Introduction

The global burden of gout is huge, and gout is the most common form of inflammatory arthritis worldwide (1). The principles of effective management are well known and have been published recently as updated guidelines (2, 3); based on the rapid control of acute inflammation, the effective lowering of serum urate to the treatment target combined with effective patient education. New pharmacological treatments will help the clinician to achieve these targets, as intolerance to existing therapies and potential side effects in patients with co-morbidities are common. Besides pharmacological therapy, the importance of patient participation and education is recognized and strategies to implement effective engagement with patients have also been studied. This review will highlight recent therapeutic advances in gout, highlighting newly developed treatments as well as recent insights on the use of existing therapies.

Advances for acute gout

Colchicine and cardiovascular prevention in gout

Growing evidence suggests that inflammation is a crucial player in atherosclerosis development, and several studies have investigated the potential protective effect of various anti-inflammatory drugs on cardiovascular (CV) events, including colchicine (4).

A retrospective monocentric matched cohort study included 501 patients with gout who started colchicine therapy and were matched (based on age and gender) to 501 patients not treated with colchicine (5). Patients with gout included in the two matched groups were predominantly white males (64 %) with a mean age of 72–73. Patients were followed up to 4 years (mean follow-up duration: 1 year), and CV events were captured. In the adjusted analysis, the authors observed a 49 % reduction (HR 0.51, 95 % CI 0.30–0.88) in the risk of presenting a CV event (stroke, transient ischemic attack, myocardial infarction [MI]). A decrease in all-cause mortality was also observed among colchicine users (HR 0.27, 95 % CI 0.17 to 0.43).

A large, randomized placebo-controlled trial (COLCOT trial) included 4745 patients within 30 days after an MI who were treated with colchicine 0.5 mg once daily or placebo. The median follow-up time was 23 months. A significant reduction (5.5 % versus 7.1 %, HR 0.77, 95 % CI 0.61 to 0.96) of the risk of ischemic CV events was observed in the colchicine group compared to the placebo group. Adverse events were globally similar in both groups. Diarrhea was reported in 9.7 % of the patients treated with colchicine (placebo group: 8.9 %) (6). Recently, a prespecified sub-study of the COLCOT trial including only patients with type 2 diabetes reported a similar reduction (HR 0.65, 95 % CI 0.44 to 0.96) of the risk of ischemic CV events (7).

Another randomized placebo-controlled trial (LoDoCo2 trial) investigated the effect of colchicine on the risk of CV events in patients with chronic coronary disease. 5522 patients were treated with colchicine 0.5 mg once daily or placebo after a run-in period of one month of colchicine treatment (open label). The mean follow-up duration was 29 months. A reduction (6.8 % versus 9.6 %, HR 0.69, 95 % CI 0.57 to 0.83) of the risk of occurrence of the composite CV events endpoint was observed. Gout occurred less frequently in the colchicine group (1.4 % versus 3.4 %), but myalgia was reported more often by patients treated with colchicine (21.2 % versus 18.5 %) (8).
There is now strong evidence showing that colchicine may prevent CV events in addition to routine cardiovascular prevention drugs in various populations exposed to increased CV risk, such as patients with gout, type 2 diabetes, a history of MI or chronic coronary disease.

Thus, colchicine, which has been used for many years to treat acute gouty arthritis and prevent ULT-induced gout flares (ULT: uric acid lowering therapy), may have a place in the cardiovascular prevention armamentarium in the future.

Cytokine inhibition

Since the discovery that MSU crystals activate the NLRP3 inflammasome, inducing a complex intracellular cascade ultimately leading to the cleavage and activation of pro-IL-1β in IL-1β, this pro-inflammatory cytokine has become a primary therapeutic target to treat acute gout (9).

Anakinra, an IL-1 receptor antagonist, was the first available IL-1 blocking agent. Following an open-label and several retrospective studies that reported good efficacy of this drug in treating acute gout arthritis, including hospitalized patients with comorbidities, two randomized controlled trials were published in 2019 and 2021 with different comparators. 88 patients suffering from an acute flare of gouty arthritis were treated with anakinra 100 mg once daily for 5 days or treatment as usual (naproxen, colchicine, prednisone). The authors showed non-inferiority of anakinra compared to usual care with similar clinical improvement (10). In the second study (anaGO trial), 165 patients with acute gout-related mono- or oligo-arthritis, in whom NSAIDs or colchicine were contra-indicated, were treated with anakinra 100 mg or 200 mg once daily for 5 days or a single intramuscular injection of triamcinolone 40 mg. All treatment arms showed efficacy in treating acute gouty arthritis with a similar reduction in pain intensity (11).

Rilonacept, a fusion protein acting as a soluble decoy receptor binding IL-1α and IL-1β, has shown efficacy in treating acute gouty arthritis in a phase 3 RCT with 225 patients (12). Three RCTs studied the use of rilonacept to prevent gout flares during the initiation of uric acid lowering therapy (ULT) and observed a decrease in the number of flares in patients in the rilonacept group compared to the placebo group (13–15). However, rilonacept is no longer available for commercial reasons.

Canakinumab, an anti-IL-1β monoclonal antibody with a 26-day terminal half-life, showed efficacy in treating acute gouty arthritis in two phase 3 RCTs. They included 456 patients treated with a single dose of canakinumab 150 mg or a single intramuscular injection of triamcinolone 40 mg. A significant difference in mean pain intensity (95 % CI) on VAS (0–100 mm) at 72 h was observed (–9.8, –16.3 to –3.2 mm) (16). A phase 2 RCT investigated the efficacy of canakinumab in preventing acute gout flares when starting ULT and reported a decrease in the mean number of flares in the canakinumab group compared to the colchicine group (17). Additionally, a post hoc analysis of the CANTOS trial, which was a large RCT (10059 patients) investigating cardiovascular outcomes in patients treated with canakinumab for up to several years, showed a reduced risk for gout attacks (HR 0.4–0.48 according to various serum urate levels) with no effect on serum urate levels (18). Canakinumab was approved by the European Medicines Agency in 2013 and the US Food and Drug Administration in 2023 to treat adult patients with frequent gouty arthritis in whom colchicine, NSAIDs and steroids are either not effective, contraindicated or not tolerated.
Except for IL-1β, other pro-inflammatory cytokines are released during gout arthritis, including TNFα and IL-6. Some authors tried TNFα or IL-6 blockade, to treat refractory polyarticular tophaceous chronic gouty arthritis. Few case reports have reported a good efficacy of TNFα inhibitors (infliximab, etanercept) and anti-IL6R agent tocilizumab (sub-cutaneous and intravenous) in these patients (19, 20). However, the level of evidence is low, and there are no published controlled trials, observational studies or even case series to support their use in gout.

Advances for hyperuricemia

Pegloticase

Pegloticase is a recombinant uricase administered intravenously that degrades urate in allantoin, a soluble metabolite.
2 RCTs published in 2011 included 225 patients with severe gout who are refractory to allopurinol or intolerant. They were treated with pegloticase or placebo for 6 months. In the pegloticase group, 38 % of patients responded (serum urate level < 360 µmol/l for ≥ 80 % of the time between months 3 and 6) versus 0 % in the placebo group (21). However, the use of pegloticase was impaired by a significant rate of infusions-related reactions (IRR) (> 25 %) and a loss of efficacy related to the development of antidrug antibodies that increase pegloticase clearance (22).

Therefore, following an encouraging open-label study, an RCT (MIRROR trial) was conducted that included 152 patients with uncontrolled gout and failure or intolerance to ULT who were treated by pegloticase and oral methotrexate (MTX) 15 mg/week or pegloticase and placebo for one year (23). Patients treated with MTX and pegloticase showed a higher response rate (60 % versus 31 %) at one year, and fewer IRR (4 % versus 31 %, all occurred during the first 6 months). Of patients with tophi at baseline, the proportion with a resolution of ≥ 1 tophi was 54 % (versus 31 %) after one year of treatment (24).
The FDA has approved pegloticase in treating chronic gout in patients who are refractory to conventional therapy since 2010. The EMA also approved pegloticase but withdrew it at the manufacturer’s request in 2013.

New xanthine oxidase inhibitors (XOI)

Allopurinol and febuxostat are well established XOIs and are effective urate lowering drugs. However, safety concerns in specific situations (allopurinol hypersensitivity syndrome for allopurinol and cardiovascular safety for febuxostat) as well as drug intolerance mean that alternatives are needed. Two recent additions are topiroxostat and tigulixostat. Both are non-purine xanthine oxidase inhibitors.
Topiroxostat has been available since 2013 in Japan (25, 26), but not yet marketed in the EU or the US. Tigulixostat showed dose-dependent efficacy in urate lowering in phase 2 studies but has not yet undergone comparison with standard agents (27).

SGLT2 inhibitors

SGLT2 inhibitors (canagliflozin, dapagliflozin, empaglifozin and others) are drugs that promote the renal excretion of glucose thus reducing blood sugar levels and their use has revolutionized the management of diabetes, heart failure as well as chronic kidney disease (CKD). The principal mode of action is inhibition of glucose reabsorption by SGLT2 (sodium-glucose cotransporter 2) in the proximal renal tubule. Other mechanisms of action (inhibition of sodium transport, inhibition of oxidative stress and inflammation and glomerular pressure) may explain their beneficial effects in heart failure and CKD. As metabolic, renal and cardiac disease are major co-morbidities in the gout population, drugs that act on multiple clinical targets in the same disease are of considerable interest. A recent review has succinctly summarized the available evidence of SGLT2 inhibitor’s effects in relation to gout (28).

SGLT2 inhibitors are capable of lowering serum urate; in a meta-analysis of 62 SGLT2 inhibitor trials, the mean lowering of sUA observed was –37 umol/L (variations in sUA lowering effect were observed across the drug class) and this effect appears to be independent of the blood sugar levels (29). Urate lowering also appears to be independent of the level of renal impairment for dapagliflozin and empagliflozin (reviewed in (28)) and the concomitant intake of different urate lowering drugs (30). There are no specific studies that targeted the gout population, but gout patients were included in a number of trials of SGLT2 inhibitors and secondary analyses of the data showed that the incidence of gout flares was decreased by around 50 % in patients on SGLT2 inhibitors (28), and cohort studies of health-care databases also showed that incident gout was also reduced by a similar amount. The urate lowering mechanism of SGLT2 inhibitors is postulated to be via increasing urinary glucose excretion, which competes with urate for reabsorption by the renal transporter SLC2A9 (Glut 9); another mechanism may be an inhibitory effect on the urate transporter SLC22A12 (URAT1) (31).
The accumulated data suggest that SGLT2 inhibitors may be a useful adjunct to conventional ULT in gout, particularly in patients with cardiometabolic co-morbidities. There is no current data to support its use as a primary ULT.

Colchicine prophylaxis on starting ULT

When patients start ULT, gout flares are frequently triggered and reach a peak within the first 6 months before gradually reducing in frequency (32). These “paradoxical flares” have motivated clinicians to recommend flare prophylaxis for up to 6 months at the start of ULT in treatment guidelines. A recent study has addressed the question if slow upward titration of ULT (using allopurinol) can obviate the need for colchicine prophylaxis. Stamp and colleagues performed a RCT comparing low-dose colchicine (0.5 mg daily) with placebo during the first 6 months of allopurinol treatment. The dose of allopurinol was increased by 50 mg per month until the target sUA level of 360 umol/L was reached (33). They found that patients on placebo had more flares in the first 6 months compared to the treated group, but by 12 months, both groups had similar (but reduced) flare frequency. Based on these results, the recommendation of prophylaxis with colchicine is maintained when starting ULT.

Patient information and education

Doherty et al have shown in a randomized controlled trial that gout management outcomes (in terms of achieving target sUA levels, flare rate) are significantly improved when drug therapy is accompanied by a nurse-led patient education and follow-up program when compared to usual care (34, 35). Subsequent analyses also showed that the nurse-led care group showed greater satisfaction, was better informed about gout, and had a lower flare rate than the control group. However, these results are contingent on the health care setting, as the trial described was performed in the UK. It is likely that other approaches can influence treatment outcome. In the US, a trial comparing pharmacist-led intervention (information about the disease, telephone follow up and dose adjustment of allopurinol) showed that adherence (> 80 % of days on treatment) and achieving the sUA target of 6 mg/dL were significantly greater in the pharmacist-led arm compared to usual care (36). Finally, a trial performed in Scotland, whereby patients were randomized to receive a program to improve gout self-management (in the form of a uric acid meter for home monitoring of sUA levels, combined with an application on a smartphone to enhance awareness of treatment targets) had better rates of achieving target sUA (70 % vs. 15 %) at 6 months compared to usual care (37). These studies demonstrate that different strategies can be effective in improving treatment adherence and outcome, and the precise approach needs to consider local factors.