Discontinuation of tofacitinib and TNF inhibitors in patients with rheumatoid arthritis: analysis of pooled data from two registries in Canada.

OBJECTIVES: The 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. DESIGN: Retrospective cohort study. SETTING: Pooled data from two rheumatoid arthritis (RA) registries in Canada. PARTICIPANTS: Patients 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 MEASURES: Time 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. RESULTS: The 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. CONCLUSIONS: In 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.

The Proportion of Patients With Rheumatoid Arthritis Achieving ACR20/50/70; Consistent Patterns of a 60/40/20 as Demonstrated by a Systematic Review and Meta-analysis.

OBJECTIVES: We aimed to demonstrate that the proportion of rheumatoid arthritis patients achieving 20%/50%/70% improvement in American College of Rheumatology (ACR20/50/70) responses to Food and Drug Administration-approved biologic disease-modifying antirheumatic drugs (bDMARDs) after an inadequate response to methotrexate (MTX) and after failure of the first bDMARDs followed a consistent pattern. METHODS: This systematic review and meta-analysis was performed in accordance with MECIR (Methodological Expectations for Cochrane Intervention Reviews) standards. Two separate groups of randomized controlled trials were included: the first group included studies with biologic-naive patients who added bDMARD to MTX as intervention arm compared with the placebo plus MTX group. The second group included biologic-irresponsive (IR) patients who used a second bDMARD plus MTX after the first bDMARD failure compared with placebo plus MTX group. Primary outcome was defined as the proportion of rheumatoid arthritis patients achieving ACR20/50/70 responses at 24 ± 6 weeks. RESULTS: Twenty-one studies initiated between 1999 and 2017 were included: 15 studies for the biologic-naive group and 6 studies for the biologic-IR group. For the biologic-naive group, the proportions of patients achieving ACR20/50/70 were 61.4% (95% confidence interval [CI], 58.7%-64.1%), 37.8% (95% CI, 34.8%-40.8%), and 18.8% (95% CI, 16.1%-21.4%), respectively. For the biologic-IR group, proportions of patients achieving ACR20/50/70 were 48.5% (95% CI, 42.2%-54.8%), 27.3% (95% CI, 21.6%-33.0%), and 12.9% (95% CI, 11.3%-14.8%), respectively. CONCLUSION: We were able to systematically demonstrate that ACR20/50/70 responses to biologic-naive follow a consistent pattern of 60%, 40%, and 20%, respectively. We also demonstrated that the ACR20/50/70 responses to a biologic IR follow a certain pattern of 50%, 25%, and 12.5%, respectively.

Effectiveness and Safety of Tofacitinib in Canadian Patients With Rheumatoid Arthritis: Primary Results From a Prospective Observational Study.

OBJECTIVE: The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis. METHODS: Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale <20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36. RESULTS: Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESR-defined LDA and DAS28-CRP <3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP <2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patient-years) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent. CONCLUSION: Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in real-world patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

Safety and efficacy of filgotinib for Japanese patients with RA and inadequate response to MTX: FINCH 1 52-week results and FINCH 4 48-week results.

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.

Statin Use for Primary Cardiovascular Disease Prevention Is Low in Inflammatory Arthritis.

BACKGROUND: Patients with inflammatory arthritis (IA) are at high risk for atherosclerotic cardiovascular disease (ASCVD), yet management of dyslipidemia is infrequently prioritized. We applied Canadian dyslipidemia guidelines to determine how many patients with IA would be eligible for primary prevention with statins. METHODS: We conducted a cross-sectional study of patients with IA in a cardio-rheumatology clinic, with no known CVD and without statin therapy at cohort entry. We stratified patients by Framingham Risk Score (FRS) and summarized the proportion meeting guideline statin-indicated criteria. Multivariable logistic regression analyses determined the association of variables with statin indication after adjustment for age, sex, traditional ASCVD risk factors, and arthritis characteristics. RESULTS: Among 302 patients, most had rheumatoid arthritis (59%). Mean age was 58 years, and 71% were female. Overall, 50% of the cohort was eligible for statin therapy. The majority was low FRS risk category (68%), and the most frequent qualifier for statins was elevated apolipoprotein B (ApoB) levels or low-density lipoprotein cholesterol (LDL-c) levels. In the intermediate FRS group, 91% met criteria for statin therapy based on the presence of a coronary artery calcification (CAC) score > 0 or an elevated high-sensitivity C-reactive protein. Male sex, hypertension, elevated ApoB, and a CAC score > 0 were the factors most strongly associated with indication for statin therapy. CONCLUSIONS: Statin therapy is suboptimal in IA despite a significant number of patients meeting indication based on lipoprotein thresholds or CAC scores. Understanding the barriers and potential facilitators of implementing and interpreting these CVD screening tools in IA is needed.

Predictors of Influenza Vaccination in Early Rheumatoid Arthritis 2017-2021: Results From the Canadian Early Arthritis Cohort.

OBJECTIVE: Adults with rheumatoid arthritis (RA) are at a higher risk for infections, including influenza and related complications. We identified influenza vaccination coverage in adults newly diagnosed with RA and examined sociodemographic RA characteristics and attitudes associated with vaccination. METHODS: We used data from patients enrolled in the Canadian Early Arthritis Cohort between September 2017 and February 2021. At enrollment, participants reported their vaccination status in the previous year and completed the Beliefs About Medicines Questionnaire (BMQ). Clinical data were obtained from medical records. Logistic regression was used to identify predictors of vaccination in the year after RA diagnosis. RESULTS: The baseline analytic sample of 431 patients were mostly White (80%) women (67%) with a mean age of 56 (SD 14) years. Prediagnosis, influenza vaccine coverage was 38%, increasing to 46% post diagnosis in the longitudinal sample (n = 229). Participants with previous influenza vaccination (odds ratio [OR] 15.33; 95% confidence interval [CI] 6.37-36.90), on biologics or JAKs (OR 5.42; 95% CI 1.72-17.03), and with a higher change in BMQ Necessity-Concerns Differential scores (OR 1.08; 95% CI 1.02-1.15) had greater odds, whereas women (OR 0.32; 95% CI 0.14-0.71), participants with a non-White racial background (OR 0.13; 95% CI 0.04-0.51), and participants currently smoking (OR 0.09; 95% CI 0.02-0.37) had lower odds of influenza vaccine coverage. CONCLUSION: Influenza vaccination coverage in patients with early RA remains below national targets in adults living with a chronic condition. Discussing vaccine history and medication attitudes at initial clinic visits with new patients with RA may enhance vaccine acceptance and uptake.

Physician- and Patient-reported Effectiveness Are Similar for Tofacitinib and TNFi in Rheumatoid Arthritis: Data From a Rheumatoid Arthritis Registry.

OBJECTIVE: Tofacitinib (TOF) is an oral, small-molecule drug used for rheumatoid arthritis (RA) treatment and is one of several alternative treatments to tumor necrosis factor inhibitors (TNFi). We evaluated physician- and patient-reported effectiveness of TNFi compared to TOF, using real-world data from the Ontario Best Practices Research Initiative (OBRI). METHODS: Patients enrolled in the OBRI initiating TOF or TNFi between 2014 and 2019 were included. Patients were required to have physician- and patient-reported effectiveness outcome data, including Clinical Disease Activity Index (CDAI) and RA Disease Activity Index (RADAI), available at treatment initiation and 6 (± 2) months later. To deal with confounding by indication, we estimated propensity scores (PS) for covariates. RESULTS: Four hundred nineteen patients were included. Of those, 226 initiated a TNFi and 193 TOF, and had a mean (SD) disease duration of 8.0 (8.7) and 12.6 (9.6) years, respectively. In addition, the TNFi group was less likely to have prior biologic use (21.7%) compared to the TOF group (67.9%). The proportion of patients in CDAI low disease activity (LDA)/remission (REM) at 6 months was 36.7% and 33.2% in the TNFi and TOF groups, respectively. The generalized linear mixed models adjusting for PS quantile showed that there was no significant difference in CDAI LDA/REM (odds ratio [OR] 0.85, 95% CI 0.51-1.43) and RADAI coefficient (OR 0.48, 95% CI -0.18 to 1.14) between the 2 groups (ref: TOF). CONCLUSION: In patients with RA, physician- and patient-reported effectiveness are similar in the TNFi and TOF groups 6 months after treatment.

Efficacy and safety of filgotinib in combination with methotrexate in Japanese patients with active rheumatoid arthritis who have an inadequate response to methotrexate: Subpopulation analyses of 24-week data of a global phase 3 study (FINCH 1).

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.

A Bridge Too Far? Real-World Practice Patterns of Early Glucocorticoid Use in the Canadian Early Arthritis Cohort.

OBJECTIVE: To describe patterns of glucocorticoid use in a large real-world cohort with early rheumatoid arthritis (RA) and assess the impact on disease activity and treatment. METHODS: Data are from adults with new RA (≤1 year) recruited to the Canadian Early Arthritis Cohort (CATCH) and are stratified on the basis of whether a person was prescribed oral glucocorticoids within 3 months of study entry. Disease activity was compared over 24 months. Mixed-effects logistic regression was used for adjusted odds ratios (aORs) of escalation to biologics separately for 12 and 24 months, with random effects terms to account for prescribing patterns clustering by study site. RESULTS: Among 1891 persons, 30% received oral steroids. Users were older, were less often employed, and had shorter disease duration and higher disease activity. Disease activity improved over time, with early glucocorticoid users starting at higher levels of disease activity. Participants with early oral glucocorticoids were more likely to be on a biologic at 12 months (aOR = 2.4; 95% confidence interval [CI], 1.5-3.7) and 24 months (aOR = 1.9; 95% CI, 1.3-3.0). Despite Canadian clinical practice guidelines to limit corticosteroid use to short-term or 'bridge' therapy, 30% of patients who used oral glucocorticoids still used them 2 years later. CONCLUSION: Early steroids were prescribed sparingly in CATCH and were often indicative of more active baseline disease as well as the need for progression to biologics.

Efficacy and safety of tofacitinib modified-release 11 mg once daily plus methotrexate in adult patients with rheumatoid arthritis: 24-week open-label phase results from a phase 3b/4 methotrexate withdrawal non-inferiority study (ORAL Shift).

OBJECTIVES: To report the efficacy, safety and patient-reported outcome measures (PROs) of tofacitinib modified-release 11 mg once daily plus methotrexate in patients with rheumatoid arthritis (RA) from the open-label phase of Oral Rheumatoid Arthritis Trial (ORAL) Shift. METHODS: ORAL Shift was a global, 48-week, phase 3b/4 withdrawal study in patients with moderate to severe RA and an inadequate response to methotrexate. Patients received open-label tofacitinib modified-release 11 mg once daily plus methotrexate; those who achieved low disease activity (LDA; Clinical Disease Activity Index (CDAI)≤10) at week 24 were randomised to receive blinded tofacitinib 11 mg once daily plus placebo (ie, blinded methotrexate withdrawal) or continue with blinded tofacitinib 11 mg once daily plus methotrexate for another 24 weeks. Efficacy, PROs and safety from the open-label phase are reported descriptively. RESULTS: Following screening, 694 patients were enrolled and received tofacitinib plus methotrexate in the open-label phase. At week 24, 527 (84.5%) patients achieved CDAI-defined LDA. Improvements from baseline to weeks 12 and 24 were generally observed for all efficacy outcomes (including measures of disease activity, and response, LDA and remission rates) and PROs. Adverse events (AEs), serious AEs and discontinuations due to AEs were reported by 362 (52.2%), 20 (2.9%) and 41 (5.9%) patients, respectively. No deaths were reported. CONCLUSIONS: Tofacitinib modified-release 11 mg once daily plus methotrexate conferred improvements in disease activity measures, functional outcomes and PROs, with most (84.5%) patients achieving CDAI-defined LDA after 24 weeks of open-label treatment; the safety profile was generally consistent with the historic safety profile of tofacitinib.Funded by Pfizer Inc; NCT02831855.

Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study.

INTRODUCTION: To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). METHODS: Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. RESULTS: In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. CONCLUSIONS: Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial.

OBJECTIVE: To 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). METHODS: This 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. RESULTS: The 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. CONCLUSIONS: Filgotinib 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 NUMBER: NCT02889796.

Changes in selected haematological parameters associated with JAK1/JAK2 inhibition observed in patients with rheumatoid arthritis treated with baricitinib.

OBJECTIVE: To characterise changes in selected haematological parameters following once-daily oral baricitinib dosing. METHODS: Data 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). RESULTS: Mean 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). CONCLUSIONS: Moderate 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.

Radiographic progression based on baseline characteristics from TNF inhibitor biosimilar studies in patients with rheumatoid arthritis.

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.

Modified Disease Activity Score at 3 Months Is a Significant Predictor for Rapid Radiographic Progression at 12 Months Compared With Other Measures in Patients With Rheumatoid Arthritis.

OBJECTIVE: Progressive rheumatoid arthritis (RA) is responsible for joint damage causing disabilities, but there is no agreement on which disease measures best predict radiographic progression. We aimed to determine which disease activity measures, including the disease activity score, the modified disease activity score in 28 joints with C-reactive protein testing (M-DAS28-CRP), the Clinical Disease Activity Index, and the Health Assessment Questionnaire Disability Index, at baseline and 3 months best predicted rapid radiographic progression (RRP) in patients with early RA. METHODS: Data were used from PREMIER, a 2-year, multicenter, double-blind, active comparator controlled study with methotrexate (MTX)-naïve patients with RA and active disease for less than 3 years. Treatments included adalimumab plus oral MTX, adalimumab, or oral MTX. Only patients in the MTX arm were analyzed in this study. RRP was defined as a change in the modified total Sharp score of less than 3.5 at month 12. The logistic regression analysis assessed the impact of measures at baseline and 3 months on RRP at 12 months. Best cutoff points of the M-DAS28-CRP were also estimated by using area under the receiver operating characteristic curve. RESULTS: A total of 149 patients were included (female patients: n = 113 [75.8%]; positive rheumatoid factor: n = 127 [85.2%]; mean [SD] age: 52.9 [13.3] years; mean [SD] disease duration: 0.8 [0.9] year; mean [SD] M-DAS28-CRP: 6.3 [0.9]). After adjusting for potential confounders, only the M-DAS28-CRP at baseline (adjusted odds ratio [AOR] = 3.29; 95% confidence interval [CI]: 1.70-6.36) and 3 months (AOR = 2.56; 95% CI: 1.43-4.56) strongly predicted RRP at 12 months. M-DAS28-CRP of 4.5 and 2.6 at baseline and 3 months, respectively, maximized positive and negative predictive values for prediction of RRP. CONCLUSION: The M-DAS28-CRP was a stronger predictor at baseline and 3 months for RRP compared with other disease activity measures. Removing tender joint count and patient global assessment from the DAS28-CRP improves prediction of RRP.

Comprehensive Profiling of the Rheumatoid Arthritis Antibody Repertoire.

OBJECTIVE: Autoantibodies against citrullinated proteins are found in 64-89% of rheumatoid arthritis (RA) patients, with 88-99% specificity. This study was undertaken to create an unbiased, comprehensive profile of serum antibodies against the human proteome, including the citrullinome and the homocitrullinome, in RA patients, using a high-density peptide array. METHODS: Our high-density peptide array, consisting of >4.6 million peptides, contained the entire annotated human proteome. The 20,246 proteins were represented as overlapping 16-mer peptides. In addition to native peptides, citrullinated and homocitrullinated peptides were included, as substitutions for arginine and lysine, and provided a comprehensive screen against all possible epitopes. Twenty-six serum samples (from 8 controls and 18 RA patients) were profiled on the high-density peptide array. Using RA-specific epitopes, we constructed an 8-epitope diagnostic biomarker on a Gyrolab xPlore instrument with a cohort of 92 serum samples (from 29 controls and 63 RA patients). The diagnostic biomarker was further validated with an independent cohort of 181 serum samples (from 54 controls and 127 RA patients). RESULTS: In the initial cohort the diagnostic performance of the 8-epitope biomarker yielded 96.6% specificity and 92.1% sensitivity. The overall diagnostic performance in the validation cohort was 94.4% specificity and 85% sensitivity. In both cohorts, the performance of the 8-epitope diagnostic biomarker compared favorably against the Abnova cyclic citrullinated peptide 2 (CCP2) assay. Using data from the peptide array, we identified novel RA-specific epitopes and formed the basis of a new RA diagnostic assay. CONCLUSION: Comprehensive antibody profiling using a high-density peptide array not only identified novel RA-specific epitopes but also allowed us to construct a novel diagnostic biomarker that is as specific as and more sensitive than the Abnova CCP2 assay.

Toward Defining Primary and Secondary Nonresponse in Rheumatoid Arthritis Patients Treated with Anti-TNF: Results from the BioTRAC and OBRI Registries.

OBJECTIVE: Although most patients with rheumatoid arthritis (RA) respond to anti-tumor necrosis factor (anti-TNF) treatment, some present with initial nonresponse (1ry nonresponse) or lose initial responsiveness (2ry nonresponse). We compared the rate of real-world "nonresponse" to first anti-TNF as reported by treating physicians to the nonresponse rate per accepted definitions and recommended treat-to-target strategies. METHODS: Patients were included from the Biologic Treatment Registry Across Canada (BioTRAC) and Ontario Best Practices Research Initiative (OBRI) registries who were taking their first anti-TNF, with ≥ 1 followup visit. Posthoc reclassification of physician-reported nonresponse was based on prior achievement of 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) low disease activity (LDA), Clinical Disease Activity Index (CDAI) LDA, or good/moderate European League Against Rheumatism (EULAR) response, and actual time of physician-reported nonresponse. RESULTS: Among 736 BioTRAC and 640 OBRI patients, 13.7% and 18%, respectively, discontinued their anti-TNF because of physician-reported nonresponse. Based on reclassification using disease activity, 65.6% (BioTRAC) and 87.2% (OBRI) of 1ry nonresponders did not achieve DAS28-ESR LDA, 65.6%/90.7% CDAI LDA, and 46.9%/61.5% good/moderate EULAR response. Among 2ry nonresponders, 50.7%/47.8% did not achieve DAS28-ESR LDA, 37.7%/52.9% CDAI LDA, and 15.9%/19.6% good/moderate EULAR response before treatment discontinuation. Regarding actual time of nonresponse, 18.8% of BioTRAC and 60.8% of OBRI 1ry nonresponders discontinued at ≤ 6 months. In both registries, a high proportion of 2ry nonresponders discontinued their anti-TNF after 12 months (87.0% BioTRAC, 60.9% OBRI). CONCLUSION: Physician-reported 1ry nonresponse was more correlated with non-achievement of DAS28-ESR LDA or CDAI LDA, whereas 2ry nonresponse with actual time of discontinuation. Further work is needed to confirm the importance of response and type of response to the initial anti-TNF in identifying patients most likely to benefit from a second biologic agent treatment.

Treatment Strategies in Early Rheumatoid Arthritis Methotrexate Management: Results From a Prospective Cohort.

OBJECTIVE: To assess real-world practice patterns surrounding treatment initiation and adjustments over time for methotrexate (MTX) and non-MTX-based treatment strategies in early rheumatoid arthritis (RA). METHODS: We studied a multicenter, incident early RA cohort (enrolled 2007-2017 within 1 year of symptoms) who fulfilled American College of Rheumatology/European League Against Rheumatism criteria. Adult patients with RA were eligible if treatment with MTX (± other disease-modifying antirheumatic drugs [DMARDs]) was initiated within 90 days of cohort entry. We compared time until treatment change for 4 initial MTX-based therapies and time to second treatment change after the first change. The definition of treatment change included changing of route for MTX monotherapy, adding or stopping a DMARD or biologic, and changing dose/frequency of a DMARD or biologic. RESULTS: There was great variability of treatment at initiation and during therapy adjustment. In 1,484 patients with early RA, the majority initiated MTX monotherapy (oral or subcutaneous [SC]). Patients receiving SC MTX monotherapy changed treatment less (45% versus 79%) and remained on treatment longer (hazard ratio [HR] 0.52 [95% confidence interval (95% CI) 0.4-0.67]) than those receiving oral MTX monotherapy. Most therapy adjustments involved adding a DMARD or changing to a non-MTX DMARD. Those adults taking biologics and who were receiving triple therapy had a longer time without treatment change (HR 0.26 [95% CI 0.16-0.42] and HR 0.57 [95% CI 0.38-0.85], respectively). CONCLUSION: We found large variability in the way MTX-based therapies are prescribed in clinical practice. Our findings support the use of SC MTX monotherapy or MTX combination as initial therapy. For subsequent treatment after initial MTX-based therapy, those patients initiating either biologics or triple therapy had a longer time to treatment change than oral MTX monotherapy.

Disease activity measures at baseline predict structural damage progression: data from the randomized, controlled AMPLE and AVERT trials.

OBJECTIVE: Data from two double-blind, randomized, Phase III studies were analysed to investigate the ability of Routine Assessment of Patient Index Data 3, DAS28 (CRP), modified (M)-DAS28 (CRP) and Simplified or Clinical Disease Activity Indices to predict structural damage progression in RA. METHODS: This post hoc analysis included data from the 2-year Abatacept vs adaliMumab comParison in bioLogic-naïvE RA subjects with background MTX (AMPLE) trial in biologic-naïve patients with active RA (<5 years) and an inadequate response to MTX, and the 12-month treatment period of the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial in MTX-naïve patients with early RA (⩽2 years) and poor prognostic indicators. Adjusted logistic regression analysis assessed the relationship between baseline disease activity and structural damage progression (defined as change from baseline greater than the smallest detectable change) at 12 and 24 months in AMPLE and 6 and 12 months in AVERT. Areas under the receiver operating characteristic curves for the impact of baseline disease activity on structural damage progression were calculated. RESULTS: Adjusted logistic regression analyses included all randomized and treated patients in AMPLE (N = 646) and those who received abatacept plus MTX or MTX monotherapy in AVERT (N = 235). Baseline Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) scores significantly predicted structural progression at months 12 and 24 in AMPLE (P < 0.05) and months 6 and 12 in AVERT (P < 0.01), and were stronger predictors than Simplified or Clinical Disease Activity Indices. CONCLUSION: In this post hoc analysis of two patient populations with RA, Routine Assessment of Patient Index Data 3, DAS28 (CRP) and M-DAS28 (CRP) were good at predicting structural damage. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov: NCT00929864 (AMPLE); NCT01142726 (AVERT).