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Objective: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies., Methods: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression., Results: In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles., Conclusion: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses., (© 2020 Regeneron Pharmaceuticals Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Idiopathic granulomatous mastitis (IGM) is a disfiguring inflammatory breast disease without effective treatment. We report the largest IGM cohort treated with methotrexate (MTX) monotherapy., Methods: Chart review was performed on patients evaluated by the Stanford Immunology and Rheumatology Clinic, with histopathologically established IGM treated with MTX, and at least 1 followup appointment., Results: Nineteen female patients with a mean age of 33.5 years were identified. Most failed treatment with antibiotics, prednisone, and surgical intervention. By 15 months of treatment with MTX, 94% had disease improvement and 75% achieved disease remission., Conclusion: MTX monotherapy is an effective treatment for IGM.

Background/objective: FKB327 is a biosimilar of the antitumour necrosis factor adalimumab reference product (RP). A randomised, double-blind (DB) phase 3 study compared the efficacy of FKB327 with the RP in patients with active rheumatoid arthritis (RA) inadequately controlled with methotrexate (MTX). A subsequent randomised open-label extension (OLE) study with treatment switching assessed long-term safety, efficacy, pharmacokinetics and immunogenicity of FKB327 compared with the RP., Methods: Patients with moderate-to-severe, active RA on a stable dose of MTX were randomised 1:1 to receive FKB327 or the RP (40 mg subcutaneously every other week) for 24 weeks. Patients who completed the DB study were enrolled in the OLE and rerandomised 2:1 to receive FKB327 or the RP; two-thirds continued on the same treatment and one-third switched for 30 weeks. All patients received FKB327 through Week 76. Long-term efficacy, safety and immunogenicity were assessed., Results: Of 728 patients in the DB study, 645 were enrolled in the FKB327-OLE study. The American College of Rheumatology (ACR)20 response rates for all treatment groups at Week 30 in the OLE ranged from 83.2% to 85.9%. ACR20 response rates remained stable for all patients regardless of single- or double-switching treatment and were similar for all treatment sequences through Week 76. The safety profile and incidence of antidrug antibodies were comparable across sequences., Conclusion: Efficacy, safety and immunogenicity were similar among patients with RA treated with FKB327 or the RP for up to 2 years, and were not affected by single- or double-switching treatment., Competing Interests: Competing interests: MG has received consultant fees from Fujifilm Kyowa Kirin Biologics Co., including for the design of this trial. HK has no conflicts of interest to report. YA is an employee of Fujifilm Kyowa Kirin Biologics Co. and has received personal fees from the company, both during the conduct of the study and outside the submitted work. RM is an employee and shareholder of Mylan Inc. RA has received consultant fees from Mylan Inc and has been a paid speaker for Mylan Inc., (© 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.)

Objective: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA)., Methods: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54., Results: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II., Conclusion: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed., Trial Registration: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

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.)

Objective: Magnetic resonance imaging (MRI) was used in a phase IIb study of baricitinib in patients with RA to support dose selection for the phase III program., Methods: Three hundred one patients with active RA who were taking stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily baricitinib (1, 2, 4, or 8 mg) for up to 24 weeks. One hundred fifty-four patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and at weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3× synovitis score) and total joint damage (erosion + 2.5× cartilage loss score) scores were calculated. Treatment groups were compared using ANCOVA adjusting for baseline scores., Results: Mean changes from baseline to Week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, baricitinib 4 mg, and baricitinib 8 mg, respectively (p = 0.003 vs placebo for baricitinib 4 and 8 mg). Mean changes for osteitis were 0.00, -3.20, and -2.10 (p = 0.001 vs placebo for baricitinib 4 mg and p = 0.037 for 8 mg), respectively. Mean changes for bone erosion were 0.90, 0.10, and 0.40 (p = 0.089 for 4 mg and p = 0.275 for 8 mg), respectively, in these treatment groups., Conclusion: MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by baricitinib 4 and 8 mg. This corroborates previously demonstrated clinical efficacy of baricitinib and increases confidence that baricitinib 4 mg could reduce the radiographic progression in phase III studies. [Clinical trial registration number (www.ClinicalTrials.gov): NCT01185353].

Objective: In MOBILITY (NCT01061736), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate. We report 5-year safety, efficacy and radiographic outcomes of sarilumab from NCT01061736 and the open-label extension (EXTEND; NCT01146652), in which patients received sarilumab 200 mg every 2 weeks (q2w) + methotrexate., Methods: Patients (n=1197) with moderately to severely active RA were initially randomised to placebo, sarilumab 150 mg or sarilumab 200 mg subcutaneously q2w plus weekly methotrexate for 52 weeks. Completers were eligible to enrol in the open-label extension and receive sarilumab 200 mg q2w + methotrexate., Results: Overall, 901 patients entered the open-label extension. The safety profile remained stable over 5-year follow-up and consistent with interleukin-6 receptor blockade. Absolute neutrophil count <1000 cells/mm 3 was observed but not associated with increased infection rate. Initial treatment with sarilumab 200 mg + methotrexate was associated with reduced radiographic progression over 5 years versus sarilumab 150 mg + methotrexate or placebo + methotrexate (mean±SE change from baseline in van der Heijde-modified Total Sharp Score: 1.46±0.27, 2.35±0.28 and 3.68±0.27, respectively (p<0.001 for each sarilumab dose versus placebo)). Clinical efficacy was sustained through 5 years according to Disease Activity Score (28-joint count) using C reactive protein, Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index. The number of patients achieving CDAI ≤2.8 at 5 years was similar among initial randomisation groups (placebo, 76/398 (19%); sarilumab 150 mg, 68/400 (17%); sarilumab 200 mg, 84/399 (21%))., Conclusion: Clinical efficacy, including inhibition of radiographic progression, reduction in disease activity and improvement in physical function, was sustained with sarilumab + methotrexate over 5 years. Safety appeared stable over the 5-year period., Competing Interests: Competing interests: MCG has received research grants or consulting fees from R-Pharm, Roche/Genentech and Sanofi Genzyme. DvdH has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB. YL, SW and HvH are employees of Sanofi Genzyme and may hold stock and/or stock options in the company. GSJ is an employee of Regeneron and may hold stock and/or stock options in the company. JJG-R has received research support and/or consulting fees from Biogen, Gilead, Eli Lilly, Merck Sharp & Dohme, Pfizer and Roche. AK has received consulting fees and/or participated in speakers’ bureaus for AbbVie, Pfizer, Genentech, UCB, Sanofi/Regeneron, Celgene, Horizon and Merck. JAM-C has received consulting fees and/or participated in speakers’ bureaus for Pfizer, Merck Sharp & Dohme, Sanofi Aventis, Novartis, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Schering-Plough, Abbott, UCB, Eli Lilly and Gilead. MS has received consulting fees from R-Pharm. GRB has received research support and/or consulting fees from AbbVie, Lilly, Merck Sharp & Dohme, Pfizer, Roche, Sanofi and UCB. BS has nothing to disclose.

Objectives: To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR)., Methods: In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator's discretion., Results: Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years., Conclusion: Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.

Background: The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies., Methods: Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36)., Results: At week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58-0.84 points, FACIT-Fatigue by 6.9-11.4 points, Patient Global by 25.2-35.6 mm, and Pain by 24.2-37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24., Conclusions: Filgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA., Trial Registration: MTX add-on study: ClinicalTrials.gov , NCT01888874 . Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov , NCT01894516 . Registered on 10 July 2013.

Objective: To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353)., Methods: After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose., Results: In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128., Conclusion: In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

Objective: To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX)., Methods: Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method., Results: At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses., Conclusion: This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Background: Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT., Methods: Patients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24., Results: Both doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores., Conclusions: In this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab., Trial Registration: ClinicalTrials.gov. NCT01061736 . February 2, 2010.

Objective: To evaluate the safety and efficacy of golimumab (GOL), a human antitumor necrosis factor antibody, in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy through 5 years in the GO-FORWARD trial., Methods: Patients with active RA despite MTX therapy were randomly assigned to receive placebo + MTX (Group 1), GOL 100 mg + placebo (Group 2), GOL 50 mg + MTX (Group 3), or GOL 100 mg + MTX (Group 4). Patients in groups 1, 2, and 3 with inadequate response could enter early escape at Week 16 to GOL 50 mg + MTX or GOL 100 mg + MTX, and all remaining Group 1 patients crossed over to GOL 50 mg + MTX at Week 24. The blind was maintained through the 52-week database lock, after which treatment adjustments were permitted. Adverse events (AE) were monitored through Week 268. Efficacy was evaluated using the American College of Rheumatology (ACR) 20/50/70 responses and a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). Response rates at Week 256 were analyzed by an intent-to-treat analysis., Results: A total of 444 patients were randomized, and 313 received GOL through Week 252; 301 patients completed the safety followup through Week 268. Infections were the most common type of AE; 172 patients (39.6%) had ≥ 1 serious AE. No unexpected safety signals were observed. At Week 256, ACR20/50/70 responses were achieved by 63.1%, 40.8%, and 24.1%, respectively, of all randomized patients. About 78% of all patients achieved a good or moderate DAS28-CRP response., Conclusion: Improvements in the signs and symptoms of RA were maintained through 5 years. AE through 5 years were consistent with earlier reports of the GO-FORWARD trial; no apparent increased risk was observed over time.

Objective: To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate., Methods: In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP)., Results: At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed., Conclusion: VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels., (© 2016, American College of Rheumatology.)

Objective: To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA)., Methods: Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52., Results: Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts., Conclusion: In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade., (© 2015 sanofi-aventis U.S. LLC. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy., Methods: Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS)., Results: In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group., Conclusion: With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported., (Copyright © 2014 by the American College of Rheumatology.)

Objective: Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist., Methods: Adult patients were randomized (1:1:1) to fostamatinib [100 mg bid for 24 weeks (n=105; Group A)], or 100 mg bid for 4 weeks, then 150 mg qd (n=108; Group B), or to placebo (n=110; Group C) for 24 weeks. Nonresponders at Week 12 could enter a longterm extension study. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 24., Results: Baseline characteristics were well balanced. Significantly more patients in fostamatinib Group A (36.2%; p=0.004), but not B (27.8%; p=0.168), achieved ACR20 at Week 24 versus placebo (21.1%). Frequently reported adverse events were diarrhea, hypertension, and headache. Elevated blood pressure (≥140/90 mm Hg) at ≥1 visit was observed in 46.7%, 51.9%, and 26.6% of patients, respectively. There were 2 deaths in the study, 1 in Group B and 1 in the placebo group., Conclusion: Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo. Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.

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.)

Objective: Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA)., Methods: The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported., Results: Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA., Conclusion: These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

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 assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy., Methods: We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50-100 mg ± MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented., Results: Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ~75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX-treated patients with Week 24 HAQ-DI improvement ≥ 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively., Conclusion: Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550).

Objective: To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy., Methods: This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20., Results: Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] -2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, -2.27; monotherapy) at month 18., Conclusion: SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX., (Copyright © 2013 by the American College of Rheumatology.)

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 effects of golimumab on radiographic progression in patients with rheumatoid arthritis (RA)., Methods: Methotrexate (MTX)-naive patients (in the Golimumab Before Employing Methotrexate as theFirst-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [GO-BEFORE] study; n = 637)and patients with active RA despite MTX therapy (in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [GO-FORWARD] study; n =444) were randomly assigned to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab orplacebo was administered subcutaneously every 4 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO-FORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score., Results: In the GO-BEFORE study, the mean ± SD changes in the modified Sharp score from base line to week 52 (control period) were 1.4 ± 4.6 in group 1, 1.3 ± 6.2 in group 2 (P = 0.266), 0.7 ± 5.2 in group 3 (P = 0.015), and 0.1 ± 1.8 in group 4 (P = 0.025). In the GO-FORWARD study, changes from baseline to week 24 (control period) were 0.6 ± 2.4 in group 1, 0.3 ± 1.6 in group 2 (P = 0.361), 0.6 ± 2.7 in group 3 (P = 0.953), and 0.2 ± 1.3 in group 4 (P = 0.293)., Conclusion: Golimumab in combination with MTX inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study. Radiographic progression in the GO-FORWARD study was minimal in all treatment arms, precluding an adequate assessment of the effect of golimumab on radiographic progression in this study.

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.

Objective: To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study., Methods: Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (DeltaTSS), and percentages of progressors (DeltaTSS > 0.5)., Results: Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally intermediate. A strong, proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy. The monotherapies approximated the radiographic efficacy of adalimumab plus MTX only among remission-like responders, although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0. Concurrent clinical (DAS28 < 2.6) and radiographic (DeltaTSS

Objective: To assess the long-term impact of etanercept on fatigue in patients with recent-onset (mean duration 11 months) or established (mean duration 12 years) rheumatoid arthritis (RA)., Methods: Patients participating in either of 2 multicenter, randomized, double-blind clinical trials were included. In one trial, patients with recent-onset RA received either etanercept 25 mg twice weekly or methotrexate in a double-blind fashion for 12 months, then open label for 12 months. All patients then received open-label etanercept. In the second trial, patients with established RA received etanercept 25 mg or placebo twice weekly for 6 months in a double-blinded fashion, then open-label etanercept. Up to 46 months of followup data were included. Fatigue was measured regularly using the Health Assessment Questionnaire vitality domain., Results: Patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months. Subsequently, patients receiving etanercept and methotrexate had 23-29% and 17-24% reductions in fatigue scores, respectively. In the group with established RA, patients who received etanercept had significantly greater reductions in fatigue than those receiving placebo during the blinded period. Patients initially receiving etanercept sustained a mean fatigue reduction of 25-36% for the entire followup. Patients achieving clinically meaningful improvement in fatigue were more likely to meet the American College of Rheumatology improvement criteria., Conclusion: Etanercept therapy reduces fatigue in patients with recent-onset or established RA. Improvement in fatigue was sustained for up to 46 months, and correlated with other RA-relevant outcomes.

Objective: To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA)., Methods: Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained., Results: For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose., Conclusion: Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate., Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis., Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial., Setting: 20 centers in the United States and Canada., Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months., Intervention: Leflunomide or matching placebo added to existing methotrexate therapy., Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis., Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate., Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Objective: To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy., Methods: In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images., Results: At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events., Conclusion: Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA.

Objective: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).Methods: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.Results: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies.Conclusions: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368. [ABSTRACT FROM AUTHOR]

Objective: The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).Methods: Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.Results: Of 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.Conclusion: Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton's tyrosine kinase in a 2-part, phase II trial (RAjuvenate; ClinicalTrials.gov: NCT02628028) in adults with active rheumatoid arthritis (RA).Methods: In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5, 10, or 30 mg or placebo once daily for 4 weeks to assess safety and tolerability. No safety signals precluded moving to Part B, where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5 mg (n = 63), 10 mg (n = 62), or 30 mg (n = 63), or placebo (n = 62) once daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary and secondary endpoints. Nonresponder imputation was used for missing data.Results: After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. One hundred and eighty-nine (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (P > 0.05 for all comparisons). Five serious adverse events occurred (n = 2, placebo; n = 3, 30 mg); there was 1 death due to a fall.Conclusion: While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods: Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results: In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion: Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1‐selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). Methods: In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. Results: At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28‐CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28‐CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib‐treated patients than placebo‐treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). Conclusion: Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib. [ABSTRACT FROM AUTHOR]

Objective: Tumor necrosis factor (TNF) and interleukin‐17A (IL‐17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). This study sought to evaluate the safety and efficacy of ABT‐122, a novel dual variable domain immunoglobulin targeting human TNF and IL‐17A, in patients with RA who have experienced an inadequate response to methotrexate. Methods: Patients with active RA who were receiving treatment with methotrexate and had no prior exposure to biologic agents (n = 222) were enrolled in a 12‐week phase II randomized, double‐blind, active‐controlled, parallel‐group study. Patients were randomized to receive either ABT‐122 at dosages of 60 mg every other week, 120 mg every other week, or 120 mg every week or adalimumab at 40 mg every other week, administered subcutaneously. The primary efficacy end point was the proportion of patients achieving a ≥20% improvement response based on the American College of Rheumatology criteria for 20% improvement (ACR20) at week 12. Results: Treatment‐emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT‐122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT‐122 60 mg every other week, 120 mg every other week, and 120 mg every week, respectively, compared with an ACR20 response rate of 68% with 40 mg adalimumab every other week. The corresponding response rates for ACR50 and ACR70 improvement in the ABT‐122 dose groups and adalimumab group were 35%, 46%, 47%, and 48%, respectively, and 22%, 18%, 36%, and 21%, respectively. Conclusion: Over the 12‐week study period, dual inhibition of TNF and IL‐17A with ABT‐122 produced a safety profile consistent with that of adalimumb used for inhibition of TNF alone. The efficacy of ABT‐122 over 12 weeks at dosages of 120 mg every other week or 120 mg every week was not meaningfully differentiated from that of adalimumab at a dosage of 40 mg every other week in patients with RA receiving concomitant methotrexate. [ABSTRACT FROM AUTHOR]

Objective: To investigate the safety and efficacy of ABT‐122, a tumor necrosis factor (TNF)– and interleukin‐17A (IL‐17A)–targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate. Methods: Patients (n = 240) were randomized to receive ABT‐122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12‐week double‐blind, parallel‐group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12‐week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis. Results: In both ABT‐122 dose groups, ACR20 response rates at week 12 (64.8–75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT‐122 dose groups (36.6–53.4% and 22.5–31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT‐122 120 mg every week, and ABT‐122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment‐emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT‐122. Conclusion: Dual neutralization of TNF and IL‐17A with ABT‐122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12‐week treatment course in patients with PsA. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies. Methods All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study). Results The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36–43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42–53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6–3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks. Conclusion ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895 [ABSTRACT FROM AUTHOR]

Background: Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, have shown safety and efficacy in the treatment of patients with active rheumatoid arthritis. We did this study to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs).Methods: We did this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries. Patients were aged 18 years or older, had active rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, and were receiving concomitant background conventional synthetic DMARDS (csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 onwards. The two separate primary endpoints were the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and the proportion of patients achieving a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy and safety analyses were done in the modified intention-to-treat population of all patients who received at least one dose of study drug. Data are presented up to week 24 of this ongoing study. The trial is registered with ClinicalTrials.gov (NCT02706847).Findings: Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 patients had received one previous bDMARD, 137 (28%) had received two, and 125 (25%) had received at least three; 451 (91%) patients completed treatment up to week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, ACR20 was achieved by 106 (65%; 95% CI 57-72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49-64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22-35) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 36-51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35-50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9-20) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall numbers of patients with adverse events were similar for the placebo group (95 [56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common adverse events occurring in at least 5% of patients in any treatment group were upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis (ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse events was higher in the upadacitinib 30 mg group (12 [7%]) than in the upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported in patients receiving placebo. More patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo.Interpretation: Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis.Funding: AbbVie Inc. [ABSTRACT FROM AUTHOR]

Objective Patients with rheumatoid arthritis (RA) have an increased risk of coronary heart disease (CHD). Some RA therapies may modify this risk, but the underlying mechanisms are unclear. The cholesterol efflux capacity of high-density lipoprotein (HDL) is associated with a reduced CHD risk in non-RA populations; however, inflammation may impair the function of HDL. The aim of this study was to evaluate whether reduced inflammation resulting from treatment with methotrexate (MTX), adalimumab (ADA), or tocilizumab (TCZ) would increase the net cholesterol efflux capacity of HDL in patients with RA. Methods A longitudinal multicenter study repository (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository) provided clinical information for and serum samples from 70 patients with RA before and 6 months after starting treatment with a new drug (MTX [n = 23], ADA [n = 22], or TCZ [n = 25]). Disease activity was measured using the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). The net cholesterol efflux capacity was measured in paired serum samples using THP-1 macrophages, and total cellular cholesterol was measured by fluorometric assay. Results The DAS28-ESR decreased with all treatments ( P < 0.001). Net cholesterol efflux capacity was not significantly changed after 6 months of new RA therapy (mean ± SD 36.9 ± 17.3% units at baseline versus 38.0% ± 16.9% units at 6 months [ P = 0.58]). However, change in net cholesterol efflux capacity was associated with change in the DAS28-ESR (ρ = −0.25, P = 0.04). In a post hoc analysis of patients with impaired net cholesterol efflux capacity at baseline, treatment with TCZ resulted in significant improvement in net cholesterol efflux capacity (21.9 ± 14.7% units at baseline versus 31.3% ± 12.8% units at 6 months [ P < 0.02]), but this was not observed with MTX or ADA. Conclusion Net cholesterol efflux capacity of HDL cholesterol did not change significantly after 6 months of new RA therapy, except in patients with impaired baseline cholesterol efflux capacity who were receiving TCZ. Change in disease activity was associated with change in the net cholesterol efflux capacity. [ABSTRACT FROM AUTHOR]

Chinese translation BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA. OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs. DESIGN: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544). SETTING: 114 centers in 19 countries. PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy. INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily. MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments. RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P 0.001) and 25.8% (CI, 16.8% to 34.8%; P 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups. LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited. CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate. PRIMARY FUNDING SOURCE: Pfizer. [ABSTRACT FROM AUTHOR]

The author reflects on the inhibition in the treatment of rheumatoid arthritis (RA). The author cites the use of mitogen-activated protein kinases (MAP) inhibitors as therapy for the treatment of inflammation and it played a major role in the development of an oral therapy for the treatment of RA. The author detailed the result of a study which focuses on monotherapy with methotrexate in patient with active RA that include patients with comparable demographies and novel therapies.

The article examines the efficacy of Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in treating rheumatoid arthritis (RA). Methodology-wise, the researchers used the A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) trial with combined methotrexate (MTX). Based on the results, they concluded that the therapy was well tolerated and doses of 200 milligram and higher showed better clinical responses as well as better reduction of C-reactive protein levels.

Background: Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy. Methods: We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6. Results: R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy. Conclusions: In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.) N Engl J Med 2010;363:1303-12. [ABSTRACT FROM AUTHOR]