HLA-B*5801 and increased risk of allopurinol-related SCAR in Han Chinese was identified [16]. Subsequently, this association has been observed in a number of other ethnic populations [17]. A gene dosage effect has also been reported recently, with those who have two HLA-B*5801 alleles having an increased risk of allopurinol-related cutaneous adverse reactions compared with the risk in carriers of a single HLA-B*5801 allele in a Han Chinese population (odds ratio = 81.47, 95% CI 19.51, 568.95) [18]. The allele frequency of HLA-B*5801 varies across different ethnic populations. The allele is most common in East Asian populations, including those of Han Chinese (13.3–20.4%) [16, 19], Korean (12.2%) and Thai (8.1%) [20] descent and found much less frequently in those of Japanese (0.6%) [21] and European descent (1.5–5.2%) [22, 23]. Although genetic factors are not currently modifiable, rapid tests to identify the presence of HLA-B*5801 are becoming available, which enable screening before commencement of therapy with allopurinol [24]. The approximate cost of genotyping varies in different countries (e.g. USA ∼$75USD, Korea ∼$63USD), and screening for HLA-B*5801 has been reported to be cost-effective in those of Korean descent with renal insufficiency [25], Thai descent [26], Asian and African American descent but not for those of Caucasian or Hispanic descent in the USA [27]. The 2012 ACR Guidelines for the management of gout recommend screening for the presence of HLA-B*5801 before commencing allopurinol in those at high risk of AHS, namely all those of Han Chinese or Thai descent and those of Korean descent with ⩾stage 3 chronic kidney disease (CKD), and avoiding use of allopurinol in those who are HLA-B*5801 positive [7]. This strategy of prospective screening and allopurinol avoidance in positive individuals has been trialled in Taiwan, and none of 2339 HLA-B*5801-negative participants who received allopurinol developed SCAR, a significant reduction from the 0.3% or seven expected cases estimated from historical incidence data [28]. It is important to note in this study that the indication in 24% of those treated with allopurinol was asymptomatic hyperuricaemia. Avoidance of allopurinol in those individuals who are positive for HLA-B*5801 is currently recommended by the Clinical Pharmacogenomics Implementation Consortium [29]. However, a recent study has reported that none of 30 HLA-B*5801-positive individuals with CKD who commenced allopurinol according to a 28 day tolerance induction protocol developed SCAR over a 90-day period [30]. Cutaneous adverse reactions can also occur in individuals negative for HLA-B*5801 [18]. Taken together, these data suggest that additional factors must be involved in development of allopurinol-related SCAR in at least some individuals, and that allopurinol may not need to be avoided in certain HLA-B*5801-positive individuals. The minor allele of ABCG2 single nucleotide polymorphism rs2231142 has also been reported to be associated with poor response to allopurinol defined as serum urate ⩾6 mg/dl despite allopurinol >300 mg/day [odds ratio = 2.71, (95%CI 1.70, 4.48), P = 6.0 × 10−5] [31]. This association remained significant after adjustment for age, sex, BMI, ethnicity, estimated glomerular filtration rate (eGFR), diuretic use and serum urate off urate-lowering therapy. Studies to determine the accuracy of dose-prediction models are required. However, the decision to avoid allopurinol based on unwillingness to use higher than creatinine clearance-based doses may also be influenced by local regulatory controls on prescribing, as well as availability and funding arrangements for alternative urate-lowering therapies. Drug concentration factors A number of variables influence the drug concentration in the blood, mainly via effects on drug clearance. Some variables are related to the drug itself, for example, dose, route of administration and metabolism/excretion mechanisms, whereas others are related to patient factors, for example, BMI, age, kidney function and concomitant medications. Allopurinol is rapidly converted to the active metabolite oxypurinol, which can be measured in plasma. Oxypurinol is primarily excreted via the kidneys, and plasma oxypurinol concentrations are inversely correlated with creatinine clearance [32]. There is a wide range of plasma oxypurinol concentrations with any given allopurinol dose in a group of patients, but within individuals there is a good correlation between allopurinol dose and plasma oxypurinol concentration [32]. In addition, concomitant furosemide therapy is associated with higher plasma oxypurinol concentrations for any given allopurinol dose [32]. Despite the evidence that the AHS risk factors, dose, kidney function and diuretic therapy, are associated with increased plasma oxypurinol concentrations, the relationship between oxypurinol concentration and AHS is less clear. Many individuals tolerate very high oxypurinol concentrations with no adverse effects or SCAR, whereas some cases of AHS have been reported in individuals with low oxypurinol concentrations [32–35]. However, in individuals who do develop SCAR, those with higher plasma oxypurinol concentrations have worse outcomes [36]. It seems that additional risk factors are required beyond plasma oxypurinol concentration alone, and the interaction or additive effect of the individual risk factors may be most important. Dose In the seminal paper on AHS by Hande et al. [37] in 1984, the dose of allopurinol, kidney function and diuretics were identified as important risk factors. However, the relationship between allopurinol dose and allopurinol-related SCAR remains controversial. When considering dose, it is important to distinguish between the starting dose of allopurinol and the dose required to achieve target serum urate; that is, the maintenance dose. In the case series by Hande et al. [37], which included 24/78 cases with asymptomatic hyperuricaemia, allopurinol was commenced at 200–400 mg daily for the majority of those who developed AHS [37]. In a retrospective case-controlled study, we have shown that a higher allopurinol starting dose was associated with an increased risk of AHS; in those who developed AHS, the mean (s.e.m.) starting dose of allopurinol was 183.5 (14.0) mg/day compared with 112.2 (6.3) mg/day (P < 0.001) in the allopurinol-tolerant controls matched on age, gender, kidney function and use of diuretics [38]. Receiver operating characteristic curve analysis indicated that the starting dose of allopurinol in 91% of AHS cases and 36% of controls was ⩾1.5 mg/U of eGFR (in milligrams per millilitre per minute). In comparison, 79% of AHS cases and 53% of controls started at a dose of ⩾2.0 mg of allopurinol per unit of eGFR. Thus, a starting dose based on an eGFR of 1.5 mg/ml/min seems a reasonable trade-off between a clinically practicable dose and the absolute risk of AHS [38]. This association with starting dose has not been observed in another study [36]. Whether this start low and slow dose-escalation strategy reduces the incidence of AHS has not been formally examined, and given the rarity of AHS it is unlikely that any clinical trial of sufficient size is going to be undertaken. However, commencing allopurinol at lower doses is a practical and simple strategy that may reduce the risk of AHS, and the ACR 2012 gout recommendations advocate a starting dose of no more than 100 mg daily for any person with gout, with a lower dose of 50 mg daily in those with ⩾stage 4 CKD [7]. The 2016 EULAR gout recommendations advocate a starting dose of 100 mg daily in those with normal renal function, and although no specific starting dose is proposed for those with CKD, it is stated that all urate-lowering therapies should be started at low dose and titrated up [8]. More controversial than the starting dose is the maintenance dose of allopurinol, particularly in those with impaired kidney function. This is evidenced by differences in allopurinol dosing recommendations from the ACR and EULAR. The ACR 2012 gout guidelines advocate a gradual allopurinol dose escalation to achieve target serum urate and state that the dose can be increased above 300 mg daily even in those with impaired kidney function with appropriate patient education and monitoring [7]. In contrast, the 2016 EULAR recommendations for the management of gout advocate limiting the dose of allopurinol based on creatinine clearance and using an alternate agent if this restricted dose fails to lower urate to the treatment target [8]. It is widely recognized that the creatinine clearance-based allopurinol dosing as outlined by Hande et al. [37] results in the majority of people not achieving target urate. For example, in a study of 250 individuals, only 19% of those on the creatinine clearance-based dose of allopurinol achieved a serum urate <0.36 mmol/l [39]. In the 12-month febuxostat compared with allopurinol in patients with hyperuricaemia and gout (FACT) study, in which eGFR had to be >50 ml/min/1.73 m2, only 88/242 (36%) of those who received fixed dose allopurinol 300 mg daily achieved urate <0.36 mmol/l at the final visit [40]. Thus, limiting the dose of allopurinol to that based on creatinine clearance is not usually effective in achieving the target urate concentration and exposes the individual to the risk of potential adverse effects during the early phase of treatment without the therapeutic benefit offered by using higher than creatinine clearance-based doses in those who tolerate the drug. There are increasing data indicating that the use of allopurinol at higher than the creatinine clearance-based dose is effective in achieving target serum urate, even in those with renal impairment [41–43]. The safety of this dose-escalation strategy has been questioned, particularly in regard to allopurinol-related SCAR. It is important to recognize that there is no evidence that restricting the maintenance dose of allopurinol reduces the risk of SCAR, and indeed, in those who tolerate the creatinine clearance-based dose and have passed through the early risk period, dose escalation may be tolerated. Although the limited number of dose-escalation studies have not shown an increase in SCAR, they have, however, not been adequately powered to detect these rare events [39, 41, 43]. It is unlikely that a clinical trial of sufficient size to answer this question will ever be undertaken. Chronic kidney disease CKD is one of the most common co-morbidities in people with gout, with data from NHANES reporting that 71% have ⩾stage 2 CKD [44]. The association between CKD and AHS is well recognized [18, 36]. In the large series of 901 AHS cases, CKD was the most common co-morbidity, occurring in 48% [4]. In most cases, kidney function is not readily modifiable; thus, when considering how to minimize the risk or prevent adverse effects, avoidance of allopurinol may be the only option. The ability to predict the dose of allopurinol required to achieve target urate would be a significant advantage. Modelling studies have not identified kidney function as an important covariate in the relationship between allopurinol dose and serum urate [45, 46]. Graham et al. [45] have, however, shown that pretreatment plasma urate is important in determining the dose of allopurinol required to achieve target urate (Table 2). Table 2 Dose of allopurinol required to achieve target urate based on pretreatment serum urate concentration Pretreatment plasma urate (mmol/l)  Predicted allopurinol dose (mg/day) to achieve urate 0.36 mmol/l  Predicted allopurinol dose (mg/day) to achieve urate 0.30 mmol/l  0.65  405  775  0.6  335  665  0.55  265  554  0.5  195  443  0.45  126  332  Pretreatment plasma urate (mmol/l)  Predicted allopurinol dose (mg/day) to achieve urate 0.36 mmol/l  Predicted allopurinol dose (mg/day) to achieve urate 0.30 mmol/l  0.65  405  775  0.6  335  665  0.55  265  554  0.5  195  443  0.45  126  332  Adapted with permission from John Wiley and Sons from Graham et al. Understanding the dose–response relationship of allopurinol: predicting the optimal dosage. Br J Clin Pharmacol 2013;76:932–8 [45]. One potential way to stratify the risk of SCAR in individuals with CKD is by the presence or absence of the HLA-B*5801 risk allele. Ng et al. [18] reported a significant increase in risk of allopurinol-related cutaneous adverse reactions in Han Chinese, including SCAR in those with HLA-B*5801 and CKD, with the highest risk in those homozygous for HLA-B*5801 and with eGFR <30 ml/min/1.73 m2 (odds ratio = 1269.45; 95% CI: 192.3, 15 260.1). Thus, using the combination of gene dose and eGFR may be better than using either risk factor alone in predicting adverse events. Avoiding the use of allopurinol in those at the highest risk, that is eGFR <30 ml/min/1.73 m2 and HLA-B*5801, may be reasonable, whereas the usual start low, go slow allopurinol dose-escalation strategy may be reasonable for those with only one of these two risk factors. Concomitant agents: diuretics The use of diuretics in patients with gout is common, because many have co-morbidities, such as hypertension and ischaemic heart disease. Concomitant therapy with diuretics poses several issues. Firstly, diuretics are associated with an increased risk of SCAR/AHS [37]. Secondly, they increase serum urate. Thirdly, at least in the case of furosemide, there is an increase in plasma oxypurinol concentration but, despite this, those receiving furosemide require higher doses of allopurinol to achieve target urate compared with those not receiving furosemide [47]. With regard to minimizing the risk of SCAR, clinicians should consider the indications for ongoing diuretic use and whether alternative agents could be used. Hence, consideration should be given to those agents which have not been associated with an increase in serum urate, such as losartan [48] and calcium channel blockers [49]. Summary Gout and allopurinol treatment are common, and although AHS is considered rare, a large number of cases have occurred, and preventative measures should be considered when patients are about to commence therapy. Patient education regarding the possibility of AHS and the need to stop allopurinol may reduce severity when it occurs. Pre-testing for HLA-B*5801 should be considered when available in at least some subgroups of Asian and African ethnicity, could also be considered in those with CKD, and may be considered more widely depending on cost. Low starting allopurinol dose, that is, 100 mg daily, or 50 mg in those with severe CKD, is likely to reduce the risk of AHS. However, the relationship of plasma drug concentration and maintenance dose to AHS risk is less clear. The risk of AHS in severe CKD patients, and the additional risk with diuretics and need for higher allopurinol doses in these patients, may be sufficient to warrant consideration of alternative therapies in some cases. Supplement: This supplement was funded by Grunenthal. 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Published: Jan 1, 2018

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