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Objective: To characterise safety of the Janus kinase-1 preferential inhibitor filgotinib in patients with moderately to severely active rheumatoid arthritis., Methods: Data were integrated from seven trials (NCT01668641, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700, NCT03025308). Results are from placebo (PBO)-controlled (through week (W)12) and long-term, as-treated (all available data for patients receiving ≥1 dose filgotinib 200 (FIL200) or 100 mg (FIL100) daily) datasets. We calculated exposure-adjusted incidence rates (EAIRs)/100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs)., Results: 3691 patients received filgotinib for 6080.7 PYE (median 1.6, maximum 5.6 years). During the PBO-controlled period, TEAEs, including those of grade ≥3, occurred at comparable rates with filgotinib or PBO; long-term EAIRs of TEAEs grade ≥3 were 6.4 and 7.6/100PYE for FIL200 and FIL100. EAIRs for deaths were 0.6/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.5 and 0.3/100PYE for FIL200 and FIL100. EAIRs for serious infection were 3.9, 3.3 and 2.4/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.6 and 3.1/100PYE for FIL200 and FIL100. EAIRs for herpes zoster were 0.6, 1.1, and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.8 and 1.1/100PYE for FIL200 and FIL100. EAIRs for major adverse cardiovascular events were 0, 1.7 and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.4 and 0.6/100PYE for FIL200 and FIL100. No venous thromboembolism occurred during the PBO-controlled period; long-term EAIRs were 0.2 and 0/100PYE for FIL200 and FIL100., Conclusions: Over a median of 1.6 and maximum of 5.6 years of exposure, safety/tolerability of FIL200 and FIL100 were similar, with a lower incidence of infections with FIL200 among the long-term, as-treated dataset., Competing Interests: Competing interests: KLW reports receiving grant/research support from AbbVie, Bristol Myers Squibb, and Pfizer and serving as a consultant for AbbVie, Bristol Myers Squibb, Eli Lilly and Co., Galapagos NV, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, Roche, Regeneron, Sanofi, and UCB. YT has received speaking fees and/or honoraria from Daiichi Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol Myers, Eisai, Chugai, AbbVie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead Sciences, Inc., Janssen; research grants from AbbVie, Mitsubishi-Tanabe, Chugai, Asahi Kasei, Eisai, Takeda, Daiichi Sankyo; and consultant fees from Eli Lilly, Daiichi Sankyo, Taisho, Ayumi, Sanofi, GSK, and AbbVie. TT reports receiving grant/research support from AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi-Tanabe, Shionogi, Takeda, and UCB Japan; serving as a consultant for Astellas, Chugai, and Eli Lilly Japan; and serving on a speaker’s bureau for AbbVie, AYUMI, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead Sciences, Inc., Mitsubishi-Tanabe, Novartis, Pfizer Japan, Sanofi, and Dainippon Sumitomo. AK is a shareholder of Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Pfizer, and Sanofi; serving as a consultant or advisor for AbbVie, Boehringer Ingelheim, Flexion, Genzyme, Gilead Sciences, Inc., Janssen, Novartis, Pfizer, Regeneron, Sanofi, and SUN Pharma Advanced Research; serving as a paid instructor for Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, and Sanofi; and serving on a speaker’s bureau for AbbVie, Celgene, Flexion, Genzyme, Horizon, Lilly, Merck, Novartis, Pfizer, Regeneron, and Sanofi. FM, DJ, KC, and BB are employees and shareholders of Gilead Sciences, Inc. AJ is an employee of Novartis, a former employee of Gilead Sciences, Inc., and a shareholder of Gilead Sciences, Inc., Novartis, and Roche. MCG is a shareholder and employee of Gilead Sciences, Inc. and has received honoraria or consulting fees from AbbVie, Amgen, Beigene, Genentech, Gilead Sciences, Inc., Lilly Pharmaceuticals, Sanofi Genzyme, RPharm, and SetPoint. RB is a shareholder and employee of Galapagos. GRB reports serving as a consultant and on a speaker’s bureau for AbbVie, Eli Lilly and Co., Galapagos, Gilead Sciences, Inc., and Pfizer. J-EG reports receiving grant/research support from Bristol Myers Squibb and Pfizer; serving as a consultant to AbbVie, Bristol Myers Squibb, Galapagos, Gilead Sciences, Inc., Pfizer, Eli Lilly and Co., and Sanofi Genzyme; and serving on a speaker’s bureau for AbbVie, Eli Lilly and Co., Roche, Sanofi Genzyme, and UCB., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated with baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor., Methods: Infections are summarised from an integrated database (8 phase 3/2/1b clinical trials and 1 long-term extension (LTE)) with data to 1 April 2017. The 'all-bari-RA' analysis set included patients who received any baricitinib dose. Placebo comparison was based on six studies with 4 mg and placebo to week 24, including four trials with 2 mg (placebo-controlled set). Dose-response assessment was based on four studies with 2 mg and 4 mg, including LTE data (2-4 mg extended set)., Results: There were 3492 patients who received baricitinib for 7860 patient-years (PY) of exposure (median 2.6 years, maximum 6.1 years). Treatment-emergent infections were higher for baricitinib versus placebo (exposure-adjusted incidence rate (IR)/100 PY: placebo 75.9, 2 mg 84.0 (p not significant), 4 mg 88.4 (p≤0.001)). The IR of serious infection was similar for baricitinib versus placebo and stable over time (all-bari-RA IR 3.0/100 PY). There were 11 cases of tuberculosis (all-bari-RA IR 0.1/100 PY); all occurred with 4 mg in endemic regions. Herpes zoster (HZ) IR/100 PY was higher for baricitinib versus placebo (placebo 1.0, 2 mg 3.1 (p not significant), 4 mg 4.3 (p≤0.01)); rates remained elevated and stable over time (all-bari-RA 3.3). Opportunistic infections, including multidermatomal HZ, were infrequent in the baricitinib programme (all-bari-RA IR 0.5/100 PY)., Conclusions: Increased rates of treatment-emergent infections including HZ were observed in patients with RA treated with baricitinib, consistent with baricitinib's immunomodulatory mode of action., Competing Interests: Competing interests: KLW has received grants from BMS and Pfizer and consultancies from AbbVie, Amgen, BMS, Eli Lilly and Company, Galapagos, Gilead, Pfizer, and UCB. MH has received grants from BMS KK, Eisai, Ono, and Takeda and consultancies from Eli Lilly and Company. MCG has received grants and consultancies from AbbVie, Eli Lilly and Company, Galapagos, and Pfizer. SL has received speaking fees and/or honoraria from Eli Lilly and Company, Novartis, and Pfizer. TT has received consultancies and speaking fees and/or honoraria from AbbVie GK, Asahi Kasei KK, Astellas, Astra-Zeneca KK, BMS KK, Chugai, Daiichi Sankyo, Eisai, Eli Lilly and Company, Janssen KK, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer Japan, Takeda, Taiho, Taisho Toyama, GSK, and UCB Japan. RF has received grants from AbbVie, Amgen, Astra-Zeneca, BMS, Celgene, Centrexion, Eli Lilly and Company, Genetech, GSK, Janssen, Merck, and Pfizer and consultancies from AbbVie, Amgen, BMS, Celgene, Celltrion, Eli Lilly and Company, GSK, Janssen, Novartis, Pfizer, Samsung, Sanofi‐Aventis, and Taiho. JDB, NLB, DLH, MI, AN, TPR, SW and CD are employees and may be shareholders of Eli Lilly and Company. JSS has received grants from AbbVie, Eli Lilly and Company, Novartis, Pfizer, and Roche and consultancies from AbbVie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Eli Lilly and Company, Gilead, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi-Aventis, and UCB. MD has received grants and consultancies from AbbVie, BMS, Eli Lilly and Company, Merck, Novartis, Pfizer, Roche and UCB., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response., Methods: Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised., Results: Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26., Conclusion: Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout., Competing Interests: Competing interests: RF has received research grants and consulting fees from AbbVie, Eli Lilly, and Pfizer. MG has served as a consultant for, and has received grants from, AbbVie, Eli Lilly, Pfizer, Galapagos, and Gilead. EM has received research grants and consulting fees from AbbVie, Eli Lilly, Pfizer, Roche, BMS, and Sandoz. LB has served as a speaker on behalf of, and received consulting fees and research grants from, Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly and Novartis. CP is an employee and shareholder of Spire Sciences, has served as a speaker on behalf of Amgen, Bristol-Myers Squibb and has served as a consultant for Centrexion, Crescendo Bioscience, Daiichi Sankyo, EMD Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Pfizer, Plexikkon, Regeneron, Roche and SetPoint. PD has received speaker fees from BMS, Sanofi, Eli Lilly, and Celltrion. AO has served as a speaker on behalf of, and has received consulting fees and/or research grants from BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly and Novartis. JVE, YL, and I-HS are employees of AbbVie and may own stock or stock options., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day., Methods: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks., Results: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups., Conclusions: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed., Competing Interests: Competing interests: TT has received consulting support and/or speakers’ bureau fees from AbbVie GK, Asahi Kasei Medical KK, Astellas Pharma, AstraZeneca KK, Bristol-Myers KK, Celtrion, Chugai Pharma, Daiichi Sankyo, Eisai, Eli Lilly and Company, Janssen Pharma KK, Merck Serono, Mitsubishi Tanabe Pharma, Nipponkayaku, Novartis Pharma KK, Pfizer Japan, Takeda Pharma and UCB Japan. MCG has received grant/research support and/or consulting support from AbbVie, Astellas, Eli Lilly and Company, Galapagos, Gilead, Pfizer and Vertex. BH has received grant/research support, consulting fees and/or speakers’ bureau fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Pfizer, Roche and UCB. ZL has nothing to disclose. LX, APC, SO, PRL, IdlT, TPR, and WM are employees of Eli Lilly and Company and may own stock or stock options in Eli Lilly and Company. RK is an employee of IQVIA. JSS has received grant/research support, consulting fees and/or speakers’ bureau fees from AbbVie, Amgen, AstraZeneca, Astro, Bristol Myers Squibb, Celgene, Celtrion, Chugai, Eli Lilly and Company, Gilead, Glaxo, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab., Methods: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity., Results: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies., Conclusions: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA., Trial Registration Number: NCT01970475; Results., Competing Interests: Competing interests: SC reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from Abbvie, Boehringer Ingelheim, Pfizer and Sandoz, outside the submitted work. MCG reports grants and personal fees from Amgen, AbbVie and Pfizer, and personal fees from Sandoz, FKb, Samsung BioEpis, Merck, Celltrion and Boehringer, during the conduct of the study. EC reports grants and personal fees from Amgen, during the conduct of the study; personal fees from Boehringer Ingelheim, Chelsea Therapeutics, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hospita, ISIS, Jazz Pharmaceuticals, Janssen, MedImmune, Merrimack Pharmaceutical, Merck, Napp, Novartis, Regeneron, Sanofi-Aventis, Schering Plough, Synovate and Tonix and grants and personal fees from Chugai Pharma, Ferring Pharmaceuticals, Novimmune, Pfizer, Pierre Fabre, Roche and UCB, outside the submitted work. FP-R reports grants from Amgen, during the conduct of the study; and personal fees from Amgen, outside the submitted work. AM reports grants and personal fees from Amgen, during the conduct of the study; grants and personal fees from AbbVie, Pfizer and Bristol-Myers Squibb, grants from Takeda, Janssen, Gilead and UCB and personal fees from GlaxoSmithKline, outside the submitted work. JLP reports lecturing and consultancy fees from Roche, Novartis, Pfizer and Lilly, outside the submitted work. NZ and PK are employees of Amgen Inc., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)., Methods: Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK)., Results: The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy., Conclusions: The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety., Competing Interests: Competing interests: MB, WR, TW, JP and MM are employed by Genentech, Inc. SL, AP-S, HB, KS and NLM are employed by F. Hoffmann-La Roche. AN is employed by Chugai Pharmaceutical. GRB has received grants and honoraria for consulting and lectures from Roche. EC has received research grant, speaker and consultancy fees from Roche and Chugai Pharmaceutical. AK has received research grants and consulted for Genentech, Inc. AO has received consulting fees, speaking fees and/or honoraria from Chugai Pharmaceutical. MCG has received grants and consulting fees and/or honoraria from Roche., (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/.)

Objectives: To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs)., Methods: In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables., Results: 527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01)., Conclusions: Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib., Trial Registration Number: NCT01721044; Results., (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/.)

Background: Adalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications., Objective: To update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA., Methods: This analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry., Results: Serious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women., Conclusions: This analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced., Trial Registration Numbers: NCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301., Competing Interests: GRB has received research grants, consulting fees and speaker's fees from AbbVie, BMS, Merck, Pfizer, Roche and UCB. RL has received consulting fees from AbbVie, Amgen, BMS, Centocor, GSK, Merck, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth and is owner of Rheumatology Consultancy BV. MCG has received research grants and consulting fees from AbbVie. AWF, NDP and APL are employees of AbbVie and may hold stock and/or options. NV is a former employee of AbbVie and may hold stock and/or options., (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: To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA)., Methods: This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system., Results: ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p<0.01) and for RAMRIS osteitis scores (p<0.01) for VX-509 300 mg. Treatment was generally well tolerated., Conclusions: VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated., Trial Registration Number: NCT01754935; results., (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/.)

Objectives: OSKIRA-4 evaluated the efficacy of fostamatinib monotherapy versus placebo on the signs and symptoms of rheumatoid arthritis over 6 weeks by Disease Activity Score C reactive protein (DAS-28(CRP)) and assessed non-inferiority to adalimumab monotherapy at Week 24 by DAS-28(CRP)., Methods: Overall, 279 patients not currently taking disease-modifying antirheumatic drugs were randomised to: (A) fostamatinib 100 mg twice daily for 24 weeks plus placebo injection every 2 weeks (PBOI); (B) fostamatinib 100 mg twice daily for 4 weeks, then 150 mg once daily up to Week 24, plus PBOI; (C) fostamatinib 100 mg twice daily for 4 weeks, then 100 mg once daily up to Week 24, plus PBOI; (D) adalimumab 40 mg every 2 weeks for 24 weeks, plus oral placebo twice daily; or (E) oral placebo twice daily for 6 weeks, plus PBOI, then a switch to arm A or B., Results: Fostamatinib demonstrated a significant improvement in DAS-28(CRP) score from baseline versus placebo at Week 6 for arms A and B, but not C. Fostamatinib was significantly less effective than adalimumab at Week 24 based on DAS-28(CRP). Adverse events observed with fostamatinib treatment were consistent with those reported in previous studies, including hypertension and diarrhoea., Conclusions: Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24., Trial Registration Number: Clinicaltrials.gov: NCT01264770., (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/)

Objectives: To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate., Methods: In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12., Results: Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib., Conclusions: Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24., Trial Registration Number: NCT01185353., (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.)

Objectives: The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated., Methods: Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ., Results: Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6., Conclusions: OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified., Trial Register Number: NCT01242488., (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.)

Objectives: To evaluate safety and efficacy of weekly (qw) and every other week (q2w) dosing of sarilumab, a fully human anti-interleukin 6 receptor α (anti-IL-6Rα) monoclonal antibody, for moderate-to-severe rheumatoid arthritis (RA)., Methods: In this dose-ranging study, patients (n=306) with active RA, despite methotrexate, were randomly assigned to placebo or one of five subcutaneous doses/regimens of sarilumab: 100 mg q2w, 150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw for 12 weeks, plus methotrexate. The primary end point was ACR20 at Week 12. Secondary endpoints included ACR50, ACR70, Disease Activity Score in 28 joints (C reactive protein). Safety, pharmacokinetics, pharmacodynamics and efficacy in population subgroups were assessed., Results: The proportion of patients achieving an ACR20 response compared with placebo was significantly higher for sarilumab 150 mg qw (72.0% vs 46.2%, multiplicity adjusted p=0.0203). Higher ACR20 responses were also attained with 150 mg q2w (67%; unadjusted (nominal) p=0.0363) and 200 mg q2w (65%; unadjusted p=0.0426) versus placebo. Sarilumab ≥150 mg q2w reduced C reactive protein, which did not return to baseline between dosing intervals. Infections were the most common adverse event; none were serious. Changes in laboratory values (neutropenia, transaminases and lipids) were consistent with reports with other IL-6Rα inhibitors., Conclusions: Sarilumab improved signs and symptoms of RA over 12 weeks in patients with moderate-to-severe RA with a safety profile similar to reports with other IL-6 inhibitors. Sarilumab 150 mg and sarilumab 200 mg q2w had the most favourable efficacy, safety and dosing convenience and are being further evaluated in Phase III., (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.)

Objectives: To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD)., Methods: Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed., Results: At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable., Conclusions: While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.

Objectives: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX)., Methods: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10)., Results: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only., Conclusions: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.

Objective: To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors., Methods: Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo)., Results: At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab., Conclusions: At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies., Clinical Trial Registration Number: NCT00689728.

Objective: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA)., Methods: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16., Results: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one)., Conclusions: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

Objectives: Evaluate relationships between MRI and clinical/laboratory/radiographic findings in rheumatoid arthritis (RA)., Methods: 637 methotrexate-naive patients (GO-BEFORE) and 444 patients with active RA despite methotrexate (GO-FORWARD) were randomly assigned to subcutaneous placebo + methotrexate, golimumab 100mg + placebo, golimumab 50mg + methotrexate, or golimumab 100mg + methotrexate every-4-weeks. In GO-BEFORE(n=318) and GO-FORWARD(n=240) substudies, MRI of dominant wrist/metacarpophalangeal joints were scored for synovitis, bone oedema and bone erosion (RA MRI scoring (RAMRIS) system). Relationships between RAMRIS scores and serum C-reactive protein (CRP), 28-joint count disease activity score (DAS28-CRP) and van der Heijde modified Sharp (vdH-S) scores were assessed., Results: Baseline and weeks 24/28 DAS28-CRP, CRP, and vdH-S generally correlated well with baseline and week 24 RAMRIS synovitis, oedema and erosion scores. Early (week 4) CRP changes correlated with later (week 12) RAMRIS synovitis/oedema change scores; earlier (week 12) changes in some RAMRIS scores correlated with later (weeks 24/28) changes in vdH-S. Significant correlations between RAMRIS change scores and clinical/radiographic change scores were weak., Conclusions: MRI and clinical/laboratory/radiographic measures generally correlated well. Associations between earlier changes in CRP and later changes in RAMRIS synovitis/osteitis were observed. Changes in MRI and clinical/radiographic measures did not correlate well, probably because MRI is more sensitive than radiographs and more objective than DAS28-CRP.

Objective: To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX)., Methods: Patients (n=444) were randomly assigned to placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX, or golimumab 100 mg plus MTX (subcutaneous injections every 4 weeks). A subset of 240 patients participated in an MRI substudy. MRIs (1.5T+contrast enhancement) of the dominant wrist and metacarpophalangeal (MCP) joints were obtained at baseline and weeks 12 and 24. Images were scored by two independent, blinded readers for synovitis (0-9 wrist only (n=240), 0-21 wrist+MCP (n=223)), bone oedema (osteitis) (0-69) and bone erosions (0-230) using the OMERACT Rheumatoid Arthritis MRI Scoring system., Results: Significant improvements in synovitis and bone oedema (osteitis) were observed in the combined golimumab plus MTX groups versus placebo plus MTX at week 12 (-1.77 vs -0.15, p<0.001 wrist+MCP and -2.00 vs 0.19, p=0.003, respectively) and week 24 (-1.91 vs -0.38, p<0.001 wrist+MCP and -1.74 vs 0.71, p=0.004, respectively). Fewer than 10% of patients had a substantial degree of erosive progression (most showed no progression) across all treatment groups (including the control group), precluding adequate evaluation of golimumab's effect on bone erosions., Conclusion: Golimumab plus MTX significantly improved MRI-detected synovitis and osteitis (prognosticators of future structural damage) versus placebo plus MTX at weeks 12 and 24. The effect of golimumab on bone erosions could not be determined by semi-quantitative scoring in these RA patients with minimal progression of bone erosions.

Objective: To evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate., Methods: Patients were randomly assigned to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3) and golimumab 100 mg plus methotrexate (group 4). At week 16, patients in groups 1, 2 and 3 who had less than 20% improvement in tender and swollen joints entered early escape. At week 24, patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate., Results: At week 16, 31%, 27% and 17% of patients in groups 1, 2 and 3, respectively, entered early escape. At week 52, 44%, 45%, 64% and 58% of patients in groups 1, 2, 3 and 4, respectively, achieved 20% improvement in the American College of Rheumatology criteria; and 34%, 31%, 42% and 53%, respectively, achieved low disease activity (< or = 3.2) according to the 28-joint disease activity score. Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections., Conclusion: The results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks. The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.

Background: Rituximab inhibited structural damage at 1 year in patients with rheumatoid arthritis (RA) who had had a previous inadequate response to tumour necrosis factor (TNF) inhibitors., Objective: To assess structural damage progression through 2 years., Methods: Intention-to-treat patients with one post-baseline radiograph (rituximab n=281; placebo n=187) received background methotrexate (MTX) and were randomised to rituximab (2 x 1000 mg infusions, 2 weeks apart) or placebo; patients were eligible for rituximab re-treatment every 6 months. By week 104, 82% of the placebo population had received > or = 1 dose of rituximab. Radiographic end points included the change in total Sharp score (TSS), erosion and joint space narrowing scores at week 104., Results: At week 104, significantly lower changes in TSS (1.14 vs 2.81; p<0.0001), erosion score (0.72 vs 1.80; p<0.0001) and joint space narrowing scores (0.42 vs 1.00; p<0.0009) were observed with rituximab plus MTX vs placebo plus MTX. Within the rituximab group, 87% who had no progression of joint damage at 1 year remained non-progressive at 2 years., Conclusions: Rituximab plus MTX demonstrated significant and sustained effects on joint damage progression in patients with RA and a previously inadequate response to TNF inhibitors.

Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis., Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed., Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24., Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively., Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

Objective: To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab., Methods: RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected., Results: Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred., Conclusions: In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

Objective: To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout., Methods: In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose., Results: 1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4)., Conclusion: Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice., Trial Registration Number: NCT00124982.

Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy., Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24., Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively., Conclusion: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

Objective: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors., Methods: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56., Results: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001)., Conclusions: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

Objective: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis., Methods: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years., Results: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment., Conclusion: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease., Trial Registration Number: NCT00124982.

Objectives: To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay., Methods: Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software., Results: Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02)., Conclusions: Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.