Effectiveness of longstanding exercise therapy compared with usual care for people with rheumatoid arthritis and severe functional limitations: a randomised controlled trial.

OBJECTIVES: To compare the effectiveness of longstanding (>52 weeks), supervised exercise therapy with usual care in adults with rheumatoid arthritis (RA) and severe functional limitations. METHODS: Participants were randomised 1:1 to the intervention (individualised goal-setting, active exercises, education and self-management regarding physical activity) or usual care. Primary endpoint was the change in the Patient-Specific Complaints activity ranked 1 (PSC1, 0-10) at 52 weeks. Secondary endpoints included the PSC activities ranked 2 and 3 (PSC2, PSC3), Health Assessment Questionnaire-Disability Index (HAQ-DI), Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL), 6-minute walk test (6MWT), Patient Reported Outcome Measurement Information System Physical Function-10 (PROMIS PF-10) and the Short Form-36 Physical and Mental Component Summary Scales (SF-36 PCS and MCS). (Serious) Adverse events (AEs) were recorded. Measurements were done by blinded assessors. Analyses at 52 weeks were based on the intention-to-treat principle. RESULTS: In total, 217 people (90% female, age 58.8 (SD 12.9) years) were randomised (n=104 intervention, n=98 usual care available for analyses). At 52 weeks, the improvement of the PSC1 was significantly larger in the intervention group (mean difference (95% CI) -1.7 (-2.4, -1.0)). Except for the SF-36 MCS, all secondary outcomes showed significantly greater improvements favouring the intervention (PSC2 -1.8 (-2.4, -1.1), PSC3 -1.7 (-2.4, -1.0), PROMIS PF-10 +3.09 (1.80, 4.38), HAQ-DI -0.17 (-0.29, -0.06), RAQoL -2.03 (-3.39, -0.69), SF-36 PCS +3.83 (1.49, 6.17) and 6MWT +56 (38, 75) m). One mild, transient AE occurred in the intervention group. CONCLUSION: Longstanding, supervised exercise therapy was more effective than usual care in people with RA and severe functional limitations. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL8235), included in the International Clinical Trial Registry Platform (https://trialsearch.who.int/Trial2.aspx?TrialID=NL8235).

Disease activity-guided dose optimisation including discontinuation of TNF-inhibitors in rheumatoid arthritis is effective for up to 10 years: an observational follow-up of the DRESS study.

OBJECTIVES: To investigate safety and effectiveness of disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis over 10 years. METHODS: Observational long-term extension of a randomised study of participants who completed the 3-year extension of the DRESS-study. After the randomised phase (month 0-18), disease activity-guided dose optimisation was allowed for all. Main outcomes were mean time-weighted DAS28-CRP; biological and targeted synthetic anti-rheumatic drug (b/tsDMARD) use per year as proportion of daily defined dose; proportion of patients reaching discontinuation; durability, effectiveness of subsequent dose reduction attempts; and radiographic progression between 3 and 10 years using the Sharp-van der Heijde score. RESULTS: 170 patients were included of whom 127 completed 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% confidence interval 2.10-2.16), whilst the b/tsDMARD dose reduced from 97% at baseline (95%CI 96% to 99%, n = 170)% to56% at year 10 (49% to 63%, n = 127). 119 of 161 participants (74%) with an optimisation attempt reached discontinuation, with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 14% to 29%). The mean dose reduction after dose optimisation was 48% (n = 159) for the first optimisation attempt and 33% for subsequent attempt (n = 86). 48% (41/86) of participants had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use. CONCLUSION: Long-term disease activity-guided dose optimisation of TNF-inhibitors in rheumatoid arthritis, including discontinuation and multiple tapering attempts, remains safe and effective.

Effect of using the Simple Erosion Narrowing Score or Sharp/van der Heijde score on power of rheumatoid arthritis clinical trials to detect differences in radiographic progression.

OBJECTIVES: The Simple Erosion Narrowing Score (SENS) is a simplification of the Sharp/van der Heijde score (SHS). Previous studies found SENS and SHS to have very similar measurement properties, but suggest that SENS has a lower discriminative ability that may result in reduced power. Therefore, we aimed to quantify the effect of using SENS rather than SHS on the power to show between-group differences in radiographic progression. METHODS: Using data from two clinical trials in rheumatoid arthritis (DRESS and BeSt), SENS was derived from the SHS. Criterion validity of the SENS in relation to the SHS was assessed by calculating the Spearman correlation. The power of both scores to show a difference between groups was compared using bootstrapping to generate 10.000 replications of each study. Then, the number of replications with a significant difference in progression (using ANCOVA adjusted for baseline scores) were compared. RESULTS: Correlations between SENS and SHS were all >0.9, indicating high criterion validity of SENS compared with SHS as a reference standard. There was one exception, the DRESS study showed a somewhat lower correlation for the change score at 18 months (0.787). The loss in power of SENS over SHS was limited to at most 19% (BeSt year 5). In addition, the difference in power between SENS and SHS is smaller at higher levels of power. CONCLUSION: SENS appears to be a reasonable alternative to SHS, with only a limited loss of power to show between-group differences in radiographic progression.

Treat-to-target vs fixed interval retreatment strategy with rituximab in rheumatoid arthritis: a retrospective cohort study.

To compare the effectiveness of retreatment of rheumatoid arthritis (RA) patients with rituximab (RTX) following the treat-to-target retreatment (TTr) or fixed interval retreatment (FIr) strategy. RA patients starting RTX treatment between January 2008 and June 2016, and receiving at least three infusion cycles were grouped by strategy (TTr, FIr or both). Primary outcome (between strategy difference in DAS28-CRP (Disease Activity Score in 28 joints calculated with C-reactive protein)) and secondary outcomes (flares, use of co-medication and mean yearly dose of RTX) were analyzed by group using linear mixed models to account for different strategies within patients. A total of 213 patients, 59 TTr (of whom 32 switched from TTr to FIr) and 186 FIr were included. No between-group difference in mean DAS28-CRP was found (0.10 DAS28-CRP point (95% CI - 0.07 to 0.26)). The TTr strategy did not result in more flares (IRR 1.13, 95%CI 0.87 to 1.47), conventional synthetic disease-modifying antirheumatic drug use (difference - 11.7%, 95%CI - 26.3% to 2.9%), or lower mean yearly RTX dose (difference 172 mg/yr, 95%CI - 355 to 11.7 mg/yr). RTX retreatment with either a TTr or FIr strategy does not seem to lead to better disease control and/or less drug use when used in a DAS28-CRP treat-to-target context. Choice of either strategy can, therefore, be made based on patient and physician preferences and logistical context.

Functional limitations of people with rheumatoid arthritis or axial spondyloarthritis and severe functional disability: a cross-sectional descriptive study.

The objective of the study is to describe the nature of functional limitations in activities and participation in people with Rheumatoid Arthritis (RA) or axial SpondyloArthritis (axSpA) with severe functional disability. Baseline data from people with RA (n = 206) or axSpA (n = 155) and severe functional disability participating in an exercise trial were used. Their three most limited activities were derived from the Patient Specific Complaint (PSC) instrument and linked to the International Classification of Functioning and Health (ICF). The frequencies of ICF categories were calculated and compared with Activities and Participation items of the ICF Core Sets for RA (32 second-level categories) and Ankylosing Spondylitis (AS) (24 second-level categories). In total 618 and 465 PSC activities were linked to 909 (72 unique in total; 25 unique second-level) and 759 (57 unique in total; 23 unique second-level) ICF categories in RA and axSpA. Taking into account all three prioritized activities, the five most frequent limited activities concerned the ICF chapter "Mobility", and included "Walking" (RA and axSpA 2 categories), "Changing basic body position" (RA and axSpA 1 category), "Stair climbing"(RA) and "Grasping" (RA),"Lifting" (axSpA) and "Maintaining a standing position" (axSpA). In RA, 21/32 (66%) and in axSpA 14/24 (58%) unique second-level categories identified in the prioritized activities are present in the Comprehensive Core Sets. Most limitations of people with RA or axSpA and severe functional disability were seen in the ICF chapter "Mobility". Most of the identified ICF categories were covered by the corresponding items of the ICF RA and AS Core Sets.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update.

OBJECTIVES: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. METHODS: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. RESULTS: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. CONCLUSIONS: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.

Infection incidence, timing, and dose dependency in rheumatoid arthritis patients treated with rituximab: a retrospective cohort study.

OBJECTIVES: Rituximab (RTX) is a safe and effective treatment for rheumatoid arthritis (RA). However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion. METHODS: RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression. RESULTS: Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared to 1000 mg (adjusted IRR 0.35, 95% CI 0.17-0.72, p = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared to later on in the treatment cycle, suggesting an association with peak concentration. CONCLUSION: Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk.

The added value of predictive biomarkers in treat-to-target strategies for rheumatoid arthritis patients: a conceptual modelling study.

OBJECTIVES: To quantify the additional value of a hypothetical biomarker predicting response to treatment for RA regarding efficacy and costs by using a modelling design. METHODS: A Markov model was built comparing a usual care T2T strategy with a biomarker-steered strategy for RA patients starting biologic therapy. Outcome measures include time spent in remission or low disease activity (LDA) and costs. Four additional scenario analyses were performed by varying biomarker or clinical care characteristics: (i) costs of the biomarker; (ii) sensitivity and specificity of the biomarker; (iii) proportion of eligible patients tapering; and (iv) medication costs. RESULTS: In the base model, patients spent 2.9 months extra in LDA or remission in the biomarker strategy compared with usual care T2T over 48 months. Total costs were €43 301 and €42 568 for, respectively, the usual care and biomarker strategy, and treatment costs accounted for 91% of total costs in both scenarios. Cost savings were driven due to patients in the biomarker strategy experiencing remission or LDA earlier, and starting tapering sooner. Cost-effectiveness was not so much driven by costs or test characteristics of the biomarker (scenario 1/2), but rather by the level of early and proactive tapering and drug costs (scenarios 3/4). CONCLUSIONS: The use of a biomarker for prediction of response to b/tsDMARD treatment in RA can be of added value to current treat-to-target clinical care. However, gains in efficacy are modest and cost gains are depending on a combination of early proactive tapering and high medication costs.

Seroconversion after a third COVID-19 vaccine is affected by rituximab dose but persistence is not in patients with rheumatoid arthritis.

OBJECTIVES: In patients with RA treated with (ultra-)low-dose rituximab (RTX), we investigated the association of dosing and timing of RTX on seroconversion after a third coronavirus disease 2019 (COVID-19) vaccination and the persistence of humoral response after a two-dose vaccination. MATERIAL AND METHODS: In this monocentre observational study, patients from the COVAC cohort were included in the third vaccine analysis if humoral response was obtained 2-6 weeks after a third vaccination in previous non-responders and in the persistence analysis if a follow-up humoral response was obtained before a third vaccination in previous responders. Dichotomization between positive and negative response was based on the assay cut-off. The association between the latest RTX dose before first vaccination, timing between the latest RTX dose and vaccination and response was analysed with univariable logistic regression. RESULTS: Of the 196 patients in the cohort, 98 were included in the third vaccine analysis and 23 in the persistence analysis. Third vaccination response was 19/98 (19%) and was higher for 200 mg RTX users [5/13 (38%)] than for 500 and 1000 mg users [7/37 (19%) and 7/48 (15%), respectively]. Non-significant trends were seen for higher response with lower dosing [200 vs 1000 mg: odds ratio (OR) 3.66 (95% CI 0.93, 14.0)] and later timing [per month since infusion: OR 1.16 (95% CI 0.97, 1.35)]. Humoral response persisted in 96% (22/23) and 89% (8/9) of patients who received RTX between the two measurements. CONCLUSIONS: Repeated vaccination as late as possible after the lowest RTX dose possible seems the best vaccination strategy. A once positive humoral response after COVID-19 vaccination persists irrespective of intercurrent RTX infusion. Study registration. Netherlands Trial Registry (https://www.trialregister.nl/), NL9342.

Therapy with JAK inhibitors or bDMARDs and the risk of cardiovascular events in the Dutch rheumatoid arthritis population.

OBJECTIVE: Caution has been advocated recently when using Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) patients with an unfavorable cardiovascular risk profile. We aimed to compare the incidences in cardiovascular events between JAKi or bDMARDs in a large population of RA patients. METHODS: RA patients starting a new bDMARD or JAKi between August 1st 2018 and January 31st 2022 have been selected from IQVIA's Dutch Real-World Data Longitudinal Prescription database, covering about 63% of outpatient prescriptions in the Netherlands. Study outcome was a cardiovascular event, defined as the start of platelet aggregation inhibitors during study period. The incidence densities of cardiovascular events were compared between JAKi and bDMARDs using multilevel Poisson regression, adjusted for exposition time and confounders. RESULTS: 15 191 unique patients were included, with 28 481 patient-years on treatment with either JAKi (2,373) or bDMARDs (26 108). Most patients were female (72%) and median age was 62 years. We found 36 cardiovascular events (1.52 events/100 patient years) during therapy with JAKi and 383 events (1.47 events/100 patient years) during therapy with bDMARDs, respectively, resulting in an adjusted incidence rate ratio (IRR) of 0.99 for JAKi compared with bDMARDs (95% confidence interval (CI), 0.70-1.41). Sub-analyses in patients >65 years, by sex, or separately for tofacitinib and baricitinib, yielded similar results. CONCLUSION: In a large Dutch general RA population, the risk of cardiovascular events seems not different between JAKi users and those using bDMARDs, although a small increase in higher risk patients cannot be excluded.

Treat-to-target dose reduction and withdrawal strategy of TNF inhibitors in psoriatic arthritis and axial spondyloarthritis: a randomised controlled non-inferiority trial.

OBJECTIVES: Tumour necrosis factor inhibitors (TNFi) are effective in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), but are associated with a small (0.6%) increase in serious infection risk, patient burden due to need for self-injection and high costs. Treat-to-target (T2T) tapering might ameliorate these drawbacks, but high-quality evidence on T2T tapering strategies is lacking in PsA and axSpA. METHODS: We performed a pragmatic open-label, monocentre, randomised controlled non-inferiority (NI) trial on T2T tapering of TNFi. Patients with PsA and axSpA using a TNFi with ≥6 months stable low disease activity (LDA) were included. Patients were randomised 2:1 to disease activity-guided T2T with or without tapering until withdrawal and followed-up to 12 months. Primary endpoint was the difference in proportion of patients having LDA at 12 months between groups, compared with a prespecified NI margin of 20%, estimated using a Bayesian prior. RESULTS: 122 patients (64 PsA and 58 axSpA) were randomised to a T2T strategy with (N=81) or without tapering (N=41). The proportion of patients in LDA at 12 months was 69% for the tapering and 73% for the no-tapering group: adjusted difference 5% (Bayesian 95% credible interval: -10% to 19%) which confirms NI considering the NI margin of 20%. The mean percentage of daily defined dose was 53% for the tapering and 91% for the no-tapering group at month 12. CONCLUSIONS: A T2T TNFi strategy with tapering attempt is non-inferior to a T2T strategy without tapering with regard to the proportion of patients still in LDA at 12 months, and results in a substantial reduction of TNFi use. TRIAL REGISTRATION NUMBER: NL 6771.

Drug levels, anti-drug antibodies and B-cell counts were not predictive of response in rheumatoid arthritis patients on (ultra-)low-dose rituximab.

OBJECTIVES: The REDO trial (REtreatment with Rituximab in RhEumatoid arthritis: Disease Outcome after Dose Optimisation) showed that ultra-low-dose rituximab (500 mg or 200 mg) was similarly effective to a 1000 mg dosage in the majority of RA patients. This pre-planned secondary analysis investigated (1) associations between rituximab dosage, drug levels, anti-drug antibodies (ADAs) and B-cell counts and (2) the predictive value of pharmacokinetic and pharmacodynamic parameters, and of patient, disease and treatment characteristics in relation to response to ultra-low-dose rituximab. METHODS: For 140 RA patients from the REDO trial, differences in drug levels, ADAs and B-cell counts were examined at baseline, and at 3 and 6 months after dosing. Treatment response was defined as absence of flare and no extra rituximab or >1 glucocorticoid injection received during follow-up. The association between potential predictors and response was investigated using logistic regression analyses. RESULTS: Lower doses of rituximab resulted in lower drug levels but did not significantly affect ADA levels or B-cell counts, and 3 (10.7%), 12 (20.7%) and 7 (13.0%) patients failed to meet the response criteria in, respectively, the 1000 mg, 500 mg and 200 mg dosage groups. Drug levels, ADAs, B-cell counts, and patient, disease and treatment characteristics were not predictive for response to ultra-low-dose rituximab. CONCLUSION: The results of this study further support the hypothesis that continued treatment with 500 or 200 mg rituximab is similarly effective to a 1000 mg dosage in RA patients doing well on rituximab. These results, combined with lack of finding a clinical dose-response relationship in the original REDO study, suggest that 200 mg rituximab is not yet the lowest effective rituximab retreatment dose in RA.

Humoral response to coronavirus disease-19 vaccines is dependent on dosage and timing of rituximab in patients with rheumatoid arthritis.

OBJECTIVES: Humoral response to vaccines in RA patients treated with rituximab (RTX) in standard dosages (≥1000 mg) is decreased. Ultra-low dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients. METHODS: A single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2-6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use. RESULTS: After two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; odds ratio 3.07, 95% CI 1.14-8.27) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39-2.01). CONCLUSION: Both increased time between latest rituximab infusion and complete vaccination, and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl/, NL9342.

18F-FDG PET-CT in rheumatoid arthritis patients tapering TNFi: reliability, validity and predictive value.

OBJECTIVES: To investigate the reliability and validity of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT scanning (FDG-PET) in RA patients with low disease activity tapering TNF inhibitors (TNFis) and its predictive value for successful tapering or discontinuation. METHODS: Patients in the tapering arm of the Dose REduction Strategies of Subcutaneous TNFi study, a randomized controlled trial of TNFi tapering in RA, underwent FDG-PET before tapering (baseline) and after maximal tapering. A total of 48 joints per scan were scored both visually [FDG-avid joint (FAJ), yes/no] and quantitatively [maximal and mean standardized uptake values (SUVmax and SUVmean)]. Interobserver agreement was calculated in 10 patients at baseline. Quantitative and visual FDG-PET scores were investigated for (multilevel) association with clinical parameters both on a joint and patient level and for the predictive value at baseline and the change between baseline and maximal tapering (Δ) for successful tapering and discontinuation at 18 months. RESULTS: A total of 79 patients underwent FDG-PET. For performance of identification of FAJs on PET, Cohen's κ was 0.49 (range 0.35-0.63). For SUVmax and SUVmean, intraclass correlation coefficients were 0.80 (range 0.77-0.83) and 0.96 (0.9-1.0), respectively. On a joint level, swelling was significantly associated with SUVmax and SUVmean [B coefficients 1.0 (95% CI 0.73, 1.35) and 0.2 (0.08, 0.32), respectively]. On a patient level, only correlation with acute phase reactants was found. FDG-PET scores were not predictive of successful tapering or discontinuation. CONCLUSIONS: Quantitative FDG-PET arthritis scoring in RA patients with low disease activity is reliable and has some construct validity. However, no predictive values were found for FDG-PET parameters for successful tapering and/or discontinuation of TNFi.

Tumour necrosis factor inhibitor dose adaptation in psoriatic arthritis and axial spondyloarthritis (TAPAS): a retrospective cohort study.

OBJECTIVES: We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA). METHODS: A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome. RESULTS: Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: -0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: -0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: -0.21, 0.27) and 0.05 (95% CI: -0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively. CONCLUSION: DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.

Rituximab dose-dependent infection risk in rheumatoid arthritis is not mediated through circulating immunoglobulins, neutrophils or B cells.

OBJECTIVES: Rituximab (RTX) is a safe and effective treatment for RA. A dose-dependent infection risk was found in the REDO trial. Some studies associate RTX use with higher infection risks, possibly explained by low immunoglobulin levels and/or neutropenia. Additionally, a higher infection risk shortly after RTX infusion is reported. The objectives of this study were (i) to compare incidence rates of infections between doses and over time, and (ii) to assess B-cell counts, immunoglobulin levels, neutrophil counts and corticosteroid/disease modifying rheumatic drug use as mediating factors between RTX study dose and infection risk. METHODS: Post hoc analyses of the REDO trial were performed. Infection incidence rates between RTX dosing groups and between time periods were compared using Poisson regression. A step-wise mediation analysis was performed to investigate if any of the factors mentioned above act as a mediator in the observed dose-dependent difference in infection risk. RESULTS: The potential mediators that were investigated (circulating B-cell counts, immunoglobulin levels, neutrophil counts and drug use) did not explain the dose-dependent infection risk observed in the REDO trial. Additionally, a trend towards a time-dependent infection risk was found, with higher infection rates shortly after RTX infusion. CONCLUSIONS: These secondary analyses of the REDO trial confirmed the observed dose-dependent infection risk. Additionally, we found that infection risks were higher shortly after RTX infusion. However, a mediating pathway was not found.

Effectiveness and tolerability of oral vs subcutaneous methotrexate in patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study was to compare the effectiveness and tolerability between oral MTX and s.c. MTX in a large group of RA patients in a real-life setting. METHODS: In this retrospective cohort study, adult patients with clinical diagnosis of RA who started MTX treatment (monotherapy or combined with HCQ) started with either oral or s.c. MTX. The primary outcome was superiority testing of between group difference in change in DAS28CRP between baseline and 3-6 months, and subsequent non-inferiority (non-inferiority margin 0.6) testing analyses in case of non-superiority. Secondary outcomes included MTX dose, side effects, laboratory abnormalities and use of comedication. RESULTS: Six hundred and forty RA patients were included: 259 started with oral MTX and 381 with s.c. MTX. There was no significant difference in ΔDAS28CRP [after adjusting for confounding, 0.13 (95% CI: -0.14, 0.40)], and oral MTX strategy was non-inferior to s.c. The mean MTX dose was slightly lower for the oral strategy [18.0 (6.9) vs 19.9 (8.2), P = 0.002], which was accompanied by a lower cumulative incidence of adverse events (41% vs 52%, P = 0.005). No differences were seen in use of other comedication. CONCLUSION: Starting with oral MTX in RA in a real-life setting is non-inferior to a s.c. MTX treatment with regard to disease activity control, at least when used in dosages up to 25 mg and on a background of HCQ co-treatment and a treat-to-target approach. In addition, tolerability was better. This supports the strategy of starting with oral MTX.

Polymyalgia rheumatica patients with and without elevated baseline acute phase reactants: distinct subgroups of polymyalgia rheumatica?

OBJECTIVES: Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disease characterised by pain and stiffness of neck, shoulder- and hipgirdle, typically with elevated acute phase reactants (APR). However, patients may present with normal APR. Our aim was to explore whether normal APR were due to 1) 'caught early in the disease', 2) misdiagnosis, or 3) a distinct subset of PMR with different clinical presentation and prognosis. METHODS: This was a retrospective cohort study on patients with clinical PMR diagnosis visiting the rheumatologists of the Sint Maartenskliniek from April 2008 to September 2017. RESULTS: Of 454 patients, 62 patients had normal, and 392 elevated APR. Normal APR patients had longer symptom duration before diagnosis (13 vs. 10 weeks; p=0.02), however, during follow-up 31% developed elevated APR. In elevated APR patients with previous APR data available while already symptomatic, 58% had earlier normal APR. Fewer normal APR patients had peripheral arthritis (2% vs. 9%;p=0.04), and anaemia (17% vs. 43%; p=0.001). More often they had a previous PMR diagnosis (16% vs. 8%; p=0.057) and a shorter median time to glucocorticoid-free remission (552 vs. 693 days; n=36 vs. 160; p=0.02). Route of GC administration differed between groups (p=0.026). Fewer patients received methotrexate; 3 vs. 12%; p=0.046). No difference in alternative diagnosis was observed. CONCLUSIONS: PMR patients with long-term normal APR seem to be a milder subset of PMR in clinical presentation and prognosis. Additionally, our data also suggest there is a subgroup with normal APR who are caught early in the disease. Misdiagnosis does not appear to play a role.

Therapeutic drug monitoring of adalimumab in RA: no predictive value of adalimumab serum levels and anti-adalimumab antibodies for prediction of response to the next bDMARD.

BACKGROUND: After adalimumab treatment failure, tumour necrosis factor inhibition (TNFi) and non-TNFi biological disease-modifying anti-rheumatic drugs (bDMARDs) are equally viable options on a group level as subsequent treatment in rheumatoid arthritis (RA) based on the current best evidence synthesis. However, preliminary data suggest that anti-adalimumab antibodies (anti-drug antibodies, ADA) and adalimumab serum levels (ADL) during treatment predict response to a TNFi as subsequent treatment. OBJECTIVE: To validate the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD. Sub-analyses were performed for primary and secondary non-responders. METHODS: A diagnostic test accuracy retrospective cohort study was done in consenting RA patients who discontinued adalimumab after >3 months of treatment due to inefficacy and started another bDMARD. Inclusion criteria included the availability of (random timed) serum samples between ≥8 weeks after start and ≤2 weeks after discontinuation of adalimumab, and clinical outcome measurements Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) between 3 to 6 months after treatment switch. Test characteristics for EULAR (European League Against Rheumatism) good response (DAS28-CRP based) after treatment with the next (non-)TNFi bDMARD were assessed using area under the receiver operating characteristic and sensitivity/specificity. RESULTS: 137 patients were included. ADA presence was not predictive for response in switchers to a TNFi (sensitivity/specificity 18%/75%) or a non-TNFi (sensitivity/specificity 33%/70%). The same was true for ADL levels in patients that switched to a TNFi (sensitivity/specificity 50%/52%) and patients that switched to a non-TNFi (sensitivity/specificity 32%/69%). Predictive value of ADA and ADL were similar for both primary and secondary non-responders to adalimumab. CONCLUSIONS: In contrast to earlier research, we could not find predictive value for response to a second TNFi or non-TNFi for either ADA or random timed ADL.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.

OBJECTIVES: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. METHODS: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. RESULTS: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. CONCLUSIONS: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.