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The effect of treatment withdrawal on patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) whose disease is in sustained remission has not been well described. This analysis aimed to compare PRO changes in patients with RA following medication withdrawal and disease worsening.SEAM-RA (Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis) was a phase 3, multicenter, randomized withdrawal, double-blind controlled study in patients with RA taking methotrexate plus etanercept and in remission (Simple Disease Activity Index ≤3.3). Patient's Global Assessment of Disease Activity, Patient's Assessment of Joint Pain, Health Assessment Questionnaire-Disability Index, and 36-Item Short-Form Health Survey were evaluated for 48 weeks following methotrexate or etanercept withdrawal. Treatment differences for patients with versus without disease worsening were evaluated using a 2-sample t test for continuous end points and log-rank test for time-to-event end points.Of 253 patients, 121 experienced disease worsening and 132 did not. All PRO scores were similar to those of a general population at baseline and deteriorated over time across the study population. The PtGA and Patient's Assessment of Joint Pain values deteriorated less in those on etanercept monotherapy compared with methotrexate monotherapy. More patients with versus without disease worsening experienced deterioration that was greater than the minimal clinically important difference (MCID) for all PROs tested. In patients with disease worsening, PtGA deterioration more than the MCID preceded Simple Disease Activity Index disease worsening.Etanercept monotherapy showed benefit over methotrexate in maintaining PRO scores. Patients with disease worsening experienced a more rapid worsening of PtGA beyond the MCID versus patients without disease worsening.Categories: autoinflammatory disease, biological therapy, DMARDs, rheumatoid arthritis.

Objective Randomized controlled trials (RCTs) in biologic-naïve rheumatoid arthritis (RA) patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 (IL-6) receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy. This observational study aimed to compare the effectiveness of TNFi vs IL-6Ri as mono- or combination therapy in biologic/targeted synthetic (b/ts) -experienced RA patients with moderate/high disease activity. Methods Eligible b/ts-experienced patients from the CorEvitas RA registry were categorized as TNFi and IL-6Ri initiators, with subgroups initiating as mono- or combination therapy. Mixed-effects regression models evaluated the impact of treatment on Clinical Disease Activity Index (CDAI), patient-reported outcomes, and disproportionate pain (DP). Unadjusted and covariate-adjusted effects were reported. Results Patients initiating IL-6Ri (n = 286) vs TNFi monotherapy (n = 737) were older, had a longer RA history and higher baseline CDAI, and were more likely to initiate as third-line therapy; IL-6Ri (n = 401) vs TNFi (n = 1315) combination therapy initiators had higher baseline CDAI and were more likely to initiate as third-line therapy. No significant differences were noted in the outcomes between TNFi and IL-6Ri initiators (as mono- or combination therapy). Conclusion This observational study showed no significant differences in outcomes among b/ts-experienced TNFi vs IL-6Ri initiators, as either mono- or combination therapy. These findings were in contrast with the previous RCTs in biologic-naïve patients and could be explained by the differences in the patient characteristics included in this study. Further studies are needed to help understand the reasons for this discrepancy in the real-world b/ts-experienced population. Key Points• Patients with rheumatoid arthritis (RA) often require switching between biologics or targeted synthetic (b/ts) disease-modifying anti-rheumatic drugs (DMARDs) to achieve their treatment target.• Head-to-head randomized controlled trials (RCTs) in biologic-naïve RA patients with high disease activity and inadequate response/intolerance to methotrexate have shown interleukin-6 receptor inhibitors (IL-6Ri) to be superior to tumor necrosis factor inhibitors (TNFi) as monotherapy; however, there are no RCTs comparing these therapies in a population previously treated with b/tsDMARDs (i.e., b/ts-experienced patients).• This observational study compared the effectiveness of TNFi vs IL-6Ri (as mono- or combination therapy) in b/ts-experienced RA patients with moderate or high disease activity and found no significant differences in clinical outcomes for the two treatments.• A discrepancy is noted between our study and RCTs, which have shown superiority of IL-6Ri therapy (albeit in biologic-naïve patients). Further analyses may help elucidate the reason for this discrepancy in the real-world b/ts-experienced population.

ObjectiveTo investigate correlations between biomarkers of bone remodelling and extracellular matrix turnover with baseline disease activity and treatment response in patients with early rheumatoid arthritis (RA).MethodsAssessingVeryEarlyRheumatoid arthritisTreatment-2 (AVERT-2;NCT02504268) included disease-modifying antirheumatic drug-naive, anti-citrullinated protein antibody (ACPA)-positive patients randomised to weekly subcutaneous abatacept+methotrexate (MTX) or abatacept placebo+MTX for 56 weeks. This post hoc exploratory subanalysis assessed the association between baseline disease activity and eight biomarkers (Spearman’s correlation coefficient), and whether baseline biomarkers (continuous or categorical variables) could predict treatment response at weeks 24 and 52 (logistic regression).ResultsPatient characteristics were similar between overall (n=752) and biomarker subgroup (n=535) populations and across treatments. At baseline, neoepitopes of matrix metalloproteinase-mediated degradation products of types III and IV collagen and of C reactive protein (CRP) showed the greatest correlations with disease activity; cross-linked carboxy-terminal telopeptide of type I collagen (CTX-I) showed weak correlation. Only CTX-I predicted treatment response; baseline CTX-I levels were significantly associated with achieving Simplified Disease Activity Index remission and Disease Activity Score in 28 joints (DAS28 (CRP)) ConclusionIn MTX-naive, ACPA-positive patients with early RA, baseline CTX-I predicted treatment response to abatacept+MTX but not abatacept placebo+MTX.

ObjectiveTo compare clinical characteristics and treatment of patients with rheumatoid arthritis (RA) across 4 Canadian cohorts.MethodsThe 4 longitudinal cohorts included the following: the Canadian Early Arthritis Cohort (CATCH; n = 2878), Ontario Best Practices Research Initiative (OBRI; n = 3734), RHUMADATA (Quebec, n = 2890), and the Rheum4U Precision Health Registry (Calgary, Alberta, n = 709). Data were from cohort inception (range 1998–2016) to 2020. Clinical characteristics and drug treatments were summarized descriptively.ResultsIn total, 10,211 patients with RA were included. The percentage of patients who entered the cohort with early RA (2 yrs of disease at enrollment) ranged from 29% (Rheum4U) to 100% (CATCH). Mean age (55 yrs), sex (74% female), and seropositivity (69%) were similar between cohorts. At the time of initial disease-modifying antirheumatic drug (DMARD) use, median Disease Activity Score in 28 joints (DAS28) varied, ranging from 2.99 (Rheum4U) to 5.19 (CATCH), but were more similar at the time of the first DMARD switch (range 3.57–5.03), first biologic (bDMARD) or targeted synthetic DMARD (tsDMARD) use (range 4.01–4.67), and second bDMARD or tsDMARD (range 3.71–4.39). The initial DMARD was most commonly methotrexate, either in monotherapy (32%, range 18–40%) or dual therapy (34%, range 29–42%). The first DMARD switch was to another DMARD monotherapy in 20% (range 10–32%), dual therapy in 49% (range 39–56%), and bDMARD or tsDMARD in 24% (range 15–28%). The first bDMARD was an anti–tumor necrosis factor in 79% (range 78–82%).ConclusionCanadian RA cohorts demonstrate some heterogeneity in treatment, which could reflect differences in inclusion criteria, calendar year, or regional differences. This project is a first step toward conducting harmonized analyses across Canadian RA cohorts.

The Rheumatoid Arthritis Flare Questionnaire (RA-FQ) is a patient-reported measure of disease activity in RA. We estimated minimal and meaningful change from the perspective of RA patients, physicians, and using a disease activity index.Data were from 3- to 6-month visits of adults with early RA enrolled in the Canadian Early Arthritis Cohort. Participants completed the RA-FQ, the Patient Global Assessment of RA, and the Patient Global Change Impression at consecutive visits. Rheumatologists recorded joint counts and MD Global. Clinical Disease Activity Index (CDAI) scores were computed. We compared mean RA-FQ change across categories using patients, physicians, and CDAI anchors.The 808 adults were mostly white (84%) women (71%) with a mean age of 55 and moderate-high disease activity (85%) at enrollment. At V2, 79% of patients classified their RA as changed; 59% were better and 20% were worse. Patients reporting they were a lot worse had a mean RA-FQ increase of 8.9 points, whereas those who were a lot better had a -6.0 decrease. Minimal worsening and improvement were associated with a mean 4.7 and - 1.8 change in RA-FQ, respectively, while patients rating their RA unchanged had stable scores. Physician and CDAI classified more patients as worse than patients, and minimal and meaningful RA-FQ thresholds differed by group.Thresholds to identify meaningful change vary by anchor used. These data offer new evidence demonstrating robust psychometric properties of the RA-FQ and offer guidance about improvement or worsening, supporting its use in RA care, research, and decision-making.

ObjectiveTo determine the risk of not being able to sustain remission after tapering methotrexate (MTX) from targeted therapy in patients with controlled rheumatoid arthritis (RA).MethodsA systematic literature search was conducted in MEDLINE, Embase, and the Cochrane Library for studies reporting remission outcomes after tapering MTX from targeted therapies in RA. Full-text articles and abstracts reported in English were included. Metaanalyses were conducted using random-effects models. Forest and funnel plots were created.ResultsA total of 10 articles were included. Studies evaluated MTX being tapered from combination treatment with tumor necrosis factor inhibitors, tocilizumab, abatacept, and tofacitinib. A total of 9 studies used a randomized design and 1 was observational. Out of 10 studies, 3 focused on early RA (ie, < 1 yr). The MTX-tapering strategy was gradual in 2 studies and rapid in 8 studies. Follow-up ranged from 3 to 18 months in randomized trials and up to 3 years in the observational study. Our metaanalysis, which included 2000 participants with RA from 10 studies, showed that patients who tapered MTX from targeted therapy had a 10% reduction in the ability to sustain remission and an overall pooled risk ratio of 0.90 (95% CI 0.84-0.97). There was no heterogeneity (I2= 0%,P= 0.94). Our funnel plot indicated minimal publication bias.ConclusionPatients with controlled RA may taper MTX from targeted therapy with a 10% reduction in the ability to sustain remission for up to 18 months. Longer follow-up studies with attention to radiographic, functional, and patient-reported outcomes are needed. The risk of disease worsening should be discussed with the patient with careful follow-up and prompt retreatment of disease worsening.

OBJECTIVE To operationalize and report on nationally endorsed rheumatoid arthritis (RA) performance measures (PMs) using health administrative data for British Columbia (BC), Canada. METHODS All patients with RA in BC ages ≥18 years were identified between January 1, 1997 and December 31, 2009 using health administrative data and followed until December 2014. PMs tested include: the percentage of incident patients with ≥1 rheumatologist visit within 365 days; the percentage of prevalent patients with ≥1 rheumatologist visit per year; the percentage of prevalent patients dispensed disease-modifying antirheumatic drug (DMARD) therapy; and time from RA diagnosis to DMARD therapy. Measures were reported on patients seen by rheumatologists, and in the total population. RESULTS The cohort included 38,673 incident and 57,922 prevalent RA cases. The percentage of patients seen by a rheumatologist within 365 days increased over time (35% in 2000 to 65% in 2009), while the percentage of RA patients under the care of a rheumatologist seen yearly declined (79% in 2001 to 39% in 2014). The decline was due to decreasing visit rates with increasing follow-up time rather than calendar effect. The percentage of RA patients dispensed a DMARD was suboptimal over follow-up (37% in 2014) in the total population but higher (87%) in those under current rheumatologist care. The median time to DMARD in those seen by a rheumatologist improved from 49 days in 2000 to 23 days in 2009, with 34% receiving treatment within the 14-day benchmark. CONCLUSION This study describes the operationalization and reporting of national PMs using administrative data and identifies gaps in care to further examine and address.

Objectives To understand the perspectives of patients and rheumatologists for tapering DMARDs in RA. Methods Using semi-structured interview guides, we conducted individual interviews and focus groups with RA patients and rheumatologists, which were audiotaped and transcribed. We conducted a pragmatic thematic analysis to identify major themes, comparing and contrasting different views on DMARD tapering between patients and rheumatologists. Results We recruited 28 adult patients with RA (64% women; disease duration 1–54 y) and 23 rheumatologists (52% women). Attitudes across both groups towards tapering DMARDs were ambivalent, ranging from wary to enthusiastic. Both groups expressed concerns, particularly the inability to ‘recapture’ the same level of disease control, while also acknowledging potential positive outcomes such as reduced drug harms. Patient tapering perspectives (whether to and when) changed over time and commonly included non-biologic DMARDs. Patient preferences were influenced by lived experiences, side effects, previous tapering experiences, disease trajectory, remission duration and current life roles. Rheumatologists’ perspectives varied on timing and patient profile to initiate tapering, and were informed by both data and clinical experience. Patients expressed interest in shared decision-making (SDM) and close monitoring during tapering, with ready access to their health-care team if problems arose. Rheumatologists were generally open to tapering (not stopping), though sometimes only when requested by their patients. Conclusion The perspectives of patients and rheumatologists on tapering DMARDs in RA vary and evolve over time. Rheumatologists should periodically discuss DMARD tapering with patients as part of SDM, and ensure monitoring and flare management plans are in place.

Objective Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination. Methods Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24‐week open‐label period. These 253 patients then entered a 48‐week, double‐blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease‐worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run‐in period. The primary end point was the proportion of patients in whom SDAI‐defined remission was maintained without disease‐worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease‐worsening, and the proportion of patients in whom SDAI‐defined remission was recaptured after initiation of rescue therapy. Results Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI‐defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI‐defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease‐worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI‐defined remission was recaptured in 70–80% in each treatment group. No new safety signals were reported. Conclusion The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI‐defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision‐making when withdrawal of therapy is being considered to reduce treatment burden in patients with well‐controlled RA.

Objectives Using patient-reported outcomes to inform clinical decision-making depends on knowing how to interpret scores. Patient-Reported Outcome Measurement Information System® (PROMIS®) instruments are increasingly used in rheumatology research and care, but there is little information available to guide interpretation of scores. We sought to identify thresholds and meaningful change for PROMIS Pain Interference and Fatigue scores from the perspective of RA patients and clinicians. Methods We developed patient vignettes using the PROMIS item banks representing a continuum of Pain Interference and Fatigue levels. During a series of face-to-face ‘bookmarking’ sessions, patients and clinicians identified thresholds for mild, moderate and severe levels of symptoms and identified change deemed meaningful for making treatment decisions. Results In general, patients selected higher cut points to demarcate thresholds than clinicians. Patients and clinicians generally identified changes of 5–10 points as representing meaningful change. The thresholds and meaningful change scores of patients were grounded in their lived experiences having RA, approach to self-management, and the impacts on function, roles and social participation. Conclusion Results offer new information about how both patients and clinicians view RA symptoms and functional impacts. Results suggest that patients and providers may use different strategies to define and interpret RA symptoms, and select different thresholds when describing symptoms as mild, moderate or severe. The magnitude of symptom change selected by patients and clinicians as being clinically meaningful in interpreting treatment efficacy and loss of response may be greater than levels determined by external anchor and statistical methods.

OBJECTIVE Higher self-reported disability (high Health Assessment Questionnaire [HAQ] score) has been associated with hospitalizations and mortality in established rheumatoid arthritis (RA), but associations in early RA are unknown. METHODS Patients with early RA (symptom duration

Objective To estimate the contributions of health-related quality of life domains to the patient global assessment of disease activity (PtGA) in rheumatoid arthritis (RA). Methods Data are drawn from baseline visits of 2 observational RA cohorts. Participants completed forms for patient-reported outcome measures, including PtGA and measures from the Patient-Reported Outcomes Measurement Information System, and clinical data were collected. Factor analysis was used to identify latent variables, and multivariable linear regression was used to estimate determinants of the PtGA. Results Patients were mostly female (81%), white (78%), and had established disease (mean ± SD 12.3 ± 10.7 years), with 62% in remission or having low disease activity. In cohort 1 (n = 196), the following 2 factors emerged: 1) daily function (moderate-to-strong [i.e., >|0.65|] loadings of physical function, pain interference, social participation, and fatigue, and weak [>0.35] loadings of sleep disturbance); and 2) emotional distress (strong loadings of depression and anxiety). In crude analysis, daily function explained up to 53% and emotional distress up to 20% of the variance in PtGA. In both cohorts, in adjusted analyses, daily function and, to a much lesser extent, swollen joint count independently predicted PtGA; age was inversely related to PtGA in cohort 1 only. Conclusion These findings suggest that in patients with RA, PtGA ratings largely reflect the extent to which patients feel they can function in everyday roles and are not impacted by mood. This suggests that higher than expected PtGA scores may offer an opportunity to discuss patient expectations regarding roles and activities and the impact of their RA symptoms on daily function.

Objective To describe clinical features associated with cancer outcomes of patients with immune checkpoint inhibitor (ICI)-associated arthritis. Methods Observational study of patients with ICI-arthritis enrolled in a single-center registry. Arthritis phenotype and activity, medications, and cancer status were recorded at every visit. We used descriptive statistic, and Kaplan-Meier curves using two-sided log-rank test and Cox regression analysis were used to identify factors associated with cancer progression-free survival (PFS). Results Forty-two patients with ICI-arthritis were followed for a median (interquartile range [IQR]) of 7.4 (1.7, 14.7) months. Fifty-seven percent were female, 33% had melanoma, and 69% received anti-programmed death ligand 1 monotherapy. Median time from ICI initiation to arthritis onset was 2.8 (0.8, 11.2) months. Sixty-two percent had a rheumatoid arthritis (RA)-like small-joint presentation; 27% of all patients were rheumatoid factor and/or cyclic citrullinated peptide positive. Median (IQR) Clinical Disease Activity Index (CDAI) on presentation was 15 (8, 24); 62% required systemic glucocorticoids, 55% required disease-modifying antirheumatic drugs (DMARDs), and 69% had ongoing arthritis at 6 months. Arthritis led to ICI discontinuation in five patients. In univariate analysis, baseline CDAI, DMARD use, earlier arthritis onset, and longer duration of follow-up were associated with shorter PFS. In multivariable Cox regression analysis controlling for DMARD use and time to arthritis onset, CDAI was a significant predictor of cancer progression (hazard ratio 1.09, 95% confidence interval [CI] 1.00-1.19, P = 0.05) CONCLUSION: ICI-arthritis most commonly presents with an RA-like phenotype. High disease activity, as measured by CDAI, may portend cancer progression.

Glen S Hazlewood,1– 3 Deborah A Marshall,1– 3 Claire EH Barber,1– 3 Linda C Li,3 Cheryl Barnabe,1– 3 Vivian Bykerk,4,5 Peter Tugwell,6 Pauline M Hull,7 Nick Bansback3,8 1Departments of Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Canada; 2McCaig Institute of Bone and Joint Health, University of Calgary, Calgary, Canada; 3Arthritis Research Canada, Vancouver, BC, Canada; 4Weill Cornell Medical College, Cornell University, New York, NY, USA; 5Department of Rheumatology, Hospital for Special Surgery, New York, NY, USA; 6Department of Medicine, Department of Epidemiology and Community Medicine, Canada Research Chair, University of Ottawa, Institute of Population Health, Ottawa, Canada; 7University of Calgary, Calgary, Canada; 8Faculty of Medicine, School of Population and Public Health, University of British Columbia, Vancouver, CanadaCorrespondence: Glen S HazlewoodDepartments of Medicine and Community Health Sciences, University of Calgary, 3280 Hospital Drive NW, 3AA10, Calgary AB T2N 4Z6, CanadaTel +1 403 220-5903Fax +1 403 210-3899Email gshazlew@ucalgary.caPurpose: To evaluate, in a proof-of-concept study, a decision aid that incorporates hypothetical choices in the form of a discrete-choice experiment (DCE), to help patients with early rheumatoid arthritis (RA) understand their values and nudge them towards a value-centric decision between methotrexate and triple therapy (a combination of methotrexate, sulphasalazine and hydroxychloroquine).Patients and Methods: In the decision aid, patients completed a series of 6 DCE choice tasks. Based on the patient’s pattern of responses, we calculated his/her probability of choosing each treatment, using data from a prior DCE. Following pilot testing, we conducted a cross-sectional study to determine the agreement between the predicted and final stated preference, as a measure of value concordance. Secondary outcomes including time to completion and usability were also evaluated.Results: Pilot testing was completed with 10 patients and adjustments were made. We then recruited 29 patients to complete the survey: median age 57, 55% female. The patients were all taking treatment and had well-controlled disease. The predicted treatment agreed with the final treatment chosen by the patient 21/29 times (72%), similar to the expected agreement from the mean of the predicted probabilities (68%). Triple therapy was the predicted treatment 24/29 times (83%) and chosen 20/29 (69%) times. Half of the patients (51%) agreed that completing the choice questions helped them tounderstand their preferences (38% neutral, 10% disagreed). The tool took an average of 15 minutes to complete, and median usability scores were 55 (system usability scale) indicating “OK” usability.Conclusion: Using a DCE as a value-clarification task within a decision aid is feasible, with promising potential to help nudge patients towards a value-centric decision. Usability testing suggests further modifications are needed prior to implementation, perhaps by having the DCE exercises as an “add-on” to a simpler decision aid.Keywords: conjoint analysis, decision tool, value concordance, methotrexate

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). To better understand tofacitinib treatment responses, we used group-based trajectory modeling to investigate distinct disease activity trajectories and associated baseline variables in patients with active RA. Methods: This post hoc analysis used data from a phase III study of methotrexate-naive patients receiving tofacitinib 5 mg twice daily. Changes in the 4-variable Disease Activity Score in 28 joints, using the erythrocyte sedimentation rate (DAS28-ESR) from baseline to month 24 were used in group-based trajectory modeling to identify distinct disease activity trajectories. Patient and disease characteristics, changes in radiographic progression and patient-reported outcomes, and safety up to month 24 were compared among trajectory groups. Results: From 346 methotrexate-naive patients, 5 disease trajectory groups, defined by DAS28-ESR scores, were identified, which progressed from high disease activity (HDA) to remission (group 1, n = 28), to low disease activity (LDA) rapidly (group 2, n = 107), to moderate disease activity (group 3, n = 98), to LDA gradually (group 4, n = 46), or remained in HDA (group 5, n = 67), at month 24. At baseline, groups 1 and 2 generally had lower disease activity and more favorable patient-reported outcomes, compared with other groups. Improvements in radiographic progression and patient-reported outcomes over 24 months were generally consistent with DAS28-ESR–predicted disease activity trajectories. Adverse event rates were generally comparable across groups. Conclusion: Distinct phenotypic subgroups identified heterogeneity in patients with RA normally analyzed as a single population. Trajectory modeling may enable separation of clinically meaningful subsets of patients with RA, and may help optimize treatment outcomes.

ObjectiveRecently, there has been consensus on domains that constitute flares in rheumatoid arthritis (RA); however, variations in patients' flare descriptions continue to be observed. This study evaluates how demographic and clinical characteristics influence these differences.MethodsParticipants enrolled in a prospective RA registry completed a qualitative survey that included the open-ended question "What does a flare mean to you?" Responses were categorized into Outcome Measures in Rheumatology (OMERACT) core and research domains. Univariate analyses evaluated demographic and clinical characteristics. Regression analyses determined independent variables associated with flare description variations.ResultsAmong 645 participants, the median Disease Activity Score in 28 joints (DAS28) with C-reactive protein was 2.1 (IQR 1.6-2.9); 58% of the participants reported at least 1 flare in the past 6 months. Participants reported a median of 3 (IQR 2-5) OMERACT domains when describing flares. Fatigue was more commonly noted among females (odds ratio [OR] 6.12;P< 0.001). Older participants were less likely to report emotional distress (OR 0.97;P= 0.03), swollen joints (OR 0.99;P= 0.04), physical function decrease (OR 0.98;P= 0.02), and a general increase in RA symptoms (OR 0.98;P= 0.005). Participants with a higher DAS28 score were less likely to report symptoms of stiffness (OR 0.70;P= 0.009), and those who experienced a flare within the last 6 months were more likely to describe flares as pain (OR 2.53;P< 0.001) and fatigue (OR 2.00;P= 0.007).ConclusionVariations in patients' flare descriptions can be driven by a patient's disease activity, the experience of a recent flare, as well as different demographic characteristics, such as age and gender. Understanding the interplay of these characteristics can guide a physician's approach to the management of patients' RA flares.

Vaccination against SARS-CoV-2 is crucial for patients with systemic rheumatic diseases (SRDs), who may be at increased risk of severe outcomes post-COVID-19.1 However, as patients with SRDs were not included in the mRNA vaccine trials (ie, Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273)), no data exist regarding whether these vaccines might trigger SRD flares. Sparse data suggest that other vaccines may be associated with SRD flares,2 3 possibly from molecular mimicry triggering immune activation or non-specific adjuvant effects. As SRD flares are associated with disease deterioration, increased flares could have serious clinical implications.4 We report the interim results of a web-based survey evaluating SRD flare incidence post-SARS-CoV-2 vaccine. The survey was e-mailed 5 March 2021 to 3545 outpatients with SRDs seen at a large rheumatology division in New York City. ICD-10 algorithms were used to identify SRDs (online supplemental material). A self-reported disease flare was defined as ‘a sudden worsening of your rheumatology condition or arthritis’ within 2 weeks of the vaccine.### Supplementary data [annrheumdis-2021-220732supp001.pdf] As of 12 April 2021, out of 1483 respondents (41.8% response rate), 1101 patients (74.2%) with SRDs reported receiving at least one dose of a SARS-CoV-2 vaccine and provided flare data (mean age: 60.8 years (14.2 years); 80.6% female; …

Objective Sarilumab, as monotherapy or in combination with conventional synthetic DMARDs, such as MTX, has demonstrated improvement in clinical outcomes in patients with RA. The primary objective of this post hoc analysis was to compare the efficacy of sarilumab (200 mg every 2 weeks) monotherapy (MONARCH study) with that of sarilumab and MTX combination therapy (MOBILITY study) at week 24. Methods The endpoints assessed were mean change from baseline in the Clinical Disease Activity Index (CDAI), 28-joint Disease Activity using CRP (DAS28-CRP), CRP, haemoglobin (Hb), pain visual analogue scale (VAS) and Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue. Least square (LS) mean change from baseline (95% CI) at week 24 for all endpoints was compared between the treatment arms for adjusted comparisons. Results This analysis included 184 patients on sarilumab monotherapy and 399 patients on sarilumab plus MTX. Differences (P Conclusion This analysis demonstrated that the efficacy of sarilumab monotherapy was similar to that of sarilumab and MTX combination therapy.

Objective Metabolic syndrome (MetS) prevalence in early rheumatoid arthritis (ERA) is conflicting. The impact of sex, including menopause, has not been described. We estimated the prevalence and factors associated with MetS in men and women with ERA. Methods A cross‐sectional study of the Canadian Early Arthritis Cohort (CATCH) was performed. Participants with baseline data to estimate key MetS components were included. Sex‐stratified logistic regression identified baseline variables associated with MetS. Results The sample included 1543 participants; 71% were female and the mean age was 54 (SD 15) years. MetS prevalence was higher in men 188 (42%) than women 288 (26%, P < 0.0001) and increased with age. Frequent MetS components in men were hypertension (62%), impaired glucose tolerance (IGT, 40%), obesity (36%), and low high‐density lipoprotein cholesterol (36%). Postmenopausal women had greater frequency of hypertension (65%), IGT (32%), and high triglycerides (21%) compared with premenopausal women (P < 0.001). In multivariate analysis, MetS was negatively associated with seropositivity and pulmonary disease in men. Increasing age was associated with MetS in women. In postmenopausal women, corticosteroid use was associated with MetS. Psychiatric comorbidity was associated with MetS in premenopausal women. MetS status was not explained by disease activity or core RA measures. Conclusion The characteristics and associations of MetS differed in men and women with ERA. Sex differences, including postmenopausal status, should be considered in comorbidity screening. With this knowledge, the interplay of MetS, sex, and RA therapeutic response on cardiovascular outcomes should be investigated.

"Legacy" patient-reported outcome measures (PROs) have been used for decades; however, they have many limitations. The National Institutes of Health-funded PRO Measurement Information System (PROMIS) was developed to be a generic, flexible, precise, and reliable tool to measure core and additional domains of physical and emotional health and social well-being. Unlike Legacy PROs, PROMIS measures can be implemented across diseases, and use a common T-score metric-based scoring system derived using item response theory. PROMIS measure scores have potential to predict scores of Legacy PROs and could be the only set of measures needed to assess PROs.

Objective To evaluate seasonal patterns of early inflammatory arthritis (IA) onset and potential associations with IA symptom onset. Methods The Canadian Early Arthritis Cohort (CATCH) is an inception cohort study of adults with early (12 months or less) IA. We used patient reports of symptom onset as a proxy of IA onset and examined the seasonal distribution of IA onset over 10 years. Influenza time series was based on laboratory‐confirmed influenza A and B from the Canadian FluWatch surveillance from 2010‐2016. Bivariate analysis of influenza and IA was performed using cross‐correlations with different time lags and Poisson regression. IA and influenza were recorded as monthly total frequencies. Results Of 2519 IA patients, 88% had confirmed rheumatoid arthritis (RA). Significantly, more IA onsets occurred in winter compared with other seasons (P = 0.03); although IA onset was more frequent in January, the difference between months was not statistically significant. Compared to months with the lowest influenza rates, months with the highest influenza rates had a statistically significant, but trivial, increase of 0.003% in the incidence of IA (incidence rate ratio (95% confidence interval): 1.00003 (1.00005; 1.000053), P = 0.02). Conclusion Although IA symptom onset occurs more frequently in winter, we found that flu outbreaks were not associated with a meaningful increase in IA symptom onset in a large, well‐characterized cohort of Canadian adults over 6 years.

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.

We appreciate the interest in our manuscript concerning the Health Assessment Questionnaire disability index (HAQ) in an early rheumatoid arthritis incident cohort (the CATCH cohort) which predicted all-cause mortality (1). We will clarify queries raised in letters to the editor (2-4).

International audience; Objective: To investigate the impact of baseline and time-varying factors on the risk of serious adverse events (SAEs) in patients during long-term certolizumab pegol (CZP) treatment.Methods: Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time-varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO.Results: Data were pooled from 8747 CZP-treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2 . Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO.Conclusion: Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP-treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.

Rheumatoid arthritis (RA) is chronic, painful, disabling condition resulting in significant impairments in physical, emotional, and social health. Our objective was to use different methods and perspectives to evaluate the responsiveness of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms (SFs) and to identify minimal and meaningful score changes.Adults with RA who were enrolled in a multisite prospective observational cohort completed PROMIS physical function, pain interference, fatigue, and participation in social roles/activities SFs, the PROMIS 29-item form (PROMIS-29), and pain and patient global assessment, and rated change in specific symptoms and RA (a little versus lot better or worse) at the second visit. Physicians recorded joint counts, physician global assessment, and change in RA at visit 2. We compared mean score differences for minimal and meaningful improvement/worsening using patient and physician change ratings and distribution-based methods, and we visually inspected empirical cumulative distribution function curves by change categories.The 348 adults were mostly female (81%) with longstanding RA. Using patient ratings, generally 1-3-point differences were observed for minimal change and 3-7 points for meaningful change. Larger differences were observed with patient versus physician ratings and for symptom-specific versus RA change. Mean differences were similar among SF versions. Prespecified hypotheses about change in PROMIS physical function, pain interference, fatigue, and participation and legacy scales were supported.PROMIS SFs and the PROMIS-29 profiles are responsive to change and generally distinguish between minimal and meaningful improvement and worsening in key RA domains. These data add to a growing body of evidence demonstrating the robust psychometric properties of PROMIS and supporting its use in RA care, research, and decision-making.

OBJECTIVE The present study was undertaken to evaluate the pregnancy experiences of women receiving care in the division of rheumatology at a major academic center in New York City during the COVID-19 pandemic. METHODS A web-based COVID-19 survey was emailed to 26,045 patients who were followed in the division of rheumatology at a single center in New York City. Women ages 18-50 years were asked about their pregnancy. We compared the COVID-19 experience between pregnant and nonpregnant women and also explored the impact of the pandemic on prenatal care and perinatal outcomes. RESULTS Among 7,094 of the 26,045 respondents, 1,547 were women ages 18-50 years, with 61 (4%) reporting being pregnant during the pandemic. The prevalence of self-reported COVID-19 was similar in pregnant and nonpregnant women (8% versus 9%, respectively; P = 0.76). Among women with COVID-19, pregnant women had a shorter duration of symptoms (P < 0.01) and were more likely to experience loss of smell or taste (P = 0.02) than nonpregnant women. Approximately three-fourths of women had a systemic rheumatic disease, with no differences when stratified by pregnancy or COVID-19 status. In all, 67% of pregnant women noted changes to prenatal care during the pandemic, and 23% of postpartum women stated that the pandemic affected delivery. CONCLUSION Among women followed in the division of rheumatology at a major center in New York City, pregnancy was not associated with increased self-reported COVID-19. Pregnancy was associated with a shorter duration of COVID-19 symptoms and a higher prevalence of loss of smell or taste. The COVID-19 pandemic impacted prenatal care for the majority of pregnant patients.

ObjectiveWe evaluated 4 national rheumatoid arthritis (RA) system-level performance measures (PM) in Alberta, Canada.MethodsIncident and prevalent RA cases ≥ 16 years of age since 2002 were identified using a validated case definition applied in provincial administrative data. Performance was ascertained through analysis of health data between fiscal years 2012/13–2015/16. Measures evaluated were as follows: proportion of incident RA cases with a rheumatologist visit within 1 year of first RA diagnosis code (PM1); proportion of prevalent RA patients who were dispensed a disease-modifying antirheumatic drug (DMARD) annually (PM2); time from first visit with an RA code to DMARD dispensation and proportion of incident cases where the 14-day benchmark for dispensation was met (PM3); and proportion of patients seen in annual follow-up (PM4).ResultsThere were 31,566 prevalent and 2730 incident RA cases (2012/13). Over the analysis period, the proportion of patients seen by a rheumatologist within 1 year of onset (PM1) increased from 55% to 63%; however, the proportion of RA patients dispensed DMARD annually (PM2) remained low at 43%. While the median time to DMARD from first visit date in people who received DMARD improved over time from 39 days to 28 days, only 38–41% of patients received treatment within the 14-day benchmark (PM3). The percentage of patients seen in yearly follow-up (PM4) varied between 73–80%.ConclusionThe existing Alberta healthcare system for RA is suboptimal, indicating barriers to accessing specialty care and treatment. Our results inform quality improvement initiatives required within the province to meet national standards of care.

Patterns of innovation can be sustained (continuous) or rapid, sometimes even ‘disruptive’. A major difference is that in order to support disruptive innovation the support networks and its infrastructure often need to be changed dynamically to accommodate a rapidly evolving landscape to establish the disruptive approach. For example, introducing electric cars disrupts the support network for gasoline cars (network of gas and service stations), and at the same time requires an entirely new system of charging stations. Such disruptions occur in science, and a wonderful example was the creation of monoclonal antibody technologies. The discovery of the principle for production of monoclonal antibodies by Cesar Milstein and Georg Kohler fueled a rapid adoption of new antibody-based technologies in all areas of medicine. This transformation was strongly supported by the open workshops that catalogued antibodies from many laboratories into distinct ‘clusters of differentiation’, thereby providing a new ‘support network’ for the global use of well validated and standardised monoclonal antibodies. This new support network helped the pharmaceutical industry transition from a major focus on small chemical molecules (screened for effects in vitro) to a new targeted approach, first with recombinant proteins, later with monoclonal antibodies with the introduction of anti-tumour necrosis factor (TNF) antibodies as an example. During the last two decades, in both the USA and Europe, the need to develop public–private partnership support networks has been recognised as a means to accelerate innovation and enable translation of the rapidly expanding cellular and molecular understanding of disease pathogenesis into the development of new therapeutic agents. In Europe, the Innovative Medicine Initiative (IMI) was formed to enhance public–private partnerships, and in the USA the Accelerating Medicines Partnership (AMP).1 Identifying, validating and testing new targets based on enhanced understanding are at the core of both AMP and IMI. To facilitate continuous …

Background In RA patients, unacceptable pain (UP) may persist despite inflammation control (refractory pain [RP]). Sarilumab is indicated (either with methotrexate or as monotherapy if methotrexate is not tolerated/appropriate) for adults with moderately-to-severely active RA with an inadequate response or intolerance to ≥ 1 conventional synthetic disease-modifying antirheumatics (csDMARD). The recommended dose is 200 mg every 2 weeks (q2w) with dose reduction to 150 mg if required for management of laboratory abnormalities. Three randomised controlled trials (RCTs) of subcutaneous sarilumab 150 or 200 mg q2w vs comparators showed meaningful improvements in pain. This analysis assessed UP and RP in these trials. Methods RCTs evaluated sarilumab 150 and 200 mg q2w vs placebo (+csDMARDs: MOBILITY/NCT01061736 and TARGET/NCT01709578) and sarilumab 200 mg q2w vs adalimumab 40 mg q2w (MONARCH/NCT02332590). Post-hoc analyses calculated odds ratios (ORs) of UP (based on patient acceptable symptom state on a threshold of visual analog scale pain >40 mm [0-100]), RP (UP+C-reactive protein Results Across all three trials, sarilumab 150 and 200 mg q2w had lower odds of UP (p < 0.05; ORs 0.39-0.46 vs placebo and 0.54 vs adalimumab). In MOBILITY, sarilumab 150 and 200 mg q2w had lower odds (p < 0.05) of RP vs placebo at Week 24 (ORs 0.60 [0.38,0.93] and 0.57 [0.37,0.87]) and Week 52 (ORs 0.64 [0.37,1.02] and 0.62 [0.37,1.02]), and RP-strict at Week 52 (0.41 [0.19,0.90] and 0.35 [0.16,0.76]). In TARGET, sarilumab 150 mg q2w had lower odds (p < 0.05) of RP-strict at Week 24. Higher pain was associated with worse FACIT-fatigue, HAQ, SJC and TJC scores (all p < 0.001). Conclusion Sarilumab was associated with lower odds of UP or RP vs adalimumab or placebo. Disclosures V. Bykerk: Consultancies; Abbvie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. Shareholder/stock ownership; Abbvie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. Grants/research support; AbbVie, Amgen, Brainstorm Therapeutics, Bristol-Myers Squibb, Genentech, Gilead, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Scipher, Union Chimique Belge. W. Wei: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. S. Boklage: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. T. Kimura: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc. S. Fiore: Shareholder/stock ownership; Sanofi. Other; Sanofi. G. St John: Shareholder/stock ownership; Regeneron Pharmaceuticals, Inc. Other; Regeneron Pharmaceuticals, Inc.

In their article, Solomon and colleagues reported prespecified safety analyses comparing adverse events in users of low-dose methotrexate plus folic acid compared with those randomly assigned to pl...

OBJECTIVE Obesity is implicated in rheumatoid arthritis (RA) development, severity, outcomes, and treatment response. We estimated the independent effects of overweight and obesity on ability to achieve sustained remission (sREM) in the 3 years following RA diagnosis. METHODS Data were from the Canadian Early Arthritis Cohort, a multicenter observational trial of early RA patients treated by rheumatologists using guideline-based care. sREM was defined as Disease Activity Score in 28 joints (DAS28)

To assess adherence to 3 system-level performance measures in a national early rheumatoid arthritis (RA) cohort.Patients enrolled in the Canadian Early Arthritis Cohort (2007-2015) who met 1987 or 2010 American College of Rheumatology/European League Against Rheumatism criteria with1 year of symptom duration and ≥1 year of followup after enrollment were included. Performance measures assessed were the percentage of RA patients seen in yearly followup, and the number of gaps between visits of12 or14 months, the percentage of RA patients treated with a disease-modifying antirheumatic drug (DMARD), and days from RA diagnosis to initiation of a DMARD. Results are shown stratified by enrollment year to assess for temporal changes in performance.A total of 1,763 early RA patients were included (mean age 54 years, 73% female, and 82% white). At enrollment, mean ± SD disease duration was 6 ± 3 months, and Disease Activity Score in 28 joints was 5.1 ± 1.5. Over 8 years, the proportion of patients seen in annual followup declined from 100% to 91%. Over followup, 42% of patients had 0 gaps in care of12 months, and 64% had 0 gaps14 months. The percentage of DMARD-treated early RA patients was and remained high (95-87%), and the percentage receiving DMARDs within 14 days of diagnosis was 75%. Median time-to-DMARD therapy was 1 day, indicating DMARDs were initiated at diagnosis (90th percentile 93 days).There was evidence of high adherence to system-level performance measures in this early RA cohort following a protocol. Small declines in performance were noted with increasing length of patient followup. Our findings are useful for performance measure benchmarking.

Objective.Adaptive trial design was developed initially for oncology to improve trial efficiency. If optimized for rheumatology, it may improve trial efficiency by reducing sample size and time.Methods.A systematic review assessed design of phase II clinical trials in rheumatoid arthritis.Results.Fifty-six trials were reviewed. Most trials had 4 groups (1 control and 3 intervention), with an average group size of 34 patients. American College of Rheumatology 20 measured at 16 weeks was the most commonly used primary endpoint.Conclusion.The next step is to undertake a systematic review of adaptive designs used in early-phase trials in nonrheumatic conditions.