ACR20 Response Rates Research Articles

Ivarmacitinib, a selective Janus kinase 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis and inadequate response to conventional synthetic DMARDs: results from a phase III randomised clinical trial

ObjectiveTo assess the efficacy/safety of ivarmacitinib, a selective Janus kinase (JAK) 1 inhibitor, in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic disease-modifying...

Efficacy of the cardiac glycoside digoxin as an adjunct to csDMARDs in rheumatoid arthritis patients: a randomized, double-blind, placebo-controlled trial.

Inflammation and angiogenesis are two main mechanisms that act as mutual pathways in rheumatoid arthritis (RA). This work aimed to study the efficacy of digoxin as an adjunct therapy to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in active RA patients. In a randomized, double-blinded, placebo-controlled study, 60 adult patients with active RA received a placebo or digoxin (0.25mg every other day) combined with csDMARDs for 6months. The American College of Rheumatology (ACR) 20, ACR50, and ACR70 response rates and the disease activity score (DAS28) were assessed for patients. Flow cytometric analysis of Th17 cells and serum concentrations of IL-17A, IL-23, HIF-1α, and VEGF were evaluated before and after three and 6months of therapy. Following three and 6months of digoxin therapy combined with csDMARDs, significant differences were detected in laboratory and clinical parameters relative to the control group. After 6months, 83.3% of patients in the digoxin group, compared to 56.7% in the control group, achieved an ACR20 response (p = 0.024). The digoxin group had a significantly higher percentage of patients who achieved DAS28 remission after 6months (p = 0.024). Notable improvements in the Health Assessment Questionnaire Disability Index, ACR50, and ACR70 were detected in the digoxin group. Digoxin was well tolerated and exerted profound immunomodulatory and anti-inflammatory effects in RA patients, and may also exhibit anti-angiogenic properties, indicating that it might be an effective adjunct to csDMARDs in treating RA. clinicaltrials.gov, identifier NCT04834557.

Efficacy and safety of filgotinib in patients with moderately active rheumatoid arthritis and an inadequate response to methotrexate.

Clinical trials restricted to moderately active RA are limited. Filgotinib is approved for treating moderate to severe active RA. This post hoc analysis assessed efficacy and safety of filgotinib in moderately active RA. In FINCH 1, patients with active moderate to severe RA and inadequate response to methotrexate received filgotinib 200 mg or 100 mg (FIL200/FIL100) once daily, adalimumab 40 mg every 2 weeks, or placebo, all with methotrexate (n = 1,755). This subgroup analysis was conducted in patients with a moderate baseline Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP; >3.2 to ≤ 5.1; n = 425 [24.2%]). A higher proportion of patients achieved DAS28-CRP <2.6, Clinical Disease Activity Index (CDAI) remission (≤2.8), low disease activity (LDA) (DAS28-CRP ≤3.2 or CDAI ≤10), and American College of Rheumatology (ACR20/50/70) responses with FIL200 and FIL100 vs placebo at Weeks 12 and 24. Week 12 ACR20 response rates (primary end point) were 77.9%, 67.8%, and 43.8%, respectively. ∼75% of patients achieved DAS28-CRP LDA by week 24 with either filgotinib dose. FIL200 and FIL100 elicited greater improvements in patient-reported outcomes than placebo. The efficacy of filgotinib, maintained through week 52, was comparable to that of adalimumab. Frequency of adverse events (AEs) was similar with filgotinib and adalimumab. Infections were the most common AEs; incidence rates were 40-53% in active treatment groups. In this subpopulation with moderately active RA, the efficacy and safety of filgotinib were similar to those in the overall FINCH 1 population (patients with active moderate to severe RA). NCT02889796.

Efficacy and safety of sarilumab in patients with rheumatoid arthritis stratified by age (

This study aimed to assess the efficacy and safety of sarilumab in older patients with active rheumatoid arthritis (RA). This is a post-hoc analysis of KAKEHASI (NCT02293902) and HARUKA (NCT02373202) trials with stratification by age (<65 and ≥65 years). Patients with moderately-to-severely active RA were treated with sarilumab in combination with methotrexate (MTX) or with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy. The primary endpoints in KAKEHASI and HARUKA trials were the American College of Rheumatology 20% improvement criteria (ACR20) responses at Week 24 and safety, respectively. Secondary endpoints were other RA disease activity measures, including Clinical Disease Activity Index (CDAI). Approximately 20% of patients were aged ≥65 years in treatment arms across both trials, except the sarilumab+csDMARDs arm (40%, 12/30). ACR20 response rates were similar between age groups across sarilumab treatment arms and similar results were obtained for CDAI scores. Safety profiles were similar between age groups except for a higher incidence of serious adverse events in patients aged ≥65 years in the sarilumab+MTX arm. In Japanese patients with RA enrolled in phase 3 studies for sarilumab, no clear difference in efficacy or safety was observed between patients aged <65 and ≥65 years.

Efficacy of risankizumab across subgroups in patients with active psoriatic arthritis: a post hoc integrated analysis of the phase 3 KEEPsAKE 1 and KEEPsAKE 2 randomized controlled trials

In the KEEPsAKE 1 (NCT03675308) and KEEPsAKE 2 (NCT03671148) phase 3 trials, risankizumab demonstrated greater efficacy compared with placebo in patients with active psoriatic arthritis (PsA). This post hoc integrated analysis evaluated achieving the following efficacy outcomes at weeks 24 and 52 by baseline demographics and clinical characteristics: ≥20%/50%/70% improvement in American College of Rheumatology response criteria (ACR20/50/70), ≥90% improvement in Psoriasis Area and Severity Index, minimal disease activity status, Low Disease Activity status (Disease Activity in Psoriatic Arthritis), and minimal clinically important difference in pain. Baseline demographics and clinical characteristics were similar between risankizumab (n = 707) and placebo (n = 700) groups. Numerically higher ACR20 response rates at week 24 (primary endpoint) were observed among the risankizumab (46.3%−60.1%) vs. placebo (15.5%−36.2%) cohorts, regardless of subgroups. At week 52, consistent proportions of patients randomized to risankizumab achieved ACR20 (48.6%−75.8%) while those initially randomized to placebo and switched to risankizumab experienced an improvement from week 24 (43.7%−63.9%), regardless of subgroups. Similar trends were observed for other efficacy measures assessing rigorous skin response criteria, composite measures of overall disease activity, and PsA-related symptoms. Risankizumab treatment was efficacious among patients with varying demographic and psoriatic disease characteristics through 52 weeks.

Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes

BackgroundTo describe the evidence of methotrexate (MTX) initiation strategies in patients with rheumatoid arthritis (RA) and, in the case of non-responders, analyse the efficacy and safety of route and dose optimisation.MethodsWe conducted a comprehensive scoping review of randomised controlled trials according to PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. PubMed, EMBASE, and Cochrane were searched without language restriction, and hand searches of relevant articles were examined.ResultsWe identified 1,367 potentially eligible studies, of which 12 were selected based on the titles and abstracts and then on the full-length articles. In naïve-MTX patients, a linear dose-response relationship for starting dose was found between 5 mg/m2/week (7.5–10 mg/week) and 10 mg/m2/week (15–22 mg/week), without toxicity correlation. A higher initial dose of MTX (25 mg vs. 15 mg) was more effective, resulting in fewer dose increases due to ineffectiveness and more dose reductions due to higher remission rates. There was also a trend towards increased gastrointestinal toxicity. Comparing different routes of administration of MTX, subcutaneous MTX showed a statistically higher ACR20 response (85%) in comparison with oral MTX (77%) (p < 0.05). The clinical efficacy and safety of accelerated and conventional start MTX regimens were comparable between 7.5 and 15 mg with a 2,5 mg dose increase every two weeks. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response and sustained remission rate than other strategies. In MTX non-responders, optimisation to SC MTX was associated with improvements in ACR20 and ACR50 rates with similar toxicity between groups. In the early RA patients subgroup, SC MTX showed higher ACR20 response rates than oral MTX, and intensive oral methods have a much higher sustained remission rate, shorter mean time to remission, and better clinical disease activity measures than conventional treatments.ConclusionsHigher starting doses of MTX and initial subcutaneous MTX made better performance in improving the ACR20 response, although the clinical effectiveness and safety of other MTX start regimens are comparable. This scoping review provides evidence in support of optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment in RA patients has failed.

Comparative Effectiveness of Bimekizumab in Psoriatic Arthritis: A Model-Based Meta-Analysis of American College of Rheumatology Response Criteria.

A model-based meta-analysis (MBMA) was conducted to compare the efficacy of bimekizumab with other psoriatic arthritis (PsA) treatment regimens using ≥ 20%/50%/70% improvements in American College of Rheumatology (ACR) criteria (ACR20/50/70) for patients with PsA. Forty-nine trials of 16 drugs were identified in the literature, comprising 21,340 patients. Trial-level covariates, including prior biologic use, concomitant methotrexate use, time since diagnosis, trial completion year, and active comparator were considered for exploratory models. The final model was selected using leave-one-out cross-validation (LOO CV) to assess predictive performance based on prespecified criteria. LOO CV was conducted for 15 trials; the final model demonstrated that 91.5% (952/1,040) of the observed treatment differences, and 96.1% of the observed ACR20/50/70 response rates were within the 95% prediction interval (PI). Median ACR50 response rates (95% PI) at week 16 in biologic-naïve patients were predicted to be 44% (40-49%) for bimekizumab 160 mg, among the highest of all treatments analyzed. Response rates for secukinumab 150 mg and risankizumab 150 mg were 28% (25-32%) and 27% (24-31%), respectively. The MBMA was also used to predict the probability of success (PoS) of potential head-to-head trials using ACR50 response as the end point with varying sample sizes: vs. secukinumab 150 mg, the PoS for bimekizumab 160 mg was 62% (N = 200) and 90% (N = 400). Versus risankizumab 150 mg, the PoS for bimekizumab 160 mg was 68% (N = 200) and 94% (N = 400). In summary, a predictive MBMA described ACR20/50/70 outcomes in PsA, allowing accurate and precise treatment comparisons and robust PoS calculations.

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial

Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. Bio-Thera Solutions and Biogen.

Sex-related differences in patient characteristics, and efficacy and safety of advanced therapies in randomised clinical trials in psoriatic arthritis: a systematic literature review and meta-analysis

Sex-related differences in clinical manifestations and disease outcomes exist in psoriatic arthritis, however, there is limited information on sex-related differences in randomised controlled trials of psoriatic arthritis. We aimed to compare patient characteristics and efficacy and safety of advanced therapies (including biological and targeted synthetic therapies) between male and female patients with psoriatic arthritis participating in randomised controlled trials. In this systematic review and meta-analysis, we searched Medline, Embase, and Central databases, and conference abstract archives, from their inception to June 10, 2022, for randomised controlled trials that assessed the efficacy of advanced therapies in psoriatic arthritis. Two reviewers extracted information on participants' characteristics and rates of American College of Rheumatology (ACR) 20 and ACR50 response and minimal disease activity (MDA) by sex. Random-effects models were used to calculate pooled effects of ACR20, ACR50, and MDA in male versus female patients by drug class. We included 54 trials (11 514 [50·9%] of 22 621 participants were female and 11 107 [49·1%] were male). Sex-disaggregated results were reported in a minority of studies (nine [17%] of 54 reported baseline characteristics by sex, 18 [33%] reported efficacy by sex, and two [4%] reported safety endpoints by sex). At baseline, male patients had lower baseline tender joint count (mean difference -3·01 [95% CI -3·83 to -2·18], health assessment questionnaire scores (-0·28 [-0·33 to -0·24]), pain scores (-4·58 [-6·86 to -2·30]), patient global assessment (-3·22 [-5·27 to -1·17]), and physician global assessment (-1·34 [-2·08 to -0·08]) than did female patients. Male patients had higher baseline psoriasis area and severity index scores (mean difference 1·95 [95% CI 0·78 to 3·11]) and C-reactive protein concentrations (2·57 [0·40 to 4·74]) than did female patients. ACR20 response by sex varied across drug classes, with higher rates in males than females with interleukin (IL)-17 inhibitors (odds ratio [OR] 1·70 [95% CI 1·38-2·11]), IL-23 inhibitor (1·46 [1·20-1·78]), IL-12 and IL-23 inhibitor (2·67 [1·39-5·09]), and tumour necrosis factor (TNF) inhibitors (1·55 [1·11-2·18]), but no difference with JAK and TYK2 inhibitors (1·10 [0·87-1·38]). Similarly, ACR50 response rates were higher in male patients versus female patients in all drug classes, with exception of JAK and TYK2 inhibitors (TNF inhibitors, OR 2·17 [95% CI 1·62-2·90]; IL-17 inhibitors, 1·93 [1·56-2·38]; IL-23 inhibitor, 1·71 [1·25-2·34]; IL-12 and 23 inhibitor, 2·43 [1·14-5·20]; and JAK and TYK2 inhibitors, 1·09 [0·73-1·62]). Male patients were more likely to reach MDA with most drug classes, including IL-17 inhibitors (OR 1·99 [95% CI 1·50-2·63]), IL-23 inhibitors (1·79 [1·29-2·50]), TNF inhibitors (2·62 [1·54-4·44]), and JAK and TYK2 inhibitors (1·77 [1·15-2·73]). Risk of bias was low for most studies. Biological sex of patients with psoriatic arthritis influences their response to advanced therapies, but the effect varies by drug class. Selective reporting might have influenced these results. Future trials should report baseline characteristics and endpoint results by sex. Canadian Rheumatology Association.

Efficacy and Safety of Tyrosine Kinase 2/Janus Kinase 1 Inhibitor Brepocitinib for Active Psoriatic Arthritis: A Phase IIb Randomized Controlled Trial.

Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor in development for treatment of several immunological diseases. Efficacy and safety of oral brepocitinib were assessed in participants with moderately-to-severely active psoriatic arthritis (PsA) for up to 52 weeks. This placebo-controlled, dose-ranging, phase IIb study randomized participants to brepocitinib 10 mg once daily (QD), 30 mg QD, 60 mg QD, or placebo, advancing to brepocitinib 30 or 60 mg QD at week 16. The primary endpoint was American College of Rheumatology (ACR)20 response rate at week 16. Secondary endpoints included response rates of ACR50/70, 75% and 90% improvement in Psoriasis Area and Severity Index (PASI75/90), and Minimal Disease Activity (MDA) at weeks 16 and 52. Adverse events (AEs) were monitored throughout. Overall, 218 participants were randomized and treated. At week 16, brepocitinib 30 and 60 mg QD groups had significantly greater ACR20 response rates (66.7% [P = 0.0197] and 74.6% [P = 0.0006], respectively), versus placebo (43.3%) and significantly higher ACR50/70, PASI75/90, and MDA response rates. Response rates were maintained or improved through week 52. AEs were mostly mild/moderate; serious AEs (15) in 12 (5.5%) participants included infections in 6 (2.8%) in brepocitinib 30 and 60 mg QD groups. No major adverse cardiovascular events or deaths occurred. Brepocitinib 30 and 60 mg QD were superior to placebo at reducing signs and symptoms of PsA. Brepocitinib was generally well tolerated throughout the 52-week study with a safety profile consistent with other brepocitinib clinical trials.

Comparison of the efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis: anetwork meta-analysis of randomized controlled trials.

This study aimed to assess the relative efficacy and safety of olokizumab at different dosages in patients with active rheumatoid arthritis (RA). We performed aBayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab administered intravenously to RA patients at 64 mg/kg every 2 or 4weeks (Q2 or Q4W). Five RCTs comprising 2609patients met the inclusion criteria. Both olokizumab Q2 and Q4W treatments achieved asignificant American College of Rheumatology 20% response (ACR20) compared with the placebo (odds ratio [OR] 3.21, 95% credible interval [CrI] 2.53-4.09; OR 3.05, 95% CrI 2.43-3.86). However, olokizumab Q2W was associated with the most favorable surface using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that olokizumab Q2W had the highest probability of being considered the best treatment option for achieving the ACR20 response rate, followed by olokizumab Q4W, adalimumab, and placebo. The ACR50 and 70response rates showed asimilar distribution pattern to the ACR20 response rate, except that olokizumab Q4W had ahigher-ranking probability than olokizumab Q2W for ACR50. The SUCRA rating likelihood of adverse events (AEs) and withdrawal due to AEs showed that aplacebo was likely to be the best intervention. Both olokizumab Q2 and Q4W were efficacious and well-tolerated treatments for active RA.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study

Objectives To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs).Methods In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP)) &lt;3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed.Results In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p&lt;0.01 for both comparisons). Achievement of DAS28 (CRP) &lt;3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patientreported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group.Conclusions Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNFi-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor.

The effect of guselkumab on inhibiting radiographic progression in patients with active psoriatic arthritis: study protocol for APEX, a Phase 3b, multicenter, randomized, double-blind, placebo-controlled trial

BackgroundGuselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression.MethodsPatients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively.DiscussionDISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04882098. Registered on 11 May 2021.

Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Relative effectiveness and safety of interleukin-6 and Janus kinase inhibitors versus adalimumab in patients with rheumatoid arthritis: a network meta-analysis.

The relative efficacy and tolerability of interleukin‑6 (IL-6) and Janus kinase (JAK) inhibitor therapies were compared with those of adalimumab in patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate (MTX). We performed aBayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of IL‑6 inhibitors, JAK inhibitors, and adalimumab in patients with RA and inadequate responses to MTX. Seven RCTs, which included 4428patients (1066 for IL‑6 inhibitors and 3362 for JAK inhibitors), met the inclusion criteria. IL‑6 inhibitors were placed at the top left of the league table diagonal (Odds ratio, OR 1.43; 95% CrI 1.12-1.82) as these were correlated with the most beneficial ACR20 response rate. Conversely, the placebo was placed at the bottom right of the league table diagonal as it was correlated with the least desirable effects. IL‑6 and JAK inhibitors produced asubstantial ACR20 response relative to adalimumab. The surface under the cumulative ranking curve (SUCRA) revealed that treatment with IL‑6 inhibitors had the greatest ability to reach the ACR20 response rate (SUCRA = 0.826), followed by treatment with JAK inhibitors (SUCRA = 0.672) and adalimumab (SUCRA = 0.001). The ACR50 and ACR70 rates displayed patterns similar to the ACR20 response rate. With regard to serious adverse events (SAEs), the SUCRA rating likelihood showed that adalimumab was likely to be the best intervention, followed by JAK and IL‑6 inhibitors. Both IL‑6 and JAK inhibitors are more effective than adalimumab and have similar effects in patients with RA and an inadequate response to MTX. Adalimumab is likely to be safer than JAK and IL‑6 inhibitors.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study

ObjectivesTo assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor...

P204 Filgotinib demonstrates clinical efficacy in rheumatoid arthritis independent of smoking status: a post-hoc subgroup analysis of three Phase 3 clinical trials

Abstract Background/Aims Filgotinib (FIL), an oral janus kinase 1 (JAK1) inhibitor, has been evaluated in three Phase 3 clinical studies (FINCH 1-3) in adults with moderately-to-severely active rheumatoid arthritis (RA). Patients with RA who currently smoke (a predisposing factor for RA) have been reported to be less likely to respond to anti-TNFα treatment and more likely to discontinue or switch treatment. However, the impact of smoking on filgotinib efficacy in RA patients is unknown. A post-hoc sub-group analysis of FINCH patient (pt) data was performed in order to identify associations with smoking status. Methods Data from 3452 RA pts participating in the FINCH3 (MTX-naïve; NCT02886728), FINCH1 (MTX-IR; NCT02889796), or FINCH2 (bDMARD-IR; NCT02873936) clinical trials were included for analysis of clinical response at weeks 12 and 24. Logistic regression models were fitted to assess the effects of smoking status on categorical clinical endpoints (ACR20/50/70, CDAI ≤ 10, DAS28[CRP] ≤3.2 or &amp;lt; 2.6). Adjustments were made for covariates selected based on previously published work1 and listed in the Figure caption. No adjustments of p-values were made for multiple testing. Results In the MTX-IR population (FINCH1), current (12% of enrolled patients) and former (13%) smokers treated with ADA+MTX had a lower week 12 ACR50 response rate compared to non-smokers (25% and 28% vs. 39%, nominal p = 0.095 and p = 0.21, respectively). In contrast, the ACR 50 response at week 12 in FIL+MTX treated pts showed no association with smoking status. Former smokers had higher response rates than non-smokers in the MTX-IR (FINCH1) and MTX naïve (FINCH3) populations. Direct comparison between non-smoking pts in the MTX-IR FIL200+MTX-arm and ADA+MTX-arm showed no significant difference in ACR50 response rate (46% vs. 39%, p = 0.08). In contrast, former and current smokers showed significantly better week 12 ACR50 response rates under FIL200+MTX treatment compared to ADA+MTX patients (former smoker: 62% vs. 28%, p = 0.0017, current smoker: 50% vs. 25%, p = 0.016. Similar observations were made at both weeks 12 and 24 for other clinical endpoints, including ACR20/50/70, DAS28(CRP) &amp;lt; 2.6 or ≤ 3.2, and CDAI ≤ 10 response criteria. Conclusion This exploratory analysis showed that current and former smokers with RA who received ADA+MTX trended toward a lower response rate compared to non-smokers. In contrast, FIL+MTX was found to be similarly efficacious independent of smoking status within both the MTX-IR and MTX-naïve RA populations. Current or former smokers were more likely to respond to FIL200mg + MTX compared to ADA+MTX across a range of endpoints. Given the small number of current and former smokers enrolled in these studies, further studies of the efficacy of JAK inhibitors and the mechanism of reduced response to anti-TNFs in patients with a history of smoking are warranted. Disclosure P. Emery: Consultancies; Pfizer, Abbvie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Lilly, Gilead, Samsung, Celltrion. Grants/research support; Abbvie, BMS, Samsung. B. Downie: Shareholder/stock ownership; Shareholder of: Gilead, Employee of: Gilead. J. Liu: Shareholder/stock ownership; Shareholder of: Gilead, Roche, Employee of: Gilead. R.E. Hawtin: Shareholder/stock ownership; Shareholder of: Gilead, Employee of: Gilead. J.R. Curtis: Consultancies; Abbvie, Amgen, BMS, Corrona, Eli Lilly, Jannsen, Myriad, Pfizer, Regeneron, Roche, and UCB. Grants/research support; Abbvie, Amgen, BMS, Corrona, Eli Lilly, Jannsen, Myriad, Pfizer, Regeneron, Roche, and UCB. G.R. Burmester: Consultancies; Abbvie, Gilead, Lilly, Pfizer. Member of speakers’ bureau; Abbvie, Gilead, Lilly, Pfizer.

Comparison of Adalimumab to Other Targeted Therapies in Rheumatoid Arthritis: Results from Systematic Literature Review and Meta-Analysis.

Few studies compared adalimumab to other targeted therapies in head-to-head randomized clinical trials (RCTs) for rheumatoid arthritis (RA), but multiple comparisons are not available. This Bayesian Network Meta-Analysis evaluated which targeted therapy is more likely to achieve ACR50 response with good safety at 24 weeks of treatment in RA. A systematic literature review was conducted for head-to-head phase 3 RCTs that compared adalimumab to other targeted therapies in combination with methotrexate (MTX) or as monotherapy to treat RA patients, and searched through MEDLINE, EMBASE, Cochrane Library and Clinicaltrial.gov. The outcomes of interest were ACR50 response and withdrawals due to adverse events at 24 weeks. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a random effect model. Sixteen studies were included in the analysis. The most favorable SUCRA for the ACR50 response rate at 24 weeks of treatment in combination with MTX was ranked by upadacitinib, followed by baricitinib, tofacitinib and filgotinib. As monotherapy, the highest probability was ranked by tocilizumab followed by sarilumab. No significant differences in safety profile among treatment options were found. Jak-inhibitors in combination with MTX and interleukin-6 antagonism as monotherapy showed the highest probability to achieve ACR50 response after 24 weeks of treatment. None of assessed targeted therapies were associated to risk of withdrawal due to adverse events. Key messages: Direct and indirect comparison between adalimumab and other targeted therapies demonstrated some differences in terms of efficacy that may help to drive RA treatment. Jak-inhibitors and interleukine-6 antagonists ranked as first in the probability to achieve ACR50 response after 24 weeks of treatment in combination with methotrexate or monotherapy, respectively.

Population Pharmacokinetic and Exposure–Response Model Simulations: Predicted Exposure and Efficacy for Maintenance Doses of Intravenous Golimumab Every 6 or 8 Weeks in Patients With Moderately to Severely Active Rheumatoid Arthritis

Golimumab is approved to treat moderate-to-severe active rheumatoid arthritis when given intravenously at weeks 0 and 4, then every 8 weeks (Q8W) with concomitant methotrexate. These analyses assessed whether a shorter dosing interval could ameliorate diminished efficacy experienced by a small proportion of patients toward the end of the dosing interval. Population pharmacokinetic and exposure-response modeling simulations were performed for intravenous golimumab 2 mg/kg at weeks 0 and 4, then Q8W or every 6 weeks (Q6W) through 1 year. A 2-compartment pharmacokinetic model with linear clearance developed based on GO-FURTHER (A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFα Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy) study data was used for pharmacokinetic simulations. A latent-variable indirect exposure-response model developed based on GO-FURTHER American College of Rheumatology (ACR) 20%/50%/70% improvement (ACR20, ACR50, and ACR70, respectively) data was used to predict clinical endpoints of ACR20/ACR50/ACR70 response rates. For Q6W and Q8W dosing, respectively, predicted median golimumab steady-state trough (Ctrough,ss) concentrations were 0.57 and 0.24 µg/mL, and Cmax at steady state values were 33.1 and 32.9µg/mL. Predicted peak median ACR20 steady-state response rates were 76.7% (Q6W) and 75.6% (Q8W). Predicted median ACR20 response rates at Ctrough,ss increased by 4.7 percentage points with Q6W (73.7%) versus Q8W (69.0%) dosing. Greater improvement in ACR20 response rates at trough time points was predicted in patients with lower golimumab trough serum concentrations. Consistent findings were observed for ACR50/ACR70 response rates. These simulations suggest that intravenous golimumab Q6W dosing increases golimumab Ctrough,ss, which may improve clinical response in the small proportion of patients with rheumatoid arthritis with waning efficacy at the end of the standard dosing interval. gov identifier: NCT00973479. Clinicaltrialsregister.eu: EudraCT 2008-006064-11.

Comparative efficacy and safety of biologic agents in patients with active rheumatoid arthritis and inadequate response to tumor necrosis factor inhibitors: A Bayesian network meta-analysis of randomized controlled trials.

This study aimed to evaluate the relative efficacy and safety of biologic agents in patients with rheumatoid arthritis (RA) who show inadequate response to tumor necrosis factor (TNF) inhibitors. A meta-analysis with the Bayesian network, combining direct and indirect randomized controlled trial (RCT) data, was conducted to examine the efficacy and safety of abatacept, rituximab, tocilizumab, sarilumab, sirukumab, and secukinumab in patients with RA who showed inadequate response to TNF inhibitors. 8 RCTs enrolling a total of 3,617 patients fulfilled the inclusion criteria. More significant American College of Rheumatology 20% (ACR20), ACR50, and ACR70 responses were obtained using therapies similar to these biologics than with placebo. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab was probably the best treatment for ACR20 response, followed by rituximab, abatacept, sarilumab, sirukumab, secukinumab 150 mg, secukinumab 75 mg, and placebo. Furthermore, identical distribution trends were observed for ACR50 response rates. In comparison, ACR70-based SUCRA rating revealed that rituximab, followed by tocilizumab, abatacept, sirukumab, secukinumab 150 mg, sarilumab, secukinumab 75 mg, and placebo might potentially result in ACR70. There was no significant difference between the number of adverse events and severe adverse events between the treatments. All biologic agents studied were effective in treating patients with TNF inhibitor-refractory RA; however, tocilizumab, rituximab, and abatacept appeared to be more efficient than sarilumab, sirukumab, and secukinumab. There were no differences between the treatments with respect to safety.