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Objective Caution has been advocated recently when using Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) patients with an unfavourable cardiovascular risk profile. We aimed to compare the incidences in cardiovascular events between JAKi and biologic DMARDs (bDMARDs) in a large population of RA patients. Methods RA patients starting a new bDMARD or JAKi between 1 August 2018 and 31 January 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 the study period. The incidence densities of cardiovascular events were compared between JAKi and bDMARDs using multilevel Poisson regression, adjusted for exposure time and confounders. Results The number of unique patients included was 15 191, with 28 481 patient-years on treatment with either JAKi (2373) 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, resulting in an adjusted incidence rate ratio (IRR) of 0.99 for JAKi compared with bDMARDs (95% 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 to be different between JAKi users and those using bDMARDs, although a small increase in higher risk patients cannot be excluded. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) is a safe and effective treatment for 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 with 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 with 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Whole-body PET with CT scanning using 18F-fluorodeoxyglucose (18F-FDG) is used occasionally in RA patients to detect arthritis. FDG-PET/CT might also detect malignancies, but the amount of incidental findings and the number of relevant malignant diseases that could be missed are currently unknown. We aimed to study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity. Methods FDG-PET/CT scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological DMARDs. The reference standard was clinical diagnosis of malignancy during the 3-year follow-up period of the study. Prevalence of extra-articular abnormalities, follow-up and treatments were summarized post hoc. Results One hundred and twenty-one scans were carried out in 79 patients. Extra-articular abnormalities were found in 59 of 121 (49%) scans, resulting in additional diagnostic procedures in 21 of 79 (26.6%) patients. Nine patients (7.4%) were suspected of malignancy; none turned out to be malignant. Six clinical malignancies that developed during follow-up were all negative on baseline FDG-PET/CT. Conclusion Whole-body FDG-PET/CT scanning used in RA patients for imaging of arthritis results in frequent incidental extra-articular findings, whereas some who apparently had normal scans also developed malignancies. Trial registration Netherlands Trial Register, www.trialregister.nl , NL6771. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents a study which assessed the prevalence of hypogammaglobulinemia (HGG) in rheumatoid arthritis (RA) patients receiving different doses of rituximab (RTX). Topics include patient characteristics, prevalence of HGG in RTX using RA patients, and reason that physicians should consider combining rituximab with MTX.

The effect of TNF-α inhibitors (TNFi), with or without concomitant NSAIDs, on radiographic progression in axial SpA remains unclear. Therefore, we performed a systematic literature review up to January 2019 to determine whether longer use of standard dose TNFi is superior vs lower duration or lower dose TNFi therapy, conventional synthetic DMARDs alone, or no therapy in inhibiting radiographic progression in patients with axial SpA. Our search yielded 373 titles of which 14 full text articles and five abstracts were eligible for quantitative analysis. Studies had an overall moderate to critical risk of bias. Data could not be pooled due to clinical and methodological heterogeneity. Individual studies showed conflicting results with mainly no significant difference in radiographic progression when comparing effect of TNFi therapy to no TNFi therapy or when comparing to less TNFi therapy until 2 years of follow-up. Results that are more significant are shown after 2 years' follow-up, mainly in subgroups with baseline syndesmophytes. Data on the additional or synergistic effect of concomitant NSAID use were inconclusive. [ABSTRACT FROM AUTHOR]

Objectives To investigate the added value of MTX-HCQ combination therapy (CTG) in early RA in a controlled cohort study. MTX monotherapy (MTG) is recommended as (part of) first choice treatment but no head-to-head comparisons are available comparing MTX–HCQ CTG with MTG. Methods RA patients from the Sint Maartenskliniek and Radboudumc Nijmegen who started MTX with or without concomitant HCQ from April 2010 to October 2015 were included. The primary outcome was the between-group ΔDAS28-CRP at 6 months, and secondary outcomes were ΔDAS28-CRP at 12 months, EULAR response at 6 and 12 months, and treatment intensification. Regression modelling was used to correct for confounding. Results We included 325 patients, with only small between-group differences at baseline. The DAS28-CRP improvement at 6 months was larger in the CTG (Δ = 0.38 (CI: 0.01, 0.76)), and the difference between groups in DAS28-CRP improvement was smaller at 12 months (Δ = 0.22 points (CI:−0.19, −0.62)). At 6 months, a higher percentage of patients had a good EULAR response in the CTG (Δ = 15% (CI: 2.7%, 27%)). This difference was reduced at 12 months (Δ = 6% (CI −6.4%, 19%)). Treatment intensification with conventional synthetic DMARDs was more likely in the MTG (Δ = 31% (CI: −43%, 19%)). The proportion of patients starting biologic DMARD treatment during the observation period was comparable (Δ = 2% (CI: −8%, 12%)). Discussion In contrast to indirect comparison review data, MTX–HCQ seems somewhat more effective after 6 months than MTX monotherapy in early RA patients. After 12 months, we observed no significant differences between the two strategies, probably due to treat-to-target efforts. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to identify the factors that play a role for patients with RA when considering dose reduction (i.e. gradual tapering until discontinuation) of biological DMARDs (bDMARDs), and to determine their relative importance. Methods A mixed methods design was used in which we identified influencing factors by performing semi-structured interviews and ranked these factors using a Maximum Difference Scaling questionnaire. Also, we looked at the influence of several patient characteristics on this ranking. Results For sub study 1 and 2, 22 and 192 patients with RA were included, respectively, in the analyses. Thirty factors were identified from the interviews—characterized into nine themes—and appraised in the questionnaire. Most respondents had a positive attitude towards bDMARD dose reduction. The study showed that patients are concerned that dose reduction will lead to a disease flare that affects their daily life (pain, function). It is important for them to know that it is possible to increase the dose if (further) reduction fails and that the bDMARD will be effective again. Patients value the opinion of their rheumatologist, and being involved in the decision to start tapering is highly ranked as well. The most important factors were consistent between different groups of patients. Conclusion The results from this study facilitate implementation of bDMARD dose reduction; they inform care providers on what is important for patients and provide a basis for shared decision making. [ABSTRACT FROM AUTHOR]

So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti- TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response. [ABSTRACT FROM AUTHOR]

The article discusses a study which showed better clinical outcomes of treat-to-target (T2T) in psoriatic arthritis (PsA) compared with usual care using minimal disease activity (MDA) criteria as treatment targets. Topics covered include a routine measurement of Psoriatic Arthritis Disease Activity Score (PASDAS) that was implemented in the study, the different stages of the implementation process, and clinical outcome of the study.

The authors discuss the role of therapeutic drug monitoring (TDM) of biologics as well as dose de-escalation strategies in rheumatoid arthritis (RA). They state that the prerequisites for TDM include a large variation in both serum levels. According to them, proactive down-titration of treatment in all the patients is strongly recommended because it is cost efficient and can prevent toxicity.