Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial.

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.

Predicting successful biologics tapering in patients with inflammatory arthritis: Secondary analyses based on the BIOlogical Dose OPTimisation (BIODOPT) trial.

AIMS: To evaluate predictors for successful biologic tapering among patients with inflammatory arthritis using baseline characteristics from the BIODOPT trial. METHODS: Adult patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis on stable biologic dose and in low disease activity ≥12 months were enrolled. Participants were randomized (2:1) to disease activity-guided biologic tapering or continuation of baseline biologic. Patients achieving successful tapering reduced their biologic dose by ≥50%, had no protocol deviations and were in low disease activity at 18 months. Modified Poisson regression with robust variance estimator was applied. RESULTS: In total, 142 patients were randomized to tapering (n = 95) or control (n = 47). Successful tapering was achieved by 32 and 2%, respectively. Tapering group was the only statistically significant independent predictor for successful tapering, risk ratio (RR): 14.0 (95% confidence interval [CI]: 1.9 to 101.3, P = .009). However, higher Short Form Health Survey 36 mental component summary (SF-36 MCS) was observed to be a predictor of potential importance, RR: 1.06 (95% CI: 0.99 to 1.13, P = .097). When limiting the analyses to the tapering group only, none of the baseline variables were statistically significant independent predictors but SF-36 MCS was still considered to be of potential importance, RR: 1.05 (95% CI: 0.99 to 1.12, P = .098). CONCLUSION: Successful tapering is a reachable target for 1 in 3 patients with inflammatory arthritis who are interested in reducing their biological therapy. No statistically significant predictors (besides allocation to tapering) were identified. Future research on mental health and tapering is encouraged.

Isolation in patients with inflammatory rheumatic diseases during COVID-19 pandemic compared to healthy individuals: a questionnaire survey.

As a result of the pandemic, many patients with an inflammatory rheumatic disease (IRD) have isolated themselves. The lack of disease management together with fear of infection could lead to changes in physical- and mental health. The aim of this study was to evaluate the social- and health behaviour in patients with an IRD compared with the behaviour of healthy individuals during the COVID-19 pandemic. The study was a questionnaire survey answered by patients with an IRD and healthy individuals (HI). The questionnaire contained seven sections with questions regarding COVID-19 and quality of life including SF-36, EQ-5D-5L, and visual analogue scale (VAS) pain, fatigue and global health. Of 1663 invited participants, 661 patients with IRD and 266 HI were included in the analyses. Patients with an IRD felt more isolated during the COVID-19 pandemic compared with HI (IRD: 9.5% (61/644), HI: 3.1% (8/259), p-value = 0.001). More HI (5.4%) had been infected with COVID-19 than patients with an IRD (1.7%). Among patients with an IRD those with worse self-reported disease activity outcomes (VAS pain, fatigue and global health, all p-value < 0.001), worse social functioning and emotional well-being were more isolated than individuals with low disease activity. Patients with an IRD feel more isolated during the COVID-19 pandemic compared to HI. Isolation seems to be most pronounced in patients with worse disease related patient-reported outcomes and lower quality of life.

Risk of flare after tapering or withdrawal of biologic/targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis or axial spondyloarthritis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis in sustained remission or with low disease activity. METHODS: Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto's odds ratio (POR) for sparse events and 95% CI. RESULTS: The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation [RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5%] and potentially increased for persistent flare [POR 1.56 (95% CI 0.97, 2.52), I2 = 0%]. Comparing TNF inhibitor (TNFi) withdrawal with continuation, a highly increased flare risk [RR 2.28 (95% CI 1.78, 2.93), I2 = 78%] and increased odds of persistent flare [POR 3.41 (95% CI 1.91, 6.09), I2 = 49%] were observed. No clear difference in flare risk between RA or axSpA was observed. CONCLUSION: A high risk for flare and persistent flare was demonstrated for TNFi withdrawal, whereas an increased risk for flare but not for persistent flare was observed for b-/tsDMARD tapering. Thus tapering seems to be the more favourable approach. REGISTRATION: PROSPERO (CRD42019136905).

Patient-reported outcome measures in systemic lupus erythematosus by a web-based application: A randomized, crossover, agreement study.

OBJECTIVES: Patient-reported outcome measures (PROMs) are evaluated in randomized controlled trials (RCTs) in patients with systemic lupus erythematosus (SLE), but not widely used in clinical practice. However, interest in incorporating PROMs into the management of SLE is increasing as PROMs provide a unique insight into the patient's perception of lupus disease activity. The objective was to assess agreement in PROMs answered using a web app versus an outpatient touchscreen among patients with SLE. METHODS: In a crossover RCT, SLE patients answered the following PROMs in a random order using the web app and the outpatient touchscreen: Systemic Lupus Erythematosus Activity Questionnaire (SLAQ) Global Health, SLAQ Symptom, SLAQ Total, SLAQ Worsening, Pain Visual Analog Scale (VAS), Fatigue VAS, Patient Global Health VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), Patient Acceptable Symptom State (PASS), and an Anchoring Question. Equivalence between the two device types was demonstrated if the 95% confidence interval (95% CI) of the difference in PROM scores was within the prespecified equivalence margin. Agreement between the two device types was assessed using mixed linear models. RESULTS: Thirty-four patients with SLE were included. Equivalence was demonstrated between the two device types for SLAQ Global Health with a difference of -0.21 (95% CI: -0.65 to 0.23). Moreover, equivalence was also found for HAQ-DI, Pain VAS, and Fatigue VAS whereas only comparability within the limits of the Minimal Clinically Important Difference (MCID) was demonstrated for VAS Patient Global Health. Statistical comparability was demonstrated for SLAQ Total, SLAQ Worsening, PASS, and Anchoring Question (no predefined MCID/equivalence margins available). However, a statistically significant difference between device types was observed for the SLAQ Symptom of -0.56 (95% CI: -1.10 to -0.01). The difference was, however, very small when considering the scale range of 0-24; thus, it was not judged to be of clinical relevance. Preference for the web app was very high (91.2%). CONCLUSION: For the first time ever, equivalence and comparability between two electronic device types for various PROMs were demonstrated among patients with SLE. Implementation of the device is expected to improve the management of SLE.

Incidence and severeness of COVID-19 hospitalization in patients with inflammatory rheumatic disease: a nationwide cohort study from Denmark.

OBJECTIVES: To estimate the incidence of COVID-19 hospitalization in patients with inflammatory rheumatic disease (IRD); in patients with RA treated with specific DMARDs; and the incidence of severe COVID-19 infection among hospitalized patients with RA. METHODS: A nationwide cohort study from Denmark between 1 March and 12 August 2020. The adjusted incidence of COVID-19 hospitalization was estimated for patients with RA; spondyloarthritis including psoriatic arthritis; connective tissue disease; vasculitides; and non-IRD individuals. Further, the incidence of COVID-19 hospitalization was estimated for patients with RA treated and non-treated with TNF-inhibitors, HCQ or glucocorticoids, respectively. Lastly, the incidence of severe COVID-19 infection (intensive care, acute respiratory distress syndrome or death) among hospital-admitted patients was estimated for RA and non-IRD sp - individudals. RESULTS: Patients with IRD (n = 58 052) had an increased partially adjusted incidence of hospitalization with COVID-19 compared with the 4.5 million people in the general population [hazard ratio (HR) 1.46, 95% CI: 1.15, 1.86] with strongest associations for patients with RA (n = 29 440, HR 1.72, 95% CI: 1.29, 2.30) and vasculitides (n = 4072, HR 1.82, 95% CI: 0.91, 3.64). There was no increased incidence of COVID-19 hospitalization associated with TNF-inhibitor, HCQ nor glucocorticoid use. COVID-19 admitted patients with RA had a HR of 1.43 (95% CI: 0.80, 2.53) for a severe outcome. CONCLUSION: Patients with IRD were more likely to be admitted with COVID-19 than the general population, and COVID-19 admitted patients with RA could be at higher risk of a severe outcome. Treatment with specific DMARDs did not affect the risk of hospitalization.

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.

OBJECTIVE: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. DESIGN: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. SETTING: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. PARTICIPANTS: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. INTERVENTIONS: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. MAIN OUTCOME MEASURES: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. RESULTS: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. CONCLUSIONS: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. TRIAL REGISTRATION: EudraCT2011-004720-35, NCT01491815.

Dosage reduction and discontinuation of biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: protocol for a pragmatic, randomised controlled trial (the BIOlogical Dose OPTimisation (BIODOPT) trial).

INTRODUCTION: The The BIOlogical Dose OPTimisation (BIODOPT) trial is a pragmatic, multicentre, randomised controlled, open-label, parallel-group, equivalence study designed to evaluate tapering of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) in sustained clinical remission or low disease activity (LDA). Traditionally, these patients maintain standard dosage of bDMARD lifelong; however, recent studies indicate that a significant proportion of patients in sustained remission or LDA can taper their bDMARD and maintain stable disease activity. Thus, this trial aims to evaluate whether a disease activity-guided tapering strategy for bDMARDs will enable a significant dosage reduction while maintaining disease activity compared with usual care. From the individual patient's standpoint as well as from a societal perspective, it would be advantageous if bDMARDs could be reduced or even discontinued while maintaining disease activity. METHODS AND ANALYSIS: A total of 180 patients with RA, PsA or axSpA treated with bDMARDs and in clinical remission/LDA during the past 12 months will be enrolled from four centres in Denmark. Patients will be randomised in a ratio of 2:1 to either disease activity-guided tapering of bDMARDs (intervention group) or continuation of bDMARDs as usual care (control group).The primary objective is the difference between the two groups in the proportion of patients who have reduced their inclusion dosage of bDMARDs to 50% or less while maintaining stable disease activity at 18 months follow-up. ETHICS AND DISSEMINATION: The study is approved by the ethics committee of Northern Jutland, Denmark (N-20170073) and by the Danish Medicine Agency. Patient research partner KHH contributed to refinement of the protocol and approved the final manuscript. Results will be disseminated through publication in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: 2017-001970-41; Pre-results.

[Acute abdominal vasculitis in rheumatic diseases].

Mesenteric vasculitis is the most common abdominal manifestation of vasculitis and can present as acute abdominal pain. Mesenteric vasculitis is most frequent in systemic lupus erythematosus and polyarteritis nodosa in adulthood and immunoglobulin A-vasculitis in childhood. Involvement of other organs is also seen. The diagnosis can be challenging, but detailed clinical assessment in combination with diagnostic tests often identifies the underlying cause. Medical treatment is used, when the abdominal manifestation is considered reversible, while surgery is used in unstable patients or patients with non-reversible conditions.