Skip to main content
Top

26-09-2014 | Gout | Article

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

Journal: Drugs & Aging

Authors: Lisa K. Stamp, Peter T. Chapman

Publisher: Springer International Publishing

Abstract

Gout is increasingly seen in the elderly population, in large part due to physiological decline in renal function with age, and as a result of therapy for comorbidities, in particular the use of diuretic therapies for hypertension and congestive heart failure. Urate-lowering therapy (ULT) is the cornerstone of successful long-term gout management with the aim of achieving a sustained reduction in urate (<0.36 mmol/L, or lower [<0.30 mmol/L] in those with tophi). After decades during which there has been relatively little interest in developing new agents to treat gout, the last 5–10 years has seen a plethora of new agents with several now used in routine clinical practice. There has also been a renewed focus on the optimal use of established ULT, specifically allopurinol, which remains the first-line therapy for most patients. There is emerging data on its use in patients with renal impairment and better recognition of risk factors of the rare but potentially lethal allopurinol hypersensitivity syndrome (AHS). Febuxostat, a new xanthine oxidase inhibitor, is now established in everyday practice. Uricosuric agents may be indicated in certain patient groups, whilst a new class of recombinant uricases (pegloticase) given by intravenous infusion may achieve dramatic and rapid urate-lowering effects. Cost and other factors have thus far limited its use to the very severe cases. Furthermore, increased understanding of urate metabolism has led to the development of a number of drugs currently under clinical evaluation. Common therapeutic targets are the urate transporters in the kidney and alternative xanthine oxidase inhibition pathways. These advances bode well for the better management of gout and hyperuricaemia in our elderly patients.
Literature
1.
Mikuls T, Farrar J, Bilker W, Fernandes S, Schumacher HR, Saag K. Gout epidemiology: results from the UK general practice research database, 1990–1999. Ann Rheum Dis. 2005;64:267–72.PubMedCrossRefPubMedCentral
2.
Khanna D, Fitzgerald J, Khanna P, Sangmee B, Singh M, Neogi T, et al. American College of Rheumatology Guidelines for the Management of Gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricaemia. Arthritis Care Res. 2012;64(10):1431–46.CrossRef
3.
Loebl WY, Scott JT. Withdrawal of allopurinol in patients with gout. Ann Rheum Dis. 1974;33(4):304–7.PubMedCrossRefPubMedCentral
4.
Gast L. Withdrawal of longterm antihyperuricemic therapy in tophaceous gout. Clin Rheumatol. 1987;6(1):70–3.PubMedCrossRef
5.
Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla J. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Care Res. 2006;55(5):786–90.CrossRef
6.
Hutton I, Gamble G, Gow P, Dalbeth N. Factors associated with recurrent hospital admissions for gout: a case-controlled study. J Clin Rheumatol. 2009;15(6):271–4.PubMedCrossRef
7.
Dalbeth N, Collis J, Gregory K, Clark B, Robinson E, McQueen F. Tophaceous joint disease strongly predicts hand function in patients with gout. Rheumatology. 2007;46:1804–7.PubMedCrossRef
8.
Becker M, Schumacher HR, Benjamin K, Gorevic P, Greenwald M, Fessel J, et al. Quality of life and disability in patients with treatment-failure gout. J Rheumatol. 2009;36(5):1041–8.PubMedCrossRef
9.
Sivera F, Andrés M, Carmona L, Kydd A, Moi J, Seth R, et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis. 2014;73(2):328–35.PubMedCrossRefPubMedCentral
10.
Becker M, Schumacher HR, Espinoza L, Wells A, MacDonald P, Lloyd E, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricaemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63. doi:10.​1186/​ar2978.PubMedCrossRefPubMedCentral
11.
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.PubMedCrossRef
12.
Hung S, Chung W, Liou L, Chu C, Lin M, Huang H, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci. 2005;102(11):4134–9.PubMedCrossRefPubMedCentral
13.
Vazquez-Mellado J, Meono 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. 2001;60:981–3.PubMedCrossRefPubMedCentral
14.
Dalbeth N, Kumar S, Stamp LK, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricaemia in patients with gout. J Rheumatol. 2006;33(8):1646–50.PubMed
15.
Yun J, Marcaida M, Eriksson K, Jamin H, Fontana S, Pichler W, et al. Oxypurinol directly and immediately activates the drug-specific T cells via the preferential ise of HLA-B*58:01. J Immunol. 2014;192:2984–93.PubMedCrossRef
16.
Stamp L, Taylor W, Jones P, Dockerty J, Drake J, Frampton C, et al. Starting dose, but not maximum maintenance dose, is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012;64(8):2529–36.PubMedCrossRef
17.
Stamp L, O’Donnell J, Zhang M, James J, Frampton C, Barclay M, 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. 2011;63(2):412–21.PubMedCrossRef
18.
Venkat Raman G, Sharman V, Lee H. Azathioprine and allopurinol: a potentially dangerous combination. J Int Med. 1990;228:69–71.CrossRef
19.
Stamp L, Barclay M, O’Donnell J, Zhang M, Drake J, Frampton C, et al. Furosemide increases plasma oxypurinol without lowering serum urate—a complex drug interaction: implications for clinical practice. Rheumatology. 2012;51(9):1670–6.PubMedCrossRef
20.
Bose B, Badve S, Hiremath S, Boudville N, Brown F, Cass A, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2014;29:406–13.PubMedCrossRef
21.
Krishnan E, Baker J, Furst D, Schumacher HR. Gout and the risk of acute myocardial infarction. Arthritis Rheum. 2006;54(8):2688–96.PubMedCrossRef
22.
Baker J, Krishnan E, Chen L, Schumacher HR. Serum uric acid and cardiovascular disease: Recent developments and where do they leave us? Am J Med. 2005;118:816–26.PubMedCrossRef
23.
Norman A, Ang D, Ogston S, Lang C, Struthers A. Effect of high dose allopurinol on exercise in patients withy chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010;375:2161–7.CrossRef
24.
Grimaldi-Bensouda L, Alpérovitch A, Aubrun E, Danchin N, Rossignol M, Abenhaim L, et al. Impact of allopurinol on the risk of myocardial infarction. Ann Rheum Dis. 2014. doi:10.​1136/​annrheumdis-2012-202972.PubMed
25.
Thansaaoulis G, Brophy J, Richard H, Pilote L. Gout, allopurinol use and heart failure outcomes. Arch Intern Med. 2010;170(15):1358–64.CrossRef
26.
Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, et al. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearance, and proteinuria in patients with normal renal function. Int Urol Nephrol. 2007;39(4):1227–33.PubMedCrossRef
27.
Feig D, Soletsky B, Johnson R. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. JAMA. 2010;300(8):924–32.CrossRef
28.
Becker M, Schumacher HR, Wortmann R, MacDonald P, Eustace D, Palo W, et al. Febuxostat compared with allopurinol in patients with hyperuricaemia and gout. N Engl J Med. 2005;353:2450–61.PubMedCrossRef
29.
Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC Geriatr. 2012;12:11. doi:10.​1186/​1471-2318-12-11.PubMedCrossRefPubMedCentral
30.
Chohan S, Becker M. Safety and efficacy of febuxostat treatment in subjects with gout and severe allopurinol adverse reactions. J Rheumatol. 2011;38(9):1957–9.PubMedCrossRef
31.
Beard S, von Scheele B, Nuki G, Pearson I. Cost-effectiveness of febuxostat in chronic gout. Eur J Health Econ. 2013. doi:10.​1007/​s10198-013-0486-z.PubMed
32.
Horikoshi R, Akimoto T, Inoue M, Morishita Y, Kusano E. Febuxostat for hyperuricaemia: experience with patients on chronic hemodialysis treatment. Clin Exp Nephrol. 2013;17:149–50.PubMedCrossRef
33.
Tojimbara T, Nakajima I, Yashima J, Fuchinoue S, Teraoka S. Efficacy and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in kidney transplant recipients. Transplant Proc. 2014;46:511–3.PubMedCrossRef
34.
Sofue T, Inui M, Hara T, Nishijima Y, Moriwaki K, Hayashida Y, et al. Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients. Drug Des Dev Ther. 2014;8:245–53.CrossRef
35.
Kang Y, Kim M, Jang H, Bae E, Yun S, Cho H, et al. Rhabdomyolysis associated with initiation of febuxostat therapy for hyperuricaemia in a patient with chronic kidney disease. J Clin Pharm Ther. 2014;39:328–30.PubMedCrossRef
36.
Kobayashi S, Ogura M, Hosoya T. Acute neutropenia associated with initiation of febuxostat therapy for hyperuricaemia in patients with chronic kidney disease. J Clin Pharm Ther. 2013;38:258–61.PubMedCrossRef
37.
Khosravan R, Grabowski B, Mayer M, Wu J, Joseph-Ridge N, Vernillet L. The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2006;46(1):88–102.PubMedCrossRef
38.
Dore M, Frenette A, Mansour A, Troyanov Y, Begin J. Febuxostat as a novel option to optimize thiopurines’ metabolism in patients with inadequate metabolite levels. Ann Pharmacother. 2014;48(5):648–51.PubMedCrossRef
39.
Wu J, Joseph-Ridge N, et al. Pharmacokinetic interactions of concomitant administration of febuxostat and NSAIDs. J Clin Pharmacol. 2006;46(8):855–66.PubMedCrossRef
40.
Grabowski B, Khosravan R, Wu J, et al. Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase. Br J Clin Pharmacol. 2010;70(1):57–64.PubMedCrossRefPubMedCentral
41.
Khosravan R, Grabowski B, Wu J, et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol. 2008;65(3):355–63.PubMedCrossRefPubMedCentral
42.
Mukoyoshi M, Nishimura S, Hoshide S, et al. In vitro drug-drug interaction studies with febuxostat, a novel non-purine selective inhibitor of xanthine oxidase: plasma protein binding, identification of metabolic enzymes and cytochrome P450 inhibition. Xenobiotica. 2008;38(5):496–510.PubMedCrossRef
43.
Whelton A, MacDonald P, Zhao L, Hunt B, Gunawardhana L. Renal function in gout: long-term treatment effects of febuxostat. J Clin Rheumatol. 2011;17(1):7–13.PubMedCrossRef
44.
Hosoya T, Kimura K, Itoh S, Inaba M, Uchida S, Tomino Y, et al. The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study. Trials. 2014;15:26.PubMedCrossRefPubMedCentral
45.
White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J. 2012;164(1):14–20. doi:10.​1016/​j.​ahj.​2012.​04.​011.PubMedCrossRef
46.
MacDonald T, Ford I, Nuki G, Mackenzie I, De Caterina R, Findlay E, et al. Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large prospective, randomised, open, blinded endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open. 2014;4(7):e005354. doi:10.​1136/​bmjopen-2014-.PubMedCrossRefPubMedCentral
47.
Reinders M, Van Roon E, Jansen T, Delsing J, Griep E, Hoekstra M, et al. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis. 2009;68:51–6.PubMedCrossRef
48.
Perez-Ruiz F, Calaabozo M, Fernardez-Lopez J, Herrero-Beites A, Ruiz-Lucea E, Garcia-Erauskin G, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomised, actively controlled study. J Clin Rheumatol. 1999;5(2):49–55.PubMedCrossRef
49.
Hautekeete M, Henrion J, Naegels S, DeNeve A, Adler M, Deprez C, et al. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver. 1995;15:25–9.PubMedCrossRef
50.
Lee M-H, Graham G, Williams K, Day R. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interests of patients? Drug Saf. 2008;31(8):643–65.PubMedCrossRef
51.
Kobayashi K, Kajiwara E, Ishikawa M, Oka H, Chiba K. Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes. Biopharm Drug Dispos. 2012;33:466–73.PubMedCrossRef
52.
Scott S, Khasawneh R, Peter I, Kornreich R, Desnick R. Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics. 2010;11:781–91.PubMedCrossRefPubMedCentral
53.
Roberts R, Wallace M, Wright D, Cadzow M, Dalbeth N, Jones P, et al. Frequency of CYP2C9 polymorphisms in polynesian people and potential relevance to management of gout with benzbromarone. Jt Bone Spine. 2014;81(2):160–3.CrossRef
54.
Uchida S, Shimada K, Misaka S, Imai H, Katoh Y, Inui N, et al. Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes. Drug Metab Pharmacokinet. 2010;25:605–10.PubMedCrossRef
55.
Zurcher R, Bock H, Thiel G. Excellent uricosuric efficacy of benzbromarone in cyclosporin-A treated renal transplant patients: a prospective study. Nephrol Dial Transplant. 1994;9:548–51.PubMed
56.
Masbernard A, Giudicelli C. Ten years experience with benzbromarone in then management of gout and hyperuricaemia. S Afr Med J. 1981;59:701–6.PubMed
57.
Heel R, Brogden R, Speight T, Avery G. Benzbromarone: a review of its pharmacological properties and therapeutic uses in gout and hyperuricaemia. Drugs. 1977;14(5):349–66.PubMedCrossRef
58.
Shimodaira H, Takahashi K, Kano K, Matsumoto Y, Uchida Y, Kudo T. Enhancement of anticoagulant action by warfarin-benzbromarone interaction. J Clin Pharmacol. 1996;36:168–74.PubMedCrossRef
59.
Locuson C, Wahlstrom J, Rock D, Rock D, Jones J. A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives. Drug Metab Dispos. 2003;31(7):967–71.PubMedCrossRef
60.
Reinders M, Van Roon E, Houtmann P, Brouwers J, Jansen T. Biochemical effectiveness of allopurinol and allopurinol-probenecid in previously benzbromarone-treated gout patients. Clin Rheum. 2007;26:1459–65.CrossRef
61.
Stocker S, Williams K, McLachlan A, Graham G, Day R. Pharmacokinetic and Pharmacodynamic Interaction between Allopurinol and Probenecid in Healthy Subjects. Clin Pharmacokinet. 2008;47(2):111–8.PubMedCrossRef
62.
Thompson G, Duff I, Robinson W, Mikkelsen W, Galindez H. Long term uricosuric therapy in gouty. Arthritis Rheum. 1962;5:384–96.PubMedCrossRef
63.
Bartels E, Matossian G. Gout: six-year follow-up on probenecid therapy. Arthritis Rheum. 1959;2(3):193–202.PubMedCrossRef
64.
Pui K, Gow P, Dalbeth N. Efficacy and tolerability of probenecid as urate-lowering therapy in gout; clinical experience in high-prevalence population. J Rheumatol. 2013;40(6):872–6.PubMedCrossRef
65.
Caspi D, Lubart E, Graff E, Habot B, Yaron M, Segal R. The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients. Arthritis Rheum. 2000;43(1):103–8.PubMedCrossRef
66.
Harris M, Bryant L, Danaher P, Alloway J. Effect of low dose daily aspirin on serum urate levels and urinary excretion in patients receiving probenecid for gouty arthritis. J Rheumatol. 2000;27(12):2873–6.PubMed
67.
Sundy J, Baraf H, Yood R, Edwards N, Gutierrez-Urena S, Treadwell E, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711–20.PubMedCrossRef
68.
Baraf H, Becker M, Gutierrez-Urena S, Treadwell E, Vazquez-Mellado J, Rehrig C, et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013;15:R137.PubMedCrossRefPubMedCentral
69.
Lipsky P, Calabrese L, Kavanaugh A, Sundy J, Wright D, Wolfson M, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014;16:R60.PubMedCrossRefPubMedCentral
70.
Hershfield M, Ganson N, Kelly S, Scarlett E, Jaggers D, Sundy J. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014;16:R63.PubMedCrossRefPubMedCentral
71.
Gentry W, Dotson M, Williams B, Hartley M, Stafford K, Bottorff M, et al. Investigation of pegloticase-associated adverse events from a nationwide reporting system database. Am J Health Syst Pharm. 2014;71(9):722–7.PubMedCrossRef
72.
Yood R, Ottery F, Irish W, Wolfson M. Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials. BMC Res Notes. 2014;7:51.CrossRef
73.
Perez-Ruiz F, Hingorani V, Welp J, Sheedy B, Manhard K, Shen Z, et al. Efficacy and safety of a range of doses of RDEA594, a novel uricosuirc agent, as a single agent in hyperuricaemic gout patients: multicentre, randomized, double-blind, placebbo controlled, phase 2 experience. Ann Rheum Dis. 2010;69(Suppl 3):121.
74.
Perez-Ruiz F, Sundy J, Krishnan E, Hingorani V, Welp J, Suster M, et al. Efficacy and safety of lesinurad (RDEA594), a novel uricosuric agent, given in combination with allopurinol in allopurinol-refractory gout patients: randomized, double-blind, placebo-controlled, phase 2B study. Ann Rheum Dis. 2011;70(Suppl 3):104.
75.
Fleischmann R, Kerr B, Yeh L-T, Suster M, Shen Z, Polvent E, et al. Pharmacodynamic, pharmacokinetic and tolerability evaluation of concomitant administration of lesinurad and febuxostat in gout patients with hyperuricaemia. Rheumatology. 2014. doi:10.​1093/​rheumatology/​ket487.
76.
Noveck R, Wang Z, Forsthoefel A, Sigmon K, Hall P, Keogh J, et al. Levotofisopam has uricosuric activity and reduces serum urate levels in patients with gout. Arthritis Rheum. 2012;64(10 (Suppl)):S356.
77.
Hollister A, Becker M, Terkeltaub R, Waugh A, Lyman S, Flynt A, et al. BCX4208 shows synergistic reductions in serum uric acid in gout patients when combined with allopurinol. Ann Rheum Dis. 2011;70(Suppl 3):183.
78.
Dobo S, Flynt A, Hollister A, Sheridan W. BCX4208, A novel urate-lowering therapy, was generally safe and well tolerated in two 3-week studies in gout subjects. Ann Rheum Dis. 2011;70(Suppl 3):188.
79.
Saha G, Karpf D, Choi Y, Roberts B. Arhalofenate, a potential novel treatment for hyperuricemia, with or without metabolic co-morbidities, in patients with gout: meta-analysis of urate lowering in four phase 2 studies in type 2 diabetes. Arthritis Rheum. 2011;63(10 (suppl)):S1014.
80.
Choi Y, Larroca V, Lucman A, Vicena V, Abarca N, Rantz T, et al. Arhalofenate is a novel dual-acting agent with uricosuric and anti-inflammatory properties. Arthritis Rheum. 2012;64(10 (supple)):S697.
81.
Okamoto K, Nishino T. Crystal structures of mammalian xanthine oxidoreductase bound with various inhibitors: allopurinol, febuxostat, and FYX-051. J Nippon Med Sch. 2008;75(1):2–3.PubMedCrossRef
82.
Hosoya T, Ohno I, Nomura S, Hisatome I, Uchida S, Fujimori S, et al. Effects of topiroxostat on the serum urate levels and urinary albumin excretion in hyperuricemic stage 3 chronic kidney disease patients with or without gout. Clin Exp Nephrol. 2014. (in press).
83.
Sundy J, Kitt M. Tranilast, a novel, potential treatment for the chronic management of hyperuricaemia in patients with gout, reduces serum uric acid in healthy subjects. Ann Rheum Dis. 2010;69(Suppl 3):607.
84.
Mandal A, Emerling D, Serafini T, Mount D. Tranilast inhibits urate transport mediated by URAT1 and GLUT9. Arthritis Rheum. 2010;62(Suppl 10):164.
85.
Miner J, Tan P. RDEA3170, a novoel, high affinity URAT1 inhibitor binds to a central domain with URAT1. Ann Rheum Dis. 2012;71(Suppl 3):446.CrossRef
86.
Ahn S, Horiba N, Ohtomo, Lee K, Kim K, Kim B, et al. The therapeutic efficacy of the novel uricosuric agent UR-1102 for hyperuricaemia and gout. Ann Rheum Dis. 2013;72(Suppl 3):704.CrossRef
87.
Warrell R, Klukovits A, Barnes K, Satyanarayana C, Cheeseman C, Piwinski J. Novel bifunctional inhibitors of xanthine oxidase and URAT1 induce profound hypouricaemia in human subjects. Ann Rheum Dis. 2014. doi:10.​1136/​annrheumdis-2014-eular.​2265.