Gout flares are driven by the innate immune system's response to monosodium urate (MSU) crystals deposited in the joints. A pivotal step in this inflammatory cascade is the activation of the NLRP3 inflammasome within resident macrophages and recruited neutrophils. This protein complex catalyzes the conversion of pro-IL-1β to its active, secreted form, Interleukin-1 beta (IL-1β). IL-1β is a potent pro-inflammatory cytokine that acts on the IL-1 receptor, triggering a downstream signaling cascade that promotes vasodilation, increased vascular permeability, and the recruitment of additional immune cells, thereby amplifying the pain, swelling, and erythema characteristic of an acute flare. Thus, targeted inhibition of the IL-1 pathway represents a rational therapeutic strategy for interrupting the core inflammatory mechanism of gout [1].

Gout is one of the most prevalent chronic inflammatory arthritis worldwide, with marked variation by geography, age, and sex. Prevalence estimates range from 1% to 4% globally, with higher rates in Western countries where 3% to 6% of adult men and 1% to 2% of women are affected. In the United States, around 3.9% of adults approximately 8.3 million individuals carry a diagnosis, and incidence continues to rise [2]. Between 1997 and 2012, the United Kingdom documented an increase in prevalence from 1.52% to 2.49%. Risk is concentrated among older adults, with prevalence exceeding 7% in men over 70 years. Disparities are evident: African American men show a prevalence of 7.0% compared to 5.4% in White men, while African American women have rates of 3.5% versus 2.0% in White women [2].

Gout is strongly linked to metabolic and cardiovascular disease. Up to 69% of patients have hypertension, 61% hyperlipidemia, 28% chronic kidney disease (CKD), and 25% diabetes mellitus, compared with 54%, 21%, 11%, and 6% respectively in the general population. Serum urate above 9 mg/dL confers a threefold higher risk of recurrent flare within one year compared with levels below 6 mg/dL [2]. Such comorbidities complicate conventional therapy, since nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids carry risks of renal, cardiovascular, or gastrointestinal toxicity [3]. Inadequate response or contraindication is common in precisely those patients with the highest flare burden.

The pathophysiology of acute flares is now well defined: monosodium urate crystals trigger NLRP3 inflammasome activation, leading to interleukin-1β release and neutrophil-driven synovitis. This provides a rationale for targeted blockade [4,5].

Canakinumab, anakinra, and rilonacept interrupt this pathway through distinct mechanisms. While clinical studies suggest benefits in rapid pain relief and flare resolution, trial heterogeneity, modest sample sizes, and incomplete long-term safety data have restricted clear guidance. Systematic evaluation of efficacy, tolerability, and durability of outcomes is required to define the place of interleukin-1 inhibitors in modern gout management [6–8].

This systematic review and meta-analysis aim to critically evaluate the efficacy, safety, and long-term outcomes of interleukin-1 inhibitors (anakinra, canakinumab, rilonacept) in managing acute gout flares. Specific objectives are:

(1) to assess their efficacy in pain reduction and symptom resolution compared with standard therapies or placebo; (2) to examine safety profiles, including adverse and serious adverse events; (3) to determine long-term outcomes such as recurrence rates and quality-of-life measures; (4) to explore heterogeneity through subgroup analyses; and (5) to synthesize evidence to support clinical decision-making and inform future research directions.

This systematic review and meta-analysis were designed and conducted in line with the PRISMA framework. A predefined protocol was registered on PROSPERO (CRD42024584173), specifying objectives, eligibility, and analysis plans before data collection began.

Eligibility criteria (PICO)

Adult patients (≥18 years) with acute gout flares were eligible if conventional therapies (NSAIDs, colchicine, corticosteroids) were contraindicated, ineffective, or intolerable. Interventions included IL-1 inhibitors (anakinra, canakinumab, rilonacept), compared with placebo or active drugs (prednisone, triamcinolone, colchicine, naproxen, indomethacin) (Table 1).

The primary endpoint was pain reduction measured on a VAS or Likert scale within 24–72 hours. Secondary outcomes included time to symptom resolution, 50% pain reduction, rescue medication use, flare recurrence, inflammatory markers (CRP, SAA), and joint swelling/tenderness (Table 1).

For the trial by Janssen et al. [9], which used a 5-point Likert scale, pain scores were converted to a 100-mm VAS equivalent for meta-analysis as per established methodology [10,11]. Safety endpoints covered overall adverse events, serious adverse events, injection-site reactions, infections, and discontinuations. Only randomized controlled trials (RCTs) were included (Table 1). Observational studies, case series, reviews, and preclinical work were excluded.

Search strategy and study selection

Comprehensive searches were performed in PubMed/MEDLINE, NIH Trials, Embase, CENTRAL, Web of Science, and ACR/EULAR (inception to July 2024). Strategies combined controlled vocabulary and free-text terms for “gout,” “gouty arthritis,” and IL-1 inhibitors. Two reviewers independently screened records in Covidence, with disagreements resolved by a third reviewer. A PRISMA flowchart documented the process (Figure 1).

Data extraction and quality assessment

Two reviewers independently extracted study characteristics (design, setting, duration), patient demographics (age, sex, comorbidities, BMI, baseline uric acid), intervention/comparator details (drug, dose, route, regimen), and all outcome data (mean values, SDs, events/total). Authors were contacted for missing information. For studies where standard deviations (SDs) were not reported, they were estimated from figures or calculated from available data (e.g., standard errors, confidence intervals); this is noted as a potential limitation Risk of bias was appraised by two reviewers assessed RoB independently using Cochrane RoB 2 across randomization, deviations, missing data, outcome measurement, and selective reporting while all studies show low risk of bias (Figure 2). For trials with multiple publications [12,13], we used the most complete report per endpoint to avoid double counting. For publications reporting multiple independent RCTs [14], each trial was extracted and analyzed separately. Pain assessment followed a pre-specified hierarchy: 72-hour data were used primarily; if unavailable, 48-hour data were used, followed by 24-hour data.

Data synthesis and statistical analysis

Analyses were conducted in R (version 4.2.2) using meta (v6.5-0) and metafor (v3.8-1). For continuous outcomes measured on the same scale (VAS pain), mean difference (MD) with 95% CI was calculated. The standardized mean difference (SMD) was considered for outcomes measured on different scales but was not required for the primary analysis; for dichotomous outcomes, risk ratios (RR) with 95% CI were used. Random-effects models (Hartung–Knapp–Sidik–Jonkman) were employed to provide more conservative confidence intervals, particularly due to the anticipated high heterogeneity among studies. Pre-specified subgroup analyses considered drug type. Meta-regression to explore the influence of baseline factors was pre-specified but not conducted due to insufficient data across studies. Publication bias was assessed by funnel plots and Egger’s test (p<0.05 threshold). A sensitivity analysis was performed excluding studies for which standard deviations were estimated from figures or calculated from other statistics (β-RELIEVED / figure-extracted variances), which confirmed the stability of the pooled results. For pain outcomes, both change-from-baseline and final value scores were pooled, as the mean difference is equivalent when baseline values are balanced, which was confirmed across the included studies. For dichotomous outcomes with zero events in one arm, a 0.5 continuity correction was applied to all cells of the 2x2 table to allow for the calculation of risk ratios.

Planned subgroup and sensitivity analyses

To explore potential sources of heterogeneity and test the robustness of our primary findings, we planned several subgroup and sensitivity analyses. Subgroup analyses were predefined for the primary outcome (72-hour pain reduction) (Figure 12) based on: (1) specific IL-1 inhibitor agent (anakinra, canakinumab, rilonacept); (2) type of comparator (active [e.g., triamcinolone, NSAIDs] vs. placebo); (3) patient comorbidity profile (studies with a high prevalence of chronic kidney disease [CKD] >30% vs. those with lower prevalence); and (4) study duration. Heterogeneity within and between subgroups was assessed using the I² statistic and a test for subgroup differences. For sensitivity analysis, we planned to sequentially exclude studies judged to be at a high risk of bias to determine their influence on the pooled effect estimate.

Assessment of publication bias

If a minimum of 10 studies were available for a given outcome, we planned to assess potential publication bias visually using funnel plots and statistically using Egger's regression test. An asymmetric funnel plot or a significant Egger's test (p<0.10) would suggest the potential for small-study effects or publication bias (Figure 11).

Patient demographics and baseline characteristics

Across the ten randomized controlled trials included in this systematic review (n=1,731), the study populations were relatively homogeneous in terms of demographic profile but exhibited notable heterogeneity in disease burden and clinical eligibility. The majority of participants were male (range 77%–94%), with mean ages between 52.4 and 63.1 years. Baseline body mass index (BMI) was reported in six trials, averaging 29.1–32.7 kg/m², consistent with the metabolic comorbidities frequently associated with gout. Hypertension was the most prevalent comorbidity (41%–67% across studies), followed by CKD, reported in 18%–32% of enrolled patients, which was a primary driver for ineligibility for NSAID or colchicine therapy. Diabetes mellitus was present in 12%–27% of cases, and hyperlipidemia in 28%–46%. The number of prior flares varied widely: three trials required ≥3 flares in the previous year, whereas others included patients with only one prior flare but with contraindication to standard agents (Table 2).

Duration of the index acute gout attack before randomization ranged from 18 to 56 hours. Baseline visual analogue scale (VAS) pain scores at the most affected joint were consistently high, with mean scores between 67.2 mm and 78.9 mm on a 100-mm scale. C-reactive protein (CRP) was elevated in all studies, with mean baseline levels between 22.5 and 47.6 mg/L. Serum uric acid levels were not consistently required for inclusion; where measured, mean baseline uric acid ranged from 7.8 to 9.6 mg/dL.

Ethnic composition was reported in four trials, predominantly Caucasian (62%–74%), with smaller proportions of Black (14%–20%) and Asian (8%–11%) patients. Two trials were multinational phase III studies (≥15 countries), increasing generalizability, whereas others were smaller single-center studies.

Intervention characteristics and comparators

Interventions varied by agent and dosing regimen. Anakinra was administered subcutaneously at 100 mg once daily for 3 consecutive days in three trials (n=417), with one study testing a 5-day regimen. Canakinumab was tested in five trials (n=1,083), most commonly as a single subcutaneous dose of 150 mg, with exploratory doses ranging from 50 mg to 300 mg. Rilonacept was evaluated in two studies (n=231) using a loading dose of 320 mg followed by weekly 160 mg injections (Table 2).

Comparators differed. In the anakinra studies, active comparators included triamcinolone 40 mg intramuscularly and naproxen 500 mg twice daily, while two used placebo. Canakinumab trials compared against triamcinolone, indomethacin, or placebo. Rilonacept was compared only with placebo. Concomitant urate-lowering therapy (ULT) was allowed in four studies if stable ≥3 months; others excluded ULT initiation or adjustment during the study period (Table 2).

Primary efficacy outcomes: Pain reduction (Table 3)

Pain reduction at 72 hours was the most consistently reported primary endpoint.

Anakinra: Across pooled anakinra trials, mean VAS pain reduction at 72 hours was –42.3 mm compared with –38.1 mm in active comparator arms (naproxen or triamcinolone). The between-group difference was not statistically significant (mean difference –3.7 mm; 95% CI –7.8 to 0.4; p=0.08). Compared with placebo, anakinra produced significantly greater pain relief (–44.9 mm vs –28.6 mm; mean difference –16.1 mm; 95% CI –20.2 to –12.0; p<0.001). At 24 hours, differences were smaller but still favored anakinra (–21.4 mm vs –15.7 mm; p=0.02).

Canakinumab: Canakinumab demonstrated superior efficacy compared with triamcinolone and placebo. At 72 hours, VAS pain scores improved by –47.2 mm in the canakinumab 150 mg group versus –36.5 mm with triamcinolone (mean difference –10.6 mm; 95% CI –13.9 to –7.3; p < 0.001). Higher doses (300 mg) achieved slightly greater reductions (–49.8 mm), though differences versus 150 mg were not statistically significant (p=0.19). Pain relief was sustained at day 7, with mean VAS reductions of –56.4 mm versus –41.7 mm for triamcinolone (p<0.001). Placebo-controlled studies showed even larger relative differences: –46.9 mm versus –27.4 mm (p<0.001).

Rilonacept: Rilonacept failed to meet primary pain endpoints. At 72 hours, mean VAS change was –30.1 mm compared with –28.5 mm for placebo (mean difference –1.6 mm; 95% CI –6.8 to 3.6; p = 0.54). Similar results were observed at day 7 (–36.8 vs –34.1 mm; p = 0.41).

Pooled analysis

Prespecified primary analysis: The meta-analysis of the prespecified primary outcome (72-hour pain on VAS) showed that IL-1 inhibitors as a class achieved significantly greater pain reduction compared with controls (pooled mean difference –9.4 mm; 95% CI –11.8 to –7.0; p<0.001), with low heterogeneity (I²=18%).

Exploratory sensitivity analysis: An exploratory analysis that pooled all pain timepoints (24–72 hours) and scales (VAS and Likert) also yielded a mean difference of –9.4 mm but with high heterogeneity (I²=87%), reflecting the clinical and methodological diversity of the included studies.

Subgroup analysis revealed superiority of canakinumab (–11.7 mm; p<0.001) and anakinra (–7.2 mm; p=0.002), while rilonacept remained non-significant. I²=18%, indicating low heterogeneity after accounting for between-study differences in the random-effects model.

Secondary efficacy outcomes

Time to resolution of symptoms: Time to complete resolution of flare symptoms was reported in six studies. Median time to resolution was 4.2 days with canakinumab versus 7.8 days with triamcinolone (hazard ratio [HR] 1.62; 95% CI 1.29–2.05; p<0.001). Anakinra shortened resolution compared with placebo (median 5.1 vs 8.3 days; HR 1.48; p=0.003) but not compared with naproxen (5.0 vs 5.3 days; p=0.62). Rilonacept again showed no difference versus placebo (6.9 vs 7.1 days; p=0.71).

Inflammatory markers: CRP and serum amyloid A (SAA) were consistently reduced with IL-1 blockade. Canakinumab reduced CRP by a mean of –21.6 mg/L at day 3 compared with –11.4 mg/L for triamcinolone (p<0.001). Anakinra achieved similar reductions (–18.7 vs –9.3 mg/L for placebo; p=0.002). SAA levels followed parallel trends, with mean reductions of –66.2 mg/L for canakinumab versus –34.9 mg/L for triamcinolone (p<0.001). Rilonacept produced modest decreases (–12.4 vs –10.2 mg/L; p=0.34).

Joint swelling and tenderness: Joint swelling scores declined more rapidly in canakinumab recipients, with mean decreases of –1.9 versus –1.1 with triamcinolone at day 3 (p<0.001). Tenderness scores showed similar trends. Anakinra produced significant improvements versus placebo (–1.5 vs –0.8; p=0.004), but differences versus naproxen were negligible (–1.3 vs –1.2; p=0.67).

Rescue medication use: Rescue analgesic use was consistently lower in IL-1 inhibitor groups. In one canakinumab study, 12% required rescue medication versus 38% with triamcinolone (relative risk [RR] 0.31; 95% CI 0.20–0.48; p<0.001). Anakinra reduced rescue use compared with placebo (15% vs 42%; RR 0.36; p<0.001) but not versus naproxen (19% vs 21%; p=0.71). Rilonacept showed no significant difference (24% vs 28%; p=0.42).

Flare prevention and recurrence

Flare recurrence risk ratios were pooled across varying follow-up lengths (e.g., 8 to 24 weeks) as a measure of the class's durable effect. A key secondary outcome was recurrence of gout flares during follow-up. Follow-up periods ranged from 4 weeks in short-term trials to 24 weeks in phase III programs.

Anakinra did not demonstrate durable flare prevention beyond the index episode. In the largest trial (n=198), recurrence within 4 weeks was 21.2% in the anakinra group versus 23.7% in the triamcinolone comparator arm (RR 0.89; 95% CI 0.56–1.42; p=0.63). In placebo-controlled settings, recurrence rates were numerically lower with anakinra (18.7% vs 27.9%) but not statistically significant (RR 0.67; 95% CI 0.39–1.16; p=0.15).

Canakinumab showed the most consistent reduction in recurrence. At 8 weeks, flare recurrence was 6.3% in the 150 mg group versus 22.1% with triamcinolone (RR 0.28; 95% CI 0.15–0.51; p<0.001). Placebo-controlled studies reported recurrence rates of 9.4% versus 34.7% (RR 0.27; 95% CI 0.16–0.43; p<0.001). Durability was evident, with sustained protection up to 24 weeks: recurrence 13.2% for canakinumab versus 39.5% for triamcinolone (HR 0.31; 95% CI 0.19–0.49; p<0.001).

Rilonacept had intermediate results. In one trial, flare recurrence over 12 weeks was 17.6% versus 25.4% for placebo (RR 0.69; 95% CI 0.41–1.16; p=0.15). A second study reported modest reductions (15.8% vs 22.3%; p=0.12). None achieved statistical significance.

Pooled analysis demonstrated that IL-1 inhibitors overall significantly reduced recurrence compared with controls (RR 0.41; 95% CI 0.29–0.58; p<0.001; I²=24%). Subgroup analysis confirmed canakinumab’s superiority (RR 0.29; p<0.001), while anakinra (RR 0.78; p=0.18) and rilonacept (RR 0.73; p=0.14) did not significantly differ from comparators.

Quality-of-life outcomes

Health-related quality of life (HRQoL) outcomes were reported inconsistently.

In the largest canakinumab phase III trial (n=456), improvements in the Health Assessment Questionnaire–Disability Index (HAQ-DI) were greater with canakinumab than with triamcinolone at week 4 (–0.49 vs –0.27; mean difference –0.22; 95% CI –0.30 to –0.14; p<0.001). EQ-5D utility scores improved by +0.16 versus +0.07 (p=0.002). The Short Form-36 (SF-36) physical component summary also improved more with canakinumab (+6.1 vs +3.8; p=0.01).

Anakinra trials showed numerical improvements but rarely reached statistical significance. For instance, in one study, HAQ-DI change at day 14 was –0.31 for anakinra and –0.24 for naproxen (p=0.27). Rilonacept trials did not assess HRQoL systematically, reporting only symptom diaries that reflected parallel results to pain endpoints.

Safety outcomes

Across the 10 trials, the overall incidence of adverse events (AEs) was 36.8% in IL-1 inhibitor groups versus 34.1% in comparator arms (RR 1.08; 95% CI 0.93–1.26; p=0.31).

• Anakinra: AE rates ranged from 28.6% to 34.9%, similar to triamcinolone and naproxen groups (p>0.05).
• Canakinumab: AE incidence was slightly higher, 42.1% vs 37.5% with triamcinolone (RR 1.12; 95% CI 0.91–1.39; p=0.29).
• Rilonacept: Comparable to placebo (31.5% vs 29.8%; p=0.67).

Serious adverse events (SAEs) were low overall. Pooled incidence was 3.8% in IL-1 inhibitor arms versus 3.2% in controls (RR 1.12; 95% CI 0.68–1.83; p=0.64). Anakinra SAEs were 2.9% vs 2.7% in comparators (p=0.91). Canakinumab showed a slightly higher SAE rate, 4.3% vs 3.1%, though not significant (p=0.21). Events included pneumonia, diverticulitis, and neutropenia. Rilonacept SAEs were rare (<3%), with no clustering of events.

Injection-site reactions (ISRs) were the most frequent AE. Overall incidence was 17.6% with IL-1 inhibitors vs 4.2% in comparators (RR 4.18; 95% CI 2.87–6.09; p<0.001). Rates were highest with anakinra (up to 25.3%), typically mild erythema or tenderness. Canakinumab showed lower rates (9.8% vs 3.2%; p<0.01), while rilonacept was intermediate (14.1% vs 4.5%; p<0.001).

Infections were mostly mild (upper respiratory tract, urinary tract), occurring in 9.7% of IL-1 inhibitor patients versus 7.3% in controls (RR 1.29; 95% CI 0.91–1.82; p=0.14). Serious infections were rare (<2%).

Treatment discontinuations due to AEs were infrequent: 3.1% with IL-1 inhibitors vs 2.4% with controls (p=0.44). The most common reason was ISR with anakinra.

Immunogenicity was assessed only in anakinra trials, where anti-drug antibodies developed in 12%–17% of patients but were not linked to loss of efficacy or increased AEs within trial duration.

Pooled quantitative meta-analysis and clinical implications

IL-1 inhibitors achieved significant pooled benefit for pain reduction (VAS): mean difference –9.4 mm (95% CI –11.8 to –7.0; p < 0.001; I²=18%). Canakinumab achieved –11.7 mm (p<0.001), anakinra –7.2 mm (p=0.002), while rilonacept did not show benefit (–1.3 mm; p=0.48). A negative mean difference (MD) favors IL-1 inhibitors, indicating greater pain reduction (lower VAS score) compared to control. A test for subgroup differences (based on drug type: anakinra, canakinumab, rilonacept) indicated a statistically significant difference between groups (Q=9.74, p=0.008).

For flare recurrence, pooled RR was 0.41 (95% CI 0.29–0.58; p<0.001; I²=24%), driven entirely by canakinumab, as anakinra and rilonacept showed no significant benefit.

For rescue medication, pooled RR was 0.39 (95% CI 0.26–0.59; p<0.001), confirming reduced need for additional analgesia in IL-1 inhibitor arms.

Safety pooled analyses showed: AEs (RR 1.08; p=0.31), SAEs (RR 1.12; p=0.64), and ISRs (RR 4.18; p<0.001). The certainty of the evidence for these critical outcomes, assessed using the GRADE approach, is summarized in Table 4. The very small study (14; n=6) was included in the qualitative synthesis but excluded from the quantitative meta-analysis due to its minimal influence and potential to skew results.

Critical synthesis and clinical implications highlight that IL-1 inhibitors reduce pain and inflammation during acute gout flares, with canakinumab showing the most robust efficacy across endpoints. Anakinra appears comparable to standard therapies such as naproxen and triamcinolone for pain control, with value in patients contraindicated to conventional treatments. Rilonacept did not meet primary pain or resolution endpoints, though modest trends suggest potential benefit in recurrence prevention with longer follow-up.

Safety was generally acceptable, though ISRs were significantly more common, particularly with anakinra. No excess risk of serious infections or systemic adverse events was observed, but long-term safety remains incompletely characterized. Differences in efficacy likely reflect pharmacokinetics: anakinra’s short half-life requires daily dosing, whereas canakinumab’s extended half-life supports sustained IL-1β suppression, explaining superior recurrence prevention.

Clinically, IL-1 inhibitors are a targeted option for refractory flares or patients contraindicated to NSAIDs, colchicine, and corticosteroids. Cost, administration, and safety monitoring limit widespread use. Future trials should compare against optimized corticosteroid regimens, assess long-term recurrence outcomes, and stratify by comorbidities such as CKD or cardiovascular disease.

Forest Plot of Hazard Ratios Across 10 Studies (Figures 3 and 4)

Forest Plot of Mean Differences Between Experimental and Control Groups Across Included Studies (Figure 5)

Pain Outcome (VAS, 0-100 mm) at 72 Hours (Figure 6)

Canakinumab-only Trials (Figure 7)

Anakinra-only Trials (Figure 8)

Rilonacept-only Trials (Figure 9)

Interpretation

Over a six-month period, treatment with Canakinumab results in an estimated additional cost of $4,540 compared with standard Triamcinolone therapy but prevents approximately 1.4 disease flares. The incremental cost per flare avoided is approximately $3,243, suggesting that while Canakinumab is substantially more expensive, it offers potential value in reducing recurrence and productivity loss (Figure 10).

Subgroup analysis showed a significant difference in 72-hour pain reduction by agent (p=0.008). Canakinumab demonstrated the greatest effect (−11.7 mm), followed by Anakinra (−7.2 mm) and Rilonacept (−1.3 mm). The overall pooled reduction was −9.4 mm with low heterogeneity (I²=18%), indicating consistent benefit across studies (Figure 12).

The role of IL-1 inhibitors in acute gout flares is anchored in the central importance of IL-1β in the inflammatory cascade [20]. Gout is driven by monosodium urate crystal deposition within the joint, which activates the NLRP3 inflammasome and leads to caspase-1 mediated IL-1β release [21,22]. This cytokine amplifies neutrophil recruitment, vascular permeability, and local tissue damage, creating the abrupt and severe pain characteristic of gout flares. Traditional therapies, such as NSAIDs, colchicine, and corticosteroids, suppress inflammation through broader mechanisms, but they are often limited by comorbidities, drug interactions, or poor tolerability [23,24].

Our results show IL-1 inhibitors directly interrupts the proximal inflammatory driver, making it a biologically rational and increasingly tested strategy [7,9,12,13,16–19,25]. The high degree of statistical heterogeneity (I² up to 87%) observed in the primary pain outcome is a key finding of this analysis. This variability is likely attributable to clinical and methodological diversity across the included trials, particularly the use of different IL-1 inhibitors (canakinumab, anakinra, rilonacept), varying active comparators (triamcinolone, NSAIDs, placebo), and differences in patient populations and baseline disease severity. To explore these sources of heterogeneity, we conducted pre-specified subgroup analyses by drug type, which confirmed that the significant overall effect was driven primarily by canakinumab. Use of rescue medication was permitted in most trials. While its use was often lower in the IL-1 inhibitor groups, its administration could have confounded the assessment of the true treatment effect on pain outcomes. The use of rescue medication, while often lower in the IL-1 inhibitor groups, represents a potential source of bias in the assessment of the true treatment effect on pain and should be considered a limitation. Anakinra, a recombinant IL-1 receptor inhibitor, offers rapid but short-lived control due to its daily dosing requirement [26]. Canakinumab, a monoclonal antibody against IL-1β, provides sustained inhibition and is approved in some regions for refractory gout, though cost and infection risk remain concerns. Rilonacept, a soluble decoy receptor, has shown efficacy in both flare treatment and prevention, though its role in routine practice is not firmly established [14]. Across trials, IL-1 inhibitors have consistently demonstrated rapid pain relief comparable or superior to conventional therapies, particularly in patients with contraindications. Safety signals are generally favorable, though injection-site reactions and infection risk require ongoing vigilance [7,9,13,16–19,25]. From a long-term perspective, questions remain about recurrence reduction, cost-effectiveness, and patient selection. While some evidence suggests IL-1 inhibitors may lower flare recurrence, durable benefits beyond initial episodes are not firmly established. These agents may find their greatest utility in highly selected patients with frequent, refractory flares, or in those intolerant of standard care. Future studies should address optimal dosing strategies, head-to-head comparisons with steroids, and biomarker-guided use. Overall, IL-1 inhibitors represent a targeted advance in gout therapy, aligning pathophysiological insight with clinical application [27].

Our findings necessitate a pragmatic framework for integrating IL-1 inhibitors into clinical practice. The distinct efficacy-safety profiles of anakinra and canakinumab suggest a role for nuanced patient selection. We propose a treatment algorithm where IL-1 inhibitors are considered for patients with acute gout flares who have contraindications, intolerance, or inadequate response to first-line therapies (NSAIDs, colchicine, corticosteroids). Within this group, canakinumab, with its superior and sustained flare prevention, may be prioritized for patients with frequent flares (e.g., ≥3 per year) where preventing recurrence is a paramount concern, despite its significantly higher cost. Conversely, anakinra, with its shorter half-life and favorable immediate cost profile, represents an excellent option for hospitalized patients or for short-term abortive therapy in those with contraindications to other agents, particularly if flare prevention is a secondary goal. A detailed cost-benefit analysis, while beyond the scope of this review, is critical for health policy. Hypothetical modeling (see Figure 10) suggests that the high drug acquisition cost of canakinumab may be offset in specific patient subgroups namely, those with very frequent flares and significant comorbidities by reducing emergency department visits, hospitalizations, and productivity losses. Future real-world economic studies are needed to validate these models and identify the cost-effectiveness thresholds for routine use.

While pain reduction is the primary goal in acute gout, our review underscores the importance of broader outcome measures. The significant improvements in HAQ-DI and EQ-5D scores with canakinumab indicate a meaningful impact on physical function and overall quality of life, outcomes highly valued by patients. Future trials should consistently include and report such patient-reported outcomes (PROs) to fully capture the therapeutic benefit beyond pain scales.

To resolve the current evidence gaps, we recommend specific future research initiatives. First, head-to-head randomized controlled trials comparing the different IL-1 inhibitors (e.g., anakinra vs. canakinumab) are needed to guide agent selection. Second, there is an urgent need to establish a standardized core outcome set for gout flare studies, encompassing pain, joint function, patient global assessment, and health-related quality of life, to facilitate future meta-analyses. Third, the optimal dosing and treatment duration for anakinra remains undefined; pragmatic trials comparing shorter (e.g., 3-day) versus longer (e.g., 5-7 day) regimens are warranted. Finally, the role of IL-1 inhibitors as a "bridge" therapy during the initiation of urate-lowering therapy in high-risk patients requires further elucidation.

Our findings from this systematic review and meta-analysis demonstrate that IL-1 inhibitors represent a potent and targeted therapeutic option for the management of acute gout flares in patients for whom conventional therapies are contraindicated or ineffective. The class provides statistically significant and clinically meaningful pain reduction, with canakinumab emerging as the most efficacious agent while also offering superior and sustained prevention of flare recurrence. Anakinra serves as a valuable alternative with efficacy comparable to standard care. Safety profile is generally acceptable, with no significant increase in overall or serious adverse events compared to active controls. A markedly higher incidence of injection site reactions is a notable class effect. The findings support the use of these biologics, especially canakinumab, in a select patient population with refractory or complex gout. However, the high heterogeneity and potential for publication bias limit the certainty of these conclusions. Future research should focus on long-term safety surveillance, head-to-head comparisons, and refining patient selection criteria to optimize the risk-benefit and cost-effectiveness ratio of these targeted therapies in clinical practice.

This work was conducted independently and not as part of institutional research activities.

Ethical approval was not required, as this meta-analysis involved only secondary analysis of previously published studies. 
The authors received no funding for this work and declared no conflicts of interest.