Patient-physician discordance impairs outcomes in early rheumatoid arthritis through less consistent treat-to-target implementation.

OBJECTIVES: We aimed to assess whether patient-physician discordance regarding disease activity affects T2T-implementation and clinical outcomes in rheumatoid arthritis (RA). METHODS: This was an analysis of the 2-year T2T-guided trial Care in early RA (CareRA). During year 1, DMARD escalations were mandated by the protocol when DAS28-CRP was >3.2. During year 2, treatment was at the rheumatologists' discretion. At each visit we assessed T2T-implementation, defined as escalating DMARDs if DAS28-CRP >3.2. Patient-physician discordance was defined by the discordance score (DS), a weighted difference between patient-reported and clinical/laboratory outcomes. Using generalised linear mixed models and multilevel mediation analysis, we studied the association between time-varying DS, T2T-implementation and the odds of remission (SDAI ≤3.3), physical functioning (HAQ-score), and radiographic progression at year 2. RESULTS: Over 2 years, 379 patients were assessed at 3129 follow-up visits. On 445 (14%) of these visits, DAS28-CRP was >3.2, and DMARDs were escalated in 217/445 (49%) of such cases. T2T-implementation declined over time and was consistently lower during the second year (year 1: 57-66%; year 2: 17-52%). Higher DS over time was negatively associated with remission and physical functioning at year 2, partly mediated by a lower proportion of T2T-adherent visits. No such association was found for radiographic progression. CONCLUSION: Even in a trial setting, T2T was applied on only around 50% of visits. T2T was less likely to be implemented with increasing patient-physician discordance regarding disease activity, which was in turn associated with less remission and worse functional outcome, but not with radiographic progression.

Longitudinal trajectories of fatigue in early RA: the role of inflammation, perceived disease impact and early treatment response.

OBJECTIVE: Fatigue is common in rheumatoid arthritis (RA). We aimed to explore its longitudinal course, predictors and association with disease activity in early RA. METHODS: Data came from the 2-year treat-to-target trial CareRA (Care in early RA) and its 3-year extension. Fatigue was measured on Visual Analogue Scale, Multidimensional Fatigue Inventory and Short Form-36 (SF-36) vitality. Longitudinal fatigue trajectories were identified with multivariate growth mixture modelling. Early predictors of fatigue and the association of fatigue and its trajectories with disease activity and clinical/psychosocial outcomes were studied with linear mixed models and multilevel mediation. RESULTS: We included 356 and 244 patients in the 2-year and 5-year analyses, respectively. Four fatigue trajectories were identified: rapid, gradual, transient improvement and early deterioration, including 10%, 14%, 56% and 20% of patients. Worse pain, mental health and emotional functioning were seen in the early deterioration group. Higher pain, patient global assessment (PGA) and disability (Health Assessment Questionnaire), lower SF-36 mental components, and fewer swollen joints at baseline predicted higher fatigue over 5 years, while early disease remission strongly improved 5-year fatigue. The association between Simple Disease Activity Index and fatigue was mediated by PGA, pain, mental health and sleep quality. CONCLUSIONS: Although fatigue evolves dynamically over time in early RA, most patients do not achieve sustained fatigue improvement despite intensive disease-modifying antirheumatic drug therapy. Higher 5-year fatigue levels were seen in patients with more perceived disease impact and fewer swollen joints at baseline. Conversely, early inflammatory disease control strongly improved long-term fatigue, pointing towards an early window of opportunity to prevent persistent fatigue.

New indicator for discordance between patient-reported and traditional disease activity outcomes in patients with early rheumatoid arthritis.

OBJECTIVE: To unravel disease impact in early RA by separately quantifying patient-reported (PRF), clinical (CF) and laboratory (LF) factors. We propose a new indicator, the discordance score (DS), for early identification and prediction of patient's unmet needs and of future achievement of sustained remission (SR) and RA-related quality of life (QoL). METHODS: Factor-scores obtained by factor analysis in the CareRA trial, allowed to compute DS, reflecting the difference between PRF and the mean of CF and LF. Improvement from baseline to week 104 (%) and area-under-the-curve (AUC) across time points per factor-score were calculated and compared between patients achieving/not achieving sustained (week 16-104) remission (DAS28CRP < 2.6) with ANOVA. Logistic and linear regressions were used to predict SR based on previous factor and discordance scores, and QoL at year 1 and 2 based on DS at week 16. RESULTS: PRF, CF and LF scores improved rapidly within 8 weeks. PRF improved 57%, CF 90% and LF 27%, in those achieving SR, compared with 32% (PRF: P = 0.13), 77% (CF: P < 0.001) and 9% (LF: P = 0.36) in patients not achieving SR. Patients achieving SR had an AUC of 15.7, 3.4 and 4.8 for PRF, CF and LF, respectively, compared with 33.2, 10.1 and 7.2 in participants not achieving SR (P < 0.001 for all). Early discordance was associated with later factor scores, QoL and self-efficacy. CONCLUSIONS: All factor scores improved rapidly, especially in patients achieving sustained remission. Patient-reported burden improved less. Discordance scores could help predicting the need for additional non-pharmacological interventions to achieve sustained remission and decrease disease impact.

Five-year treat-to-target outcomes after methotrexate induction therapy with or without other csDMARDs and temporary glucocorticoids for rheumatoid arthritis in the CareRA trial.

OBJECTIVES: To compare outcomes of different treatment schedules from the care in early rheumatoid arthritis (CareRA) trial over 5 years. METHODS: Patients with RA completing the 2-year CareRA randomised controlled trial were eligible for the 3-year observational CareRA-plus study. 5-year outcomes after randomisation to initial methotrexate (MTX) monotherapy with glucocorticoid bridging (COBRA-Slim) were compared with MTX step-up without glucocorticoids or conventional synthetic disease-modifying antirheumatic drug (DMARD) combinations with glucocorticoid bridging, per prognostic patient group. Disease activity (Disease Activity Score based on 28 joints calculated with C reactive protein (DAS28-CRP)) and functionality (Health Assessment Questionnaire (HAQ)) were compared between treatment arms using longitudinal models; safety and drug use were detailed. RESULTS: Of 322 eligible patients, 252 (78%) entered CareRA-plus, of which 203 (81%) completed the study. Treatments for high-risk patients resulted in comparable DAS28-CRP (p=0.539) and HAQ scores over 5 years (p=0.374). Low-risk patients starting COBRA-Slim had lower DAS28-CRP (p<0.001) and HAQ scores (p=0.041) than those starting only on MTX. At study completion, 114/203 (56%) patients never had their original DMARD therapy intensified, with comparable rates between all treatments. Safety was comparable between treatments in high-risk patients. In low-risk patients, there were 18 adverse events in 10 COBRA-Slim and 36 in 17 patients treated with initial MTX monotherapy (p=0.048). Over 5 years, 22% of patients initiated biologics, 25% took glucocorticoids for >3 months and 17% for >6 months outside the bridging period. CONCLUSIONS: All intensive treatments with glucocorticoids bridging demonstrated excellent 5 year outcomes. Initiating COBRA-Slim was comparably effective as more complex treatments for high-risk patients with early RA and more effective than initial MTX monotherapy for low-risk patients with limited need for biologics and chronic glucocorticoid use.

Having a co-morbidity predicts worse outcome in early rheumatoid arthritis despite intensive treatment: a post hoc evaluation of the pragmatic randomized controlled CareRA trial.

OBJECTIVES: To quantify the prevalence of co-morbidities in patients with early RA and determine their prognostic value for effectiveness outcomes in a randomized trial. METHODS: We included patients from the 2-year pragmatic randomized CareRA trial, who had early RA (diagnosis < 1 year), were DMARD naïve and then treated-to-target with different remission induction schemes. Prevalence of co-morbidities was registered at baseline and the Rheumatic Diseases Comorbidity Index (RDCI; range 0-9) was calculated. We tested the relation between baseline RDCI and outcomes including disease activity (DAS28-CRP), physical function (HAQ index), quality of life (SF-36 domains) and hospitalizations over 2 years, using linear mixed models or generalized estimating equations models. RESULTS: Of 379 included patients, 167 (44%) had a RDCI of minimum 1. RDCI scores of 1, 2 or ≥3 were obtained in 65 (17%), 70 (19%), and 32 (8%) participants, respectively. The most frequent co-morbidity was hypertension (22%). Patients with co-morbidities had significantly higher HAQ (ß = 0.215; 95% CI: 0.071, 0.358), DAS28-CRP (ß = 0.225; 95% CI: 0.132, 0.319) and lower SF-36 physical component summary scores (ß =-3.195; 95% CI: -4.844, -1.546) over 2 years than patients without co-morbidities, after adjusting for possible confounders including disease activity and randomized treatment. Patients with co-morbidities had over time lower chances of achieving remission (OR = 0.724; 95% CI: 0.604, 0.867) and a higher risk of hospitalization (OR = 3.725; 95% CI: 2.136, 6.494). CONCLUSION: At disease onset, almost half of RA patients had at least one clinically important co-morbidity. Having co-morbidities was associated with worse functionality and disease activity outcomes over 2 years, despite intensive remission induction treatment. TRIAL REGISTRATION: Clinical trials NCT01172639.

Two-year cost-effectiveness of different COBRA-like intensive remission induction schemes in early rheumatoid arthritis: a piggyback study on the pragmatic randomised controlled CareRA trial.

OBJECTIVES: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients. METHODS: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices. RESULTS: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars. CONCLUSIONS: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment. TRIAL REGISTRATION NUMBER: NCT01172639.

Strategy using a new antigenic test for rapid diagnosis of Streptococcus pneumoniae infection in respiratory samples from children consulting at hospital.

BACKGROUND: Despite vaccination programs, Streptococcus pneumoniae remains among the main microorganisms involved in bacterial pneumonia, notably in terms of severity. The prognosis of pneumococcal infections is conditioned in part by the precocity of the diagnosis. The aim of this study was to evaluate the impact of a Rapid Diagnostic Test (RDT) targeting cell wall polysaccharide of Streptococcus pneumoniae and performed directly in respiratory samples, on the strategy of diagnosis of respiratory pneumococcal infections in children. RESULTS: Upper-respiratory tract samples from 196 children consulting at hospital for respiratory infection were tested for detecting S. pneumoniae using a newly-designed RDT (PneumoResp, Biospeedia), a semi-quantitative culture and two PCR assays. If positive on fluidized undiluted specimen, the RDT was repeated on 1:100-diluted sample. The RDT was found highly specific when tested on non-S. pneumoniae strains. By comparison to culture and PCR assays, the RDT on undiluted secretions exhibited a sensitivity (Se) and negative predictive value (NPV) of more than 98%. By comparison to criteria of S. pneumoniae pneumonia combining typical symptoms, X-ray image, and culture ≥107 CFU/ml, the Se and NPV of RDT on diluted specimens were 100% in both cases. CONCLUSIONS: In case of negative result, the excellent NPV of RDT on undiluted secretions allows excluding S. pneumoniae pneumonia. In case of positive result, the excellent sensitivity of RDT on diluted secretions for the diagnosis of S. pneumoniae pneumonia allows proposing a suitable antimicrobial treatment at day 0.

Effectiveness of different combinations of DMARDs and glucocorticoid bridging in early rheumatoid arthritis: two-year results of CareRA.

OBJECTIVES: To investigate whether MTX should be combined with an additional DMARD and bridging glucocorticoids as initial treatment for patients with early RA to induce an effective long-term response. METHODS: The Care in early RA study is a two-year investigator-initiated pragmatic multicentre randomized trial. Early RA patients, naïve to DMARDs and glucocorticoids, were stratified based on prognostic factors. High-risk patients were randomized to COBRA-Classic (n = 98): MTX, sulfasalazine, prednisone step-down from 60 mg; COBRA-Slim (n = 98): MTX, prednisone step-down from 30 mg; or COBRA-Avant-Garde (n = 93): MTX, leflunomide, prednisone step-down from 30 mg. Low-risk patients were randomized to COBRA-Slim (n = 43); or Tight Step Up (TSU) (n = 47): MTX without prednisone. Clinical/radiological outcomes at year 2, sustainability of response, safety and treatment adaptations were assessed. RESULTS: In the high-risk group 71/98 (72%) patients achieved a DAS28-CRP < 2.6 with COBRA-Slim compared with 64/98 (65%) with COBRA-Classic and 69/93 (74%) with COBRA-Avant-Garde (P = 1.00). Other clinical/radiological outcomes and sustainability of response were similar. COBRA-Slim treatment resulted in less therapy-related adverse events compared with COBRA-Classic (P = 0.02) or COBRA-Avant-Garde (P = 0.005). In the low-risk group, 29/43 (67%) patients on COBRA-Slim and 34/47 (72%) on TSU achieved a DAS28-CRP < 2.6 (P = 1.00). On COBRA-Slim, low-risk patients had lower longitudinal DAS28-CRP scores over 2 years, a lower need for glucocorticoid injections and a comparable safety profile compared with TSU. CONCLUSION: All regimens combining DMARDs with glucocorticoids were effective for patients with early RA up to 2 years. The COBRA-Slim regimen, MTX monotherapy with glucocorticoid bridging, provided the best balance between efficacy and safety, irrespective of patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01172639.

Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial.

OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.

Treat-to-target fixed dose rituximab retreatment versus fixed interval retreatment with disease activity-guided rituximab dose optimisation for patients with rheumatoid arthritis: study protocol for a multicentre randomised controlled superiority trial focusing on long-term disease impact (RITUXERA).

BACKGROUND: The optimal retreatment strategy with rituximab for rheumatoid arthritis (RA) remains a point of discussion. Depending on local guidelines, rituximab can either be administered at fixed intervals or when losing disease control, balancing therapeutic effectiveness with drug overexposure. However, treatment based on loss of disease control may significantly affect patients' lives, provoking uncertainty and potentially leading to progressive joint damage. Moreover, as low-dose rituximab proved to be effective in treating RA while decreasing toxicity, drug exposure may be limited by tapering down rituximab doses guided by disease activity. METHODS: RITUXERA is a 104-week open-label multicentre randomised controlled superiority trial. In total, 134 patients with RA treated with rituximab will be 1:1 randomised when in need of retreatment (DAS28-CRP ≥ 3.2 with previous rituximab administration at least 24 weeks earlier) to either a treat-to-target-driven fixed dose retreatment strategy (usual care group) or fixed interval disease-activity guided dose optimisation strategy (experimental group). The usual care group will be retreated with fixed rituximab doses (1 × 1000 mg IV) in case of loss of disease control (DAS28-CRP ≥ 3.2). The experimental group will receive a 24-weekly rituximab treatment while tapering down the dose in a decreasing sequence if DAS28-CRP ≤ 3.2: 1 × 1000 mg IV (maximal dose), 1 × 500 mg IV, and 1 × 200 mg IV (minimal dose). If DAS28-CRP exceeds 3.2 at the six-monthly retreatment, patients will receive and remain on the previous effective dose. Study visits are planned every 12 weeks. Primary outcome is the comparison of longitudinal patient-reported disease impact over 104 weeks, measured with the Rheumatoid Arthritis Impact of Disease (RAID) instrument, analysed using a linear mixed model. Main secondary outcome is the comparison of longitudinal disease activity (DAS28-CRP) over 104 weeks. DISCUSSION: The RITUXERA trial aims to explore the optimal retreatment strategy with rituximab for RA in terms of long-term patient-reported disease impact, by proposing a fixed interval disease activity-guided dose optimisation strategy as compared to a treat-to-target fixed dose strategy. TRIAL REGISTRATION: CTIS 2023-506638-59-01 (registration date: 07 September 2023), ClinicalTrials.gov NCT06003283 (registration date: 17 August 2023).

To flare or not to flare: patients' and rheumatologists' perceptions on the on-flare retreatment strategy of rituximab in rheumatoid arthritis.

Background: Several retreatment strategies exist for rituximab in rheumatoid arthritis (RA). In some countries, reimbursement criteria require a loss of disease control for rituximab retreatment. Understanding the patients' and rheumatologists' perceptions regarding this retreatment strategy would be informative in identifying the optimal treatment administration schedule. Objectives: This study aimed to uncover patients' and rheumatologists' perceptions regarding retreatment strategies of rituximab. Design: Qualitative study - semi-structured interviews. Methods: Patients with RA, treated with rituximab, and rheumatologists were invited to participate in a qualitative study consisting of individual, in-depth, semi-structured interviews. Interviews were analysed according to the Qualitative Analysis Guide of Leuven. Results: A total of 16 patients and 13 rheumatologists were interviewed. Benefits (e.g. decreased risk of overtreatment, cost savings and long-lasting effectiveness of rituximab) and barriers (e.g. fluctuating disease activity, slow mode of action and increased glucocorticoid use) of on-flare retreatment were identified. To effectively treat on-flare, flares must first be identified timely. Both stakeholder groups acknowledged that patients are capable of recognizing flares. However, the patient's ability to discriminate between inflammatory and other types of pain was perceived as difficult. Furthermore, patients and rheumatologists stressed that patients must timely seek professional help in case of a flare, followed by a swift response from the rheumatologists. Remarkably, retreatment was approached in various ways among rheumatologists, and not always adhering strictly to the on-flare reimbursement criteria. Conclusion: This study revealed that both stakeholder groups perceived the heterogeneity in recognition of and reaction to a flare as important in influencing the effectiveness of the on-flare retreatment strategy. Moreover, this study identified the benefits and barriers of treating on-flare, which could be informative for daily practice decisions.

Effects of implementing a vaccination tool in the electronic medical record on vaccination coverage of patients with immune-mediated inflammatory diseases: a prospective cohort study.

BACKGROUND: The rising incidence of immune-mediated inflammatory diseases (IMID) requires innovative management strategies, including effective vaccination. We aimed to assess the impact of an electronic medical record (EMR)-integrated vaccination tool on vaccination coverage among patients with inflammatory bowel diseases (IBD), rheumatological and dermatological conditions. METHODS: A prospective observational study compared vaccination coverage before (2018) and after (2021) implementing the module. Vaccination data for influenza, pneumococcus, hepatitis B and tetanus, and potential predictors were collected from 1430 IMID patients (44.9% male, median age (interquartile range [IQR]) 54 (40-66) years, 789 with IBD, 604 with rheumatological and 37 with dermatological conditions). Data were analysed using McNemar, chi-square tests and multinominal logistic regression. RESULTS: Significant increases in pneumococcus (56.6% to 73.1%, p < .001) and hepatitis B vaccination (62.2% to 75.9%, p < .001) were observed. Influenza vaccination rates increased among IBD (76.2% to 80.5%, p = .006) but remained stable overall (73.1% to 73.2%, p = 1.000). Tetanus vaccination rates decreased (71.5% to 55.0%, p < .001). The proportion of fully vaccinated patients (against influenza in the past year for patients >50 years old and/or under immunosuppressive therapy, against pneumococcus in the past 5 years for patients >65 years old and/or under immunosuppressive therapy and additionally against hepatitis B for IBD patients) rose from 41.3% to 54.8% (p < .001 all using McNemar). Factors associated with vaccinations included age, immunosuppressive therapy and education level. CONCLUSIONS: Increased vaccination coverage was measured after implementing the vaccination tool. The COVID19 pandemic and the 2018 measurement might have increased vaccination awareness. Education of patients and healthcare professionals remains crucial.

Patients' and rheumatologists' perceptions on dose reduction of rituximab in rheumatoid arthritis.

OBJECTIVE: The recommended dose of a rituximab course for the treatment of Rheumatoid Arthritis (RA) consists of two infusions of 1000 mg with a 2-week interval. Evidence is growing that a lower dose could be as effective. We aimed to investigate patients' and rheumatologists' perceptions on dose reduction of rituximab. METHODS: Patients with RA treated with rituximab, and rheumatologists were invited for a qualitative study via individual semi-structured interviews. Participants were recruited based on purposive sampling to ensure diversity. Interviews were analysed according to the principles of grounded theory and the constant comparative method. RESULTS: Sixteen patients and 13 rheumatologists were interviewed. Patients and rheumatologists perceived the benefits of rituximab dose reduction for reasons of safety and societal costs. Furthermore, available evidence for the effectiveness of lower doses was mentioned as an argument in favour, in addition to the possibility to tailor the dose based on the patients' clinical manifestations. However, patients and rheumatologists had concerns about the potential loss of effectiveness and quality of life. Moreover, some rheumatologists felt uncomfortable with dose reduction due to insufficient experience with rituximab in general. Patients and rheumatologists emphasised the importance of shared decision-making, underscoring the pivotal role of physicians in this process by explaining the reasoning behind dose reduction. CONCLUSION: Although some concerns on effectiveness were perceived, both patients and rheumatologists saw potential benefits of dose reduction in terms of safety, societal costs, and application of a personalised approach. As a result, most rheumatologists and patients showed a willingness to consider dose reduction strategies.

Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial.

OBJECTIVES: To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt. METHODS: CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups. RESULTS: Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%). CONCLUSION: Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104. TRIAL REGISTRATION NUMBER: NCT03649061. CTR PILOT APPROVAL BELGIUM: S59474, EudraCT number: 2017-004054-41.

Psychosocial Burden Predicts Sustained Remission in Early Rheumatoid Arthritis: Unraveling the Complex Interplay of Well-Being and Disease Activity.

OBJECTIVE: This study investigated how psychosocial aspects of disease affect the probability of achieving sustained remission in early rheumatoid arthritis (RA) and explored the directionality of this relationship. METHODS: Data were analyzed from the randomized controlled Care in Early RA trial. Sustained remission was defined as a continued Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) of <2.6 from weeks 16 to 104. Patients completed the Short Form 36 (SF-36) health survey, Revised Illness Perception Questionnaire (IPQ-R), and the Utrecht Coping List. These psychosocial variables were studied at baseline and at week 16 as predictors of sustained remission with logistic regression. Next, subgroups of patients in remission at week 16 were identified by Latent Profile Analysis based on these psychosocial indicators. Time to first loss of remission was then compared between groups by Cox proportional hazards regression. Finally, directionality of associations between psychosocial indicators and DAS28-CRP was explored with cross-lagged panel models (CLPMs). RESULTS: Sustained DAS28-CRP remission was associated with higher SF-36 scores and less passive coping at baseline and with higher SF-36 scores and more positive IPQ-R outcomes at week 16. Among patients in DAS28-CRP remission at week 16 (n = 287), 2 subgroups were identified: a low psychosocial burden group (n = 231 of 287) and a high psychosocial burden group (n = 56 of 287). The low psychosocial burden group retained remission longer (hazard ratio 0.51 [0.35-0.73]). In the CLPM, temporal relationships between psychosocial well-being and DAS28-CRP were complex, bidirectional, and disease-phase dependent. CONCLUSION: Suboptimal psychosocial well-being and negative illness perceptions predicted lower probability of sustained remission in an early RA cohort. Illness perceptions appeared to become more clinically relevant with time. Finally, 1 in 5 patients showed worse psychosocial outcomes despite early remission, and these patients tended to lose remission earlier.

Validation and predictive capacity of a Dutch version of the FLARE-RA questionnaire within the context of a TNFi-tapering trial.

Flare Assessment in Rheumatoid Arthritis (FLARE-RA) is a self-administered tool aiming to capture current or recent flares in rheumatoid arthritis (RA). We aimed to externally validate the FLARE-RA instrument and its existing cutoffs for flare detection within a bDMARD-tapering context in established RA. Data were analyzed from the Tapering Etanercept in Rheumatoid Arthritis (TapERA) trial, which studied the feasibility of tapering etanercept in patients with established RA in sustained remission. The English FLARE-RA was translated and cross-culturally adapted into Dutch, and internal consistency and test-retest reliability were evaluated with Crohnbach's alpha and intraclass correlation coefficient (ICC). Participants completed the FLARE-RA 3-monthly for 12 months. Accuracy and optimal cutoffs of FLARE-RA to detect DAS28-defined flares were assessed using area under the receiver operating characteristic curves (AUC). Association of FLARE-RA scores with current and future flares was studied using logistic generalized estimating equations (GEE). The Dutch FLARE-RA showed excellent internal consistency and test-retest reliability (Cronbach's alpha 0.96; ICC 0.96 [95% CI 0.70-1.00]). Discriminatory capacity of FLARE-RA to detect flares was acceptable (AUC 0.77, 0.80, and 0.72 for global, arthritis, and general symptoms subscales, respectively), with an optimal global score cutoff of 4/10. In GEE-models, higher FLARE-RA scores were associated with increased odds of both current and future flares. We successfully translated and cross-culturally adapted the FLARE-RA into a Dutch version and validated its capacity to detect flares in a bDMARD-tapering context in established RA. Finally, higher FLARE-RA scores might indicate an increased risk of future flares.Trial registration: EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-004631-22/BE , EudraCT number 2012-004,631-22. Key Points • Translation and cross-cultural adaptation of the FLARE-RA resulted in a Dutch version with excellent internal consistency and test-retest reliability. • The FLARE-RA is a valid instrument to detect current OMERACT-defined flares within a bDMARD tapering setting, with an optimal global score cutoff of 4/10. • Higher scores on the FLARE-RA are associated with increased risk of future flares, which could be particularly relevant when considering DMARD tapering.

Effectiveness and feasibility of a mobile health self-management intervention in rheumatoid arthritis: study protocol for a pragmatic multicentre randomised controlled trial (AEGORA).

BACKGROUND: Rheumatoid arthritis (RA) considerably impacts patients' lives. Patients' confidence in their ability to manage this impact, or self-efficacy, can be supported with self-management interventions. One approach is to use mobile health (mHealth) applications, which can additionally provide insight into disease impact by remotely monitoring patient-reported outcomes. However, user engagement with mHealth-apps is variable, and concerns exist that remote monitoring might make patients overly attentive to symptoms. METHODS: App-based Education and GOal setting in RA (AEGORA) is a multicentre, pragmatic randomised controlled trial investigating an mHealth-based self-management intervention to improve self-efficacy and remotely monitor disease impact in patients with RA. The intervention is provided via an adapted version of the application Sidekick (Sidekick Health, Reykjavik, Iceland) and consists of education, goal setting, lifestyle advice, and remote assessment of the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire. Across two centres, 120 patients will be recruited and randomised (2:1:1) to usual care or intervention group A/B (study app with weekly/monthly prompts to complete the RAID, respectively). Outcomes are assessed at baseline and after 4-6 months. The primary endpoint is a clinically important improvement (≥ 5.5/110) in the Arthritis Self-Efficacy Scale in the combined intervention group compared to usual care. Secondary endpoints are (a) non-inferiority regarding pain catastrophising, as a measure of symptom hypervigilance; (b) superiority regarding the RAID, sleep quality, and physical activity; and (c) participant engagement with the study app. Finally, the relationship between engagement, prompted frequency of RAID questionnaires, and the primary and secondary outcomes will be explored. DISCUSSION: The AEGORA trial aims to study the effectiveness of mHealth-based, multicomponent self-management support to improve self-efficacy in the context of RA, while providing potentially valuable insights into temporal disease activity dynamics and the feasibility and possible negative effects of remote symptom monitoring in this population. TRIAL REGISTRATION: Clinicaltrials.gov NCT05888181. Retrospectively registered on March 23, 2023. Study inclusion started on March 3, 2023.

Evolution of patient characteristics in the era of biologic treatment of psoriatic arthritis: 18-year Belgian experience from the Leuven Spondyloarthritis Biologics Cohort (BioSPAR).

OBJECTIVES: Biologic treatments have revolutionized the management of PsA by significantly improving clinical manifestations and preventing structural damage. Both result in better quality of life and improved physical functioning. Since the introduction of the first TNF inhibitor (TNFi) in the early 2000s, therapeutic options for PsA are increasing steadily, and a new generation of biologics, including anti-IL-17 and anti-IL-23 strategies, allows distinct targeted approaches. The purpose of this study was to investigate whether the demographic, clinical and disease characteristics of PsA patients who are selected for first-line biologic treatment has changed over time since the introduction of biologics. METHODS: Patients with a clinical diagnosis of PsA were included in the KU Leuven BioSPAR registry, a prospective cohort of SpA and PsA patients treated with biologics and targeted synthetic DMARDs (tsDMARDs), such as apremilast and Janus kinase inhibitors. Demographics, prior DMARD use, disease characteristics and disease activity parameters were recorded at the initiation of biologic treatment and subsequently every 3 months for the first 2 years and later every 6 months. The patient data were compared in three treatment periods, corresponding to availability of the first and second generation of TNFi and the third generation of biologics. RESULTS: Analysis of 185 Caucasian patients with PsA from our prospective cohort showed longer disease duration and higher disease activity, with higher tender joint count, swollen joint count and CRP in the first period compared with the later time periods. The demographic characteristics and prior DMARD use did not change over time. Skin and nail psoriasis were more frequent in earlier compared with the later treatment periods. The bio-DMARD survival rate was similar in the early and later treatment periods. CONCLUSION: The population of patients selected for treatment escalation has changed over time since the introduction of biologics. Our results suggest that with years of experience, PsA patients might be considered earlier and for therapy intensification in patients with less active disease in comparison to profiles in the early days of biologic treatment.

Treatment response and several patient-reported outcomes are early determinants of future self-efficacy in rheumatoid arthritis.

BACKGROUND: Self-efficacy, or patients' confidence in their ability to control disease and its consequences, was recently prioritised in EULAR recommendations for inflammatory arthritis self-management strategies. However, it remains unclear which factors influence self-efficacy in early rheumatoid arthritis (RA). METHODS: Data were analysed from the 2-year RCT Care in early RA (CareRA), which studied remission-induction treatment regimens for early RA. Participants completed the Arthritis Self-Efficacy Scale (ASES), Short-Form 36 (SF-36), Revised Illness Perception Questionnaire (IPQ-R), Utrecht Coping List (UCL), RAQoL and Health Assessment Questionnaire (HAQ). Depending on time to first remission (DAS28-CRP < 2.6) and persistence of remission, treatment response was defined as persistent response, secondary failure, delayed response, late response or non-response. The association between ASES scores and clinical/psychosocial factors was explored with Spearman correlation and multivariate linear mixed models. Baseline predictors of week 104 ASES were identified with exploratory linear regression followed by multiple regression of significant predictors adjusted for DAS28-CRP, HAQ, treatment arm, treatment response, cumulative CRP/SJC28 and demographic/serologic confounders. RESULTS: All 379 patients had a recent diagnosis of RA and were DMARD-naïve at study initiation. Most patients were women (69%) and RF/ACPA-positive (66%), and the mean (SD) age was 52 (13) years. For all tested outcome measures, better perceived health correlated with higher self-efficacy. While patient-reported factors (HAQ, SF-36, RAQoL, IPQ-R, pain, fatigue and patient's global assessment) showed moderate/strong correlations with ASES scores, correlations with physician-reported factors (physician's global assessment, SJC28), TJC28 and DAS28-CRP were weak. Only more favourable outcomes on patient-reported factors and DAS28-CRP were associated with higher ASES scores at each time point. An earlier, persistent treatment response predicted higher ASES scores at both weeks 52 and 104. Significant baseline predictors of week 104 ASES included HAQ; SF-36 mental component score, vitality, mental health and role emotional; IPQ-R illness coherence, treatment control, emotional representations and consequences; UCL Passive reacting; and the RAQoL. CONCLUSIONS: Patient-reported outcomes and treatment response were early determinants of long-term self-efficacy in an early RA trial. These results provide further relevance for the window of opportunity in an early treat-to-target strategy and could help to timely identify patients who might benefit from self-management interventions. TRIAL REGISTRATION: EudraCT 2008-007225-39.