Having More Tender Than Swollen Joints Is Associated With Worse Patient-Reported Outcomes in Patients With Early RA.

BACKGROUND/OBJECTIVE: In patients with rheumatoid arthritis (RA), high tender-swollen joint differences (TSJDs) have been associated with worse outcomes. A better understanding of the phenotype and impact of high TSJD on patient-reported outcomes (PROs) in early RA may lead to earlier personalized treatment targeting domains that are important to patients today. Our objectives were to evaluate the impact of TSJD on updated PROs in patients with early RA over 1 year and to determine differences in associations by joint size. METHODS: This longitudinal cohort study followed patients with active, early RA enrolled in the Canadian Early Arthritis Cohort between 2016 and 2022, who completed clinical assessments and PROMIS-29 measures over 1 year. Twenty-eight joint counts were performed and TSJDs calculated. Adjusted associations between TSJD and PROMIS-29 scores were estimated using separate linear-mixed models. Separate analyses of large versus small-joint TJSDs were performed. RESULTS: Patients with early RA (n = 547; 70% female; mean [SD] age, 56 [15] years; mean [SD] symptom duration, 5.3 [2.9] months) were evaluated. A 1-point increase in TSJD was significantly associated with worse PROMIS T-scores in all domains: physical function (adjusted regression coefficient, -0.27; 95% confidence interval [CI], -0.39, -0.15), social participation (adjusted regression coefficient, -0.34; 95% CI, -0.50, -0.19), pain interference (adjusted regression coefficient, 0.49; 95% CI, 0.35, 0.64), sleep problems (adjusted regression coefficient, 0.29; 95% CI, 0.16, 0.43), fatigue (adjusted regression coefficient, 0.34; 95% CI, 0.18, 0.50), anxiety (adjusted regression coefficient, 0.23; 95% CI, 0.08, 0.38), and depression (adjusted regression coefficient, 0.20; 95% CI, 0.06, 0.35). Large-joint TSJD was associated with markedly worse PROs compared with small-joint TSJD. CONCLUSIONS: Elevated TSJD is associated with worse PROs particularly pain interference, social participation, and fatigue. Patients with more tender than swollen joints, especially large joints, may benefit from earlier, targeted therapeutic interventions.

Having More Tender Than Swollen Joints is Associated With Worse Function and Work Impairment in Patients With Early Rheumatoid Arthritis.

OBJECTIVE: Patients with early rheumatoid arthritis (RA) may present with more tender than swollen joints, which can persist. Elevated tender-swollen joint difference (TSJD) is often challenging, because there may be multiple causes and it may contribute to overestimating disease activity. Little is known about the phenotype and impact of TSJDs on patient function. Our objective was to evaluate the impact of TSJD on functional outcomes in early RA and to see whether associations vary by joint size. METHODS: Data were from patients with active, early RA (≤12 months) enrolled in the Canadian Early Arthritis Cohort, who completed assessments of general function (Multidimensional Health Assessment Questionnaire [MDHAQ]), upper extremity (UE) function (Quality of Life in Neurological Disorders [Neuro-QoL] UE scale), and work/activity impairment (Work Productivity and Activity Impairment RA) over their first year of follow-up. A total of 28 joint counts were performed. TSJDs were calculated. Adjusted associations between TSJDs and functional outcomes were estimated in separate multivariable linear mixed effects models. Separate analyses were performed for large- versus small-joint TSJD. RESULTS: Patients (N = 547) were 70% female, mean age 56 (SD 15) years, mean disease duration 5.3 (SD 2.9) months. At baseline, 287 (52%) had TSJD >0 (43% involved large joints and 34% small joints), decreasing to 32% at 12 months. A one-point increase in TSJD was significantly associated with worse function (MDHAQ: adjusted mean change 0.10, 95% confidence interval [CI] 0.08-0.13; Neuro-QoL UE function T score: adjusted mean change -0.59, 95% CI -0.76 to -0.43; and greater work impairment: adjusted mean change 1.95%, 95% CI 0.85%-3.05%). Higher large-joint TSJDs were associated with the worst functional outcomes. CONCLUSION: Having more tender than swollen joints is common in early RA and is associated with worse function, most notably when involving large joints. Early identification and targeted intervention strategies may be needed.

Association of COVID-19 Vaccinations With Flares of Systemic Rheumatic Disease: A Case-Crossover Study.

OBJECTIVE: We aimed to determine the association of COVID-19 vaccination with flares of systemic rheumatic disease (SRD). METHODS: Adults with systemic rheumatic disease (SRD) in a single-center COVID-19 Rheumatology Registry were invited to enroll in a study of flares. COVID-19 vaccine information from March 5, 2021, to September 6, 2022, was obtained from chart review and self-report. Participants self-reported periods of SRD flare and periods without SRD flare. "Hazard periods" were defined as the time before a self-report of flare and "control periods" as the time before a self-report of no flare. The association between flare and COVID-19 vaccination was evaluated during hazard and control periods through univariate conditional logistic regression stratified by participant, using lookback windows of 2, 7, and 14 days. RESULTS: A total of 434 participants (mean ± SD age 59 ± 13 years, 84.1% female, 81.8% White, 64.5% with inflammatory arthritis, and 27.0% with connective tissue diseases) contributed to both the hazard and control periods and were included in analysis. A total of 1,316 COVID-19 vaccinations were identified (58.5% Pfizer-BioNTech, 39.5% Moderna, and 1.4% Johnson & Johnson); 96.1% of participants received at least one dose and 93.1% at least two doses. There was no association between COVID-19 vaccination and flares in the subsequent 2, 7, or 14 days (odds ratio [OR] 1.46, 95% confidence interval [CI] 0.86-2.46; OR 1.09, 95% CI 0.76-1.55; and OR 0.85, 95% CI 0.64-1.13, respectively). Analyses stratified on sex, age, SRD subtype, and vaccine manufacturer similarly showed no association between vaccination and flare. CONCLUSION: COVID-19 vaccination was not associated with flares in this cohort of participants with SRD. These data are reassuring and can inform shared decision-making on COVID-19 immunization.

Factors Associated With COVID-19 Vaccine Hesitancy in Rheumatology Outpatients in New York City.

OBJECTIVE: The aim of this study was to measure COVID-19 vaccine hesitancy among rheumatology outpatients from an early COVID-19 "hotspot" during the initial period of vaccine availability. METHODS: In March 2021, a Web-based survey was sent to 7505 adults seen at a Rheumatology Division in New York City. We evaluated characteristics associated with 3 categories of COVID-19 vaccination status: declined, undecided, and willing/already received. We used multinomial logistic regression models to calculate relative risk ratios assessing predictors of vaccination status. RESULTS: Among 2384 (32%) respondents (80% female, 87% White, 59% with systemic rheumatic disease), 2240 (94.0%) were willing/already received COVID-19 vaccination, 88 (3.7%) were undecided, and 56 (2.3%) declined. Compared with those willing/already vaccinated, those declining or undecided were younger, more likely identified as Black or Hispanic/Latinx, and had lower household income and educational attainment. Immunosuppressive medication use did not differ among groups. After multivariable adjustment, every 1-year increase in age was associated with a 0.96 lower relative risk of declining or being undecided versus willing/already vaccinated. Respondents identifying as Black versus White had a higher relative risk ratio of being undecided (4.29 [95% confidence interval, 1.96-9.36]), as did those identifying as Hispanic/Latinx versus non-Hispanic/non-Latinx (2.81 [95% confidence interval, 1.29-6.09]). Those declining vaccination were least likely to believe in general vaccine importance or the safety and efficacy of the COVID-19 vaccine. CONCLUSIONS: Among rheumatology patients in New York City with and without systemic rheumatic disease, COVID-19 vaccine uptake was high after its initial availability. Sociodemographic but not medication-related factors were associated with vaccine hesitancy; these findings can inform future rheumatology vaccination programs.

Associations Between Rheumatoid Arthritis Clinical Factors and Synovial Cell Types and States.

OBJECTIVE: Recent studies have uncovered diverse cell types and states in the rheumatoid arthritis (RA) synovium; however, limited data exist correlating these findings with patient-level clinical information. Using the largest cohort to date with clinical and multicell data, we determined associations between RA clinical factors with cell types and states in the RA synovium. METHODS: The Accelerated Medicines Partnership Rheumatoid Arthritis study recruited patients with active RA who were not receiving disease-modifying antirheumatic drugs (DMARDs) or who had an inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors. RA clinical factors were systematically collected. Biopsies were performed on an inflamed joint, and tissue were disaggregated and processed with a cellular indexing of transcriptomes and epitopes sequencing pipeline from which the following cell type percentages and cell type abundance phenotypes (CTAPs) were derived: endothelial, fibroblast, and myeloid (EFM); fibroblasts; myeloid; T and B cells; T cells and fibroblasts (TF); and T and myeloid cells. Correlations were measured between RA clinical factors, cell type percentage, and CTAPs. RESULTS: We studied 72 patients (mean age 57 years, 75% women, 83% seropositive, mean RA duration 6.6 years, mean Disease Activity Score-28 C-reactive Protein 3 [DAS28-CRP3] score 4.8). Higher DAS28-CRP3 correlated with a higher T cell percentage (P < 0.01). Those receiving MTX and not a biologic DMARD (bDMARD) had a higher percentage of B cells versus those receiving no DMARDs (P < 0.01). Most of those receiving bDMARDs were categorized as EFM (57%), whereas none were TF. No significant difference was observed across CTAPs for age, sex, RA disease duration, or DAS28-CRP3. CONCLUSION: In this comprehensive screen of clinical factors, we observed differential associations between DMARDs and cell phenotypes, suggesting that RA therapies, more than other clinical factors, may impact cell type/state in the synovium and ultimately influence response to subsequent therapies.

The Gap in Knowledge about Tapering Targeted Therapy being used as Monotherapy in Rheumatoid Arthritis: A Systematic Review.

BACKGROUND: Up to 30% of patients with RA are being treated with biologic (b)-disease modifying anti-rheumatic drugs (DMARDs) as monotherapy. Monotherapy with Interleukin (IL)-6 inhibitors(i) and Janus-kinase (JAK)-i has been shown to be effective. Whether patients can taper targeted therapy (bDMARDs and JAK-i) used as monotherapy (targeted monotherapy) is unknown. OBJECTIVE: To determine the feasibility of tapering of targeted monotherapy in patients with controlled RA. METHODS: We conducted a literature search in Medline, Embase and Cochrane Library for prospective studies reporting remission outcomes after tapering targeted monotherapy in RA patients, from 1/2014 - 8 /2021. RESULTS: 5 randomized studies which met our inclusion criteria, evaluating tapering of monotherapy with tumor necrosis factor-inhibitors, tocilizumab, abatacept and baricitinib in RA. Studies were heterogeneous. Three trials studied early RA. Three studies gradually tapered therapy, including 1 dose reduction study. Three studies tapered both biological and conventional-synthetic (cs)-DMARDs. No study compared stopping targeted monotherapy to continuing it. Remission rates were low 14-28% across all studies that stopped targeted monotherapy. The highest remission rate of 72% was reported by the dose reduction study. Trials that studied early RA reported remission rates after tapering ranging 27-72%. Trials tapering therapy in established RA reported rates of remission from 14-20%. CONCLUSION: There is a crucial gap in published literature to inform on tapering targeted monotherapy in patients with RA. Stopping targeted monotherapy is unlikely to maintain disease control in RA. Dose reduction strategies and early treatment of disease may be associated with more successful tapering, and warrant future study.

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes.

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in 'At-Risk' populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5 low naïve B cell population was expanded in ACPA-positive FDRs. Further, we developed an "RA immunophenotype score" classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.

Anticitrullinated peptide antibody epitope expansion and the HLA DRB1 'shared epitope' are less common in seropositive checkpoint inhibitor-induced inflammatory arthritis than in longstanding rheumatoid arthritis.

BACKGROUND: Immune checkpoint inhibitors (ICI) can potentially cause ICI-inflammatory arthritis (ICI-IA), which often resembles rheumatoid arthritis (RA). In this study, we examined the degree of anticitrullinated peptide antibodies (ACPA) epitope expansion in CCP+ICI-IA and patients with RA. METHODS: We used clinical data and serum from ICI-IA and patients with RA with early disease as well as longstanding disease. A custom, bead-based antigen array was used to identify IgG ACPA reactivities to 18 putative RA-associated citrullinated proteins. Hierarchical clustering software was used to create a heatmap to identify ACPA levels. Additionally, HLA DRB1 typing was performed on ICI-IA patients as well as controls of patients treated with ICI that did not develop ICI-IA (ICI controls). RESULTS: Compared to patients with CCP+RA, patients with CCP+ICI-IA were older (p<0.001), less likely to have positive rheumatoid factor (p<0.001) and had a shorter duration of symptoms (p<0.001). There were less ACPA levels and a lower number of distinct ACPA epitopes in the serum of patients with ICI-IA compared with longstanding patients with RA (p<0.001). Among those tested for HLA DRB1, there were no differences in the frequency of the shared epitope between those with ICI-IA and ICI controls. CONCLUSION: Patients with ICI-IA had lower ACPA titres and targeted fewer ACPA epitopes than longstanding patients with RA, and there were no significant differences in the presence of the shared epitope between those that developed ICI-IA and ICI controls. It remains to be determined if ICI-IA represents an accelerated model of RA pathogenesis with ICI triggering a transition from preclinical to clinical disease.

Comparative effectiveness of TNF inhibitor vs IL-6 receptor inhibitor as monotherapy or combination therapy with methotrexate in biologic-experienced patients with rheumatoid arthritis: An analysis from the CorEvitas RA Registry.

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.

Factors Associated With Maintenance of Remission Following Change From Combination Therapy to Monotherapy in Patients With Rheumatoid Arthritis.

OBJECTIVE: Some patients with rheumatoid arthritis (RA) who persist in remission may decide to stop their therapy. We evaluated baseline characteristics associated with remaining in remission or low disease activity (LDA) following medication withdrawal. METHODS: The Study of Etanercept and Methotrexate in Combination or as Monotherapy in Subjects With Rheumatoid Arthritis (SEAM-RA) was a phase III, multicenter, randomized withdrawal, double-blind, controlled study in patients with RA on methotrexate (MTX) + etanercept (ETN). If remission (Simplified Disease Activity Index [SDAI] ≤ 3.3) was sustained through a 24-week run-in period, patients then entered a 48-week double-blind period and were randomized 2:2:1 to receive MTX monotherapy, ETN monotherapy, or continue combination therapy. Multivariate logistic regression analysis was performed to identify baseline factors associated with remission or LDA at the end of both periods. RESULTS: Of 371 patients enrolled, 253 entered the double-blind period. After adjusting for other factors, covariates associated with achieving SDAI remission at the end of the run-in period included younger age, longer duration of MTX treatment, and less severe clinical disease variables. Covariates associated with maintaining remission/LDA at the end of the 48-week double-blind period included lower patient global assessment of disease activity (PtGA), lower C-reactive protein, rheumatoid factor (RF) negativity, longer RA duration in the MTX arm, shorter duration of ETN treatment, and lower magnesium. CONCLUSION: These findings indicate patients with overall lower disease activity are more likely to remain in SDAI remission/LDA after switching from combination therapy to monotherapy. RF-negative status and lower PtGA scores were strongly associated with increased likelihood of remaining in remission/LDA with MTX or ETN monotherapy. (SEAM-RA; ClinicalTrials.gov: NCT02373813).

The trajectory of clinical responses in patients with early rheumatoid arthritis who achieve sustained remission in response to abatacept: subanalysis of AVERT-2, a randomized phase IIIb study.

BACKGROUND: AVERT-2 (a phase IIIb, two-stage study) evaluated abatacept + methotrexate versus methotrexate alone, in methotrexate-naive, anti-citrullinated protein antibody-positive patients with early (≤ 6 months), active RA. This subanalysis investigated whether individual patients who achieved the week 24 Simplified Disease Activity Index (SDAI) remission primary endpoint could sustain remission to 1 year and then maintain it following changes in therapy. METHODS: During the 56-week induction period (IP), patients were randomized to weekly subcutaneous abatacept 125 mg + methotrexate or abatacept placebo + methotrexate. Patients completing the IP who achieved SDAI remission (≤ 3.3) at weeks 40 and 52 entered a 48-week de-escalation (DE) period. Patients treated with abatacept + methotrexate were re-randomized to continue weekly abatacept + methotrexate, or de-escalate and then withdraw abatacept (after 24 weeks), or receive abatacept monotherapy. Proportions of patients achieving sustained SDAI and Boolean remission, and Disease Activity Score in 28 joints using C-reactive protein (DAS28 [CRP]) < 2.6, were assessed. For patients achieving early sustained SDAI remission at weeks 24/40/52, flow between disease activity categories and individual trajectories was evaluated; flow was also evaluated for later remitters (weeks 40/52 but not week 24). RESULTS: Among patients treated with abatacept + methotrexate (n/N = 451/752) at IP week 24, 22% achieved SDAI remission, 17% achieved Boolean remission, and 42% achieved DAS28 (CRP) < 2.6; of these, 56%, 58%, and 74%, respectively, sustained a response throughout IP weeks 40/52. Among patients with a sustained response at IP weeks 24/40/52, 82% (14/17) on weekly abatacept + methotrexate, 81% (13/16) on abatacept monotherapy, 63% (12/19) who de-escalated/withdrew abatacept, and 65% (11/17) on abatacept placebo + methotrexate were in SDAI remission at end of the DE period; rates were higher than for later remitters in all arms except abatacept placebo + methotrexate. CONCLUSIONS: A high proportion of individual patients achieving clinical endpoints at IP week 24 with abatacept + methotrexate sustained their responses through week 52. Of patients achieving early and sustained SDAI remission through 52 weeks, numerically more maintained remission during the DE period if weekly abatacept treatment continued. TRIAL REGISTRATION: NCT02504268 (ClinicalTrials.gov), registered July 21, 2015.

Improvement or Worsening of Disease Activity After Switch to Sarilumab in Patients With Rheumatoid Arthritis With a Partial Response to Adalimumab.

OBJECTIVE: The aim of this study was to assess the effect of switching from adalimumab to sarilumab monotherapy in partial responders with rheumatoid arthritis from the MONARCH randomized trial and its open-label extension (OLE). METHODS: Partial response was defined as improvement in Clinical Disease Activity Index (CDAI) of 12 or 6 units (baseline score: >22 or >10 and ≤22, respectively). Proportions of adalimumab partial responders with meaningful worsening or improvement at OLE weeks 12 and 24 were evaluated using 2 CDAI thresholds (≥6 and ≥12 points), 28-joint Disease Activity Score using erythrocyte sedimentation rate (≥0.6 and ≥1.2 points), Health Assessment Questionnaire Disability Index (≥0.22 and ≥0.30 points), Simple Disease Activity Index (≥7 and ≥13 points), physician and patient global assessments (≥10 and ≥20), and 28-joint swollen and tender joint counts (≥1 and ≥2 joints). Outcomes were analyzed using mixed-effect models with repeated measures for observed cases. The p values were produced using Wilcoxon tests. RESULTS: Of 369 enrolled patients, 320 (87%) entered the OLE and 155 switched from adalimumab to sarilumab; 59% (91/155) were partial responders. At week 24, 4%-17% and 2%-12% of partial responders experienced a worsening using the lower and higher thresholds, respectively, whereas 47%-78% and 27%-66% experienced improvement. CONCLUSIONS: Partial responders to adalimumab who switched to sarilumab had a low likelihood of experiencing meaningful worsening, with most patients showing meaningful improvement or no change in disease activity. This may help alleviate patients' fears of worsening when considering switching to a treatment with a different mechanism of action.

Sustained Remission and Outcomes with Abatacept plus Methotrexate Following Stepwise Dose De-escalation in Patients with Early Rheumatoid Arthritis.

INTRODUCTION: One target of rheumatoid arthritis (RA) treatment is to achieve early sustained remission; over the long term, patients in sustained remission have less structural joint damage and physical disability. We evaluated Simplified Disease Activity Index (SDAI) remission with abatacept + methotrexate versus abatacept placebo + methotrexate and impact of de-escalation (DE) in anti-citrullinated protein antibody (ACPA)-positive patients with early RA. METHODS: The phase IIIb, randomized, AVERT-2 two-stage study (NCT02504268) evaluated weekly abatacept + methotrexate versus abatacept placebo + methotrexate. PRIMARY ENDPOINT: SDAI remission (≤ 3.3) at week 24. Pre-planned exploratory endpoint: maintenance of remission in patients with sustained remission (weeks 40 and 52) who, from week 56 for 48 weeks (DE period), (1) continued combination abatacept + methotrexate, (2) tapered abatacept to every other week (EOW) + methotrexate for 24 weeks with subsequent abatacept withdrawal (abatacept placebo + methotrexate), or (3) withdrew methotrexate (abatacept monotherapy). RESULTS: Primary study endpoint was not met: 21.3% (48/225) of patients in the combination and 16.0% (24/150) in the abatacept placebo + methotrexate arm achieved SDAI remission at week 24 (p = 0.2359). There were numerical differences favoring combination therapy in clinical assessments, patient-reported outcomes (PROs) and week 52 radiographic non-progression. After week 56, 147 patients in sustained remission with abatacept + methotrexate were randomized (combination, n = 50; DE/withdrawal, n = 50; abatacept monotherapy, n = 47) and entered DE. At DE week 48, SDAI remission (74%) and PRO improvements were mostly maintained with continued combination therapy; lower remission rates were observed with abatacept placebo + methotrexate (48.0%) and with abatacept monotherapy (57.4%). Before withdrawal, de-escalating to abatacept EOW + methotrexate preserved remission. CONCLUSIONS: The stringent primary endpoint was not met. However, in patients achieving sustained SDAI remission, numerically more maintained remission with continued abatacept + methotrexate versus abatacept monotherapy or withdrawal. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02504268. Video abstract (MP4 62241 KB).

Patients with rheumatoid arthritis (RA) experience inflamed and damaged joints. RA is an autoimmune disease in which proteins called autoantibodies, particularly anti-citrullinated protein autoantibodies, target the patient's own joint tissue and organs by mistake, leading to symptomatic inflammation. Successful treatment can decrease the disease's activity to a state known as remission. Patients in remission may experience little or no symptoms and it may be possible for some to then be able to decrease their treatment. Here, we report the results of a large, international study that looked at two treatments, abatacept and methotrexate, in patients with RA and anti-citrullinated protein autoantibodies. The study had two parts. Firstly, to see how many patients had success (remission) with weekly abatacept and/or methotrexate treatment, and secondly, to see if remission was maintained when treatment was either continued or decreased and stopped. The study showed that the number of patients in remission 6 months after treatment started was not greatly different between patients treated with both abatacept and methotrexate and those treated with just methotrexate. Those taking abatacept and methotrexate together had better remission rates 1 year later. More patients also stayed in remission when they continued to receive both abatacept and methotrexate compared with those who were just treated with abatacept or when their abatacept treatment was decreased and stopped. More patients stayed in remission when abatacept was decreased than when it was stopped. The results from this study may help determine possible future treatment reduction and/or withdrawal plans for some patients with RA.

Clonal associations of lymphocyte subsets and functional states revealed by single cell antigen receptor profiling of T and B cells in rheumatoid arthritis synovium.

Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in GZMK+ cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), NR4A1+ activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.

Meaningful Improvement and Worsening in Patients Who Do Not Achieve Low Disease Activity and Switch Therapy to a New Biologic or Targeted Disease-Modifying Antirheumatic Drug: Results From the CorEvitas RA Registry.

OBJECTIVE: The aim of this study was to assess the change in disease activity associated with switching from 1 biologic/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) to another in patients with rheumatoid arthritis who did not achieve low disease activity (LDA) after 6 to 12 months of their initial treatment. METHODS: This observational study included patients from the CorEvitas Rheumatoid Arthritis Registry, who initiated a b/tsDMARD at the index visit (prebaseline), had any clinical disease activity index (CDAI) improvement but did not achieve LDA/remission at the subsequent visit (baseline), and switched therapy at baseline or between baseline and follow-up visits. Regardless of the preswitch CDAI value, 2 thresholds of CDAI change were used to define meaningful improvement and worsening for all patients: ≥6 units and ≥12 units; no meaningful change was defined as any change between -6 to +6 units and -12 to +12 units, based on respective thresholds. RESULTS: Of 1226 patients fulfilling the inclusion criteria, 93 (7.6%) switched therapy at baseline or between baseline and follow-up, after an inadequate response at the baseline visit. At follow-up, meaningful worsening occurred in 30.1% and 12.9% of switchers, whereas the remaining switchers achieved meaningful improvement (34.4% and 20.4%) or had no meaningful change (35.5% and 66.7%), based on the thresholds of ≥6 and ≥12 units, respectively. CONCLUSIONS: Rheumatoid arthritis patients, who had not achieved LDA and switched b/tsDMARD, were more likely to have meaningful improvement or no change, rather than meaningful worsening. These data may help some patients overcome their hesitancy to switch therapy, potentially improving clinical outcomes.

Understanding Differences in Patient Descriptions of Rheumatoid Arthritis Flares Using OMERACT Core Domains.

OBJECTIVE: Recently, 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. METHODS: Participants 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. RESULTS: Among 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). CONCLUSION: Variations 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.

Long-Term Durability of Certolizumab Pegol in Patients with Rheumatoid Arthritis Over 5 Years: An Analysis of Pooled Clinical Trial Data.

INTRODUCTION: There is a paucity of data on how patient characteristics may affect the long-term durability of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA). This study therefore aimed to investigate CZP durability and reasons for discontinuation over 5 years between different subgroups of patients with RA. METHODS: Data were pooled from 27 clinical trials in RA patients. Durability was defined as the percentage of patients randomized to CZP at baseline who were still on CZP treatment at a given timepoint. Post hoc analyses of clinical trial data on CZP durability and reasons for discontinuation among different patient subgroups were conducted using Kaplan-Meier curves and Cox proportional hazards modeling. Patient subgroups included: age (18- < 45/45- < 65/ ≥ 65 years), gender (male/female), prior tumor necrosis factor inhibitor (TNFi) use (yes/no), and disease duration (< 1/1- < 5/5- < 10/ ≥ 10 years). RESULTS: Among 6927 patients, the durability of CZP was 39.7% at 5 years. Patients aged ≥ 65 years had a 33% greater risk of CZP discontinuation than patients 18- < 45 years (hazard ratio [95% confidence interval]: 1.33 [1.19-1.49]) and patients with prior TNFi use had a 24% greater risk of discontinuing CZP than patients without (1.24 [1.12-1.37]). Conversely, greater durability was observed among patients who had a baseline disease duration of ≥ 1 year. Durability did not differ in the gender subgroup. Of the 6927 patients, the most common reason for discontinuation was inadequate levels of efficacy (13.5%); followed by adverse events (11.9%); consent withdrawn (6.7%); lost to follow-up (1.8%); protocol violation (1.7%); other reasons (9.3%). CONCLUSIONS: CZP durability was comparable with durability data on other bDMARDs in RA patients. Patient characteristics that were associated with greater durability included younger age, TNFi-naïvety, and disease duration ≥ 1 year. Findings may be helpful in informing clinicians on a patient's likelihood of discontinuing CZP, based on their baseline characteristics.

Effects of Disease-Worsening Following Withdrawal of Etanercept or Methotrexate on Patient-Reported Outcomes in Patients With Rheumatoid Arthritis: Results From the SEAM-RA Trial.

BACKGROUND/OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.