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Objectives: Effective steroid-sparing therapies for the treatment of sarcoidosis are lacking; IL-6 antagonists may reduce sarcoidosis disease activity. This study assessed the safety and efficacy of the IL-6 receptor antagonist, sarilumab, in subjects with glucocorticoid-dependent sarcoidosis., Methods: This phase II, double-blind, placebo-controlled, randomized withdrawal trial enrolled 15 subjects with biopsy-proven sarcoidosis at Stanford University from November 2019 to September 2022. In period 1, subjects were treated with open-label s.c. sarilumab 200 mg every 2 weeks for 16 weeks, with predefined tapering of prednisone. Subjects who completed period 1 without a sarcoidosis flare entered period 2 and were randomized to continue sarilumab or to receive matching placebo for 12 weeks. The end points included flare-free survival, as well as changes in pulmonary function tests, chest imaging, patient-reported outcomes, and laboratory values., Results: Fifteen subjects were enrolled in the study (median age 57 years, 80% male, 73.3% White), and 10 subjects successfully completed period 1. During period 1, 4 of the 15 subjects (26.7%) discontinued due to worsening of their sarcoidosis, and CT chest imaging worsened in 5 of the 15 subjects (35.7%). During period 2, 0 of 2 subjects in the sarilumab group and 1 of 8 subjects (12.5%) in the placebo group had a flare. Treatment with sarilumab 200 mg was generally well tolerated in subjects with sarcoidosis., Conclusion: In this double-blind, placebo-controlled, randomized withdrawal trial, a meaningful signal of improvement in subjects with sarcoidosis treated with sarilumab was not observed. Given the small numbers in this study, no definitive conclusions can be drawn., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT04008069., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA)., Methods: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest., Results: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE)., Conclusion: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objectives: To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936)., Methods: This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks., Results: Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population., Conclusions: Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA., (© 2021 Japan College of Rheumatology.)

Objective: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis)., Methods: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive., Results: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg., Conclusion: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years., Trial Registration: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The aim of this integrated analysis is to evaluate the long-term safety and tolerability of ixekizumab in adults with psoriasis, PsA and axial SpA., Methods: Integrated safety data from 21 clinical trials are presented by indication in patients who received at least one dose of ixekizumab. Adverse events (AEs) and treatment-emergent adverse events (TEAEs) adjusted incidence rates (IRs) per 100 patient-years (PY) up to 5 years' exposure are reported., Results: A total of 8228 patients with an ixekizumab exposure of 20 895.9 PY were included in this analysis. The most common TEAEs were nasopharyngitis, upper respiratory tract infection and injection-site reactions. Across populations, IRs were low for AEs leading to discontinuation (IRs ≤5.1 per 100 PY), serious AEs (IRs ≤6.0 per 100 PY) and death (IRs ≤0.3 per 100 PY). The most reported TEAEs of special interest were infections (IRs ≤35.8 per 100 PY). Patients rarely reported malignancies (IR ≤0.8), IBD including ulcerative colitis and Crohn's disease (IR ≤0.8) and major adverse cardiovascular events (IR ≤0.5). TEAEs were most commonly reported the first 2 years of exposure with ixekizumab and IR decreased over the years (infections, injection-site reactions and depression) or remained constant over the entire treatment period (serious infections, major adverse cardiovascular events, malignancies and IBD)., Conclusion: This long-term analysis on the safety of ixekizumab was consistent with previously published reports and did not show any new safety signals. The safety profile and tolerability reported in this integrated analysis remained consistent with the known safety profile for ixekizumab., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes., Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200., Results: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters., Conclusion: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-α. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions., Methods: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed., Results: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time., Conclusion: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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.

Objectives: To assess the long-term safety and efficacy of ixekizumab, an IL-17A antagonist, in patients with active PsA., Methods: In SPIRIT-P2 (NCT02349295), patients (n = 363) with previous inadequate response to TNF inhibitors entered the double-blind period (weeks 0-24) and received placebo or ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) following a 160-mg starting dose at week 0. During the extension period (weeks 24-156), patients maintained their original ixekizumab dose, and placebo patients received IXEQ4W or IXEQ2W (1:1). We present the accumulated safety findings (week 24 up to 156) at the time of this analysis for patients who entered the extension period (n = 310). Exposure-adjusted incidence rates (IRs) per 100 patient years are presented. ACR responses are presented on an intent-to-treat basis using non-responder imputation up to week 52., Results: From week 24 up to 156 (with 228 patient years of ixekizumab exposure), 140 [61.3 IR] and 15 (6.6 IR) patients reported infections and serious adverse events, respectively. Serious adverse events included one death and four serious infections. In all patients initially treated with IXEQ4W and IXEQ2W at week 0 (non-responder imputation), ACR20 (61 and 51%), ACR50 (42 and 33%) and ACR70 (26 and 18%) responses persisted out to week 52. Placebo patients re-randomized to ixekizumab demonstrated efficacy as measured by ACR responses at week 52., Conclusion: During the extension period, the overall safety profile of ixekizumab remained consistent with that observed with the double-blind period, and clinical improvements persisted up to 1 year.

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.

Objective: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety., Methods: RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight., Results: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use., Conclusion: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.

Objectives: To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ)., Methods: Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure., Results: In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean ( s . d .) change, -2.17 (2.16) × 10 9 /l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 10 9 /l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose., Conclusion: Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort., Methods: Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP., Results: Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated., Conclusion: Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated., Trial Registration: ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)