Faculty Bibliography

BACKGROUND:While treat-to-target urate-lowering therapy (ULT) is endorsed as best practice in gout management, limited data exist on its impact on health-related quality of life (HRQoL). We assessed the impact of treat-to-target ULT on HRQoL among participants receiving protocolized gout care, identifying factors associated with HRQoL and HRQoL change. METHODS:This was a post-hoc analysis of a 72-week randomized trial, pooling data from allopurinol and febuxostat treatment arms. The VR-12 and EQ-5D-3L were administered at baseline, 24-, 48-, and 72-weeks. HRQoL changes over follow-up were examined using paired t-tests. Factors associated with baseline HRQoL were evaluated using multivariable linear regression. General estimating equations (GEE) were used to identify determinants of HRQoL change over follow-up. RESULTS:Participants (n=878) in this analysis were 98.9% male, had a mean age of 62.4 years, and 67.4% self-reported White race. HRQoL scores overall, and particularly the domains of physical function, mobility and pain, improved significantly over 72-weeks (p<0.001) with improvements noted by 24-weeks. Poorer enrollment HRQoL was associated with younger age, non-White race, tophi (for EQ-5D-3L), higher serum urate, and greater comorbidity. Baseline factors associated with HRQoL improvements over 72-weeks of ULT included lower C-reactive protein and lower comorbidity scores with similar changes observed by ULT assignment. CONCLUSIONS:Treat-to-target ULT in gout is accompanied by HRQoL improvements evident by 24-weeks and sustained through 72-weeks. HRQoL gains with treat-to-target ULT are most prominent in the domains of physical function, mobility, and pain and are greatest in those with lower baseline levels of inflammation and comorbidity.

OBJECTIVE:Though gout guidelines endorse treat-to-target urate-lowering therapy (ULT), its long-term durability following treat-to-target implementation has not been extensively studied. Examining follow-up data from a trial implementing treat-to-target management, we evaluated the frequency and determinants of ULT persistence. METHODS:This analysis examined participants completing the 72-week STOP Gout trial with available follow-up data extending 2-years post-study. Participants were followed passively using administrative and electronic health record data with persistence defined by a ULT dispensing episode overlapping with the 2-year post-study time point. Associations of participant factors with ULT persistence were examined using multivariable logistic regression. RESULTS:Participants in this analysis (n = 638) were predominantly male (99 %) and had a mean age of 62.7 years. At 2-years post-study, 66 % continued ULT. Adjusting for covariates, ≥2 rheumatology visits post-study (vs. none) was associated with greater ULT persistence (aOR 1.75; 95 % CI 1.13-2.72). ULT persistence was lower in individuals reporting Black/African American race (aOR 0.56; 95 % CI 0.36-0.87), Hispanic ethnicity (aOR 0.21; 95 % CI 0.09-0.50), and better quality-of-life at the beginning of post-study follow-up. Though not reaching significance, achievement of serum urate goal at 48-weeks during STOP Gout study demonstrated a borderline association with greater long-term persistence (aOR 1.68; 95 % CI 0.99-2.85). CONCLUSION/CONCLUSIONS:Though interventions implementing treat-to-target ULT have demonstrated efficacy in trials, this study suggests that such interventions may have limited durability following transitions back to real-world gout management. The issue of limited treatment durability appears to be compounded among underrepresented patient populations and improved in the context of ongoing rheumatological care.

INTRODUCTION/BACKGROUND:Patients receiving the standard prophylaxis dose of colchicine for gout flares are at increased risk for developing toxicity if there are pre-existing renal impairment or drug-drug interactions. Guidelines recommend exercising caution, deferring dose adjustment to the clinician's discretion. METHODS:Pharmacokinetic study data for colchicine oral solution in healthy subjects was used to build a pharmacokinetic model. Using the derived pharmacokinetic disposition parameters from the best fit model and the derived parameters of clearance in patients with renal impairment, simulation of colchicine plasma levels to target 0.5-3 ng/mL with colchicine oral solution was undertaken for various dose levels in different degrees of renal impairment. RESULTS:) would have excursions up to 10% and 36%, respectively, above the maximum tolerated level. Administering a lower dose such as 0.3 mg daily by splitting the conventional 0.6 mg tablet or by administering 0.6 mg once every-other-day (QOD) in moderate renal impairment would result in plasma colchicine levels in subtherapeutic range (< 0.5 ng/mL) for 20-70% of the dosing interval. CONCLUSION/CONCLUSIONS:Analysis of pharmacokinetic model data confirms that the majority of patients with renal impairment taking colchicine solid dosage formulations will be above or below therapeutic levels, exposing them to potential side effects. However, more precise dosing with colchicine oral solution of 0.48 mg (4 mL) or 0.5 mg tablet available in certain countries for moderate renal impairment and 0.3 mg (2.5 mL) for severe renal impairment are associated with optimal levels and safer for patients with renal impairment. No dosage adjustment is needed for patients with mild renal impairment.

Gout is a disease of hyperuricemia (HU) leading to monosodium urate crystal deposition in the joint, resulting in inflammation and joint damage. Recently, efforts have been made to characterize the intestinal microbiome of patients who suffer from HU and gout, and pre-clinical studies have evaluated the utility of prebiotics and probiotics in alleviating gout. Herein we review recent notable studies addressing these topics. In brief, the "gouty" microbiome is characterized by reduced diversity, an elevated Bacteroides: Firmicutes ratio, and reduced presence of Akkermansia and Bifidobacterium. In anserine models, supplementation with Lactobacillus probiotic strains appears to reduce serum urate (SU) and HU-induced inflammation. Murine models suggest that the chicory-derived prebiotic inulin may reduce SU, and oral supplementation with the anti-inflammatory short-chain fatty acid butyrate may lower SU by enhancing urate excretion and alleviate HU-induced tissue inflammation. Many of these studies are limited by modest numbers of participants and/or incompletely documented experimental controls, and, in the case of animal models, questionable reproducibility in humans. Many studies have been geographically limited. There remains a need for more information regarding the features of the "gouty" microbiome in wider populations, as well as for additional well-controlled probiotic and prebiotic studies in more physiologically relevant animal models prior to clinical trials.

OBJECTIVE:Controversy persists regarding the optimal management of gout in routine primary care. There is a lack of clarity on whether treating to a target serum urate (TTT-SU) versus treating to avoid symptoms (TTASx) is more effective. METHODS:We designed a randomized controlled comparative effectiveness trial aimed at patients in primary care who have known gout, have elevated SU levels, and had at least one flare in the previous 12 months. The trial was designed to be pragmatic and incorporated structured input from primary care physicians, rheumatologists, and patients. The TTASx strategy group will receive weeklong courses of typical therapies for gout flares, such as colchicine, naproxen, or an oral glucocorticoid. The TTT-SU strategy group will receive urate-lowering therapy (primarily allopurinol) with dose titration to maintain an SU level <6 mg/dL, colchicine (or naproxen) prophylaxis for the first six months of urate-lowering therapy, and access to the same flare therapies as the TTASx group. Two clinicians (nurses or physicians) per site will be trained in each strategy to manage the patients in each arm without contamination. Gout flares are the primary outcome and are assessed every two weeks by trained study staff masked to treatment assignment using a validated questionnaire. The secondary outcome is quality of life. Blood pressure control, kidney function, glycemic control, and coronary atherosclerosis are exploratory secondary outcomes. RESULTS:Several sites have started prescreening using automated search strategies in their patients' electronic health records. Of the first 1,381 patients found in primary care practices with a history of gout, 691 patients (50%) passed prescreening checks. These potentially eligible participants have a median age of 67 years, 85% are men, median SU levels are 7.2 mg/dL, and 18% are taking low dosages of allopurinol. These patients have been targeted for recruitment efforts that are underway now. CONCLUSION/CONCLUSIONS:This randomized controlled active comparator strategy trial will answer a key question in the treatment of patients with gout in primary care: the comparative effectiveness of TTT-SU versus TTASx in gout. Secondary and exploratory outcomes will add important information regarding the broader extra-articular and quality-of-life effects of lowering SU levels.

Gout, the most common inflammatory arthritis, affects as many as 5.1% of the adult population. Classically, gout is conceived as four sequential phenotypic states: 1) asymptomatic hyperuricemia 2) acute gout flare 3) inter-critical gout (gout between flares); and 4) tophaceous gout. However, these four states are paralleled by a fifth state, consisting of vascular involvement. The mechanisms and consequences of vascular gout are incompletely elucidated. In vitro and animal models indicate that soluble urate adversely affects vascular endothelium and smooth muscle. The recent discovery that soluble urate can be transported intracellularly to alter cell metabolism and epigenetics (trained innate immunity) suggests additional impacts of urate on leukocytes and endothelium. Once gout has progressed to flares, the vasculature is exposed to inflammatory mediators, both during flares and to a lesser but persistent extent inter-critically, suggesting additional mechanisms of gout's effect. We have reported that patients with gout have diminished endothelial function measured by brachial artery flow-mediated dilation. ACR gout guideline-concordant treatment improves endothelial function but is less effective in patients with cardiometabolic comorbidities. Moreover, treatment of gout patients with the anti-inflammatory colchicine and urate lowering therapy improves endothelial function and reduces the risk of both incident coronary artery disease (CAD), and MACE in patients with established CAD.

OBJECTIVE:This report evaluates rheumatologists' stated adherence to and agreement with the 2020 American College of Rheumatology (ACR) Guideline for the Management of Gout. METHODS:A 57-item questionnaire was administered to a sample of US rheumatologists. Stated adherence scores were based on several guideline recommendations reported to be followed by rheumatologists in practice, whereas stated agreement scores were based on whether respondents always followed the recommendations. RESULTS:≤ 0.05). Approximately 78% of rheumatologists claimed to follow the guideline for initiating urate-lowering therapy (ULT), and 89% were likely to prescribe allopurinol as a first-line ULT. Claimed adherence to recommendations for dosing was lower (febuxostat: 43%; allopurinol: 39%). Rheumatologists from academic settings were more likely to prescribe an interleukin-1 inhibitor for gout flares. CONCLUSION/CONCLUSIONS:The self-reported practice of the surveyed US rheumatologists was generally concordant with the 2020 ACR Guideline for the Management of Gout. However, there were gaps in guideline knowledge and stated adherence among rheumatologists, mainly concerning the dosing of treatment regimens.

RATIONALE & OBJECTIVE/OBJECTIVE:We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD). STUDY DESIGN/METHODS:Prespecified sub cohort analysis of a randomized controlled trial. SETTING/METHODS:at baseline. EXPOSURE/METHODS:Trial participants with CKD and gout and serum urate (sUA) concentration ≥6.8 mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal sUA of <6.0 mg/dl (<5.0 mg/dl with tophi) (Phase 1) and maintained during weeks 25-48 (Phase 2). Gout flare was assessed between weeks 49-72 (Phase 3). OUTCOME/RESULTS:Gout flare between weeks 49-72 (Phase 3) was the primary outcome. Secondary outcomes included sUA goal achievement and ULT dosing at end of Phase 2, and serious adverse events (SAEs). ANALYTICAL APPROACH/METHODS:Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm. RESULTS:351 of 940 participants (37.3%) had CKD; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; p=0.02) despite similar attainment of sUA goal (79% vs. 81%; p=0.6) by the end of Phase 2. Acute kidney injury (AKI) was more common in participants with stage 3 CKD randomized to allopurinol compared to febuxostat. LIMITATIONS/CONCLUSIONS:Limited power to assess infrequent safety events, largely male, older population. CONCLUSIONS:Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen.