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Objective: To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX)., Methods: This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities., Results: The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms., Conclusions: Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab., Trial Registration Number: NCT02889796., Competing Interests: Competing interests: BC received honoraria from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Lilly, Merck, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB; and research grants from Novartis, Pfizer and Roche. AK received honoraria or consulting fees from AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead Sciences, Janssen, Novartis, Pfizer, Regeneron, Sanofi and Sun Pharma Advanced Research; was a paid instructor or speaker for AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron and Sanofi; and holds shares in Amgen, Gilead Sciences, GlaxoSmithKline, Pfizer and Sanofi. YT has received speaking fees and/or honoraria from AbbVie, Asahi Kasei, Astellas, Bristol-Myers, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi Tanabe, Novartis, Pfizer, Sanofi and YL Biologics; and research grants from AbbVie, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Takeda and UCB. DvdH received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma; and is the Director of Imaging Rheumatology BV. JAS, UK and S-CB report nothing to disclose. HSBB has received honoraria or consulting fees from AbbVie, Gilead Sciences, Horizon and Merck; and research grants or support from AbbVie, Sanofi, Regeneron, Eli Lilly, Pfizer, Selecta Biosciences, Gilead Sciences, Horizon, Janssen and Pfizer. FM, BB, LY and YG are employees and shareholders of Gilead Sciences. MCG has received honoraria or consulting fees from AbbVie, Amgen, BeiGene, Genentech, Gilead Sciences, Lilly Pharmaceuticals, Sanofi Genzyme, RPharm and SetPoint. He is also an employee and shareholder of Gilead Sciences. CT is an employee and shareholder of Galapagos NV. JSS, AJ and NM are former employees of Gilead Sciences and may hold shares. RBML has received honoraria or consulting fees from AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Galapagos NV, Novartis, Pfizer and UCB. EK has received honoraria or consulting fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, F Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Lilly Pharmaceuticals, Merck, Myriad Autoimmune, Pfizer, Sandoz, Sanofi Genzyme and Samsung Bioepis; has received speaking fees from AbbVie, Amgen, Bristol-Myers Squibb, F Hoffmann-La Roche, Janssen, Merck, Pfizer, Sanofi Genzyme and UCB; and has received research grants or support from AbbVie, Amgen, Gilead Sciences, Lilly Pharmaceuticals, Merck, Pfizer, PuraPharm and Sanofi. PN has received honoraria or consulting fees, grants or research support, or been a member of a speakers bureau for AbbVie, Bristol-Myers Squibb, Celgene, Gilead Sciences, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and UCB., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure., Methods: This 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24., Results: The primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was -1.0 and -0.94 with FIL200+MTX and FIL100+MTX, respectively, versus -0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments., Conclusions: FIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX., Competing Interests: Competing interests: RW reports grant/research support from and serving as a consultant for Celltrion, Galapagos, and Gilead Sciences. WFCR reports serving as a consultant for Gilead Sciences. DvdH reports serving as a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eisai, Eli Lilly and Co., Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma; and is director of Imaging Rheumatology BV. DWTC reports receiving grants from AbbVie, Gilead Sciences, Pfizer, and Sanofi; and serving as a consultant for AbbVie and Pfizer. WS reports receiving consulting fees from Janssen Research and Development, and research support from GlaxoSmithKline. JK reports research grants paid to his institution from AbbVie, Genentech, Gilead Sciences, Pfizer, and UCB; and has received personal fees from AbbVie, Alvotech,Suisse AG, Amgen, Boehringer Ingelheim GmbH, Celltrion Healthcare Co., Janssen Biotech, Merck Sharp & Dohme Corp., Mylan, Novartis AG, Pfizer, Samsung Bioepis, Sandoz, and UCB. AC reports no conflicts of interest. BB, FM, ZY, and YG are shareholders and employees of Gilead Sciences. CT is a shareholder and employee of Galapagos NV. JSS is a shareholder and former employee of Gilead Sciences; and current employee and shareholder of Pandion Therapeutics. NM is a shareholder and former employee of Gilead Sciences, and current employee of Ichnos Sciences. AJ is a shareholder and former employee of Gilead Sciences. ODM reports serving on a speaker’s bureau for Americas Health Foundation, Amgen, and Pfizer. RBML reports serving as a consultant for AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., Galapagos NV, Novartis, Pfizer and UCB. TA reports grant/research support from AbbVie, Alexion, Astellas, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., and Pfizer; and has served as a consultant for AbbVie, Chugai, Daiichi Sankyo Co., Eli Lilly Japan K.K., Gilead Sciences, Pfizer, and UCB Japan Co.; and has served on a speakers bureau for AbbVie, Astellas, Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Daiichi Sankyo Co., Eisai Co., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Pfizer, Takeda Pharmaceutical Co., and UCB Japan Co. GRB reports serving as a consultant and on a speaker’s bureau for AbbVie, Eli Lilly and Co., Pfizer, and Gilead Sciences., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol., Methods: Patients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (200, 400 or 600 mg/day) or matching placebo in combination with their prestudy allopurinol dose (200-600 mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4 weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout., Results: Patients (n=208) received ≥1 dose of blinded medication. Lesinurad 200, 400 and 600 mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p<0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to <90 mL/min). The incidence of ≥1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600 mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events., Conclusions: Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone., Trial Registration Number: NCT01001338., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout., Methods: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set., Results: The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively)., Conclusions: The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To evaluate the long-term safety (up to 3 years) of treatment with pegloticase in patients with refractory chronic gout., Methods: This open-label extension (OLE) study was conducted at 46 sites in the USA, Canada and Mexico. Patients completing either of two replicate randomised placebo-controlled 6-month trials received pegloticase 8 mg every 2 weeks (biweekly) or every 4 weeks (monthly). Safety was evaluated as the primary outcome, with special interest in gout flares and infusion-related reactions (IRs). Secondary outcomes included urate-lowering and clinical efficacy., Results: Patients (n=149) received a mean±SD of 28±18 pegloticase infusions and were followed for a mean of 25±11 months. Gout flares and IRs were the most frequently reported adverse events; these were least common in patients with a sustained urate-lowering response to treatment and those receiving biweekly treatment. In 10 of the 11 patients with a serious IR, the event occurred when uric acid exceeded 6 mg/dl. Plasma and serum uric acid levels remained <6 mg/dl in most randomised controlled trial (RCT)-defined pegloticase responders throughout the OLE study and were accompanied by sustained and progressive improvements in tophus resolution and flare incidence., Conclusions: The safety profile of long-term pegloticase treatment was consistent with that observed during 6 months of RCT treatment; no new safety signals were identified. Improvements in clinical status, in the form of flare and tophus reduction initiated during RCT pegloticase treatment in patients maintaining goal range urate-lowering responses were sustained or advanced during up to 2.5 years of additional treatment.

Background: Recent studies suggest that blockade of the NLRP3 (cryopyrin) inflammasome interleukin 1beta (IL1beta) pathway may offer a new treatment strategy for gout., Objective: To explore the potential utility of rilonacept (IL1 Trap) in patients with chronic active gouty arthritis in a proof-of-concept study., Methods: This 14-week, multicentre, non-randomised, single-blind, monosequence crossover study of 10 patients with chronic active gouty arthritis included a placebo run-in (2 weeks), active rilonacept treatment (6 weeks) and a 6-week post-treatment follow-up., Results: Rilonacept was generally well tolerated. No deaths and no serious adverse events occurred during the study. One patient withdrew owing to an injection-site reaction. Patients' self-reported median pain visual analogue scale scores significantly decreased from week 2 (after the placebo run-in) to week 4 (2 weeks of rilonacept) (5.0 to 2.8; p<0.049), with sustained improvement at week 8 (1.3; p<0.049); 5 of 10 patients reported at least a 75% improvement. Median symptom-adjusted and severity-adjusted joint scores were significantly decreased. High-sensitivity C-reactive protein levels fell significantly., Conclusions: This proof-of-concept study demonstrated that rilonacept is generally well tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomised, controlled studies of IL1 antagonism such as with rilonacept for this clinical indication.