TY - JOUR T1 - Genetically proxied IL-6 receptor inhibition and risk of polymyalgia rheumatica JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 1480 LP - 1482 DO - 10.1136/annrheumdis-2022-222578 VL - 81 IS - 10 AU - Sizheng Steven Zhao AU - Dipender Gill Y1 - 2022/10/01 UR - http://ard.bmj.com/content/81/10/1480.abstract N2 - Polymyalgia rheumatica (PMR) is among the commonest inflammatory rheumatic diseases for which the cornerstone of treatment is long-term glucocorticoids.1 Adverse effects of glucocorticoids in elderly and often comorbid individuals can lead to significant additional morbidity. Steroid-sparing treatment options are limited and remain a major unmet need. Interleukin 6 (IL-6) signalling is thought to play a key role in PMR pathophysiology, and open-label studies of IL-6 receptor inhibition (IL-6Ri) have shown promising efficacy.2 Open-label studies are susceptible to bias, while effective blinding may be challenging since IL-6Ri reduces C-reactive protein (CRP), which can unblind participants. Natural variation in the gene that encodes a protein drug target can offer insight into the clinical effects of perturbing that target pharmacologically.3 We leveraged large population-level data to examine the effect of genetically proxied IL-6Ri on risk of PMR.To proxy IL-6Ri, we used seven previously identified variants (online supplemental table S1) within or near the IL6R gene (±300 kilobases), which encode the receptor of IL-6; these variants were uncorrelated (r2 <0.1) and associated with circulating CRP levels at genome-wide significance (p<5×10−8) from a genome-wide association study of 204 402 European individuals.4 These instruments were validated through associations … ER -