EULAR 2022 (VIRTUAL)—When it comes to inflammatory arthritis, most rheumatology providers would agree that gout is by far the most treatable type. However, most patients and primary care providers might disagree. Why the disconnect?
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Gout therapies are effective … when properly prescribed. Therein lies the rub. At the 2022 Congress of the European Alliance of Associations for Rheumatology (EULAR), Thomas Bardin, MD, rheumatology department, Hôpital Lariboisière, and professor emeritus, Université de Paris Cité, France, shared his expertise on refractory gout and whether or not it should actually exist in 2022.
Definitions & Causes
Refractory gout is defined as the persistence of clinical manifestations of gout due to the inability to reduce the serum urate (SU) concentration below the target 6.0 mg/dL mg/dL.1 It’s characterized by long disease duration and features of severe disease like frequent flares, polyarticular involvement, tophi, destructive arthropathy and/or chronic inflammatory arthritis. Refractory gout is also associated with many comorbidities and high economic costs.2,3 The U.S. Food and Drug Administration estimated, when approving pegloticase in 2009, that about 1% of gout patients had refractory disease, but this number is a moving target.4
“The cause of refractory gout is obviously mismanagement, and there are multiple sources,” Professor Bardin said. Insufficient prescription and dosing of urate-lowering therapy (ULT) remains a major culprit. Poor adherence to therapy results in lack of disease control, which is fueled in part by a general lack of patient and healthcare provider education about gout management. Drug intolerances and contraindications further complicate the picture.5,6 The list goes on.
Historically, intolerance to allopurinol—mainly due to cutaneous reactions—has been a source of refractory gout. However, Professor Bardin et al. demonstrated the majority of patients with cutaneous intolerance to allopurinol can tolerate febuxostat.7 He remarked, “Usually I wait for a month [after an allopurinol reaction]—a little longer in the case of drug rash with eosinophilia and systemic symptoms (DRESS)—and start febuxosat at a dose of 40 mg daily, increasing it slowly. In my experience, you can get the patient back to target [SU].”
In the rare cases of patients with skin and/or liver intolerance to both allopurinol and febuxostat, Professor Bardin recommended the use of uricosurics.
ULT Dosing & Chronic Kidney Disease
Many regulatory agencies across the world limit the maximum dosage of allopurinol according to creatinine clearance due to the increased risk of fatal skin reactions. Unfortunately, such restrictions translate into the failure to titrate allopurinol to a dose that reaches SU targets.8
In these circumstances, Professor Bardin recommended the use of febuxostat. He explained, “You can use febuxostat in chronic kidney disease (CKD) if the estimated glomerular filtration rate (eGFR) is greater than 30 mL/min/1.73m2 [because] it’s mainly metabolized by the liver.”
Febuxostat isn’t approved for patients with an eGFR less than 30 mL/min/1.73m2 because these patients were excluded from pivotal trials. However, data from small series have shown febuxostat can be well tolerated in these patients and efficacious.9 Professor Bardin shared, “I must say that I do use febuxostat in patients with severe renal failure. I start with a very low dose and slowly increase to target, while closely monitoring the patient.”
Professor Bardin noted that the recommendations for gout management in CKD differ between professional organizations (e.g., ACR and EULAR). “But in general, there are ways to deal with this problem, and we can get most of them to an appropriate [SU] target,” he said.
When it comes to end-stage renal disease, Professor Bardin reminded us that we’ve known since the 1960s that “hemodialysis is a good way to manage gout.”10 In addition, renal transplantation used to be a frequent cause of refractory gout due to calcineurin inhibitors causing hyperuricemia, and azathioprine barring the concomitant use of xanthine oxidase inhibitors. “But that problem has now been solved by mycophenolate mofetil, [which is safe to use in combination with allopurinol],” he added.11
Flare prophylaxis is a crucial and oft-overlooked component of gout care. However, comorbidities like CKD and type 2 diabetes mellitus can complicate drug selection. Colchicine, non-steroidal anti-inflammatory drugs and prednisone may all be contraindicated or undesirable options for certain patients.
Professor Bardin offered, “In patients who cannot be prescribed typical medications for flare prophylaxis, consider canakinumab. It’s not approved for [this indication], but has a long duration of action. ULT could be introduced and optimized after one canakinumab dose, which can remain effective up to one year.”12 Additional options might include other interleukin (IL) 11 inihibitors (e.g., anakinra) or tocilizumab in the instance of IL-1 blockade failure.13,14
‘I really believe that refractory gout is neglected gout & shouldn’t be seen anymore.’ —Thomas Bardin, MD
Using Comorbidities to our Advantage
Lastly, Professor Bardin pointed out that most gout patients have comorbidities, and we can use several of their other medications to help reduce hyperuricemia. In hypertension, losartan and calcium channel blockers are uricosuric.15 In hyperlipidemia, fenofibrate lowers SU and may reduce gout attacks.16 Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to significantly decrease SU levels, and many drugs in this class have multiple indications (e.g., type 2 diabetes mellitus, CKD with albuminuria, heart failure).17
Refractory Gout: Myth
Professor Bardin said, “Refractory gout should be prevented and shouldn’t exist. Difficult-to-treat gout is not refractory gout. And severe gout is not always refractory.”
To illustrate his point, Professor Bardin shared data from his experiences treating gout in Vietnam. “When we introduced EULAR treatment recommendations at one center in Vietnam,” he said, “we looked at the first 100 severe gout patients with no previous ULT and no renal failure. To achieve target SU, we had to use a mean allopurinol dose of 520 mg +/-165 mg per day. It was striking to see how life changing allopurinol was for these patients. Flares disappeared, tophi decreased, and quality of life and level of function improved.”
Over the past decade, major advances in gout care have truly rendered refractory gout a myth. Standard gout therapies like allopurinol and febuxostat—when properly prescribed and taken—are effective for most patients.
Patient and provider education is paramount to gout management success. In tougher cases, we have more options than we did previously, and hyperuricemia can be reduced via medications for comorbidities. Professor Bardin concluded, “I really believe that refractory gout is neglected gout and shouldn’t be seen anymore.”
Samantha C. Shapiro, MD, is an academic rheumatologist and an affiliate faculty member of the Dell Medical School at the University of Texas at Austin. She is also a member of the ACR Insurance Subcommittee.
- Fels E, Sundy JS. Refractory gout: What is it and what to do about it? Curr Opin Rheumatol. 2008 Mar;20(2):198–202.
- Thottam GE, Krasnokutsky S, Pillinger MH. Gout and metabolic syndrome: A tangled web. Curr Rheumatol Rep. 2017 Aug 26;19(10):60.
- Edwards NL, Sundy JS, Forsythe A, et al. Work productivity loss due to flares in patients with chronic gout refractory to conventional therapy. J Med Econ. 2011;14(1):10–15.
- U.S. Food and Drug Administration, Center for Drug Evaluation and Research, Division of Anesthesia, Analgesia, and Rheumatology Products. AAC Briefing Document Krystexxa (Pegloticase). 2009.
- Doherty M, Jenkins W, Richardson H, et al. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: A randomised controlled trial. Lancet. 2018 Oct 20;392(10156):1403–1412.
- Doherty M, Jansen TL, Nuki G, et al. Gout: Why is this curable disease so seldom cured? Ann Rheum Dis. 2012 Nov;71(11):1765–1770.
- Bardin T, Chalès G, Pascart T, et al. Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment. Joint Bone Spine. 2016 May;83(3):314–317.
- Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol. 2006 Aug;33(8):1646–1650.
- Kim SH, Lee SY, Kim JM, Son CN. Renal safety and urate-lowering efficacy of febuxostat in gout patients with stage 4-5 chronic kidney disease not yet on dialysis. Korean J Intern Med. 2020 Jul;35(4):998–1003.
- Duncan H, Elliott W, Horn DB, et al. Haemodialysis in the treatment of gout. Lancet. 1962 Jun 9;1(7241):1209–1211.
- Jacobs F, Mamzer-Bruneel MF, Skhiri H, et al. Safety of the mycophenolate mofetil-allopurinol combination in kidney transplant recipients with gout. Transplantation. 1997 Oct 15;64(7):1087–1088.
- Schlesinger N, Alten RE, Bardin T, et al. Canakinumab for acute gouty arthritis in patients with limited treatment options: Results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Ann Rheum Dis. 2012 Nov;71(11):1839–1848.
- Calvo-Aranda E, Sanchez-Aranda FM. Efficacy of subcutaneous tocilizumab in a patient with severe gout refractory to anakinra. Rheumatology (Oxford). 2021 Nov 3;60(11):e375–e377.
- Saag KG, Khanna PP, Keenan RT, et al. A randomized, phase II study evaluating the efficacy and safety of anakinra in the treatment of gout flares. Arthritis Rheumatol. 2021 Aug;73(8):1533–1542.
- Choi HK, Soriano LC, Zhang Y, Garciá Rodriǵuez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: Population based case-control study. BMJ. 2012 Jan;344:d8190.
- Waldman B, Ansquer JC, Sullivan DR, et al. Effect of fenofibrate on uric acid and gout in type 2 diabetes: A post-hoc analysis of the randomised, controlled FIELD study. Lancet Diabetes Endocrinol. 2018 Apr;6(4):310–318.
- Zhao Y, Xu L, Tian D, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2018 Feb;20(2):458–462.