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Contains fulltext : 305207.pdf (Publisher’s version ) (Closed access), 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.in

Contains fulltext : 305355.pdf (Publisher’s version ) (Open Access), OBJECTIVE: In axial spondyloarthritis (axSpA), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) are recommended for use in treat-to-target (T2T) strategies. However, BASDAI disease states may be a less suitable T2T instrument than ASDAS, since BASDAI contains non-disease activity related items. The objective of our study was to investigate the construct validity of BASDAI and ASDAS disease states. METHOD: We performed a single-centre cross-sectional study on BASDAI and ASDAS construct validity in long-term BASDAI T2T-treated axSpA patients. Our hypothesis was that BASDAI is less representative of disease activity than ASDAS owing to the focus on pain and fatigue, and missing an objective item, e.g. C-reactive protein (CRP). This was operationalized using several subhypotheses. RESULTS: The study included 242 axSpA patients. BASDAI and ASDAS disease states showed a similar relation to Patient Acceptable Symptom State and T2T protocol adherence. The proportions of patients with high BASDAI and ASDAS disease activity fulfilling Central Sensitization Inventory and fibromyalgia syndrome criteria were similar. The correlation with fatigue was moderate for both BASDAI (Spearman's rho 0.64) and ASDAS (Spearman's rho 0.54) disease states. A high ASDAS was strongly correlated with increased CRP (relative risk 6.02, 95% CI 3.0-12.09), while this correlation was not seen for BASDAI (relative risk 1.13, 95% CI 0.74-1.74). CONCLUSION: Our study showed moderate and comparable construct validity for BASDAI- and ASDAS-based disease activity states, with the expected exception of association with CRP. Therefore, no strong preference can be given for either measure, although the ASDAS seems marginally more valid.

Contains fulltext : 304904.pdf (Publisher’s version ) (Closed access)

Item does not contain fulltext, OBJECTIVES: To develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis. METHODS: Following EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a-5) and grade (A-D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously. RESULTS: The task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity-guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4). CONCLUSION: These points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment.

Contains fulltext : 291040.pdf (Publisher’s version ) (Open Access), OBJECTIVES: Immunomodulatory agents are safe and effective as treatment for various immune-mediated inflammatory diseases (IMIDs), but are associated with a slightly increased infection risk. It is uncertain whether, in the event of an infection, continuation or temporary interruption of immunomodulatory agents leads to better outcomes. Owing to this uncertainty, it is of importance to explore the perspectives of health-care providers (HCPs) and patients on this topic. In this study, we set out to identify and provide an overview of reasons for both treatment strategies. METHODS: Semi-structured interviews were conducted with HCPs involved in the pharmacological treatment of IMIDs and with IMID patients using one or more immunomodulatory agent. Purposive sampling was used to enrich data variation. Interviews were conducted until data saturation was reached and subsequently analysed using qualitative content analysis. RESULTS: In total, 13 HCPs and 19 IMID patients were interviewed. A wide range of reasons for both treatment strategies were identified, categorized into 10 overarching themes, including IMID characteristics, infection characteristics and the patient-HCP relationship. CONCLUSION: In this interview study, we identified various reasons for continuation or temporary interruption of immunomodulatory agents during infections for both IMID patients and HCPs. We found overlapping themes, such as IMID characteristics; however, the content and interpretation of these themes might differ between HCPs and patients. Both HCPs and patients mentioned that the decision for a treatment strategy is often about weighing benefits against risks (e.g. infection severity vs disease flare).

01 januari 2023, Item does not contain fulltext, 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 an

01 april 2023, Item does not contain fulltext, Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10(-8) was considered significant, whereas a P-value of ≤ 5 × 10(-6) was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10(-8) to 4.86 × 10(-6) ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation.

Radboud University, 16 juni 2023, Promotores : Broeder, A.A. den, Hoogen, F.H.J. van den Co-promotor : Verhoef, L.M., Item does not contain fulltext

Contains fulltext : 292668.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, 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.

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Item does not contain fulltext, The TREAT EARLIER was aimed at testing whether methotrexate could prevent the evolution from clinically suspect arthralgia to Rheumatoid Arthritis. Although the primary outcome was negative, symptoms did improve during and after use of methotrexate. Here we discuss how to interpret these findings, and place the study in the existing evidence.

Contains fulltext : 296082.pdf (Publisher’s version ) (Closed access), 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.

Item does not contain fulltext, Tocilizumab and sarilumab are IL-6-receptor antagonists registered for rheumatoid arthritis (RA), with equal effectiveness and safety. Switching from tocilizumab to sarilumab could be a strategy to reduce injection burden, in case of drug shortages, and to reduce costs. This study therefore aims to investigate the effectiveness and safety of switching patients with RA with well-controlled disease under tocilizumab treatment to sarilumab. Patients with RA with low Disease Activity Score 28 (DAS28;-CRP < 2.9 or < 3.5 with clinical judgment), on stable dose tocilizumab (> 6 months) were offered to switch to sarilumab. Patients who switched and consented were followed for 6 months. Sarilumab was started at 200 mg and double the last tocilizumab interval. Co-primary outcomes at 6 months were (i) the 90% confidence interval (CI) of DAS28-CRP change from baseline compared with the non-inferiority margin of 0.6 and (ii) the 90% CI of the proportion of patients persisting with sarilumab, compared with a prespecified minimum of 70%. Of 50 invited patients, 25 agreed to switch to sarilumab, and 23 patients switched and were included. One patient was lost to follow-up immediately after inclusion, therefore 22 patients are included in the analyses. At 6 months, mean change in DAS28-CRP was 0.48 (90% CI: 0.11-0.87), compared with the non-inferiority margin of 0.6. Sarilumab persistence was 68% (90% CI: 51-82%, 15 out of 22 patients), compared with the prespecified minimum of 70%. Non-medical switching from tocilizumab to sarilumab in patients doing well on tocilizumab failed to show non-inferiority regarding disease activity and drug persistence.

Contains fulltext : 300005.pdf (Publisher’s version ) (Open Access), OBJECTIVE: Assessing the construct validity of the Patient-Reported Outcomes Measurement Information System Physical Function 10-Item Short Form (PROMIS PF-10) in a subpopulation of rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA) patients with severe limitations in physical functioning (PF). METHOD: RA/axSpA patients with severe functional limitations completed the PROMIS PF-10, Health Assessment Questionnaire - Disability Index (HAQ-DI for RA) or Bath Ankylosing Spondylitis Functional Index (BASFI for axSpA), 36-item Short Form Health Survey (SF-36), EuroQol 5-dimensions 5-level (index score, EQ-VAS), and performed the Six-Minute Walk Test (6MWT). Construct validity was assessed by computing Spearman rank or Pearson correlation coefficients and testing hypotheses about correlations between the PROMIS PF-10 and measures of PF and quality of life. RESULTS: Data from 316 patients (180 RA/136 axSpA, 91.7%/47.8% female, mean ± sd age 58.6 ± 13.2/54.0 ± 11.3 years) were analysed. The median (IQR) PROMIS PF-10 score was 34.5 (31.4-37.6) in RA and 36.0 (32.8-38.3) in axSpA patients. The PROMIS PF-10 correlated strongly with the HAQ-DI, BASFI, and EQ-5D-5L index score (r > 0.6), moderately with the SF-36 Physical Component Summary score, EQ-VAS, and 6MWT (0.30 ≤ r ≤ 0.60), and weakly with the SF-36 Mental Component Summary score (r < 0.30). Five of six hypotheses (83%) were confirmed in both groups. CONCLUSION: The overall strong correlation of the PROMIS PF-10 with measures of PF and moderate to weak correlations with outcomes measuring different constructs were confirmed in subpopulations of RA and axSpA patients with severe functional limitations, supporting its construct validity., 01 november 2023

Radboud University, 27 januari 2022, Promotor : Hoogen, F.H.J. van den Co-promotores : Maas, A. van der, Broeder, A.A. den, Contains fulltext : 241557.pdf (Publisher’s version ) (Open Access)

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Item does not contain fulltext, OBJECTIVES: Research on effectiveness and cost-effectiveness of longstanding exercise therapy in patients with axial SpondyloArthritis (axSpA) or Rheumatoid Arthritis (RA) is scarce, and mainly concerned patients with a relatively favorable health status. We aim to evaluate the effectiveness and cost-effectiveness of longstanding exercise therapy compared to usual care in the subgroup of patients with axSpA or RA and severe limitations in functioning. METHODS: In two separate, parallel randomized controlled trials the effectiveness and cost-effectiveness of longstanding, active exercise therapy (52 weeks) compared with usual care (1:1) will be evaluated. The longstanding, active exercise therapy will focus on improving individual limitations in daily activities and participation and will be given by a trained physical therapist in the vicinity of the participant. For each diagnosis, 215 patients with severe limitations in activities and participation will be included. Assessments are performed at baseline, 12, 26, and 52 weeks. The primary outcome measure of effectiveness is the individual level of functioning (activities and participation), as measured with the Patient-Specific Complaints instrument at 52 weeks. For cost-effectiveness analyses, the EuroQol (EQ-5D-5L) and questionnaires on healthcare use and productivity will be administered. The economic evaluation will be a cost-utility analysis from a societal perspective. After 52 weeks, the patients in the usual care group are offered longstanding, active exercise therapy as well. Follow-up assessments are done at 104, 156, and 208 weeks. CONCLUSION: The results of these studies will provide insights in the effectiveness and cost-effectiveness of longstanding exercise therapy in the subgroup of axSpA and RA patients with severe functional limitations.

Contains fulltext : 249014.pdf (Publisher’s version ) (Open Access), BACKGROUND: Biological disease-modifying antirheumatic drugs (bDMARDs) are effective in the treatment of rheumatoid arthritis. However, as bDMARDs may also lead to adverse events and are expensive, tapering them is of great clinical interest. Tapering according to disease activity-guided dose optimization (DGDO) does not seem to affect long term remission rates, but flares are frequent during this process. Our objective was to develop a model for the prediction of flares during bDMARD tapering using data from routine care and to evaluate its potential clinical impact. METHODS: We used a joint latent class model to repeatedly predict the probability of a flare occurring within the next 3 months. The model was developed using longitudinal data on disease activity (DAS28) and other routine care data from two clinics. Predictive accuracy was assessed in cross-validation and external validation was performed with data from the DRESS (Dose REduction Strategy of Subcutaneous tumor necrosis factor inhibitors) trial. Additionally, we simulated the reduction in number of flares and bDMARD dose when implementing the model as a decision aid during bDMARD tapering in the DRESS trial. RESULTS: Data from 279 bDMARD courses were used for model development. The final model included two latent DAS28-trajectories, bDMARD type and dose, disease duration, and seropositivity. The area under the curve of the final model was 0.76 (0.69-0.83) in cross-validation and 0.68 (0.62-0.73) in external validation. In simulation of prediction-aided decisions, the mean number of flares over 18 months decreased from 1.21 (0.99-1.43) to 0.75 (0.54-0.96). The reduction in he bDMARD dose was mostly maintained, increasing from 54 to 64% of full dose. CONCLUSIONS: We developed a dynamic flare prediction model, exclusively based on data typically available in routine care. Our results show that using this model to aid decisions during bDMARD tapering may significantly reduce the number of flares while maint

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Item does not contain fulltext, OBJECTIVE: To perform a COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN)-based systematic literature review of measurement properties of the Polymyalgia Rheumatica Activity Score (PMR-AS). METHODS: PubMed, EMBASE, and CINAHL were broadly searched. English full-text articles, with (quantitative) data on ≥ 5 patients with PMR using the PMR-AS were selected. Seven hypotheses for construct validity and 3 for responsiveness, concerning associations with erythrocyte sedimentation rate, physical function, quality of life, clinical disease states, ultrasound, and treatment response, were formulated. We assessed the structural validity, internal consistency, reliability, and measurement error, or the hypotheses on construct validity or responsiveness of the PMR-AS based on COSMIN criteria. RESULTS: Out of the identified 26 articles that used the PMR-AS, we were able to use 12 articles. Structural validity, internal consistency, construct validity, and responsiveness were assessed in 1, 2, 8, and 3 articles, respectively. Insufficient evidence was found to confirm structural validity and internal consistency. No data were found on reliability or measurement error. Although 60% and 67% of hypotheses tested for construct validity and responsiveness, respectively, were confirmed, there was insufficient evidence to meet criteria for good measurement properties. CONCLUSION: While there is some promising evidence for construct validity and responsiveness of the PMR-AS, it is lacking for other properties and, overall, falls short of criteria for good measurement properties. Therefore, further research is needed to assess its role in clinical research and care.

Contains fulltext : 282879.pdf (Publisher’s version ) (Open Access), BACKGROUND: Biologics for psoriasis are registered in standard dosages. In patients with low disease activity, reduction of the dose by interval prolongation can prevent overtreatment, and lower risks and costs. However, fear for increased anti-drug antibody (ADA) formation due to interval prolongation of biologics is an important barrier. OBJECTIVE: To investigate the course of serum drug concentrations, ADA levels, and predictors for successful dose reduction of adalimumab, ustekinumab, and etanercept for psoriasis. METHODS: Patients were randomized to dose reduction (DR) or usual care (UC) and followed for one year. The course and extent of detectable ADA levels were expressed as proportions/relative risks for DR vs. UC. Association of baseline characteristics with successful tapering was investigated with log-binomial regression analysis. RESULTS: In total, 118 patients were included. In adalimumab-treated patients, no significant difference in the proportion of patients with relevant ADA levels in DR vs. UC was seen. For ustekinumab, relevant ADA development was absent in both groups. Baseline trough levels were not predictive for successful DR. CONCLUSIONS: Immunogenicity may not increase by interval prolongation in psoriasis patients with low disease activity. This pilot provides important and reassuring insight into the pharmacological changes after dose tapering of adalimumab, etanercept, and ustekinumab.

Item does not contain fulltext, Patients with inflammatory rheumatic diseases (IRDs) do not have an increased risk for coronavirus disease 2019 (COVID-19) compared with the general population. However, it remains uncertain whether subgroups of patients with IRD using different immunosuppressive antirheumatic drugs carry a higher risk for severe COVID-19 compared with other patients with IRD. The aim of this study is to identify risk factors for severe COVID-19, requiring hospitalization in patients with IRD. This is a multicenter nested case control study conducted in the Netherlands. Cases are hospital known patients with IRD requiring hospitalization for COVID-19 between March 1, 2020, and May 31, 2020. Controls are hospital known patients with IRD not requiring hospitalization for COVID-19 in this period, included at a 4:1 ratio. Patient, disease, and treatment characteristics were extracted from electronic medical records and a questionnaire. Potential risk factors were analyzed using unconditional logistic regression, corrected for confounders and multiple testing. Eighty-one cases and 396 controls were included. General risk factors of older age and obesity apply to patients with IRD as well (odds ratio (OR) for age ≥ 75 3.5, 95% confidence interval (CI) 1.9-6.3, OR for body mass index ≥ 40 4.5, 95% CI 1.5-14). No significantly increased ORs for COVID-19 hospitalization were found for any antirheumatic agent or IRD. A protective effect was found for use of methotrexate (OR 0.53, 95% CI 0.31-0.92). In conclusion, similar to the general population, elderly and obese patients with IRD have a higher risk for hospitalization for COVID-19. We did not identify a specific antirheumatic agent or IRD to increase the risk of COVID-19 hospitalization in patients with IRD, except for a possible protective effect of methotrexate.

Item does not contain fulltext, 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.

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Item does not contain fulltext, 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.

Item does not contain fulltext, 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 (Delta) 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 kappa 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.

Item does not contain fulltext, 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.

Contains fulltext : 287480.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 251805.pdf (Publisher’s version ) (Open Access), 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.

Contains fulltext : 252946.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 229433.pdf (publisher's version ) (Open Access), A dose reduction strategy for adalimumab, etanercept and ustekinumab in patients with psoriasis who have stable and low disease activity has recently been compared with usual care in the CONDOR study (CONtrolled DOse Reduction) of biologics in patients with psoriasis with low disease activity. The aim of the current study was to perform a cost-utility analysis with a 12-month time horizon alongside this trial, using prospectively measured healthcare costs and quality-adjusted life years, based on Short-Form Six-Dimension utilities. Bootstrap analys-es were used to calculate the decremental cost-utility ratio and the incremental net monetary benefit. The dose reduction strategy resulted in a mean cost saving of €3,820 (95th percentile -€3,099 to -€4,509) per patient over a period of 12 months. There was an 83% chance that dose reduction would result in a reduction in quality adjusted life years (mean -0.02 (95th percentile -0.06 to 0.02). In conclusion, dose reduction of biologics resulted in substantial cost savings with an acceptable reduction in quality of life.

Contains fulltext : 220900.pdf (Publisher’s version ) (Closed access), 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.