Update on Gout Management: what’s old and what’s new

Abstract

Purpose of review:

The global burden of gout is rising, as are the prevalence of associated comorbidities, all-cause mortality, and societal costs. In this review, we discuss recent advances in epidemiology and treatment strategies for gout.

Recent findings:

Genetic factors and obesity are prominent contributors to hyperuricemia and gout, while dietary factors contribute to less variance in serum urate, though can still have some contribution to population attributable risk. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network outlined appropriate terminology regarding gout, which will aid in communication about various aspects of the disease. The 2020 American College of Rheumatology gout guideline offers comprehensive evidence-based recommendations for the management of hyperuricemia using urate-lowering therapy, prophylaxis when initiating urate-lowering therapy, treatment of gout flare, and adjunctive management strategies. There is improved understanding of risk factors for allopurinol hypersensitivity syndrome and safe use of allopurinol in chronic kidney disease. Trial data have provided new insights regarding cardiovascular risk with febuxostat. Several new drug therapies are being tested for both urate-lowering efficacy and gout flare management.

Summary:

Although there have been significant advances in understanding of risk factors and treatment approaches, gout remains suboptimally managed. There is substantial need for improving gout management efforts and gout education among patients and clinicians.

Introduction

Gout is the most common inflammatory arthritis and is caused by monosodium urate crystals deposited in the joints in people with hyperuricemia. In this review, we summarize the current understanding of the epidemiology of gout, recent treatment guideline recommendations, management considerations in special populations, and treatments in the pipeline.

Rising prevalence and burden of disease

Over the last 30 years, there was a 100% increase in prevalence of gout, which is out of proportion to the 42% increase in the world population or the rise in life expectancy (1). The Global Burden of Disease Study in 2017 estimated that approximately 41.2 million adults are living with gout worldwide, more than double the number of people living with rheumatoid arthritis (1, 2). The prevalence of gout in the US alone is 9.2 million (3.9% of US adults) (3). The incidence and prevalence of gout are higher in racial/ethnic minorities and in older adults (4).

Gout is associated with a 17% higher all-cause mortality risk than those without gout, with cardiovascular disease (CVD) being the most common cause of death (5). Additionally, renal disease was associated with 1.78 times higher risk of cause-specific mortality in those with gout compared to those without (5). Although a decrease in excess risk of premature mortality compared to the general population has been observed in rheumatoid arthritis over time (6), this trend has not been observed in gout, with similar excess risk of mortality for patients diagnosed with gout in 1999–2006 as compared to 2007–2014 (7).

Gout contributes to tremendous healthcare costs. A 2015 meta-analysis estimated all-cause annual direct costs among employed patients ranging from $4733 to $9353 per capita (8). Costs are higher for older adults ($16,925) and patients with treatment refractory gout ($18,362) (8). Emergency department visits for gout increased from 2006–2012 by 14%, and healthcare charges increased by 80% in the US (9). Whereas hospitalization rates for rheumatoid arthritis patients declined by 67% from 1993 to 2011, hospitalization rates doubled for patients with gout (10). Furthermore, patients with gout incur high indirect costs related to the work impairment and productivity loss (8).

Gout Management

The terms “acute” and “chronic” gout have contributed to a false dichotomy in regards to decisions about timing and indications for urate-lowering therapy (ULT), leading to a misconception that only patients with “chronic” gout require ULT. A consensus statement by the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) to clarify labels for gout disease elements has highlighted that terms such as “acute” and “chronic” gout should not be used, and instead the terms “gout flare”, “intercritical gout” and “chronic gouty arthritis” are recommended (13). Accordingly, the 2020 ACR gout guideline does not use the terms “acute gout” and “chronic gout” in its discussion of gout management.

Management of hyperuricemia: Urate-lowering therapy

The cornerstone of gout treatment is the reduction of urate using ULT, which includes xanthine oxidase inhibitors (XOI) (allopurinol and febuxostat), uricosuric agents (probenecid, benzbromarone, lesinurad, dotinurad), and recombinant porcine-like uricase that metabolizes urate to allantoin, pegloticase. Not all therapies are available in all markets.

Indications for ULT:

The 2020 American College of Rheumatology (ACR) gout guideline strongly recommends initiating ULT in patients with one or more clinically evident tophi, radiographic damage reflecting gouty bony erosion, or two or more gout flares annually. ULT was also conditionally recommended for patients with more than one gout flare annually, and for patients with comorbid stage ≥ 3 chronic kidney disease (CKD), serum urate level >9 mg/dl, or kidney stones (14). Allopurinol is strongly recommended as the preferred first line agent for all patients, including those with moderate to severe CKD, unless there are contraindications such as hypersensitivity to prior allopurinol exposure or consideration of potential high risk due to HLA-B*5801 (14). Dosing considerations for various ULTs available in the US are outlined in Table 1.

Table 1:

Approved urate-lowering therapies currently available on the market in the US

Drug (FDA approval date)	Dosing and considerations in CKD	Select side effects	Select drug interactions/ considerations
Allopurinol(1966)	Start at dose ≤100 mg/day and titrate by ≤100 mg every 2–4 weeks to goal serum urate; max FDA recommended dose 800 mg/day GFR<30: start at 50 mg/day and titrate by 50 mg every 2–4 weeks to goal serum urate. Okay to use in patients with ESRD on dialysis	• Mobilization gout flares when initiating ULT  • Rash  • Hematologic abnormalities  • Hepatotoxicity  • AHS/DRESS syndrome especially if HLA-B58:01 positive	• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine  • Increased likelihood of ampicillin induced rash
Febuxostat (2009)	Start at 40 mg/day and titrate to 80 mg/day if serum urate not at goal GFR 15–29ml/min: doses above 40mg/day not recommended per FDA label, but studies indicate that doses up to 80 mg/day may be safe. Limited data on febuxostat use in patients with ESRD on dialysis	• Mobilization gout flares when initiating ULT  • Nausea  • Arthralgias  • Rash  • Unclear potential cardiovascular risk  • Hepatic abnormalities  • Hypersensitivity reactions/DRESS	• Potentiation of immunosuppressive effects of azathioprine and 6-mercapropurine
Probenecid (1979)	Start at 250 mg twice daily with dose titration to maximal effective dose of 2000 mg/day GFR<30 ml/min: probenecid not recommended due to lack of efficacy in setting of inadequate renal function	• Mobilization gout flares when initiating ULT  • Rash, flushing  • GI intolerance  • Urolithiasis	• Prolonged half-life of penicillin and ampicillin  • High dose aspirin may reduce probenecid’s uricosuric effect
Pegloticase (2010)	8 mg IV every 2 weeks Check serum urate prior to each infusion after 1st dose, and stop if serum urate > 6 mg/dL No dose adjustment needed in patents with CKD or ESRD on dialysis *Discontinue all ULT prior to initiation of pegloticase to avoid masking loss of urate response	• Contraindicated in G6PD deficiency (hemolysis, methemoglobulinemia)  • Mobilization gout flares  • Nausea, vomiting  • Anaphylaxis and serious infusion reactions related to anti-drug antibodies  • Caution in patients with CHF

Starting ULT during a gout flare is conditionally recommended by the 2020 ACR gout guideline, reflecting the need for shared decision making (14). This is similar to the 2012 ACR gout guideline, with additional studies considered in the updated 2020 guideline in which some trial data did not suggest a large risk for the theoretical concern about prolonging a flare (15–17). Ensuring appropriate patient education and follow-up may be challenging when a patient is in the midst of an intensely painful flare. On the other hand, patients may be more motivated to make significant changes immediately while seeking care for a flare.

Treat-to-target strategy (T2T):

Titrating ULT to achieve a target serum urate level of < 6 mg/dL is strongly recommended over fixed dosing in the ACR gout guideline (14), supported by data from a number of randomized controlled trials (RCTs) regarding clinical benefits. In the pegloticase RCT, there was a significant reduction in flares and tophi at 6 months (18). In a febuxostat RCT in early gout, there was a significant reduction in gout flares noted only after 6 months (19). In a UK RCT, patients randomized to a T2T nurse-led intervention were significantly more likely to achieve a serum urate of < 6 mg/dL and have lower flare frequency and greater tophus resolution at 2 years (20). Other studies have also been supportive of a T2T approach, including pharmacy led T2T programs that were more effective than usual care in patients achieving target urate levels (21, 22). In patients who do not achieve target urate level despite XOI, uricosurics, and other interventions and who continue to have frequent flares or non-resolving tophi, pegloticase is recommended (14). For patients on therapy, it is conditionally recommended to continue ULT indefinitely (14).

Prophylaxis when starting ULT:

When initiating ULT, the 2020 ACR gout guideline strongly recommends administering prophylactic anti-inflammatories such as NSAIDS, colchicine, or prednisone to prevent gout flares (14). A stepwise dose escalation of febuxostat from 10 to 40 mg/day has been demonstrated to be comparable with addition of colchicine prophylaxis to fixed dose febuxostat 40 mg daily for the prevention of gout flares during ULT titration (23).

Gout flare management

The ACR guideline strongly recommends NSAIDs, colchicine, or glucocorticoids (oral or intra-articular) as first-line therapy for the management of gout flares, without differentiating between particular agents, over anti-IL-1 therapy (14). Of note, in patients who are already on colchicine prophylaxis, colchicine could be used for flare treatment as long as liver and kidney function permit, and there are no major contraindications or drug-drug interactions. IL-1 inhibitors, anakinra and canakinumab, though currently not FDA-approved for such use, are reserved for those unresponsive to therapy or who are unable to tolerate NSAIDS, colchicine and steroids.

Data on direct comparative effectiveness of interventions for gout flare management are minimal. A 2021 network meta-analysis reported that canakinumab has a potential advantage compared to other anti-inflammatory interventions for pain reduction and joint tenderness at day 2 (24). IV and IM steroids may also be superior to ibuprofen, COX-2 inhibitors, colchicine and oral corticosteroids in pain reduction at day 2. Acetic acid derivative NSAIDs are probably superior to ibuprofen NSAIDS for joint swelling reduction at day 2.

Dietary and lifestyle modifications

Recent studies have highlighted the importance of genetic factors and obesity as being prominent determinants of hyperuricemia. A 2018 meta-analysis reported that the variance in urate levels due to genetics was higher than dietary factors (11). However, while variances in hyperuricemia explained by obesity, nonadherence to the DASH diet, alcohol use, and diuretic use were overall low, the population attributable risk of obesity was estimated to be 44%; in contrast, for the DASH diet and alcohol use, the population attributable risks were 9% and 8%, respectively (12).

While ULT is the mainstay of gout management, dietary and lifestyle modifications may be useful adjuncts to ULT. Dietary interventions alone often do not lead to significant urate reduction in patients with gout and caution should be undertaken when discussing dietary factors to avoid patient blaming (25). Nonetheless, weight loss may improve urate levels and risk of flares, and is recommended by the ACR gout guideline, which also conditionally recommends limiting consumption of alcohol, purines and high fructose corn syrup. No recommendations could be made regarding cherry/cherry extract, omega-3 fatty acids, and dairy due to a paucity of data (14).

Specific conditions or treatment considerations

Allopurinol Hypersensitivity Syndrome:

Allopurinol hypersensitivity syndrome, AHS, is a rare, but highly fatal, adverse reaction to allopurinol. Starting dose is an important risk factor for AHS (26, 27); as such, allopurinol should be started at 100mg/d for those with normal or mildly impaired renal function (up to CKD stage 3), or at 50mg/d for those with CKD stage 4 or worse; this lower starting dose approach also mitigates risk of flares (14). Another important risk factor for AHS is the HLA-B*58:01 allele, which is associated with a 80–580-fold increased likelihood of AHS (28, 29). Prevalence of HLA-B*58:01 allele is ~7.4% in Han Chinese, Korean, and Thai populations, ~3.8% in African Americans, and 0.7% in whites (30). However, numerous ethnic groups have not had prevalence of HLA-B*58:01 reported. Nonetheless, testing for HLA-B*58:01 allele is conditionally recommended in Southeast Asian and African American patients (14).

In settings where HLA-B*5801 testing is not available or cost-prohibitive to patients, starting at a low dose and slowly titrating up with close monitoring is a feasible approach (14). It should also be recognized that febuxostat is associated with drug rash with eosinophilia and systemic symptoms (DRESS), through a different mechanism than HLA-B*5801.

Management of Gout in CKD:

In addition to the dosing recommendations regarding allopurinol in CKD summarized above, patients on hemodialysis or peritoneal dialysis can also safely receive allopurinol (31). Febuxostat does not require dose adjustments for CrCl≥30mL/min; for CrCl 15–29mL/min, it is recommended to use no more than 40mg/day according to the FDA label. RCT data suggest that febuxostat may be safe to use in patients with GFR≥15 ml/min (32), but there is limited data on its use in advanced CKD, dialysis and transplant (31, 33). Uricosurics are not effective at low CrCl levels; probenecid is not recommended for those with CrCl<30ml/min (14). Pegloticase can be used in patients with advanced CKD, including patients on dialysis, without dose adjustment (31). For prophylaxis while initiating ULT, NSAIDs and often colchicine may not be an option for patients with CKD; in such case, low-dose steroids may need to be used, though not ideal; consideration of anti-IL-1β therapy may be reasonable.

There has been substantial interest in whether ULT may have a beneficial effect on renal function among people with CKD outside of the context of gout. However, two recent RCTs suggested that allopurinol use was not associated with reduction in renal disease progression in patients with CKD who were at high risk, though questions remain about appropriateness of study sample given the underlying cause of CKD in one RCT (type 1 diabetes) and potential issues with power in the other RCT (34, 35).

Cardiovascular risk and XOI:

While there are biologic hypotheses supporting potential detrimental effects of serum urate on CVD, ULT RCTs have not supported these hypotheses and have in fact raised concerns about potential adverse CV consequences of febuxostat in particular. The FDA-mandated post-marketing Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities Trial, CARES, raised concerns about potential higher all-cause and CV mortality with febuxostat compared with allopurinol (36). However, valid interpretation of these findings is challenging due to 57% dropout, 45% lost-to-follow-up, and 85% of events occurring after drug discontinuation, including 23–28% of deaths occurring within 30 days of drug discontinuation (37). In contrast, the EMA-mandated post-marketing Febuxostat versus Allopurinol Streamlined Trial, FAST, did not find an elevated risk of CV events in the febuxostat group compared with allopurinol and had excellent follow-up and much lower drug discontinuation (38). The FDA placed a black box warning on febuxostat in light of the results of the CARES trial. The 2020 ACR gout guideline took the CARES trial results and the FDA black box warning into account and made a conditional recommendation to switch therapy in patients on febuxostat with a history of CVD or a new CV event (14). Subsequently, with the FAST trial results providing some reassurance about lack of elevated risk with febuxostat, it is anticipated that the next treatment guideline will take these newer data into consideration (39).

Pegloticase and immunogenicity:

A challenge in the use of pegloticase is the development of anti-drug antibodies with resultant risk for infusion reactions and anaphylaxis (18, 40). A rise in serum urate levels in between pegloticase infusions above 6mg/dL signals a risk for infusion reaction or anaphylaxis. Only about 42% of patients maintain serum urate levels below 6 mg/dL over a 6-month treatment course with pegloticase (18). A prospective clinical trial enrolled 14 patients who were treated with methotrexate 15mg per week for 4 weeks prior to and during pegloticase treatment and reported that 79% of patients maintained therapeutic response at 6 months (41). Mycophenolate mofetil (MMF) was also demonstrated to be effective in mitigating immunogenicity of pegloticase: at 12 weeks, serum urate below 6 mg/dL was achieved in 86% of participants in the MMF group as compared to 40% in placebo; maintenance of serum urate below 6mg/dL at 24 weeks was achieved in 68% versus 30% in the MMF and placebo groups, respectively (42). The optimal immunosuppressive regimen with pegloticase to prevent anti-drug antibody formation remains to be determined.

How is gout managed in the real world?

Despite availability of effective therapy, ULT is greatly underutilized in gout management. Based on a study of commercial health insurance enrollees from the US, the number of ULT users per 1000 gout patients was estimated to be 567 in 2009, and this number increased only slightly to 656 in 2019 (43). Another claims based analysis reported that less than 80% of patients with gout, including those with tophaceous gout, received prescriptions for ULT, and prescription coverage was for less than 50% of the year (44). Adherence is also poor at about 46%, with 54% to 87% of patients experiencing a gap in therapy (45).

Among ULT options, patients are almost exclusively prescribed allopurinol. Febuxostat’s use peaked at ~10% of all ULT prescriptions in 2013–2014; following the CARES trial data and addition of the FDA black box warning, its use diminished (43). Probenecid is prescribed infrequently, accounting for less than 5% of all ULT prescriptions (43). Pegloticase prescriptions represent less than 0.1% and the same was true for lesinurad prior to it coming off the market (43).

Gout is often managed by primary care physicians. The 2017 American College of Physicians (ACP) gout management guideline differs from all Rheumatology specialty guidelines from the past decade, including ACR, European League against Rheumatism, and British Society of Rheumatology (14, 46–48). Specifically, the ACP guideline does not offer clear recommendations for initiation of ULT, serum urate target levels or T2T (49). While the bulk of gout care occurs in primary care, a recent study showed that having a visit with a rheumatologist reduces patients’ emergency room utilization, emphasizing that there is a tremendous room for improvement of gout management outside of rheumatology (44).

Drugs in the pipeline

There are numerous drugs that are currently in the pipeline for gout management, some of which are summarized in Table 2. The general categories of drug mechanisms being explored are related to renal urate excretion, minimizing immunogenicity of uricase-based therapy, additional targets on the purine metabolism pathway, and leveraging the GI system for urate excretion. In addition, IL-1 inhibition and inflammasome targets are among the programs in development for gout flare management.

Table 2:

Ongoing Clinical Trials in Gout^*

Drug	Mechanism of Action	Study Phase
Urate Lowering Therapy
Inhibition of urate reabsorption in the kidney
Dotinurad	Inhibitor of urate transporter 1 (URAT1)	Phase 3
SHR4640	Inhibitor of URAT1	Phase 3
SAP-001	Inhibitor of URAT1	Phase 2
D-0120	Inhibitor of URAT1	Phase 1/2
XNW3009	small molecule hURAT1 inhibitor	Phase 1
AC-201**	Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney	Phase 2
Xanthine oxidase inhibitors
ABP-671	Novel xanthine oxidase inhibitor	Phase 2
LC350189	Novel xanthine oxidase inhibitor	Phase 1
Metabolizers of serum urate
SEL-212	Combination product of pegadricase, proprietary pegylated uricase, co-administered with ImmTOR, designed to mitigate formation of anti-drug antibodies	Phase 3
ALLN-346	Engineered urate oxidase that acts in the gastrointestinal tract	Phase 2
SSS11	PEGylated recombinant candida urate oxidase	Phase 1
Gout Flare Management
RPH-104	Novel heterodimeric fusion protein that inhibits IL-1	Phase 2
AC-201**	Inhibitor of production and activity of caspase-1 and Il-1b and selective inhibitor of re-absorption transporters in kidney	Phase 2
Anakinra in CKD or renal transplant	IL-1 receptor antagonist	Phase 2/3
Adrenocorticotropic hormone (ACTH)	Activation of melanocortin type 3 receptor; adrenal corticosteroid release	n/a

^*based on clinicaltrials.gov search until September 2021

^**dual mechanism for flare and ULT

Conclusion

Overall, although knowledge about the pathophysiology of gout and management principles have been augmented greatly, there is tremendous room for improvement in practice implementations as well as patient and clinician education.

Key points.

1. Gout is a common condition that is associated with higher all-cause mortality risk compared to the general population and significant health care costs.

2. Diet alone is typically insufficient for management of hyperuricemia in patients with gout.

3. The 2020 ACR Gout Guideline has provided a strong recommendation for a treat-to-target strategy for those in whom management of gout is indicated, with a target serum urate of <6 mg/dL.

4. Novel drug therapies for urate-lowering, including xanthine oxidase inhibition and harnessing renal or gastrointestinal urate excretion, minimizing immunogenicity of uricase-based therapy, and additional anti-inflammatory therapeutic targets are being developed and tested in trials.