Control Of Urate Levels Research Articles

GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells

Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.

Evaluation of supported self-management in gout (GoutSMART): a randomised controlled feasibility trial

Improved outcomes for patients with gout are associated with the control of urate levels; yet, less than 40% of patients in the UK are currently offered urate lowering therapy, and it is typically offered without titration to target. Supported self-management has been shown to benefit patients with chronic health conditions; therefore, we aimed to determine whether a supported gout self-management approach, incorporating treatment-to-target urate, helped participants reach target urate levels. In this randomised controlled feasibility study, conducted in one hospital in Edinburgh, UK, we included patients (aged ≥18 years) with gout and a physician recommendation for initiation or escalation of urate lowering therapy. We randomised participants in a 2:1 ratio to a supported self-management group or a usual care group using the GoutSMART smartphone app. Participants in the self-management group were given a urate self-testing meter and received direct advice from clinicians on escalation of urate lowering therapy through the app. Participants were identified following referral to rheumatology, or using the Scottish Health Research Register, and they were screened and offered a detailed management plan before randomisation. Participants in the usual care group had a limited version of the app, which only allowed it to function as a health diary, and their gout management plan was implemented by their general practitioner. The primary outcome was the percentage of participants achieving a urate target of 0·30 mmol/L or less at 24 weeks, and analysis was by intent to treat. The trial was registered with ClinicalTrials.gov, NCT03274063, and there is an extension study ongoing. There was no masking of participants or assessors. Between April 5, 2019, and March 19, 2020, 60 (65%) of 92 patients screened were enrolled to the study. The mean age was 52.8 years (SD 14.6); 56 (93%) of the participants were male, and 4 (7%) were female. 58 (97%) of participants were White. 40 participants were assigned to the self-supported management group and 20 participants were assigned to the usual care group. A urate target of 0·30 mmol/L or less at 24 weeks was reached by 29 (73%) participants in the supported self-management group compared with 3 (15%) participants in the usual care group (risk difference 0·58 [95% CI 0·37-0·78]; p<0·0001). 90% of participants completed the study with no difference in the drop-out rate or adverse events between the two groups. Supported self-management of gout results in substantially improved attainment of urate targets compared with usual care, and it is well tolerated. Larger trials will be needed to fully evaluate the clinical and cost-effectiveness of this approach. Edinburgh & Lothians Health Foundation.