Key Points
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Allopurinol is a highly effective, cheap and simple therapy for gout if dosing is adequate and patients adhere to the therapy
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Serious allopurinol-related adverse events (for example, allopurinol hypersensitivity syndrome [AHS]) are rare, but are associated with high morbidity and mortality
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Risk factors for allopurinol-related serious adverse events include recent introduction of allopurinol, the presence of the HLA-B*58:01 allele, a higher starting dose, renal impairment and the concomitant use of diuretics
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Allopurinol hypersensitivity is primarily mediated by an oxypurinol-specific T-cell response
Abstract
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.
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Change history
03 March 2016
In the version of this article initially published online, incorrect information was given regarding the source of Figure 3. This figure was reproduced from Stamp, L. K. et al. Allopurinol and kidney function: an update. Joint Bone Spine 83, 19–24 (2016). The error has been corrected for the HTML and PDF versions of the article.
References
Reiter, S., Simmonds, H. A., Zollner, N., Braun, S. L. & Knedel, M. Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol. Clin. Chim. Acta 187, 221–234 (1990).
Stamp, L. et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in chronic gout, including in those with renal impairment. Arthritis Rheum. 63, 412–421 (2011).
Kim, S., Newcomb, C., Margolis, D., Roy, J. & Hennessy, S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res. (Hoboken) 65, 578–584 (2013).
Hande, K., Noone, R. & Stone, W. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am. J. Med. 76, 47–56 (1984).
Vázquez-Mellado, J., Meoño Morales, E., Pacheco-Tena, C. & Burgos-Vargas, R. Relationship between adverse events associated with allopurinol and renal function in patients with gout. Ann. Rheum. Dis. 60, 981–983 (2001).
Hung, S. et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc. Natl Acad. Sci. USA 102, 4134–4139 (2005).
Emmerson, B. T., Hazelton, R. A. & Frazer, I. H. Some adverse reactions to allopurinol may be mediated by lymphocyte reactivity to oxypurinol. Arthritis Rheum. 31, 436–440 (1988).
Lockard, O., Harmon, C., Nolph, K. & Irvin, W. Allergic reaction to allopurinol with cross-reactivity to oxypurinol. Ann. Intern. Med. 85, 333–335 (1976).
Braden, G., Warzynski, M., Golightly, M. & Ballow, M. Cell-mediated immunity in allopurinol-induced hypersensitivity. Clin. Immunol. Immunopathol. 70, 145–151 (1994).
Yun, J. et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01. J. Immunol. 192, 2984–2993 (2014).
Yun, J. et al. Allopurinol hypersensitivity is primarily medicated by dose-dependent oxypurinol-specific T cell response. Clin. Exp. Allergy 43, 1246–1255 (2013).
[No authors listed] Excess of ampicillin rashes associated with allopurinol or hyperuricemia. A report from the Boston Collaborative Drug Surveillance Program, Boston University Medical Center. N. Engl. J. Med. 286, 505–507 (1972).
McInnes, G., Lawson, D. & Jick, H. Acute adverse reactions attributed to allopurinol in hospitalised patients. Ann. Rheum. Dis. 40, 245–249 (1981).
Halevy, S. et al. Allopurinol is the most common cause of Stevens–Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J. Am. Acad. Dermatol. 58, 25–32 (2008).
Kardaun, S. et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br. J. Dermatol. 169, 1071–1080 (2013).
Sekula, P. et al. Comprehensive survival analysis of a cohort of patients with Stevens–Johnson syndrome and toxic epidermal necrolysis. J. Invest. Dermatol. 133, 1197–1204 (2013).
Husain, Z., Reddy, B. & Schwartz, R. DRESS syndrome: part II. Management and therapeutics. J. Am. Acad. Dermatol. 68, 709.e1–709.e9 (2013).
Ramasamy, S. et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950–2012. Drug Saf. 36, 953–980 (2013).
Gutierrez-Macias, A., Lizarralde-Palacios, E., Martinez-Odriozola, P. & Miguel-De la Villa, F. Fatal allopurinol hypersensitivity syndrome after treatment of asymptomatic hyperuricaemia. Br. Med. J. 331, 623–624 (2005).
Lupton, G. & Odom, R. Severe allopurinol hypersensitivity syndrome. J. Am. Acad. Dermatol. 72, 1361–1368 (1979).
Arellano, F. & Sacristan, J. Allopurinol hypersensitivity syndrome: a review. Ann. Pharmacother. 27, 337–343 (1993).
Lonjou, C. et al. A European study of HLA-B in Stevens–Johnson syndrome and toxic epidermal necrolysis related to five high risk drugs. Pharmacogenet. Genomics 18, 99–107 (2008).
Kaniwa, N. et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens–Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 9, 1617–1622 (2008).
Tassaneeyakul, W. et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet. Genomics 19, 704–709 (2009).
Goncalo, M. et al. HLA-B*58:01 is a risk factor for allopurinol-induced DRESS and Stevens–Johnson syndrome/toxic epidermal necrolysis in a Portuguese population. Br. J. Dermatol. 169, 660–665 (2013).
Kang, H. et al. Positive and negative associations of HLA class I alleles with allopurinol-induced SCARs in Koreans. Pharmacogenet. Genomics 21, 303–307 (2011).
Stamp, L. et al. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 64, 2529–2536 (2012).
Li, R. et al. Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford) 51, 721–729 (2012).
Winnard, D. et al. National prevalence of gout derived from administrative health data in Aotearoa New Zealand. Rheumatology (Oxford) 51, 901–909 (2012).
Zhu, Y., Pandya, B. & Choi, H. Prevalence of gout and hyperuricemia in the US general population. Arthritis Rheum. 63, 3136–3141 (2011).
Saito, Y. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin. Pharm. Ther. http://dx.doi.org/10.1002/cpt.161.
Chung, W. H. 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. http://dx.doi.org/10.1136/annrheumdis-2014-205577.
Dalbeth, N., Kumar, S., Stamp, L. K. & Gow, P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricaemia in patients with gout. J. Rheumatol. 33, 1646–1650 (2006).
Khanna, D. et al. 2012 American College of Rheumatology guidelines for the management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricaemia. Arthritis Care Res. (Hoboken) 64, 1431–1446 (2012).
Zhang, W. et al. EULAR evidence based recommendations for gout. Part II: management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann. Rheum. Dis. 65, 1312–1324 (2006).
Day, R. et al. Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol. Clin. Pharmacokinet. 46, 623–644 (2007).
Stamp, L. et al. Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level. Clin. Pharm. Ther. 90, 392–398 (2011).
Stamp, L. et al. Furosemide increases plasma oxypurinol without lowering serum urate—a complex drug interaction: implications for clinical practice. Rheumatology (Oxford) 51, 1670–1676 (2012).
Elion, G., Yu, T. F., Gutman, A. & Hitchings, G. Renal clearance of oxipurinol, the chief metabolite of allopurinol. Am. J. Med. 45, 69–77 (1968).
Chung, W. et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens–Johnson syndrome and toxic epidermal necrolysis. Nat. Med. 14, 1343–1350 (2008).
Puig, J., Casas, E., Ramos, T., Michan, A. & Mateos, F. Plasma oxypurinol concentration in a patient with allopurinol hypersensitivity. J. Rheumatol. 16, 842–844 (1989).
Casas, E. et al. The allopurinol hypersensitivity syndrome: its relation to plasma oxypurinol levels. Adv. Exp. Med. Biol. 253A, 257–260 (1989).
Emmerson, B., Gordon, R., Cross, M. & Thomson, D. Plasma oxypurinol concentrations during allopurinol therapy. Br. J. Rheumatol. 26, 445–449 (1987).
Stamp, L. et al. Relationship between serum urate and plasma oxypurinol—is there a target plasma oxypurinol to achieve serum urate <6mg/dl? Arthritis Rheum. 60, S561 (2009).
Yawalkar, N. et al. Infiltration of cytotoxic T cells in drug-induced cutaneous eruptions. Clin. Exp. Allergy 30, 847–855 (2000).
Lee, M. et al. Initiating allopurinol therapy: do we need to know the patient's human leucocyte antigen status? Int. Med. J. 42, 411–416 (2012).
Jung, J. et al. An effective strategy to prevent allopurinol-induced hypersensitivity by HLA typing. Genet. Med. http://dx.doi.org/10.1038/gim.2014.195.
Jung, J. W. et al. HLA-B58 can help the clinical decision on starting allopurinol in patients with chronic renal insufficiency. Nephrol. Dial. Transplant. 26, 3567–3572 (2011).
Nassif, A. et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J. Allergy Clin. Immunol. 114, 1209–1215 (2004).
Shiohara, T., Ushigome, Y., Kano, Y. & Takahashi, R. Crucial role of viral reactivation in the development of severe drug eruptions: a comprehensive review. Clin. Rev. Allergy Immunol. http://dx.doi.org/10.1007/s12016-014-8421–8423.
Daubner, B. et al. Multiple drug hypersensitivity: normal TREG cell function but enhanced in vivo activation of drug-specific T cells. Allergy 67, 58–66 (2012).
Shiohara, T., Inaoka, M. & Kano, Y. Drug-induced hypersensitivity syndrome (DIHS): a reaction induced by a complex interplay among herpes viruses and antiviral and antidrug immune responses. Allergol. Int. 55 1–8 (2006).
Picard, D. et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci. Transl. Med. 2, 46ra62 (2010).
Chohan, S. & Becker, M. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J. Rheumatol. 38, 1957–1959 (2011).
Narzi, D. et al. Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides. J. Mol. Biol. 415, 429–442 (2012).
Fabian, H. et al. HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution. J. Mol. Biol. 376, 798–810 (2008).
Becker, M. et al. Febuxostat compared with allopurinol in patients with hyperuricaemia and gout. N. Engl. J. Med. 353, 2450–2461 (2005).
Park, D. J. et al. Cost-effectiveness analysis of HLA-B5801 genotyping in the treatment of gout patients with chronic renal insufficiency in Korea. Arthritis Care Res. (Hoboken) 67, 280–287 (2015).
Saokaew, S., Tassaneeyakul, W., Maenthaisong, R. & Chaiyakunapruk, N. Cost-effectiveness analysis of HLA-B*5801 testing in preventing allopurinol-induced SJS/TEN in Thai population. PLoS ONE 9, e94294. (2014).
Hershfield, M. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin. Pharmacol. Ther. 93, 153–158 (2013).
Phillips, E. & Mallal, S. Pharmacogenetics of drug hypersensitivity. Pharmacogenomics 11, 973–987 (2010).
Mallal, S. et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 359, 568–579 (2008).
Santiago, F., Gonçalo, M., Vieira, R., Coelho, S. & Figueiredo, A. Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS). Contact Dermatitis 62, 47–53 (2010).
Bose, B. et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol. Dial. Transplant. 29, 406–413 (2014).
Singer, J. & Wallace, S. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum. 29, 82–87 (1986).
Cockcroft, D. W. & Gault, M. H. Prediction of creatinine clearance from serum creatinine. Nephron 16, 31–41 (1976).
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L.K.S. declares she has received consulting and speaker fees from Astra Zeneca. The other authors declare no competing interests.
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Stamp, L., Day, R. & Yun, J. Allopurinol hypersensitivity: investigating the cause and minimizing the risk. Nat Rev Rheumatol 12, 235–242 (2016). https://doi.org/10.1038/nrrheum.2015.132
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DOI: https://doi.org/10.1038/nrrheum.2015.132
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