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In a phase 3 randomized trial of 1307 patients with rheumatoid arthritis receiving background methotrexate, the oral JAK1 and JAK2 inhibitor baricitinib showed superior efficacy to placebo and to the anti–tumor necrosis factor α monoclonal antibody adalimumab. Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. Progress in treatment with the use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and biologic DMARDs that target tumor necrosis factor (TNF) has made clinical remission a realistic target. 1 Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis. 2 Baricitinib, an orally available small molecule, provides reversible inhibition of JAK1 and JAK2 and has shown clinical efficacy in studies . . .

ObjectiveTo determine the comparative effectiveness of oral versus subcutaneous methotrexate (MTX) as initial therapy for patients with early rheumatoid arthritis (ERA).MethodsPatients with ERA (symptoms ≤1 year) initiating MTX therapy were included from a multicentre, prospective cohort study. We compared the effectiveness between starting with oral versus subcutaneous MTX over the first year. Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy (Disease Activity Score-28 (DAS-28), DAS-28 remission and Health Assessment Questionnaire-Disability Index (HAQ-DI)).Results666 patients were included (417 oral MTX, 249 subcutaneous MTX). Patients prescribed subcutaneous MTX were prescribed a higher dose of MTX (mean dose over first three months 22.3 mg vs 17.2 mg/week). At 1 year, 49% of patients initially treated with subcutaneous MTX had changed treatment compared with 77% treated with oral MTX. After adjusting for potential confounders, subcutaneous MTX was associated with a lower rate of treatment failure ((HR (95% CI) 0.55 (0.39 to 0.79)). Most treatment failures were due to inefficacy with no difference in failure due to toxicity. In multivariable models, subcutaneous MTX was also associated with lower average DAS-28 scores (mean difference (−0.38 (95% CI −0.64 to −0.10)) and a small difference in DAS-28 remission (OR 1.2 (95% CI 1.1 to 1.3)). There was no significant difference in sustained remission or HAQ-DI (p values 0.43 and 0.75).ConclusionsInitial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA.

ObjectivesThe similarity in retention of tumour necrosis factor inhibitors (TNFi) and tofacitinib (TOFA) was previously reported separately by the Ontario Best Practices Research Initiative and the Quebec cohort Rhumadata. However, because of small sample sizes in each registry, we aimed to confirm the findings by repeating the analysis of discontinuation of TNFi compared with TOFA, using pooled data from both these registries.DesignRetrospective cohort study.SettingPooled data from two rheumatoid arthritis (RA) registries in Canada.ParticipantsPatients with RA starting TOFA or TNFi between June 2014 and December 2019 were included. A total of 1318 patients were included TNFi (n=825) or TOFA (n=493).Outcome measuresTime to discontinuation was assessed using Kaplan-Meier survival and Cox proportional hazards regression analysis. Propensity score (PS) stratification (deciles) and PS weighting were used to estimate treatment effects.ResultsThe mean disease duration in the TNFi group was shorter (8.9 years vs 13 years, p<0.001). Prior biological use (33.9% vs 66.9%, p<0.001) and clinical disease activity index (20.0 vs 22.1, p=0.02) were lower in the TNFi group.Discontinuation was reported in 309 (37.5%) and 181 (36.7%) TNFi and TOFA patients, respectively. After covariate adjustment using PS, there was no statistically significant difference between the two groups in discontinuation due to any reason HR=0.96 (95% CI 0.78 to 1.19, p=0.74)) as well as discontinuation due to ineffectiveness only HR=1.08 (95% CI 0.81 to 1.43, p=0.61)).TNFi users were less likely to discontinue due to adverse events (AEs) (adjusted HRs: 0.46, 95% CI 0.29 to 0.74; p=0.001). Results remained consistent for firstline users.ConclusionsIn this pooled real-world data study, the discontinuation rates overall were similar. However, discontinuation due to AEs was higher in TOFA compared with TNFi users.

Objectives To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment. Methods We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008). Results The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach. Conclusion Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.

ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).MethodsThis 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.ResultsThe proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.ConclusionsFilgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Trial registration numberNCT02889796.

Objective Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction. Methods Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson’s correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression. Results A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson’s correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA ( P  < 0.001). Conclusions In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach. Clinical trial registration numbers EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results

Our objective was to identify distinct trajectories of disease activity state (DAS) and assess variation in radiographic progression, function and quality of life over the first two years of early rheumatoid arthritis (ERA). The CATCH (Canadian early ArThritis CoHort) is a prospective study recruiting ERA patients from academic and community rheumatology clinics in Canada. Sequential DAS28 scores were used to identify five mutually exclusive groups in the cohort (n = 1,586) using growth-based trajectory modeling. Distinguishing baseline sociodemographic and disease variables, treatment required, and differences in radiographic progression and quality of life measures over two years were assessed. The trajectory groups are characterized as: Group 1 (20%) initial high DAS improving rapidly to remission (REM); Group 2 (21%) initial moderate DAS improving rapidly to REM; Group 3 (30%) initial moderate DAS improving gradually to low DAS; Group 4 (19%) initial high DAS improving continuously to low DAS; and Group 5 (10%) initial high DAS improving gradually only to moderate DAS. Groups differed significantly in age, sex, race, education, employment, income and presence of comorbidities. Group 5 had persistent steroid requirements and the highest biologic therapy use. Group 2 had lower odds (OR 0.22, 95%CI 0.09 to 0.58) and Group 4 higher odds (OR 1.94, 95%CI 0.90 to 4.20) of radiographic progression compared to Group 1. Group 1 had the best improvement in physical function (Health Assessment Questionnaire 1.08 (SD 0.68) units), Physical Component Score (16.4 (SD 10.2) units), Mental Component Score (9.7 (SD 12.5) units) and fatigue (4.1 (SD 3.3) units). In conclusion, distinct disease activity state trajectories explain variable outcomes in ERA. Early prediction of disease course to tailor therapy and addressing social determinants of health could optimize outcomes.

Introduction ORAL Surveillance, a post-authorisation safety study of patients with rheumatoid arthritis (RA) enriched for cardiovascular (CV) risk, demonstrated increased risk of major adverse CV events (MACE) and malignancies (excluding non-melanoma skin cancer [NMSC]) for tofacitinib versus tumour necrosis factor inhibitors (TNFi). This analysis of a real-world Canadian observational study evaluated tofacitinib safety/effectiveness in patients meeting or not meeting CV risk criteria. Methods CANTORAL included patients with moderate-to-severe RA initiating tofacitinib (10/2017–07/2020; N  = 504) . Interim data (data-cut: 07/2021) were stratified as CV risk-enriched (CV+ ; patients ≥ 50 years with ≥ 1 additional CV risk factor) or not CV risk-enriched (CV−; ≥ 50 years without additional CV risk factors and 18–49 years with/without CV risk factors). Safety and persistence were evaluated to month (M) 36. Effectiveness outcomes to M18 included Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA)/remission (CANTORAL co-primary endpoints) and Disease Activity Score in 28 joints, C-reactive protein (DAS28-4[CRP]) < 3.2/ < 2.6. Results Overall, 272/232 patients were included in CV+ /CV− cohorts (full analysis set) (435/356 patient-years [safety analysis set]). Incidence rates (events/100 patient-years) in CV+ /CV− cohorts were 138.5/112.5 for treatment-emergent adverse events (AEs); 17.0/5.6 for serious AEs; 1.2/0.3 for deaths; 5.5/1.7 for serious infections; 1.4/1.1 for herpes zoster; 1.6/0.0 for MACE; 2.1/0.3 for malignancies (excluding NMSC); 0.7/0.6 for NMSC; 0.5/0.0 for venous thromboembolic events. Persistence was generally comparable between cohorts. In CV+ /CV− cohorts, at M6, CDAI LDA and remission rates were 51.5%/54.6% and 12.0%/19.6%; DAS28-4(CRP) < 3.2/ < 2.6 rates were 44.0%/39.3% and 31.5%/28.8%, respectively; effectiveness was generally maintained to M18. Conclusions In concordance with studies of background risk, AEs were more common in patients with CV risk enrichment, particularly those aged ≥ 65 years. Tofacitinib effectiveness/persistence were generally similar regardless of CV risk enrichment. These findings support individualised treatment benefit–risk assessment, including CV assessment/management, to optimise RA outcomes.

ObjectiveTo characterise changes in selected haematological parameters following once-daily oral baricitinib dosing.MethodsData were pooled from eight randomised clinical trials (four phase 3, three phase 2, one phase 1b) and one long-term extension. Changes in haematological parameters were evaluated up to 128 weeks (N=2387); overall safety of baricitinib was assessed up to 6 years (N=3492).ResultsMean absolute neutrophil counts decreased (−1.36×109/L) within 1 month, followed by stabilisation within the normal reference range through week 128. The incidence of serious infections was not elevated in patients with neutropenia during the 24-week placebo-controlled period. Mean lymphocyte counts increased (+0.30×109/L) within 1 month, then decreased to baseline (weeks 12–24). Mean platelet counts increased at week 2 (+51×109/L), then decreased towards baseline. Overall, mean haemoglobin concentrations decreased (−0.12 mmol/L), then returned to baseline; however, reduced baseline haemoglobin concentrations observed in the highest baseline high-sensitivity C reactive protein quartile increased over time. Permanent drug discontinuation occurred due to laboratory abnormalities related to neutrophil count in 8 (0.2%), lymphocyte counts in 6 (0.2%), platelet counts in 8 (0.2%), and haemoglobin levels in 16 (0.5%) of all baricitinib-treated patients (N=3492 with 7993 total person-years of exposure).ConclusionsModerate decreases in neutrophils were seen during baricitinib treatment; however, serious infection was uncommon in patients with neutropenia. Transient increases were observed in lymphocytes and platelets, which returned to baseline over time. Changes in haemoglobin concentration were generally small. Haematological abnormalities seldom led to drug discontinuation.