Year in Review 2023: Gout Clinical Research

Abstract

Gout is the most common inflammatory arthritis, with a growing global disease burden. This conference report summarizes nine impactful publications dating from 11/2022 to 10/2023 to inform and improve clinical care in gout. The articles we present here collectively address diverse facets of gout research, including gout epidemiology, predictive biomarkers, the occurrence of complications relating to gout flares, and gout management strategies.

1. Introduction

Gout remains a considerable challenge for patients with an increasing global disease burden [1,2], and there remain many pertinent and unresolved questions regarding its optimal management. Since the 2022 Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) meeting, there have been significant research contributions to the clinical understanding of gout.

This conference report summarizes nine impactful publications that were published between 11/2022 and 10/2023 that are important to gout clinical practice. The articles that we present here address gout epidemiology, predictive biomarkers, the occurrence of complications relating to gout flares, and gout management strategies.

This conference report represents an expanded overview of the plenary presentation “Year in Review: Gout Clinical Research” that was delivered at the ninth G-CAN annual scientific meeting in La Jolla, California, in November 2023.

2. Conference Sections

2.1. Trends in Prevalence of Gout Among US Asian Adults, 2011–2018

While prior studies have explored gout disparities among black individuals, there remains little information regarding gout epidemiology in Asian individuals in Western countries, particularly in the United States (US). Understanding gout prevalence trends among Asian individuals, who constitute the fastest-growing racial and ethnic group in the US [3], is important for both gout clinical care and public health awareness.

This study [4] examined the prevalence of gout and serum urate concentrations among US adults. The researchers conducted a population-based, cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018. Additionally, data from the UK Biobank (2006–2021) were used to validate findings. The analysis considered race-specific gout prevalence and serum urate levels and explored temporal trends while accounting for various covariates, including sociodemographic, lifestyle, and clinical factors.

The study included 22,621 participants and revealed that the overall prevalence of gout in the US increased from 3.6% in 2011–2012 to 5.1% in 2017–2018. Notably, gout affected a total of 12.1 million individuals in the US in 2017–2018, comparable to the population of Ohio or Illinois. The age- and sex-adjusted prevalence of gout among Asian individuals in the US doubled during this period, from 3.3% (95% CI, 2.1–4.5%) to 6.6% (95% CI, 4.4–8.8%), exceeding all other racial groups in 2017–2018 (Figure 1). Serum urate concentrations also increased among Asian individuals between 2011 and 2018 (p for trend = 0.009). Adjusting for socioclinical factors, particularly body mass index (BMI), intensified the disparity, with Asian individuals having a higher odds ratio for gout (fully adjusted OR 2.62; 95% CI, 1.59–4.33) and excess serum urate concentrations (0.50 mg/dL; 95% CI, 0.37–0.62 mg/dL) compared to white individuals. These findings were replicated in the UK Biobank.

This study suggests that gout now affects Asian individuals at a higher rate than any other racial or ethnic group in the US. The disparity between Asian and white adults does not seem to be associated with socioclinical factors. This contrasts with the disparity in gout prevalence observed between black and white US adults, in which the differences seem to be largely explained by such factors [5]. The strengths of this study include its use of a nationally representative sample of US adults and the replication of findings in a second cohort. Its limitations include the potential underestimation of gout cases due to self-reporting and the inability to examine specific subgroups within the Asian and Hispanic populations. These findings support the need for more race-specific research regarding gout epidemiology, risk factors, and management strategies. Specifically, further investigations are warranted to understand the mechanisms underlying the increasing burden of gout among Asian adults.

2.2. Gout and Excess Risk of Severe SARS-CoV-2 Infection Among Vaccinated Individuals: A General Population Study

The COVID-19 pandemic has resulted in global disruption, and despite the availability of effective vaccines, millions of new cases, including breakthrough infections, continue to emerge. Concerns also remain regarding evolving variants. Gout is associated with comorbidities, including obesity and cardiovascular disease [6], that elevate the risk of SARS-CoV-2 infection [7,8]. Elevated serum urate levels in gout patients may contribute to a pro-inflammatory state, complicating SARS-CoV-2 outcomes [9]. Conflicting studies on the association between gout and SARS-CoV-2 infection [10,11], conducted before widespread vaccination, highlighted the need for additional data on vaccine efficacy in patients with gout.

Researchers conducted two cohort studies to assess the risk of SARS-CoV-2 infection and severe outcomes in individuals with gout compared to the general population, considering COVID-19 vaccination status [12]. The study utilized data from The Health Improvement Network (THIN), an electronic medical record database including records from 790 general practices and approximately 17 million individuals in the United Kingdom (UK), offering a population-based cohort reflective of the UK population. The analysis compared the risk of breakthrough SARS-CoV-2 infection, hospitalization, and death among individuals with gout and the general population after COVID-19 vaccination (vaccinated cohort). Additionally, a similar approach was applied to assess these risks among unvaccinated individuals (unvaccinated cohort). The cohort definitions involved follow-up starting from vaccination or 8th December 2020, depending on vaccination status, with outcomes measured until development of the outcome of interest or the end of the study period. The primary outcome was a confirmed diagnosis of SARS-CoV-2 infection, with secondary outcomes including hospitalization for SARS-CoV-2 infection and death.

The study included a vaccinated cohort of 54,576 individuals with gout and 1,336,377 without gout, in addition to an unvaccinated cohort of 61,111 with gout and 1,697,168 without gout. In the vaccinated cohort, individuals with gout had a significantly higher risk of breakthrough SARS-CoV-2 infection compared to the general population (adjusted HR 1.24; 95% CI, 1.19–1.30) (

Table 1. Associations between gout and the risks of breakthrough SARS-CoV-2 infection, 30-day hospitalization, and 30-day death in the vaccinated cohort (Reprinted from [12]).

	Gout (n = 54,576)	Non-Gout (n = 1,336,377)
Breakthrough SARS-CoV-2 infection
No. of infections	1955	52,468
Mean follow-up, months	7.87	6.98
Weighted IR, per 1000 person-months ꝉ	4.68	3.76
Weighted RD, per 1000 person-months (95% CI) ꝉ	0.91 (0.62, 1.20)	0.00 (referent)
Weighted HR (95% CI) ꝉ	1.24 (1.19, 1.30)	1.00 (referent)
Weighted RD, per 1000 person-months (95% CI) ⱡ	0.71 (0.41, 1.09)	0.00 (referent)
Weighted HR (95% CI) ⱡ	1.18 (1.12, 1.24)	1.00 (referent)
30-day hospitalization
No. of hospitalizations	184	1,956
Mean follow-up, months	7.85	6.98
Weighted IR, per 1000 person-months ꝉ	0.42	0.28
Weighted RD, per 1000 person-months (95% CI) ꝉ	0.15 (0.07, 0.24)	0.00 (referent)
Weighted HR (95% CI) ꝉ	1.54 (1.31, 1.81)	1.00 (referent)
Weighted RD, per 1000 person-months (95% CI) ⱡ	0.10 (0.01, 0.18)	0.00 (referent)
Weighted HR (95% CI) ⱡ	1.30 (1.10, 1.53)	1.00 (referent)
30-day death
No. of deaths	28	141
Mean follow-up, months	7.86	6.99
Weighted IR, per 1000 person-months ꝉ	0.06	0.04
Weighted RD, per 1000 person-months (95% CI) ꝉ	0.03 (−0.01, 0.06)	0.00 (referent)
Weighted HR (95% CI) ꝉ	1.74 (1.14, 2.67)	1.00 (referent)
Weighted RD, per 1000 person-months (95% CI) ⱡ	0.02 (−0.02, 0.05)	0.00 (referent)
Weighted HR (95% CI) ⱡ	1.36 (0.87, 2.13)	1.00 (referent)

Abbreviations: IR = incidence rate; RD = rate difference; 95% CI = confidence interval; HR = hazard ratio. ꝉ Results obtained after partially adjusted exposure scores. ⱡ Results obtained after fully adjusted exposure scores.

). Gout was also associated with increased risks of hospitalization (adjusted HR 1.30; 95% CI, 1.10–1.53) and 30-day death (adjusted HR 1.36; 95% CI, 0.87–2.13). The unvaccinated cohort demonstrated similar associations, though the risk of 30-day death was not significantly different. Sex-specific analyses suggested that women with gout might be more susceptible to severe outcomes of COVID-19, such as hospitalization and death, compared to men with gout. Sensitivity analyses supported the robustness of the findings.

This large population-based study revealed that individuals with gout faced higher risks of SARS-CoV-2 infection, 30-day hospitalization, and 30-day death compared to the general population, regardless of vaccination status. The susceptibility to severe COVID-19 outcomes, particularly hospitalization and death, appeared to be higher in women with gout than in men. This study is particularly relevant as previous research on rheumatic diseases and SARS-CoV-2 infection did not specifically focus on gout [13], and clinical guidelines did not address gout during the pandemic [14]. While a prior study found no significant difference in breakthrough infections between individuals with gout and the general population after COVID-19 vaccination [10], this study suggests that individuals with gout remain more susceptible even following vaccination. The biological mechanisms linking gout to SARS-CoV-2 infection, such as the potential impact of impaired innate immunity in gout, need further investigation. The findings underscore the importance of additional measures for individuals with gout, especially women, to mitigate the risks of SARS-CoV-2 infection and its potentially severe consequences.

2.3. Prediagnostic Glycoprotein Acetyl Levels and Incident and Recurrent Flare Risk Accounting for Serum Urate Levels: A Population-Based, Prospective Study and Mendelian Randomization Analysis

Despite progress in identifying risk factors, questions persist in understanding the mechanisms underlying progression to clinical gout, as prolonged hyperuricemia is necessary but not sufficient for its development [15]. The metabolome, serving as an intermediate trait between genotype and phenotype, is well suited for investigating gout mechanisms and prediction. Previous small-scale studies have implicated certain amino acid profiles in gout risk, particularly in Asian men [16,17], but the generalizability of such findings beyond specific populations has remained unclear.

This prospective metabolomics study [18], conducted within the UK Biobank cohort, sought to identify metabolomic biomarkers associated with the future risk of incident gout and recurrent flares in order to better understand the molecular underpinnings of gout development and progression. This study utilized data from over 100,000 participants enrolled between 2006 and 2010 to assess 168 metabolic biomarkers, including lipoprotein lipids, fatty acids, glycolysis metabolites, and amino acids. The researchers conducted both hypothesis-free and hypothesis-driven analyses. The former aimed to discover novel biomarkers associated with incident gout, while the latter evaluated eight metabolites previously implicated in gout risk. The study followed participants over time, employing Cox proportional hazards modeling and Poisson regression for statistical analyses.

The key findings indicated a significant association between glycoprotein acetyls (GlycA), a stable inflammation marker reflecting neutrophil overactivity [19,20], and the risk of incident gout and recurrent flares, even after adjusting for serum urate levels (incident gout HR 1.52 with 95% CI, 1.22–1.88, and recurrent flare RR 1.90 with 95% CI, 1.27–2.85). Additionally, other metabolites, including lipids, glycine, glutamine, and branched-chain amino acids, exhibited associations with gout risk before serum urate levels were accounted for. Mendelian randomization analyses corroborated a causal role of GlycA in the context of gout risk.

This study’s findings suggest a potential role for specific metabolites, particularly GlycA, in the metabolic–neutrophilic synovitis pathways in gout. These associations have implications for predicting gout flares and identifying novel therapeutic targets. However, the study was constrained by its focus on a population of European ancestry and the potential for residual or unmeasured confounding. Future directions include expanding the research to non-European-ancestry populations and exploring specific components of GlycA to deepen our understanding of metabolomic contributions to gout.

2.4. Risk of Venous Thromboembolism with Gout Flares

While gout had been previously linked to increased venous thromboembolism (VTE) incidence [21,22,23,24], the temporal association between gout flares and VTE had not been previously explored. Investigators hoped to better characterize this relationship, theorizing that gout flares, characterized by intense inflammation, could transiently elevate VTE risk, noting recent data demonstrating a transient increase in the risk of cardiovascular events (defined as an acute myocardial infarction or stroke) in association with gout flares [25].

To examine this question, researchers employed a self-controlled case series design [26]. Their analysis included data from the Clinical Practice Research Datalink, covering over 18 million individuals in the UK. The study cohort included 314 patients with incident gout, and the exposed period was defined as the 90 days following primary care consultation or hospitalization for a gout flare. Incidence rate ratios (IRRs) for VTE during specific intervals were calculated with adjustments for age and season.

Among the 314 patients with incident gout, the VTE incidence was 1.8-fold higher during the 90-day exposed period (adjusted IRR 1.83; 95% CI, 1.30–2.59). The increase in risk was highest during the first 30 days of the exposed period (adjusted IRR 2.31; 95% CI, 1.39–3.82), and no association was observed during days 31–60 and 61–90 of the exposed period (Figure 2). Sensitivity analyses that excluded participants with VTE risk factors supported the main findings. This study highlights a transient but substantial increase in the relative risk of VTE following gout flares, emphasizing the importance of considering VTE risk in individuals with gout.

This population-based study is important in that it establishes a temporal association between gout flares and a transient increase in VTE rates. The strengths of the study include its generalizability and adjustment for time-varying confounders. Its limitations include the small sample size, the potential for not capturing milder gout flares that did not result in patients seeking medical attention, and the inability to distinguish the contribution of gout flares to VTE risk from that of the anti-inflammatory medications used to treat flares. The findings suggest the need for increased awareness and counseling for patients with gout regarding the elevated VTE risk post-flare. Additionally, the study supports existing guidelines advocating for long-term treat-to-target urate-lowering therapy (ULT) with flare prophylaxis for those patients who are initiating ULT and those with recurrent gout flares. Further research is encouraged to explore preventive measures, such as thromboprophylaxis, in patients recently experiencing gout flares.

2.5. Sodium–Glucose Cotransporter-2 Inhibitors (SGLT2is) in Gout

Unfortunately, the prevalence and incidence of gout continue to rise globally [2], and a mortality gap between individuals with gout and the general population persists [27,28]. There remains a critical need for effective interventions to alleviate the substantial global burden posed by this disease. Optimally, patients would be treated in a manner that both addresses gout symptoms and eliminates this disparity in mortality.

Sodium–glucose cotransporter-2 inhibitors (SGLT2is) were initially approved for the treatment of type 2 diabetes, but it is now known that these agents offer benefits beyond glycemic control, demonstrating efficacy in reducing chronic kidney disease progression, hospitalizations for heart failure, major adverse cardiovascular events, and all-cause mortality [29,30]. Notably, several studies have demonstrated that SGLT2is also lower serum urate levels and the risk of incident gout among patients without gout at baseline [31,32,33,34,35]. However, it was previously unknown whether SGLT2is also lowered the risk of recurrent gout flares and all-cause mortality among patients with established gout. Two studies relevant to these questions were published last year.

2.5.1. Comparative Effectiveness of Sodium–Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalization

The authors of this study [36] compared gout flares and cardiovascular events among patients with prevalent gout and diabetes initiating SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP-4is), another second-line glucose-lowering agent not associated with serum urate levels or cardiovascular risk. The researchers performed a propensity score-matched cohort study using data from Population Data BC, a group of population-based linked administrative databases with deidentified provincial health data. Adults with gout and type 2 diabetes who had a first-ever dispensing of SGLT2is or DPP-4is between 1 January 2014 and 30 June 2022 were included in the study. The primary outcome was recurrent gout flare counts during follow-up, defined as (1) emergency department visits or hospitalizations with a primary discharge diagnosis of gout or (2) recorded ICD-9 or ICD-10 codes for gout at an outpatient visit, together with colchicine, intra-articular or oral corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) dispensed within one week.

The study found that the flare rates among SGLT2i initiators were significantly lower than those among DPP-4i initiators, with an adjusted rate ratio of 0.66 (95% CI, 0.57–0.75) and a rate difference of −27.4 per 1000 person-years. Additionally, SGLT2i initiation was associated with a reduced risk of myocardial infarction (adjusted HR 0.69; 95% CI, 0.54–0.88) compared to DPP-4i initiation. The protective association persisted across demographic subgroups and regardless of ULT or diuretic use. This suggests that SGLT2is could simultaneously address the burden of recurrent gout flares and adverse cardiovascular sequelae in this patient population.

The study’s strengths include its implementation of an active comparator new-user design, minimizing confounding by indication and prevalent-user biases. Additionally, rigorous propensity score matching (including comorbidities, medications, baseline flare rates, and healthcare utilization) resulted in well-balanced baseline characteristics between groups, reducing possible selection bias. The use of a general population-based database enhanced the generalizability of the findings, and multiple sensitivity analyses supported the robustness of the results. Its limitations include the potential for residual unmeasured confounding and the inability to capture flares not requiring medical attention, potentially underestimating the total flare count experienced by the cohort. The serum urate level and duration of ULT were not captured in the Population Data BC health data and so were not included in the study’s propensity score model, which also introduced the potential for selection bias. Additionally, the study’s population was limited to those with diabetes.

2.5.2. Gout Flares and Mortality After Sodium–Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes

A second publication on this topic [37] reported the results of a population-based cohort study that utilized UK primary care data from the IQVIA Medical Research Database (IMRD) spanning from 2013 to 2022 to compare the risks of recurrent gout flares and all-cause mortality between individuals initiating SGLT2i treatment and those opting for other antidiabetic medications—specifically, DPP-4is or glucagon-like peptide-1 receptor agonists (GLP-1 RAs). All patients in the study had both gout and type 2 diabetes.

Within the cohort, comprising 1548 individuals initiating SGLT2is and 4383 initiating GLP-1 RAs or DPP-4is, it was found that those initiating SGLT2is demonstrated a 21% reduction in recurrent gout flares (HR 0.79; 95% CI, 0.65–0.97) and a 29% lower all-cause mortality rate compared to active comparators (HR 0.71; 95% CI, 0.52–0.97). In absolute terms, this equated to 20.4 (95% CI, 1.2–39.6) fewer gout flares and 6.1 fewer deaths (95% CI, 1.6–10.6) per 1000 person-years among those initiating SGLT2is versus active comparators.

This study suggests that SGLT2i use is associated with reduced risks of recurrent gout flares and all-cause mortality in patients with gout and type 2 diabetes; additionally, the integration of SGLT2is into the treatment regimen of individuals with gout and type 2 diabetes could not only alleviate the recurrent gout flare burden but also contribute to narrowing the mortality gap observed in this population. These promising results align with those of the preceding study and other prior research indicating the positive impact of SGLT2is on reducing serum urate levels and preventing the onset of gout. The study’s limitations include the potential misclassification of gout flares and the absence of hospitalization data. Despite these limitations, the study’s strengths, including its rigorous design, use of propensity score overlap weighting, and comprehensive analysis, provide valuable insights that warrant further exploration and consideration in clinical practice and treatment guidelines.

Together, these studies suggest that SGLT2is offer a myriad of potential benefits for patients with gout. Type 2 diabetes, chronic kidney disease, and heart failure, the three main indications for SGLT2i treatment, are highly prevalent among patients with gout. Therefore, a substantial proportion of patients with gout are expected to have a cardiometabolic comorbidity indication for SGLT2i treatment. Furthermore, SGLT2is can reduce recurrent gout flare rates and lower the risk of major adverse cardiovascular events and all-cause mortality in patients with gout and type 2 diabetes, who are at increased risk of premature mortality. These findings advocate for the potential inclusion of SGLT2is in treatment regimens for individuals with gout, aiming not only to manage gout symptoms but also to address the associated increased mortality risk in gout patients. Such integration into clinical practice could enhance patient outcomes by mitigating gout flare frequency and severity while concurrently offering cardiovascular protective effects, aligning with broader therapeutic goals in these patients.

2.6. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings

Pegloticase, an FDA-approved PEGylated uricase enzyme, effectively treats uncontrolled gout by rapidly reducing serum urate levels through the conversion of urate to allantoin. However, the development of antidrug antibodies can lead to a loss of efficacy and infusion reactions [38,39,40], resulting in premature treatment discontinuation. While prior studies supported the use of immunomodulating therapies alongside pegloticase to enhance response rates and reduce antidrug antibody formation [41,42,43], there had not previously been a randomized controlled trial to definitively establish the impact of immunomodulation on pegloticase response rates.

Researchers designed this study [44] as a phase IV, multicenter, randomized, double-blind, placebo-controlled trial aimed to assess the efficacy and safety of pegloticase plus oral methotrexate (MTX; 15 mg weekly) versus pegloticase plus placebo in adults with uncontrolled gout. The study enrolled participants with serum urate levels of ≥7 mg/dL, gout refractory to conventional therapy (defined as a failure to normalize serum urate levels and/or intolerance to oral urate-lowering therapy), and ongoing gout symptoms (presence of ≥1 tophus, recurrent acute gout flares [≥2 flares in the 12 months prior to screening], and/or chronic gouty arthritis). Following a 2-week oral MTX tolerance test, eligible patients were randomized 2:1 to receive pegloticase plus MTX or pegloticase plus placebo, with key efficacy and safety assessments conducted during months 6 and 12 of the 52-week treatment period. Patients discontinued oral urate-lowering therapy ≥7 days prior to beginning the MTX tolerance period (6 weeks before the initial pegloticase infusion).

This study found a significantly higher treatment response in those receiving pegloticase plus MTX at month 6 compared to the placebo group (71.0% versus 38.5%, respectively; between-group difference of 32.3% [95% CI, 16.3% to 48.3%], p < 0.0001 for the between-group difference). During the first 6 months of treatment, 81.3% of patients in the MTX group experienced adverse events (AEs) compared to 95.9% of patients in the placebo group, with the most common AE being gout flare in both groups. The infusion reaction rate was considerably lower with MTX cotherapy compared to placebo (4.2% versus 30.6%, respectively; p < 0.001). Note that this paper did not report the 52-week outcomes.

The authors concluded that in patients with uncontrolled gout that is intolerant or refractory to oral ULT, pegloticase plus MTX resulted in a significantly higher treatment response and lower infusion reaction incidence compared to pegloticase plus placebo. MTX cotherapy was also associated with a lower incidence of antidrug antibody development, indicating its potential to attenuate pegloticase immunogenicity. The study’s strengths include its large, prospective, randomized, placebo-controlled design, supporting the superiority of pegloticase plus MTX in terms of efficacy and safety. There remains a need for further research on serum urate management following pegloticase therapy and how long to continue pegloticase in those who are not tolerant of xanthine oxidase inhibitors. As methotrexate is avoided in patients with an eGFR of <30 mL/minute/1.73 m², this also raises the question of alternative immunomodulating therapies in the CKD population.

2.7. Safety of Colchicine and NSAID Prophylaxis When Initiating Urate-Lowering Therapy for Gout: Propensity Score-Matched Cohort Studies in the UK Clinical Practice Research Datalink

While colchicine and NSAIDs have long been used for prophylaxis against paradoxical gout flares during ULT initiation, and this practice is recommended in gout management guidelines [45,46,47,48], there are relatively few data on the risk of AEs when these agents are utilized for prophylaxis. This led investigators to seek stronger evidence regarding the safety of flare prophylaxis.

The researchers used electronic, coded healthcare datasets capturing a representative sample of the UK population to perform two matched retrospective cohort studies [49]. The first cohort compared the risk of AEs in gout patients starting allopurinol with colchicine prophylaxis versus those who started allopurinol with no prophylaxis. The second compared patients with gout starting allopurinol with NSAID prophylaxis versus those who started allopurinol with no prophylaxis. Each exposed individual was matched 1:1 to an unexposed individual for age (within 3 years), gender, index date (within 3 years), and propensity score for receiving colchicine or NSAIDs, noting that the propensity score was based on characteristics including comorbidities, number of medications, number of prior gout consultations and hospital admissions for gout, and prescriptions that may interact with colchicine recorded in the 30 days preceding the index date.

A two-stage individual patient data (IPD) meta-analysis involving 13,945 individuals with gout initiating allopurinol with colchicine prophylaxis showed that AEs were significantly more common with colchicine prophylaxis compared to no prophylaxis, including diarrhea (HR 2.22; 95% CI 1.83–2.69), myocardial infarction (MI) (HR 1.55; 95% CI 1.10–2.17), neuropathy (HR 4.75; 95% CI 1.20–18.76), myalgia (HR 2.64; 95% CI 1.45–4.81), and bone marrow suppression (HR 3.29; 95% CI 1.43–7.58) (

Table 2. Incidence rates per 10,000 person-years (95% CI) and risk of adverse events with colchicine exposure in CPRD GOLD and Aurum databases separately and combined (Reprinted from [49]).

	Colchicine			No Prophylaxis
	Event	Person-Years	Incidence Rate per 10,000 Person-Years (95% CI)	Event	Person-Years	Incidence Rate per 10,000 Person-Years (95% CI)	HR (95% CI)
Diarrhea
GOLD	75	0.0470	1604.9 (1280.5–2038.9)	69	0.1184	581.4 (459.3–746.9)	2.50 (1.72–3.61)
Aurum	191	0.3197	596.1 (517.6–690.3)	151	0.5600	270.4 (230.8–318.9)	2.12 (1.69–2.66)
Combined			784.4 (694.0–886.5)			341.9 (298.9–391.2)	2.22 (1.83–2.69)
Nausea and vomiting
GOLD	9	0.0464	195.5 (103.9–414.8)	9	0.1169	77.3 (41.1–164.0)	2.50 (0.90–6.99)
Aurum	67	0.3189	209.7 (165.7–269.4)	80	0.5572	143.7 (115.8–180.6)	1.25 (0.89–1.76)
Combined			208.1 (165.4–261.7)			135.7 (109.8–167.6)	1.34 (0.97–1.85)
Bone marrow suppression
GOLD	*	0.0463	64.9 (20.3–318.9)	*	0.1173	8.5 (0.2–47.5)	2.75 (0.28–26.55)
Aurum	16	0.3176	50.4 (31.4–86.4)	8	0.5567	14.4 (7.4–2.3)	3.38 (1.38–8.30)
Combined			51.9 (32.3-83.5)			13.9 (6.8–28.3)	3.29 (1.43–7.58)
Neuropathy
GOLD	7	0.0464	151.4 (73.7–364.1)	*	0.1172	17.2 (3.7–172.2)	9.36 (1.85–47.45)
Aurum	*	0.3179	3.2 (0.1–17.5)	*	0.5565	3.6 (0.8–36.1)	0.86 (0.07–11.32)
Combined			110.8 (5.15–238.3)			7.9 (2.0–30.6)	4.75 (1.20–18.76)
Myalgia
GOLD	13	0.0464	281.7 (166.8–515.8)	10	0.1175	85.7 (47.1–173.6)	4.80 (1.96–11.78)
Aurum	13	0.3182	40.9 (24.2–75.0)	13	0.5568	23.4 (13.8–42.9)	1.64 (0.74–3.66)
Combined			107.6 (72.1–160.4)			40.8 (26.6–62.6)	2.64 (1.45–4.81)
Myocardial infarction
GOLD	12	0.0464	260.8 (151.0–492.0)	9	0.1171	77.4 (41.1–164.4)	2.15 (0.87–5.33)
Aurum	60	0.3179	189.0 (147.4–246.6)	69	0.5554	124.1 (98.4-158.9)	1.47 (1.02–2.11)
Combined			199.0 (157.2–251.9)			118.1 (94.1–148.0)	1.55 (1.10–2.17)
Any adverse event
GOLD	123	0.0474	2584.2 (2158.7–3119.4)	106	0.1189	889.0 (732.7–1089.3)	2.62 (1.96–3.50)
Aurum	320	0.3209	997.6 (892.9–1118.2)	302	0.5594	540.4 (482.1–607.8)	1.72 (1.45–2.03)
Combined			1292.3 (1174.0–1422.4)			613.3 (555.0–677.8)	1.91 (1.65–2.20)

* N < 5. CPRD, Clinical Practice Research Datalink.

).

The incidence of any AE per 10,000 person-years was higher in the colchicine-exposed group, with a hazard ratio of 1.91 (95% CI, 1.65–2.20), revealing an increased risk associated with colchicine prophylaxis during allopurinol initiation. A two-stage IPD meta-analysis involving 25,980 individuals with gout initiating allopurinol with NSAID prophylaxis revealed that AEs were significantly more common with NSAID prophylaxis compared to no prophylaxis (

Table 3. Incidence rates per 10,000 person-years (95% CI) and risk of adverse events with NSAID exposure in CPRD GOLD and Aurum databases separately and combined (Reprinted from [49]).

	NSAID			No Prophylaxis
	Event	Person-Years	Incidence Rate per 10,000 Person-Years (95% CI)	Event	Person-Years	Incidence Rate per 10,000 Person-Years (95% CI)	HR (95% CI)
Acute kidney injury
GOLD	26	0.1053	242.9 (166.1–370.0)	29	0.2576	110.9 (77.5–164.4)	2.11 (1.17–3.81)
Aurum	86	0.6021	142.5 (115.4–178.0)	122	1.0130	120.1 (100.5–144.7)	1.45 (1.08–1.94)
Combined			160.7 (132.9–194.5)			118.3 (100.4–139.4)	1.56 (1.20–2.03)
Angina
GOLD	63	0.1046	604.4 (472.3–786.7)	93	0.2553	362.7 (295.6–450.1)	1.92 (1.35–2.74)
Aurum	261	0.5959	438.7 (388.2–497.8)	343	1.0008	342.3 (307.4–382.3)	1.53 (1.30–1.82)
Combined			466.6 (417.2–521.8)			346.5 (314.6–381.7)	1.60 (1.37–1.86)
Myocardial infarction
GOLD	20	0.1056	190.7 (124.8–306.5)	31	0.2581	121.7 (86.5–177.0)	1.68 (0.91–3.10)
Aurum	90	0.6021	150.3 (122.6–186.2)	94	1.0130	92.3 (75.6–114.0)	1.95 (1.44–2.64)
Combined						98.9 (82.7–118.2)	1.89 (1.44–2.48)
Peptic ulcer disease
GOLD	15	0.1054	143.1 (87.8–249.9)	8	0.2580	31.2 (15.9–70.0)	8.52 (3.38–21.50)
Aurum	40	0.6024	66.7 (49.4–92.5)	61	1.0130	60.6 (47.4–78.6)	1.20 (0.80–1.82)
Combined			81.7 (62.4–106.9)			56.5 (44.5–71.8)	1.67 (1.14–2.44)
Any adverse event
GOLD	103	0.1043	984.3 (809.3–1209.6)	137	0.2546	536.6 (452.3–641.6)	2.18 (1.63–2.90)
Aurum	408	0.5930	688.7 (623.4–763.0)	529	0.9953	531.7 (486.7–581.9)	1.53 (1.33–1.75)
Combined			740.2 (676.3–810.2)			532.7 (492.0–576.8)	1.63 (1.44–1.85)
CPRD, Clinical Practice Research Datalink; NSAID, non-steroidal anti-inflammatory drug

), including angina (HR 1.60; 95% CI, 1.37–1.86), acute kidney injury (HR 1.56; 95% CI, 1.20–2.03), MI (HR 1.89; 95% CI, 1.44–2.48), and peptic ulcer disease (HR 1.67; 95% CI, 1.14–2.44). The incidence of any AE per 10,000 person-years was higher in the NSAID-exposed group, with a hazard ratio of 1.63 (95% CI, 1.44–1.85), indicating an increased risk associated with NSAID prophylaxis during allopurinol initiation.

The authors concluded that although serious side effects were more common with colchicine or NSAID prophylaxis versus no prophylaxis, the incidence of individual adverse events was low (defined as <200 per 10,000 treated patient-years), except for diarrhea for colchicine and angina for NSAIDs. While the authors framed the results as providing reassurance for patients and clinicians, the notably increased absolute risks of serious adverse events with both colchicine and NSAID use are certainly concerning. However, it is also important to recognize that many of these findings—most notably the increased risk of MI in those on colchicine—conflict with the findings of prior randomized controlled trials [50,51,52,53] and therefore raise the question of potential residual confounding. The substantial difference in follow-up duration between the drug and no-drug groups could also lead to selection bias associated with censoring. While the study was notable for its large sample size and highlighted potential risks associated with the prophylactic use of colchicine and NSAIDs, emphasizing the importance of considering the balance between benefits and risks in treatment decisions for gout, additional analyses and studies will be required to validate this study’s findings.

2.8. Is Colchicine Prophylaxis Required with Start-Low Go-Slow Allopurinol Dose Escalation in Gout? A Non-Inferiority Randomised Double-Blind Placebo-Controlled Trial

Initiating urate-lowering therapy is associated with an increased risk of gout flares [54,55], leading to the recommendation of anti-inflammatory prophylaxis for 3–6 months [45]. As a high starting dose of allopurinol has been recognized as a risk factor for allopurinol hypersensitivity syndrome [56], a “start-low go-slow” strategy is now advised wherein allopurinol is commenced at 50–100 mg daily and gradually uptitrated to achieve the target serum urate (SU) level [57]. It has been theorized that this gradual dose escalation therapy may not be associated with an increased risk of gout flares, so anti-inflammatory prophylaxis may not be needed with this approach. Investigators sought to further examine this possibility.

The researchers designed a 12-month double-blind, placebo-controlled non-inferiority trial [58] conducted in two centers to determine whether placebo is non-inferior to low-dose colchicine in reducing gout flares during the first 6 months of allopurinol treatment with a gradual dose escalation approach, and to assess the frequency of adverse events associated with colchicine prophylaxis compared to placebo. The study enrolled adults with gout defined by the 2015 American College of Rheumatology (ACR) gout classification criteria [59], with all participants having experienced at least one self-reported gout flare in the preceding 6 months, meeting ACR recommendations for starting ULT, and having an SU level of ≥6 mg/dL at screening. The participants were randomized 1:1 to colchicine 0.5 mg daily or placebo. All participants commenced allopurinol at the baseline visit with dosing depending on their eGFR and increased monthly thereafter until the SU level was less than 6 mg/dL for three consecutive visits. The primary outcome was the mean number of gout flares between 0 and 6 months with a pre-specified non-inferiority margin of 0.12 gout flares per month.

The primary outcome analysis revealed that the placebo group had more gout flares compared to the colchicine group, failing to meet the prespecified non-inferiority margin. Secondary outcomes showed a significantly lower mean number of gout flares per month in the colchicine group during the first 3 months, with a subsequent rise after discontinuation at 6 months, while the placebo group did not exhibit this pattern. The net result was no overall difference in the mean number of gout flares per month over the full 12-month study period. A safety analysis indicated more serious adverse events in the colchicine group, with two deaths occurring in this group, though these were not thought to be related to colchicine.

The authors concluded that placebo was not non-inferior (i.e., inferior) to colchicine 0.5 mg daily in preventing gout flares during the first 6 months of allopurinol treatment using a gradual dose escalation method. This study suggests that a 6-month period with low-dose colchicine during allopurinol initiation suppresses gout flares, though it may be followed by a rise in gout flares after the discontinuation of colchicine. This suggests that anti-inflammatory prophylaxis beyond 6 months may be beneficial for some individuals. The strengths of this study include its well-powered design, double-blinding, high follow-up rates, and diverse study population, while its potential limitations include the absence of a quantification of gout flare severity and the exclusion of patients with stage 4 or 5 chronic kidney disease. These results may inform discussions and shared decision making between individuals with gout and their healthcare providers regarding the risks and benefits of colchicine for gout flare prophylaxis when starting allopurinol.

3. Concluding Remarks

The findings presented in these publications are significant, covering various facets of gout clinical care from comorbidity management to urate-lowering therapy and paradoxical gout flare prophylaxis.

There is continued excitement surrounding the potential use of sodium–glucose cotransporter-2 inhibitors (SGLT2is) for the secondary prevention of gout flares. They not only reduce flare rates but also lower the risk of myocardial infarction compared to dipeptidyl peptidase 4 inhibitors (DPP-4is), suggesting a dual benefit in addressing both gout flares and cardiovascular risks. Additionally, another study indicated that SGLT2i use is associated with reduced risks of recurrent gout flares and all-cause mortality in patients with gout and type 2 diabetes. These findings highlight the potential integration of SGLT2is into treatment regimens to alleviate gout flare burdens and narrow the mortality gap between patients with gout and the general population.

In the realm of gout prophylaxis during urate-lowering therapy initiation, the potential risks associated with colchicine and NSAID prophylaxis were evaluated, contributing to a nuanced understanding of treatment strategies and their potential associated risks.

Beyond treatment strategies, additional studies contribute valuable insights into the multifaceted aspects of gout. One study explored the temporal association between gout flares and venous thromboembolism (VTE), revealing a significant increase in VTE incidence within the 30 days following a gout flare. This emphasizes a transient but substantial rise in VTE risk after gout flares, suggesting implications for long-term treat-to-target urate-lowering therapy. Moreover, a prospective metabolomics study within the UK Biobank cohort uncovered a significant association between glycA levels and gout risk, offering a potential marker for predicting flares and identifying therapeutic targets. An examination of the prevalence of gout among US Asian adults highlighted the rising burden in this demographic, emphasizing the need for tailored public health interventions. Lastly, in the context of the COVID-19 pandemic, a study underscored the higher risks of breakthrough SARS-CoV-2 infection, hospitalization, and death among vaccinated individuals with gout, emphasizing the importance of tailored measures among this patient population.