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Peter C Taylor, 1 Neil Betteridge, 2 T Michelle Brown, 3 John Woolcott, 4 Alan J Kivitz, 5 Cristiano Zerbini, 6 Diane Whalley, 7 Oyebimpe Olayinka-Amao, 3 Connie Chen, 8 Palle Dahl, 9 Dario Ponce de Leon, 10 David Gruben, 11 Lara Fallon 12 1Botnar Research Centre, University of Oxford, Oxford, UK; 2Neil Betteridge Associates, London, UK; 3Patient-Centered Outcomes Assessment Group, RTI Health Solutions, Research Triangle Park, NC, USA; 4Patient and Health Impact, Health Economics and Outcomes Research, Pfizer Inc, Collegeville, PA, USA; 5Altoona Center for Clinical Research, Duncansville, PA, USA; 6Department of Rheumatology, Centro Paulista De Investigação Clinica, São Paulo, Brazil; 7Patient-Centered Outcomes Assessment Group, RTI Health Solutions, Manchester, UK; 8Xeljanz, Rheumatology, Inflammation & Immunology Medical Affairs, Pfizer Inc, New York, NY, USA; 9Medical Affairs, International Developed Markets, Inflammation & Immunology, Pfizer Inc, Ballerup, Denmark; 10Medical Affairs Latin-America, Pfizer Inc, New York, NY, USA; 11Statistical Research and Data Science Center, Pfizer Inc, Groton, CT, USA; 12Global Medical Affairs, Pfizer Inc, Montreal, QC, CanadaCorrespondence: Peter C TaylorBotnar Research Centre, University of Oxford, Windmill Road, Headington, Oxford OX3 7LD, UKTel +441865 227323Email peter.taylor@kennedy.ox.ac.ukPurpose: Current knowledge of the reasons for patients’ preference for rheumatoid arthritis (RA) treatment modes is limited. This study was designed to identify preferences for four treatment modes, and to obtain in-depth information on the reasons for these preferences.Patients and Methods: In this multi-national, cross-sectional, qualitative study, in-depth interviews were conducted with adult patients with RA in the United States, France, Germany, Italy, Spain, Switzerland, the United Kingdom, and Brazil. Patients’ strength of preference was evaluated using a 100-point allocation task (0– 100; 100=strongest) across four treatment modes: oral, self-injection, clinic-injection, and infusion. Qualitative descriptive analysis methods were used to identify, characterize, and summarize patterns found in the interview data relating to reasons for these preferences.Results: 100 patients were interviewed (female, 75.0%; mean age, 53.9 years; mean 11.6 years since diagnosis). Among the four treatment modes, oral administration was allocated the highest mean (standard deviation) preference points (47.3 [33.1]) and was ranked first choice by the greatest percentage of patients (57.0%), followed by self-injection (29.7 [27.7]; 29.0%), infusion (15.4 [24.6]; 16.0%), and clinic-injection (7.5 [14.1]; 2.0%). Overall, 56.0% of patients had a “strong” first-choice preference (ie, point allocation ≥ 70); most of these patients chose oral (62.5%) vs self-injection (23.2%), infusion (10.7%), or clinic-injection (3.6%). Speed and/or ease of administration were the most commonly reported reasons for patients choosing oral (52.6%) or self-injection (55.2%). The most common reasons for patients not choosing oral or self-injection were not wanting to take another pill (37.2%) and avoiding pain due to needles (46.5%), respectively.Conclusion: These data report factors important to patients regarding preferences for RA treatment modes. Patients may benefit from discussions with their healthcare professionals and/or patient support groups, regarding RA treatment modes, to facilitate shared decision-making.Keywords: drug administration, patient perspective, qualitative research, surveys

S Sam Lim,1 Alan J Kivitz,2 Doug McKinnell,3 M Edward Pierson,4 Faye S O’Brien4 1Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA, USA; 2Altoona Center for Clinical Research, Altoona, PA, USA; 3Deloitte Life Sciences Advisory, Basel, Switzerland; 4Clinical Operations, Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA Purpose: We elicited patient experiences from clinical trial simulations to aid in future trial development and to improve patient recruitment and retention.Patients and methods: Two simulations of draft Phase II and Phase III anifrolumab studies for systemic lupus erythematosus (SLE)/lupus nephritis (LN) were performed involving African-American patients from Grady Hospital, an indigent care hospital in Atlanta, GA, USA, and white patients from Altoona Arthritis and Osteoporosis Center in Altoona, PA, USA. The clinical trial simulation included an informed consent procedure, a mock screening visit, a mock dosing visit, and a debriefing period for patients and staff. Patients and staff were interviewed to obtain sentiments and perceptions related to the simulated visits.Results: The Atlanta study involved 6 African-American patients (5 female) aged 27–60 years with moderate to severe SLE/LN. The Altoona study involved 12 white females aged 32–75 years with mild to moderate SLE/LN. Patient experiences had an impact on four patient-centric care domains: 1) information, communication, and education; 2) responsiveness to needs; 3) access to care; and 4) coordination of care; and continuity and transition. Patients in both studies desired background material, knowledgeable staff, family and friend support, personal results, comfortable settings, shorter wait times, and greater scheduling flexibility. Compared with the Altoona study patients, Atlanta study patients reported greater preferences for information from the Internet, need for strong community and online support, difficulties in discussing SLE, emphasis on transportation and child care help during the visits, and concerns related to financial matters; and they placed greater importance on time commitment, understanding of potential personal benefit, trust, and confidentiality of patient data as factors for participation. Using these results, we present recommendations to improve study procedures to increase retention, recruitment, and compliance for clinical trials.Conclusion: Insights from these two studies can be applied to the development and implementation of future clinical trials to improve patient recruitment, retention, compliance, and advocacy. Keywords: systemic lupus erythematosus, lupus nephritis, clinical trial simulation, patient recruitment, patient retention

ObjectiveTo assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA).DesignSubjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up.Results61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO).ConclusionSM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. CLINICALTRIALS.Gov registrationNCT02095548.

OBJECTIVE: Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. METHODS: One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. RESULTS: The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. CONCLUSION: Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the efficacy of the cyclooxygenase-2 selective inhibitor celecoxib in treating patients with psoriatic arthritis (PsA) in flare. METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study compared the efficacy and safety of celecoxib 400 mg (n=201) or celecoxib 200 mg (n=213) once daily (qd) with placebo (n=194) in treating the signs and symptoms of PsA in flare. The primary efficacy measure was the number of patients responding to treatment according to the American College of Rheumatology Responders Index 20% (ACR-20) at week 12. Efficacy and safety were assessed for all randomized patients who received at least 1 dose of study medication. RESULTS: At the week-12 primary endpoint, approximately 50% of patients in each treatment group were responders according to the ACR-20 criteria, and no statistically significant treatment differences between treatment groups were observed. However, at week 2, the ACR-20 response rates for the celecoxib 400 mg (49%) and 200 mg (39%) groups were significantly higher than for the placebo group (28%) (P<0.001 and P=0.016, respectively). Within the celecoxib 400 mg group, ACR-20 response rates were similar at weeks 2, 6 (46%), and 12 (49%). In contrast, in the celecoxib 200 mg and placebo treatment groups, ACR-20 response rates increased 7 and 16%, respectively, from week 2 to week 6, and remained relatively unchanged from week 6 to week 12. There were no statistically significant differences in ACR-20 response rates between the celecoxib 400 mg and 200 mg groups at any time point. Treatment with celecoxib 200 and 400 mg qd was statistically superior to placebo treatment at weeks 2 and 6 for Patient's Assessment of Arthritis Pain. Both doses of celecoxib were well tolerated. CONCLUSIONS: Celecoxib 400 mg and 200 mg qd were efficacious and well tolerated in treating the signs and symptoms of PsA in flare after 2 weeks of treatment. However, although the clinical effects of celecoxib 400 mg and 200 mg qd were observed for 12 weeks, there was a high placebo response at these time points, and there were no differences relative to placebo treatment at week 12.Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Etanercept has been shown to improve the articular and cutaneous manifestations of psoriatic arthritis (PsA). In this study, we further evaluated the safety, efficacy, and effect on radiographic progression of etanercept in patients with PsA. METHODS: Patients with PsA (n = 205) were randomized to receive placebo or 25 mg etanercept subcutaneously twice weekly for 24 weeks. Patients continued to receive blind-labeled therapy in a maintenance phase until all had completed the 24-week phase, then could receive open-label etanercept in a 48-week extension. Efficacy and safety were evaluated at 4, 12, and 24 weeks and at 12-week intervals thereafter. Radiographs of the hands and wrists were assessed at baseline and 24 weeks, at entry to the open-label phase, and after 48 weeks in the study. RESULTS: Etanercept significantly reduced the signs and symptoms of PsA and psoriasis. At 12 weeks, 59% of etanercept patients met the American College of Rheumatology 20% improvement criteria for joint response, compared with 15% of placebo patients (P < 0.0001), and results were sustained at 24 and 48 weeks. At 24 weeks, 23% of etanercept patients eligible for psoriasis evaluation achieved at least 75% improvement in the Psoriasis Area and Severity Index, compared with 3% of placebo patients (P = 0.001). Radiographic disease progression was inhibited in the etanercept group at 12 months; the mean annualized rate of change in the modified total Sharp score was -0.03 unit, compared with +1.00 unit in the placebo group (P = 0.0001). Etanercept was well tolerated. CONCLUSION: Etanercept reduced joint symptoms, improved psoriatic lesions, inhibited radiographic progression, and was well tolerated in patients with PsA. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee. DESIGN: A 6-week, randomized, parallel-group, double-blind, placebo-controlled study. SETTING: One hundred thirteen outpatient sites in the United States. PARTICIPANTS: A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months). INTERVENTIONS: Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks. MEASUREMENTS: The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment. RESULTS: The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P=.018) or placebo (26.7%; P<.001 vs rofecoxib or nabumetone). Median time to first report of a good or excellent PGART response was significantly shorter in patients treated with rofecoxib (2 days) than with nabumetone (4 days, P=.002) and placebo (>5 days, P<.001) (nabumetone vs placebo; P=.007). The safety profiles of rofecoxib and nabumetone were generally similar, including gastrointestinal, hypertensive, and renal adverse events. CONCLUSION: Rofecoxib 12.5 mg daily demonstrated better efficacy over 6 weeks of treatment and quicker onset of OA efficacy over the first 6 days than nabumetone 1,000 mg daily. Both therapies were generally well tolerated. [ABSTRACT FROM AUTHOR]

Context: In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition.Objective: To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis.Design: Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998.Setting: Seventy-nine clinical sites in the United States and Canada.Patients: A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study.Interventions: Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231).Main Outcome Measures: Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups.Results: All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31 % for naproxen.Conclusion: In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical response at week 52 in patients with ankylosing spondylitis (AS) who received secukinumab 300 vs 150 mg after inadequate response to 150 mg at week 16., Methods: ASLeap (NCT03350815) was a randomized, double-blind, parallel-group, multicentre, phase 4 trial. After 16 weeks of open-label secukinumab 150 mg (Treatment Period 1), patients who did not achieve inactive disease (Ankylosing Spondylitis Disease Activity Score [ASDAS] <1.3) at both Weeks 12 and 16 were considered to have an inadequate response and were randomized 1:1 to receive secukinumab 300 or 150 mg every 4 weeks until week 52 (Treatment Period 2). The primary efficacy variable was achievement of ASDAS <1.3 at week 52 using week 16 as baseline. Safety was evaluated by the incidence of treatment-emergent adverse events through week 52., Results: Of 322 patients treated with secukinumab in Treatment Period 1, 207 (64.3%) had inadequate response. Similar proportions of patients with inadequate response randomized to secukinumab 300 mg (n = 101) and 150 mg (n = 105) in Treatment Period 2 completed the study (83.8% and 84.3%, respectively). At week 52, 8.8% and 6.7% of patients receiving secukinumab 300 and 150 mg, respectively, achieved ASDAS <1.3. The incidence of treatment-emergent adverse events was similar in both groups through week 52. No new safety signals were observed., Conclusion: Patients with AS who did not achieve ASDAS <1.3 after receiving secukinumab 150 mg for 16 weeks experienced similar clinical response and safety through week 52 regardless of dose escalation., Trial Registration: ClinicalTrials.gov, NCT03350815., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA)., Methods: Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons., Results: Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m 2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05)., Conclusions: In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300 mg than 150 mg., (© 2024. The Author(s).)

Objectives: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase., Methods: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety., Results: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only., Conclusions: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase., Clinical Trial Registration: NCT03905512., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To evaluate the long-term safety and efficacy of sarilumab with/without conventional synthetic (cs)DMARDs in RA., Methods: The analyses evaluated two open-label extensions (OLEs): EXTEND and MONARCH OLE, which included patients from six randomized trials. Patients received sarilumab 200 mg once every 2 weeks (q2w) for at least 264 weeks up to 516 weeks (EXTEND: Sarilumab Monotherapy and Sarilumab + csDMARD groups) or for 276 weeks (MONARCH OLE: Continuation and Switch groups). Primary endpoints included safety, immunogenicity and changes in laboratory parameters. Secondary endpoints included clinical signs and symptoms along with health-related quality-of-life (HRQOL) questionnaires., Results: The Sarilumab Monotherapy (n = 111), Continuation (n = 165) and Switch (n = 155) groups received sarilumab monotherapy, while the Sarilumab + csDMARD group (n = 1910) received sarilumab in combination with csDMARDs. Incidence of one or more treatment-emergent adverse events was 126 (Sarilumab Monotherapy group), 169 (Sarilumab + csDMARD group), 159 (Continuation group) and 159 (Switch group) events/100 patient-years. Neutropenia was the most common adverse event. Neutropenia was not associated with an increased incidence of infections. Most neutropenia cases normalized on-treatment. Adverse events of special interests, such as malignancies, major adverse cardiovascular events, venous thromboembolism and gastrointestinal perforations, were rare. Immunogenicity was low and not associated with hypersensitivity reactions or discontinuations due to lack or loss of efficacy. Improvements in clinical signs and symptoms and HRQOL, observed during the initial blinded trials, were maintained throughout the OLE assessment period., Conclusions: Long-term sarilumab treatment with/without csDMARDs in patients with RA revealed no new safety findings. Efficacy and HRQOL were maintained or further increased over the open-label assessment period., Trial Registration: EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652; MONARCH OLE, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02332590, NCT02332590., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020., Methods: The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX., Results: In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients., Conclusions: Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Introduction: This exploratory analysis of FINCH 1 (NCT02889796) examined filgotinib (FIL) efficacy and safety in a subgroup of patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX; MTX-IR) who had four poor prognostic factors (PPFs)., Methods: Patients with MTX-IR received placebo up to week (W)24 or FIL200 mg, FIL100 mg, or adalimumab up to W52; all received MTX. Efficacy and safety data were stratified by four PPFs versus fewer than four PPFs: seropositivity, high-sensitivity C-reactive protein (CRP) ≥ 6 mg/L, Disease Activity Score in 28 joints with CRP > 5.1, and erosions on X-rays., Results: At baseline, 687/1755 patients had four PPFs. At W12, whether with four PPFs or fewer than four PPFs, response rates on all American College of Rheumatology (ACR) measures were significantly greater with FIL200 and FIL100 versus placebo. At W52, FIL200 ACR20/50/70 response rates remained at least numerically higher versus adalimumab in both subgroups. At W52, FIL200 reduced modified total Sharp score (mTSS) change versus adalimumab in patients with four or fewer than four PPFs., Conclusions: In high-risk (four PPFs) patients with MTX-IR RA, FIL200 and FIL100 showed similar reductions in disease activity versus placebo at W12 as in patients with fewer than four PPFs. mTSS in patients receiving FIL200 changed little from W24 to W52, while that in patients receiving FIL100 progressed comparably to patients who received adalimumab. Tolerability was comparable across treatment arms and subgroups., (© 2022. The Author(s).)

Objective: To assess the long-term safety, tolerability, and efficacy of bimekizumab in patients with active ankylosing spondylitis (AS)., Methods: Patients with active AS who completed the dose-ranging, 48-week BE AGILE randomized controlled trial were eligible to participate in an open-label extension (OLE) study, in which patients received 160 mg of bimekizumab every 4 weeks. We present the safety and efficacy results through 156 weeks. Missing efficacy data were imputed using nonresponder imputation analysis for binary outcomes and multiple imputation for continuous outcomes., Results: From weeks 0-156, 280 of 303 patients (exposure-adjusted incidence rate 141.0 per 100 patient-years) experienced ≥1 treatment-emergent adverse event; the most frequent adverse events were nasopharyngitis (8.1 per 100 patient-years) and upper respiratory tract infection (5.0 per 100 patient-years). Additionally, 67 of 303 patients (9.8 per 100 patient-years) had mild to moderate localized fungal infections (28 of 303 patients had Candida infections [3.7 per 100 patient-years] and 23 of 303 patients had oral candidiasis [3.0 per 100 patient-years]), 10 patients had serious infections (1.3 per 100 patient-years), and no cases of active tuberculosis were reported. Active inflammatory bowel disease (1.1 per 100 patient-years), anterior uveitis (0.7 per 100 patient-years), and adjudicated major adverse cardiovascular events (0.3 per 100 patient-years) were infrequent. The efficacy of bimekizumab treatment demonstrated at week 48 was sustained in the OLE study. At week 156, nonresponder imputation analysis showed that 53.7% of patients (72.6% of observed cases) met the Assessment of SpondyloArthritis international Society criteria for 40% improvement and 28.0% of patients (37.9% of observed cases) achieved partial remission; Ankylosing Spondylitis Disease Activity Scores were reduced from baseline (mean ± SEM 3.9 ± 0.1) to week 48 (2.1 ± 0.1) and week 156 (1.9 ± 0.1) (multiple imputation). Patients showed sustained improvements in pain, fatigue, physical function, and health-related quality of life., Conclusion: The safety profile of bimekizumab was found to be consistent with previously demonstrated findings, and no new safety signals were identified. The efficacy of bimekizumab in patients with AS was sustained through 3 years of treatment., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To assess the safety and biological activity of rozibafusp alfa, a first-in-class bispecific antibody-peptide conjugate targeting inducible costimulator ligand (ICOSL) and B cell activating factor (BAFF), in patients with rheumatoid arthritis (RA)., Methods: This phase 1b, double-blind, placebo-controlled, multiple ascending dose study included 34 patients (18-75 years; 82.4% female) with active RA (Disease Activity Score of 28 joints-C-reactive protein [DAS28-CRP] >2.6, on stable methotrexate) randomized 3:1 to receive rozibafusp alfa (n = 26, in four ascending dose cohorts of 70, 140, 210, and 420 mg) or a placebo (n = 8) subcutaneously once every 2 weeks for 10 weeks (six total doses), with 24 weeks of follow-up. The primary end point was the incidence of treatment-emergent adverse events (TEAEs). Additional assessments included serum pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and RA disease activity measures (DAS28-CRP, Patient Global Assessment of Disease, and Physician Global Assessment of Disease)., Results: TEAEs occurred in 96.2% and 87.5% of patients receiving rozibafusp alfa and the placebo, respectively; most were mild or moderate in severity. Two (7.7%) patients treated with rozibafusp alfa reported serious TEAEs; none were considered treatment related. Multiple doses of rozibafusp alfa showed nonlinear PK (mean t 1/2  = 4.6-9.5 days) and dose-related, reversible PD (>90% ICOSL receptor occupancy in 210- and 420-mg cohorts; reduction in naïve B cells and increase in memory B cells in all cohorts). Five (20%) patients developed anti-rozibafusp alfa antibodies, with no apparent impact on safety. RA disease activity showed greater numerical improvement from baseline with rozibafusp alfa versus the placebo in the 210- and 420-mg cohorts., Conclusion: Multiple ascending doses of rozibafusp alfa were well tolerated, with PK and PD reflecting dual ICOSL and BAFF blockade. Findings support further clinical evaluation of rozibafusp alfa in autoimmune disease., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: The objective of this work was to assess the efficacy and safety of risankizumab in psoriatic arthritis (PsA) over 76 weeks., Methods: In this double-blind, dose-ranging phase 2 study, adults with active PsA were randomized 2:2:2:1:2 to risankizumab 150 mg at weeks 0, 4, 8, 12, and 16 (arm 1), 150 mg at weeks 0, 4, and 16 (arm 2), 150 mg at weeks 0 and 12 (arm 3), 75 mg at week 0 (arm 4), or placebo (arm 5). Patients completing week 24 could receive risankizumab 150 mg in a 52-week open-label extension study. Efficacy assessments included American College of Rheumatology (ACR) responses, Psoriasis Area Severity Index (PASI) responses, minimal disease activity (MDA), and 28-joint Disease Activity Score based on C-reactive protein (DAS28[CRP])., Results: Of 185 randomized patients, 173 (93.5%) completed week 16 and 145 (78.4%) entered the open-label extension. Significantly more patients in each risankizumab arm achieved ACR20 at week 16 versus placebo (primary endpoint: pooled arms 1 + 2 [59.5%] versus placebo [35.7%]; treatment difference [90% CI] 24.0 [9.3, 38.7]; P = 0.007). Similarly, significantly more patients in most risankizumab arms achieved ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) versus placebo at week 16. These benefits of risankizumab were maintained long term. Treatment-emergent adverse events were comparable across treatment arms. Risankizumab 150 mg was well tolerated over 76 weeks., Conclusions: Risankizumab improved joint and skin symptoms versus placebo in patients with active PsA over 16 weeks; improvements were sustained long term. Risankizumab was well tolerated over the long term with no new safety findings., Trial Registration Numbers: NCT02719171 and NCT02986373., (© 2022. The Author(s).)

Objective: This pooled analysis of 3 randomized, placebo-controlled trials (16-24 week treatment and 8-24 week follow-up) assessed safety of subcutaneous tanezumab (2.5-10 mg every 8 weeks) in 1,840 patients with hip or knee osteoarthritis., Methods: Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation (APS) were prospectively assessed in 3 trials. Joint safety events (primary osteonecrosis, rapidly progressive osteoarthritis [RPOA], subchondral insufficiency fracture, and pathologic fracture; adjudicated by an independent expert committee) and TEAEs potentially associated with sympathetic neuropathy were prospectively assessed in 2 trials., Results: During the treatment period, overall TEAE rates were 51.7% for placebo and 39.5-54.8% for tanezumab 2.5-10 mg; treatment discontinuation rates were 2.0% for placebo and 0-1.3% for tanezumab. Rates of composite joint safety events (predominantly RPOA type 1) over the treatment plus follow-up period were 0% for placebo and 0.5-3.2% for tanezumab 2.5-5 mg (5 mg was statistically greater than placebo); total joint replacement rates with tanezumab (5.9-7.0%) were not significantly different from placebo (4.5%). Rates of TEAEs of APS (predominantly paresthesia and hypoesthesia) were 2.2% for placebo and 3.2-12.8% for tanezumab 2.5-10 mg. Rates of TEAEs potentially associated with sympathetic neuropathy (predominantly bradycardia and orthostatic hypotension) were 0.8% for placebo and 0.5-2.8% for tanezumab 2.5-5 mg (exposure-adjusted rates were not significantly different from placebo)., Conclusion: Tanezumab was generally well tolerated. TEAEs of APS (mostly mild and transient) and joint safety events were infrequent but more common with tanezumab than placebo. A tanezumab dose of 2.5 mg demonstrated a more favorable safety profile than higher doses., (© 2021 Pfizer Inc. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA)., Methods: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16., Results: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p = 0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment., Conclusions: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA., Trial Registration Number: NCT03881059., Competing Interests: Competing interests: PJM: research grants: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma and UCB; consulting and/or speaker fees: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN Pharma and UCB. AAD: consulting and/or advisory boards: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB; research grants: AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer and UCB. DvdH: consulting fees: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB Pharma; Director: Imaging Rheumatology. FB: research grants: Pfizer, Janssen, Chugai, Celgene and Roche; consultancies/speaker fees: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche, Chugai, Bristol Myers Squibb and UCB Pharma. AJK: shareholder: Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences and Novartis; paid consultant: AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research and Gilead Sciences; speakers bureau: Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie. JN: research grants to foundation: AbbVie, Amgen, Eli Lilly, Genentech, Novartis, UCB, Pfizer, Gilead and Bristol Myers Squibb. SS, MN, SB: employees and shareholders of Bristol Myers Squibb. JK: employee of Bristol Myers Squibb at time of the study conduct., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Apremilast monotherapy was evaluated up to 5 years in PALACE 4 (fourth PsA Long-term Assessment of Clinical Efficacy study) DMARD-naïve patients with PsA., Methods: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice a day. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data., Results: A total of 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported conventional synthetic DMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign and symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0. Over 50% of patients achieved a HAQ Disability Index minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term., Conclusions: Apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated., Trial Registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423., (© 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: Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX)., Methods: Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX., Results: In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients., Conclusions: Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

Objective: Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA)., Methods: This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters., Results: Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week., Conclusion: Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week., Trial Registration: ClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes., (© 2021. The Author(s).)

Background: The molecular signature response classifier (MSRC) is a blood-based precision medicine test that predicts nonresponders to tumor necrosis factor-ɑ inhibitors (TNFi) in rheumatoid arthritis (RA) so that patients with a molecular signature of non-response to TNFi can be directed to a treatment with an alternative mechanism of action., Research Design and Methods: This study evaluated decision choice and treatment outcomes resulting from MSRC-informed treatment selection within a real-world cohort., Results: Therapy selection by providers was informed by MSRC results for 73.5% (277/377) of patients. When MSRC results were not incorporated into decision-making, 62.0% (62/100) of providers reported deviating from test recommendations due to insurance-related restrictions. The 24-week ACR50 responses in patients prescribed a therapy in alignment with MSRC results were 39.6%. Patients with a molecular signature of non-response had significantly improved responses to non-TNFi therapies compared with TNFi therapies (ACR50 34.8% vs 10.3%, p-value = 0.05). This indicates that predicted non-responders to TNFi therapies are not nonresponders to other classes of RA targeted therapy. Significant changes were also observed for CDAI, ACR20, ACR70, and for responses at 12 weeks., Conclusions: Adoption of the MSRC into patient care could fundamentally shift treatment paradigms in RA, resulting in substantial improvements in real-world treatment outcomes.

Introduction: Despite of higher disease burden, lower efficacy to biologics has been reported in female compared to male patients with ankylosing spondylitis (AS). The aim of this study was to evaluate the efficacy and safety of secukinumab by sex in patients with active AS from five phase 3 studies (MEASURE 1-5) through 52 weeks., Methods: Baseline demographics, disease characteristics and efficacy outcomes at Weeks 16 and 52 were summarized for males versus females. Baseline predictor analysis used multivariable logistic regression for binary outcome measures or generalized linear model for continuous outcome measures to assess the impact of sex as one of the independent variables on selected efficacy outcomes at Week 52., Results: Overall, 1031 males and 396 females were included in this analysis. Smoking status, hs-CRP, prior exposure to TNF inhibitors, BASMI occiput-to-wall and tragus-to-wall distance (cm) were higher in males, whereas MASES was higher in females. Efficacy outcomes i.e., ASAS40 responses and BASDAI change from baseline at Weeks 16 and 52 were generally comparable between males and females. Response rates were found to be significantly higher in male patients when compared with female patients only for ASDAS-CRP inactive disease (ID) at Week 52., Conclusion: Comparable efficacy and safety outcomes were observed between male and female patients with active AS treated with secukinumab over 52 weeks. Further, sex was not an independent predictor of treatment response to secukinumab as assessed by ASAS40 responder rates and BASDAI change from baseline; association of ASDAS-CRP ID responder rates with sex warrants further exploration., Trial Registration: ClinicalTrials.gov; NCT01358175, NCT01649375, NCT02008916, NCT02159053, and NCT02896127., (© 2021. The Author(s).)

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis., Methods: For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete., Findings: Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794·6 days [SD 329·2] in long-term extension study, 879·0 days [396·6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48·8 years (SD 11·8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0·1 patients with events [95% CI 0·0-0·3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1·7 (1·2-2·5) for herpes zoster (non-serious and serious); 1·0 (0·6-1·6) for serious infections; 0·4 (0·1-0·8) for opportunistic infections; 0·7 (0·4-1·2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0·9 (0·5-1·5) for NMSC; 0·2 (0·1-0·6) for major adverse cardiovascular events; 0·1 (0·0-0·3) for pulmonary embolism; and 0·4 (0·1-0·8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36., Interpretation: This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies., Funding: Pfizer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: To study the efficacy and safety of fasinumab in moderate-to-severe, chronic low back pain (CLBP)., Methods: In this phase II/III, double-blind, placebo-controlled study, patients with CLBP aged ≥35 years with inadequate pain relief/intolerance to acetaminophen, non-steroidal anti-inflammatory drugs and opioids were randomised to fasinumab 6 or 9 mg subcutaneous every 4 weeks (Q4W), 9 mg intravenous every 8 weeks (Q8W) or placebo. Primary endpoint was change from baseline to week 16 in average daily low back pain intensity (LBPI) numeric rating score. Key secondary efficacy variables included Roland-Morris Disability Questionnaire (RMDQ) and Patient Global Assessment (PGA). The results are based on a modified intent-to-treat analysis of 563/800 planned patients when enrolment was stopped early given emerging signals of joint risk in other osteoarthritis (OA) studies at doses being tested here., Results: Significant placebo-adjusted LBPI reductions at week 16 were observed for fasinumab 9 mg Q4W and Q8W (least squares mean (standard error) -0.7 (0.3); both nominal p<0.05), but not 6 mg (-0.3 (0.3); p=0.39). RMDQ and PGA improvements to week 16 were greatest for fasinumab 9 mg intravenous. Numerically greater efficacy occurred in patients with, versus those without, peripheral OA (pOA) over 16 weeks. Treatment-emergent adverse events (AEs) occurred in 274/418 (65.6%) patients in the combined fasinumab groups and 94/140 (67.1%) placebo patients. Joint AEs, mostly rapid progressive OA type 1, were more frequent in the combined fasinumab groups (19 events in 16 patients (3.8%) vs 1 event in 1 patient (0.7%) for placebo); all except one occurred in pOA patients., Conclusions: Fasinumab highest doses, but not lower dose, improved both CLBP pain and function. Most joint AEs occurred in pOA patients, consistent with earlier findings in symptomatic OA. Further study is needed of patients with CLBP with and without pOA to determine optimal benefit-risk., Competing Interests: Competing interests: PD, SJD, CAE, HG, GPG, NS, DMW and GDY are employees of Regeneron Pharmaceuticals. JG reports consulting fees from Pfizer and participation in other activities with Regeneron Pharmaceuticals outside the submitted work. AJK reports participation in other activities with Altoona Center for Clinical Research, PC, during the conduct of the study; and other activities from AbbVie, Celgene, Horizon, Janssen, Merck, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron Pharmaceuticals, SUN Pharma Advanced Research, Boehringer Ingelheim, Flexion, Amgen and Gilead, outside the submitted work. NS reports grants from Regeneron Pharmaceuticals during the conduct of this study; and personal fees from Regeneron Pharmaceuticals and Orthofix, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To report the primary (1-year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA)., Methods: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non-loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open-label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non-US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)-naive patients. Safety analyses included all patients who received ≥1 dose of study treatment., Results: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open-label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi-naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported., Conclusion: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal., Methods: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5-20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov (NCT01976364) and is complete., Findings: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI -0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [-0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy)., Interpretation: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety., Funding: Pfizer Inc., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: The PrismRA ® test identifies rheumatoid arthritis (RA) patients who are unlikely to respond to anti-tumor necrosis factor (anti-TNF) therapies. This study evaluated the clinical and financial outcomes of incorporating PrismRA into routine clinical care of RA patients., Methods: A decision-analytic model was created to evaluate clinical and economic outcomes in the 12-month period following first biologic treatment. Two treatment strategies were compared: (1) observed clinical decision-making based on a 175-patient cohort receiving an anti-TNF therapy as their first biologic after failure of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and (2) modeled clinical decision-making of the same population using PrismRA results to inform first-line biologic treatment choice. Modeled costs include biologic drug pharmacy, non-biologic pharmacy, and total medical costs. The odds of inadequate response to anti-TNF therapies and various components of patient care were calculated based on PrismRA results., Results: Identifying predicted inadequate responders to anti-TNF therapies resulted in a modeled 38% increase in ACR50 response to first-line biologic therapies. The fraction of patients who achieved an ACR50 response to any therapy (TNFi and others) within the 12-month period was 33% higher in the PrismRA-stratified population than in the unstratified population (59 vs. 44%, respectively). When therapy prescriptions were modeled according to PrismRA results, cost savings were modeled for all financial variables: overall costs (4% decreased total, 19% decreased on ineffective treatments), total biologic drug pharmacy (4% total, 23% ineffective), non-biologic pharmacy (2% total, 19% ineffective), and medical costs (6% total, 19% ineffective). Female sex was the clinical metric that showed the greatest association with inadequate response to anti-TNF therapies (odds ratio 2.42, 95% confidence interval 1.20, 4.88)., Conclusions: If PrismRA is implemented into routine clinical care as modeled, predicting which RA patients will have an inadequate response to anti-TNF therapies could save > $7 million in overall ineffective healthcare costs per 1000 patients tested and increase targeted DMARD response rates in RA.

Abstract: This randomized, double-blind, phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5 or 10 mg every 8 weeks), or oral tramadol prolonged-release (100-300 mg/day). Primary endpoint was change in low back pain intensity (LBPI) at week 16 for tanezumab vs placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire at week 16, and change in LBPI at week 2 for tanezumab vs placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10 mg met the primary endpoint by significantly improving LBPI at week 16 vs placebo; least squares (LS) mean (95% CI) difference = -0.40 (-0.76 to -0.04; P = 0.0281). Tanezumab 10 mg significantly improved all key secondary endpoints. Tanezumab 5 mg did not meet the primary endpoint (LS mean [95% CI] treatment difference vs placebo = -0.30 [-0.66 to 0.07; P = 0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5 mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97 to 1.70; P = 0.0846]), and 46.3% in the tanezumab 10 mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09 to 1.91; P = 0.0101]). Prespecified joint safety events were more frequent with tanezumab 10 mg (2.6%) than tanezumab 5 mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10 mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10 mg significantly improved pain and function vs placebo in patients with difficult-to-treat chronic low back pain. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Introduction: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). We report the interim safety, tolerability, and efficacy of tofacitinib in PsA patients in OPAL Balance, a 3-year, open-label, long-term extension study (data cut-off: August 2017; database not locked, data may change)., Methods: Eligible patients from two phase (P) 3 (P3) tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered OPAL Balance ≤ 3 months after completing the P3 study or discontinuing for reasons other than study-drug-related adverse events (AEs). Patients received open-label tofacitinib 5 mg twice daily (BID), with adjustments to 10 mg BID permitted post-month (M) 1. Certain concomitant conventional synthetic disease-modifying antirheumatic drugs were allowed. Primary endpoints were incidence/severity of AEs and laboratory abnormalities, and changes from baseline in laboratory parameters (reported up to M36 and M30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30., Results: A total of 686 patients were treated; at data cut-off, 68.2% remained in the study. Mean (range) treatment duration was 641 (1-1032) days; total treatment duration was 1153.2 patient-years. By M36, 79.6, 13.8, and 8.6% of patients reported AEs, serious AEs, and discontinuations due to AEs, respectively. Five deaths occurred; one within the risk period (incidence rate [IR; patients with events/100 patient-years] 0.1). IRs for AEs of special interest were: all (non-serious and serious) herpes zoster, 1.7; serious infections, 0.9; opportunistic infections, 0.3 (all disseminated/multi-dermatomal herpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0; major adverse cardiovascular events, 0.3; pulmonary embolisms, 0.1; and arterial thromboembolisms, 0.4. No patients had deep vein thrombosis. Alanine aminotransferase and aspartate aminotransferase levels were elevated  ≥  3-fold the upper limit of normal in 4.0 and 2.2% of patients, respectively. Changes in laboratory parameters were generally stable over time, although lymphocyte counts decreased slightly. Efficacy was maintained through M30., Conclusions: In this interim analysis of OPAL Balance, tofacitinib safety and efficacy in patients with PsA appeared to be consistent with those of the P3 studies. Efficacy was maintained over time., Trial Registration: ClinicalTrials.gov identifier: NCT01976364.

Background: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin 17A, has shown significant and sustained improvement in the signs and symptoms of ankylosing spondylitis over 3 years in the MEASURE 2 study. We report the 5-year (end-of-study) results of subcutaneous secukinumab 150 mg in the MEASURE 2 study., Methods: MEASURE 2 was a phase 3, double-blind, randomised, placebo-controlled, study done in 13 countries and 53 centres. Patients with ankylosing spondylitis who were 18 years of age or older and fulfilled the modified New York criteria were randomly assigned to receive secukinumab (150 mg or 75 mg) or placebo subcutaneously at baseline and weeks 1, 2, and 3, and then every 4 weeks from week 4. At week 16, patients initially given placebo were randomly assigned again (placebo switchers) to receive secukinumab 150 mg or 75 mg. Efficacy results are reported for patients initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at week 16. An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning week 140. We assessed efficacy endpoints at week 260 (5 years), including Assessment of Spondyloarthritis International Society (ASAS) 20 and ASAS 40, inactive disease according to ankylosing spondylitis disease activity score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI50, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index, Short Form-36 Physical Component Summary, and ASAS partial remission. Analyses were stratified by anti-tumour necrosis factor (TNF) status (anti-TNF-naive and anti-TNF inadequate response). The safety analysis included all patients who received one dose or more of secukinumab. We report data as observed without accounting for missing data. The MEASURE 2 study was registered with ClinicalTrials.gov, NCT01649375., Findings: 219 patients were randomly assigned during the trial and 150 (68%) completed 5 years of treatment, including 82 (77%) of 106 patients in the secukinumab 150 mg group and 68 (65%) of 105 in the secukinumab 75 mg group. Efficacy analysis in the secukinumab 150 mg group included 53 patients who completed the study and one additional patient who was assessed in the treatment period weeks 212-260, but did not complete the study. 134 (61%) of 219 patients were anti-TNF-naive and 85 (39%) were anti-TNF inadequate responders. ASAS responses at 5 years with secukinumab 150 mg were 36 (67%) of 54 patients (ASA20) and 27 (50%) patients (ASAS40). Sustained improvement was observed across other efficacy endpoints with secukinumab 150 mg at 5 years. At 5 years, the proportion of patients achieving efficacy endpoints of BASDAI 50 response was 53% (44/83); ASAS 5/6 response was 51% (42/83); ASDAS-CRP inactive disease was 21% (17/81); and ASAS partial remission was 25% (21/83). Exposure-adjusted incidence rates with any secukinumab dose for selected adverse events were 1·0 per 100 patient-years (95% CI 0·4-1·9) for Candida infections, 0·5 (0·1-1·2) for Crohn's disease, 0·4 (0·1-1·1) for ulcerative colitis, 0·6 (0·2-1·4) for major adverse cardiovascular events, 0·5 (0·1-1·2) for uveitis, and 0·6 (0·2-1·4) for malignant or unspecified tumours., Interpretation: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in patients with ankylosing spondylitis after 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports., Funding: Novartis Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Our objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade ® ) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study., Methods: In this phase III, double-blind, active-controlled study, patients with moderate-to-severe active RA were initially randomized to PF-SZ-IFX or IFX-EU, each with methotrexate (treatment period [TP] 1; N = 650). At week 30, patients receiving PF-SZ-IFX continued PF-SZ-IFX; patients receiving IFX-EU were re-randomized to continue IFX-EU or switch to PF-SZ-IFX (TP2; n = 566). From weeks 54 to 78, all patients received open-label treatment with PF-SZ-IFX (TP3; n = 505). Efficacy, safety, and immunogenicity data were analyzed during TP3., Results: Efficacy was sustained and comparable across groups at week 78, with American College of Rheumatology criteria for ≥ 20% clinical improvement response rates of 75.9% (biosimilar group), 77.8% (week 30 switch group), and 68.3% (week 54 switch group). The incidence of treatment-emergent adverse events was 28.9%, 29.4%, and 30.2%, respectively. The proportion of patients who were antidrug antibody (ADA) positive and neutralizing antibody positive (as a percentage of ADA-positive patients) was stable and comparable between groups., Conclusions: Results to week 78 continue to support the efficacy, safety, and immunogenicity of PF-SZ-IFX in patients with moderate-to-severe active RA. There were no clinically meaningful differences between groups, independent of a single treatment transition from IFX-EU to PF-SZ-IFX at week 30 or week 54., Trial Registration Number: NCT02222493.

Background: Secukinumab is an interleukin-17A inhibitor used in the treatment of patients with active psoriatic arthritis. In the phase 3 FUTURE 2 trial, secukinumab showed sustained improvement in clinical outcomes over 2 years. Because scarce data exists on the long-term treatment with biological therapies in patients with psoriatic arthritis, we aimed to assess and describe the 5-year (end-of-study) results on the efficacy and safety of secukinumab 300 mg and 150 mg doses, as well as dose escalation, from the FUTURE 2 study., Methods: FUTURE 2 is a phase 3, double-blind, placebo-controlled study done at 76 centres in Asia, Australia, Canada, Europe, and the USA. Patients with active psoriatic arthritis aged 18 years or older were randomly assigned to either secukinumab (300 mg, 150 mg, or 75 mg) or placebo weekly from baseline and then every 4 weeks from week 4. Secukinumab dose was escalated from 150 mg to 300 mg and from 75 mg to 150 mg or 300 mg starting at week 128, if active signs of disease were observed in patients, on the basis of the physician's assessment, with the escalated dose maintained thereafter. We assessed key efficacy endpoints at week 260 (5 years) for secukinumab 300 mg and 150 mg, including American College of Rheumatology (ACR) and Psoriasis Area and Severity Index (PASI) responses. The safety analysis included all patients who received one or more doses of secukinumab. We report data as observed. This study is registered with ClinicalTrials.gov, NCT01752634., Findings: At randomisation, 65% of patients were naive to tumour necrosis factor inhibitors and 47% were receiving concomitant methotrexate. Of 397 patients randomly assigned in FUTURE 2, 248 (62%) completed 5 years of treatment, including 64 (64%) of 100 patients in the original secukinumab 300 mg group, 65 (65%) of 100 in the 150 mg group, 59 (60%) of 99 in the 75 mg group, and 60 (61%) of 98 in the placebo group. Overall, 127 (52%) of 242 patients required dose escalation during the study. ACR responses at 5 years were 71 (74%; ACR20), 50 (52%; ACR50), and 31 (32%; ACR70) of 96 evaluable patients in the secukinumab 300 mg group, and 67 (70%; ACR20), 41 (43%; ACR50), and 28 (29%; ACR70) of 96 evaluable patients in the secukinumab 150 mg group. From 24 to 32 weeks and from 48 to 84 weeks after dose escalation from secukinumab 150 mg to 300 mg, the proportions of ACR and PASI non-responders decreased, whereas the proportions of ACR and PASI responders increased. During the entire treatment period, the most frequent treatment-emergent serious adverse event was serious infection (exposure-adjusted incidence 1·7, 95% CI 1·1-2·5; n=25) in the any secukinumab group. No new or unexpected safety signals were reported., Interpretation: Secukinumab 300 mg and 150 mg provided sustained improvement in the signs and symptoms of psoriatic arthritis, with consistent safety over 5 years. This study supports the clinical benefit and safety of long-term treatment with secukinumab in patients with psoriatic arthritis., Funding: Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Spebrutinib (CC-292) is an orally administered, covalent, small-molecule inhibitor of Bruton's tyrosine kinase (BTK), part of the B-cell and Fc receptor signaling pathways. This study evaluated spebrutinib pharmacology and mechanism of action over a 4-week treatment period in patients with active rheumatoid arthritis (RA)., Methods: Primary human B cells, T cells, natural killer cells, macrophages, dendritic cells, basophils, and osteoclasts were treated with spebrutinib in vitro. Clinical pharmacodynamics were studied in 47 patients with active RA on background methotrexate therapy randomized to oral spebrutinib 375 mg/day or placebo., Results: In vitro, spebrutinib inhibited B-cell proliferation more potently than T-cell proliferation and reduced both lymphoid and myeloid cytokine production and degranulation, as well as osteoclastogenesis. Clinical efficacy trended higher in spebrutinib-treated RA patients, with 41.7% (10/24) achieving ≥ 20% improvement in ACR response criteria (ACR20) versus 21.7% (5/23) of placebo patients at week 4 (P = 0.25). Treatment-emergent adverse events were comparable between treatment groups. In spebrutinib-treated patients, median BTK occupancy in peripheral blood was 83%, and significant increases in total CD19 + and mature-naive CD27 - CD38 - IgD + B cells and decreases in transitional CD27 - CD38 + B cells were observed. Spebrutinib significantly reduced serum chemokines chemokine ligand 13 (CXCL13), macrophage inflammatory protein-1β (MIP-1β), and the bone resorption biomarker carboxy-terminal collagen cross-linking telopeptide (CTX-I) (P < 0.05). Clinical response to spebrutinib was associated with lower increases in CD19 + B cells and greater decreases in CXCL13 and MIP-1β from baseline to week 4. High CD19 + B cells and low CTX-I at baseline were associated with better spebrutinib clinical response., Conclusions: Spebrutinib inhibited various leukocyte responses in vitro, including those of B cells and osteoclasts. In this small study in RA patients, spebrutinib was well tolerated, showed a downward trend for symptoms, significantly modulated B-cell populations, and reduced markers of chemotaxis and osteoclast activity., Trial Registration: NCT01975610.

Background: Primary Sjögren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjögren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjögren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjögren's syndrome., Methods: This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic classification criteria for primary Sjögren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by clinical disease activity, as measured by the change in European League Against Rheumatism Sjögren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029., Findings: Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5·21 points (95% CI 0·96-9·46; one-sided p=0·0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo., Interpretation: To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjögren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjögren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further., Funding: Novartis Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study., Methods: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease., Results: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed., Conclusion: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports., (© 2020 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)