OBJECTIVES:Ultra-low dose rituximab is an effective treatment in rheumatoid arthritis (RA). Subcutaneous (SC) administration may further facilitate rituximab treatment, reduce infection risk, and reduce costs. This study aimed to assess non-inferiority of SC versus intravenous (IV) rituximab regarding pharmacokinetic and -dynamic (PKPD) outcomes. METHODS:In this randomised, open-label, non-inferiority study, RA patients with stable low disease activity on ultra-low dose rituximab (500 mg or 200 mg every 6 months) were 1:1 randomised to receive rituximab 336 mg SC or 200 mg IV, stratified by previous rituximab dose. Primary outcome was non-inferiority of SC to IV rituximab, based on the estimated rituximab serum concentration area under the curve during the first 6 months (AUC0-6 months), with a non-inferiority margin of 0.8. AUCs were estimated using PK modelling. Secondary outcomes included change in DAS28-CRP compared to a NI-margin of 0.6. RESULTS:Thirty-five patients were randomised (17 IV, 18 SC). The geometric mean ratio for AUC0-6m was 0.99 (90%-CI 0.82 to 1.20), with minimal bias (mean predication error: IV 13.1 (1.86%); SC -3.40 (-0.47%)) but moderate random prediction error (root mean square error: IV 140 (19.8%); SC 142 (19.5%)) for the AUC estimates. Mean change in DAS28-CRP was non-inferior for SC rituximab (-0.39, 95%-CI -0.77 to -0.004). CONCLUSION:Our data suggest non-inferior pharmacokinetics for SC rituximab; however, this cannot be definitively concluded due to uncertainty of the AUC estimates. Nevertheless, based on PK/PD parameters, ultra-low dose SC rituximab could be an alternative for ultra-low dose IV rituximab.

IntroductionThis study conducted a meta-analysis across three large European cohorts (UKBB, FinnGen, and REPAIR), including 12,660 rheumatoid arthritis (RA) cases, 2,446 radiographic axial spondyloarthritis (r-axSpA) cases, and over 530,000 shared controls.MethodsTen independent SNPs in CARMIL1, GRM4, ITPR3, PRSS16, ZNF322, HTT, IKZF1, MANEA, and MGAM2 were analyzed, and functional characterization was performed through cytokine and protein assessments as well as eQTL analyses.ResultsTen independent SNPs were significantly associated with both RA and r-axSpA. Risk alleles included HTTrs363075A, IKZF1rs12718261A, MANEArs72920280T, and MGAM2rs73158426G, while CARMIL1rs72831267C, GRM4rs2495964G, ITPR3rs77601296A, ITPR3rs9469540T, PRSS16rs72843633T, and ZNF322rs6901425G had protective effects. Functional analysis showed that GRM4rs2495964G was linked to decreased CCL25 levels (p = 0.00030), and ITPR3rs9469540T to reduced IL10 production after LPS stimulation (p = 1.3×10−4). The ZNF322rs6901425G allele was associated with reduced TNFB and increased TGM2 levels (p = 9.60×10−4 and p = 3.00×10−4), both involved in immune signaling and tissue remodeling. Disease-specific associations were found in BTN2A1, BTN3A2, and H2BC11. The BTN2A1rs1977199A allele was protective in RA (OR = 0.93) but increased r-axSpA risk (OR = 1.23), and was associated with reduced IL22 (p = 0.00016) and elevated HO-1 in obese individuals (p = 6.73×10−6). In contrast, BTN3A2rs9393716G and H2BC11rs66462181C increased RA risk but were protective in r-axSpA, linked to decreased HO-1 and IL6 (p = 2.43×10−5, 3.287times;10−4, 1.18×10−4). These SNPs also acted as eQTLs for immune-related genes such as BTN3A2, HMGN4, and TRIM38.DiscussionOur findings highlight novel shared and disease-specific variants and key immunoregulatory mediators—IL10, IL22, IL6, CCL25, and HO-1—offering insights for disease stratification and therapeutic targeting.

Objectives:This study aimed to evaluate the time from early-stage systemic sclerosis (SSc), to the onset of significant disease progression. A secondary objective was to identify early clinical features most strongly associated with disease progression. Additionally, the study examined the course of microvascular changes over time. Methods:In this prospective longitudinal cohort study (Hit Hard and Early trial, 3 years open label follow-up), we included patients who met the adjusted Very Early Diagnosis of Systemic Sclerosis criteria, with puffy fingers for less than 3 years. Disease progression was defined as skin or organ involvement. Microvascular changes were tracked through serial nailfold videocapillaroscopy, and Kaplan-Meier estimates were used to analyse time to disease progression. Baseline predictors of progression were explored with univariate logistic regression. Results:Thirty patients were included, 70% female, with a median duration of puffy fingers of 5.5 months. Anticentromere antibodies were present in 73%, and 75% showed an active nailfold capillaroscopy pattern at baseline. Over 3 years, 43% (95% CI: 25.6%-61.2%) developed clinically significant disease progression, predominantly manifesting as pitting scars, digital ulcers, and/or skin thickening. Mean capillary density declined over time, and 55% of patients with an early SSc capillaroscopy pattern progressed to an active or late pattern within 24 months. Conclusions:A large proportion of patients showed clinically relevant disease progression within 3 years. In spite of the limited sample size, the strong association between anti-ribonucleoprotein (anti-RNP) antibodies and disease progression underlines the prognostic value of this biomarker. Frequent and standardised nailfold capillaroscopy imaging provided insights into microvascular changes.

Objectives:Rituximab (RTX) is an effective and safe treatment for rheumatoid arthritis (RA), but is associated with an increased risk of reactivation of hepatitis B virus (HBV) infection. Therefore, (inter)national guidelines recommend HBV screening prior to initiation of RTX treatment. However, the incidence of HBV in RA patients in nonendemic areas is expected to be very low, with known suboptimal screening adherence. This study aims to assess the added diagnostic value of routine serological HBV screening in RA patients initiating RTX. Methods:This retrospective single-centre cohort study included all patients with a clinical diagnosis of RA intending to initiate RTX between April 2012 and April 2024. Data on patient and disease characteristics, HBV screening results, and additional laboratory results were collected. Adherence to HBV screening, proportion of positive test results (hepatitis B surface antigen or core antibody positive), and incidence of HBV reactivation were assessed. Results:Of 975 included patients, 270 (28 %) were serologically screened for HBV. Six of those (2.2 %) had a positive screening result, of whom 3 eventually did not receive RTX. All 6 had a known HBV history or risk factor. No active HBV infections were observed after initiating RTX (mean follow-up 6.97 years), regardless of screening. Conclusions:Routine serological HBV screening identified very few previously unrecognised infections, and-in spite of screening adherence being low-no HBV reactivations occurred. Routine serological HBV screening, therefore, seems redundant in a low-risk population and should be reserved for patients with known risk factors.

Background It is currently unclear what the optimal treatment strategy is after failing an IL-6Ri in rheumatoid arthritis (RA), switching to another mode of action (MOA) DMARD, or cycling to a next IL-6Ri. We set out to compare the effectiveness of these strategies. Methods In this retrospective cohort study, RA patients who have ever used an IL-6Ri were included (termed “first IL-6Ri cohort”). Within this cohort, two subcohorts were developed: a cycle subcohort, comprising patients who received a second IL-6Ri and a (matched) switch subcohort, comprising patients who received another MOA b/tsDMARD. Effectiveness was measured as restricted mean drug survival time (RMST) over a 36-month period and DAS28-CRP scores, adjusted for baseline, after 3, 6 and 12 months. The cycle subcohort was compared to the first IL-6Ri cohort and the switch subcohort. Results 1,054 patients were included, of whom 134 and 267 in the cycle and switch subcohorts respectively. RMST of the cycle subcohort was lower than the first IL-6Ri cohort (-4.5 months (95% CI: -7.1 to -1.8)), but comparable to the switch subcohort (-2.1 months (95% CI: -5.3 to 1.2)). After 6 months, mean DAS28-CRP score of the cycle subcohort was higher compared to the first IL-6Ri cohort but comparable to the switch subcohort. Conclusions Effectiveness of a second IL-6Ri is lower compared to the first IL-6Ri, but comparable to other MOA switch options. Therefore, treatment choices after IL-6Ri failure in RA can be made based on other factors than drug MOA and may thus include a second IL-6Ri.

OBJECTIVES:The Polymyalgia Rheumatica Activity Score (PMR-AS) is the best validated composite disease activity measure in PMR to date, but its reliability, measurement error and discriminative validity have not been studied. METHODS:Inter-rater reliability, measurement error and discriminative validity were assessed in a cross-sectional cohort of PMR patients in routine care (April-August 2025). For inter-rater reliability and measurement error, five physicians scored the PMR-AS, with two independently evaluating each patient at the same visit. Test-retest reliability and measurement error were assessed using data from two randomized trials in newly diagnosed PMR (2019-2024, EULAR/ACR criteria positive). Patients with two visits 2-4 weeks apart and no reported change in disease state were included. Analyses included intraclass correlation coefficients (ICCs), standard error of measurement (SEM), smallest detectable change (SDC/SDD) and ROC analyses. Agreement between disease activity categories (PMR-AS <10 and ≥10) was evaluated using Cohen's kappa (ᴋ). RESULTS:A total of 124 patients contributed to the inter-rater analyses and 38 for test-retest analyses. For inter-rater reliability, the PMR-AS showed excellent agreement (ICC 0.93, 95% CI 0.90-0.95). Test-retest reliability was lower (ICC 0.66, 95% CI 0.38-0.82), reflecting lack of variability in disease activity (median PMR-AS 1.6). Measurement error was notable (inter-rater: SEM 2.46, SDD 6.83; test-retest: SEM 2.07, SDC 5.75), but discriminative validity was good (AUC 0.93, ᴋ 0.69). CONCLUSION:The PMR-AS demonstrated excellent inter-rater reliability and discriminative validity, supporting its use for classification of disease activity. However, its measurement error may limit interpretation of small intra-individual changes.

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 RA (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 analysis of covariance 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.

This study investigated severity, course and patterns of fatigue surrounding subcutaneous biological disease-modifying antirheumatic drug (bDMARD) injection in inflammatory rheumatic disease (IRD) patients using ecological momentary assessments and investigated self-reported adverse drug reactions (ADRs). In this prospective cohort study, IRD patients completed fatigue severity numeric rating scales (0–10) in web-based ecological momentary assessments in three waves of five days surrounding bDMARD injection. The course of fatigue was measured by the change in fatigue from pre-dosing to post-dosing scores and was classified as: worsening, improving or no clinically relevant change. A pattern was defined as a course of worsening, improving or no clinically relevant change in fatigue in at least two out of three waves for patients completing assessments across all three waves. ADRs could be reported on day five of each wave. In total 609 participants completed ecological momentary assessments surrounding 1541 bDMARD injections. Overall average fatigue severity across all three waves was 4.5 (± SD 2.4) and 78

OBJECTIVES:A substantial proportion of patients with rheumatoid arthritis (RA) discontinue adalimumab due to ineffectiveness. The next treatment step can be another tumour necrosis factor inhibitor (TNFi) or a biological/targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Therapeutic drug monitoring (TDM) of serum drug levels may help guide this choice. This study evaluated whether switching treatments based on adalimumab trough levels is more effective than random switching. METHODS:In this 24-week, multicentre, triple-blinded, randomised controlled trial, patients with RA who stopped adalimumab due to inefficacy (disease activity score based on 28 joint count and C-reactive protein [DAS28-CRP] >2.9) were enrolled. Participants were randomly assigned (1:1) to a TDM-based or random switching (control) strategy. The primary outcome was the difference in mean time-weighted DAS28-CRP between groups at 24 weeks. RESULTS:From July 2020 to November 2023, 83 consecutive patients with RA were included, with 78 initiating a new b/tsDMARD (TDM-based group: n = 38; control: n = 40). The mean time-weighted DAS28-CRP was 3.15 in both groups (TDM: SD, 0.99; control: SD, 1.01; 95% CI of difference: -0.46 to 0.47). There were no significant differences between the groups in flare rates, escape medication use, disease activity, or adverse events. Receiver operating characteristic analyses in the control group found no predictive value of adalimumab levels for response to TNFi or non-TNFi. CONCLUSIONS:Switching treatments based on adalimumab trough levels was not more effective than random switching in patients with RA who failed adalimumab treatment. Therefore, serum drug level measurements to guide therapy choices in this context is not recommended.

OBJECTIVES:To compare a bDMARD mode of action cycle vs swap treatment strategy in patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) after first tumour necrosis factor inhibitor (TNFi) discontinuation. METHODS:In December 2019, our local treatment protocol for PsA and axSpA changed from a cycle strategy (first TNFi to second TNFi) to a swap strategy (first TNFi to IL-17i). We performed a retrospective comparison of the 3-year drug retention rate using multivariable Cox regression (ref: cycle group) and disease activity (DAS28-CRP for PsA, BASDAI for axSpA) in patients with a clinical diagnosis of PsA and axSpA. For subgroup analyses, Cox regression models were stratified by sex, reason of first TNFi discontinuation, and (non-)radiographic status in axSpA. RESULTS:In PsA patients (n=406), there was no overall significant difference in drug retention between strategies (HR: 1.17 (95% CI: 0.87 to 1.58), p=0.29), but male PsA patients had a significant higher risk for treatment discontinuation following a swap strategy. In axSpA patients (n=335), the swap strategy was overall associated with a higher risk of treatment discontinuation (HR: 1.46 (95% CI: 1.03 to 2.07), p=0.04). Patients who discontinued their first TNFi due to inefficacy and patients diagnosed with radiographic axSpA were at significant higher risk for treatment discontinuation following a swap strategy. No significant differences in disease activity were found for treatment strategies in PsA or axSpA. CONCLUSION:In PsA, the cycle and swap treatment strategy performed similarly, while in axSpA, the cycle strategy was associated with a significant higher drug retention rate.

There are no clinically meaningful differences between bio-originators (BO) and their biosimilars (BS) in safety and efficacy. However, differences in pharmaceutical properties, such as volume and excipient, can occur. This study aimed to compare outcomes between patients transitioning from the modernized adalimumab BO (0.4 mL/no citrate) to BS1 (0.8 mL/citrate) and from BS1 to BS2 (0.4 mL/no citrate) and outcomes for new starters. In this retrospective exploratory cohort study of RA, PsA, and axial SpA patients receiving adalimumab, the (adjusted) 12-month drug survival rates were compared between the transition from the modernized BO to BS1 (Cohort 1, 2021) and from BS1 to BS2 (Cohort 2, 2023) in existing users, and for adalimumab-naïve new starters of the originator and BS1 and BS2 (Cohorts 3 to 5). Subanalyses included drug survival separately for inefficacy and intolerability. In existing users, 983 patients transitioned to BS1, 1082 patients to BS2, with 659 patients in both cohorts. Drug survival rates at 12 months were 73% (95% CI: 70-76) and 90% (95% CI: 88-92), respectively (P < 0.001), adjusted hazard rate ratio (HRR) 0.32 (95% CI: 0.26-0.40) in favor of BS2. The HRR for discontinuation due to inefficacy and tolerability were 0.50 (95% CI: 0.37-0.67) and 0.20 (95% CI: 0.14-0.28), respectively, both favoring BS2. In adalimumab-naïve new starters also, better survival for the originator and BS2 were seen compared with BS1. In conclusion, adalimumab BS1 showed a significantly lower drug survival than BS2, primarily due to lower tolerability. These findings suggest that pharmaceutical differences can have an important impact on drug survival.

BACKGROUND:Scarcity of data on the value of long-term routine laboratory toxicity monitoring (lt-RLTM) during disease-modifying antirheumatic drug (DMARD) use results in frequent monitoring in clinical practice. OBJECTIVE:To determine the cumulative incidence of abnormal and very abnormal laboratory monitoring results among patients with rheumatoid arthritis (RA) and to characterize the clinical context for the incidence of new very abnormal results. DESIGN:Retrospective cohort study. SETTING:The Netherlands, July 2008 to April 2020. PATIENTS:Patients with RA undergoing lt-RLTM after at least 6 months of DMARD use. MEASUREMENTS:Cumulative probabilities of abnormal and very abnormal results were calculated for alanine aminotransferase (>100 and >300 U/L), estimated glomerular filtration rate (eGFR; <60 and <45 mL/min/1.73 m2), hemoglobin (Hb; <7.5 mmol/L [females] or <8 mmol/L [males] and <6 mmol/L), leukocyte count (<3.5 and <2.0 × 109/L), and platelet count (<140 and <100 × 109/L). Chart review for newly occurring very abnormal results was performed for clinical context. RESULTS:4774 patients underwent 59 555 lt-RLTM test sets over 18 383 patient-years. The cumulative probabilities of very abnormal laboratory results for the 5 tests varied from 0.2% (leukocyte count) to 6.6% (eGFR) at 2 years and from 0.3% (leukocyte count) to 11% (eGFR) at 5 years. New very abnormal results (n = 449) mostly occurred after a dose increase (6.5%), were often already known or suspected (47.7%), were considered to be unrelated to DMARD use (24.1%), or did not lead to action (35.8%). The incidence of less serious abnormal results was higher, as high as 39% for eGFR less than 60 mL/min/1.73 m2 and 61% for Hb level below 7.5 mmol/L for females or below 8 mmol/L for males. LIMITATION:The possibility that regular monitoring contributed to lack of serious adverse outcomes cannot be excluded. CONCLUSION:Routine laboratory monitoring after 6 months of DMARD use revealed that most very abnormal laboratory results were already clinically anticipated and often occurred after dose escalation, although the cumulative incidence of some less serious abnormal results was quite high. Strategies for lt-RLTM warrant reconsideration. PRIMARY FUNDING SOURCE:None.