Nathan Den Broeder

Objectives: Ultra-low-dose rituximab is an effective treatment in RA. S.c. administration may further facilitate rituximab treatment, reduce infection risk and reduce costs. This study aimed to assess non-inferiority of s.c. vs i.v. rituximab regarding pharmacokinetic and pharmacodynamic outcomes. Methods: In this randomized, 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 randomized to receive rituximab 336 mg s.c. or 200 mg i.v., stratified by previous rituximab dose. Primary outcome was non-inferiority of s.c. to i.v. rituximab, based on the estimated rituximab serum concentration area under the curve during the first 6 months (AUC0–6m), with a non-inferiority margin of 0.8. AUCs were estimated using PK modelling. Secondary outcomes included change in DAS28-CRP compared with a non-inferiority margin of 0.6. Results: Thirty-five patients were randomized (17 i.v., 18 s.c.). The geometric mean ratio for AUC0–6m was 0.99 (90% CI 0.82–1.20), with minimal bias [mean predication error: i.v. 13.1 (1.86%); s.c. −3.40 (−0.47%)] but moderate random prediction error [root mean square error: i.v. 140 (19.8%); s.c. 142 (19.5%)] for the AUC estimates. Mean change in DAS28-CRP was non-inferior for s.c. rituximab (−0.39, 95% CI −0.77 to −0.004). Conclusion: Our data suggest non-inferior pharmacokinetics for s.c. rituximab; however, this cannot be definitively concluded due to uncertainty of the AUC estimates. Nevertheless, based on pharmacokinetic and pharmacodynamic parameters, ultra-low-dose s.c. rituximab could be an alternative for ultra-low-dose i.v. rituximab.

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. 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. Retrospective cohort study. The Netherlands, July 2008 to April 2020. Patients with RA undergoing lt-RLTM after at least 6 months of DMARD use. Cumulative probabilities of abnormal and very abnormal results were calculated for alanine aminotransferase (>100 and >300 U/L), estimated glomerular filtration rate (eGFR; 2), hemoglobin (Hb; 9/L), and platelet count (9/L). Chart review for newly occurring very abnormal results was performed for clinical context. 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. The possibility that regular monitoring contributed to lack of serious adverse outcomes cannot be excluded. 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. None.

Background: Immunomodulatory agents (IA) are commonly used to treat inflammatory rheumatic diseases (IRDs). Guidelines typically recommend temporarily interrupting IA during infections, but evidence supporting this approach is limited and continuation may be equally safe or even preferable. The objective of this study was to compare these 2 treatment strategies. Methods: We conducted a large multi-center, open-label, randomized controlled trial (Dutch Trial Register (NL8922), in which infection-free IRD patients on IA were randomized 1:1 to either continue or temporarily interrupt IA treatment when experiencing their first clinically relevant infection. Primary outcome was the proportion of patients with a serious infection (requiring hospitalization or intravenous treatment), analyzed in the modified intention-to-treat (mITT) population using the Cochran-Mantel-Haenszel method. The mITT population included all patients who experienced a clinically relevant infection during follow-up. Secondary analyses included Complier Average Causal Effect (CACE) models to account for non-adherence. Results: Of 1142 patients enrolled (1667 patient years of follow-up), 474 developed a clinically relevant infection (mITT population). Serious infections occurred in 12 of 233 patients (5.15%) in the interruption group and in 9 of 241 (3.73%) in the continuation group, adjusted risk difference was 1.71% (95% CI −1.99 to 5.39). CACE analysis showed a risk difference of 4.51 (95% confidence interval [CI]: −7.32 to 16.34) in favor of continuation. Conclusions: These findings suggest that temporary interruption and continuation of IA result in similar risk and outcome of infections in IRD patients. Although his study is limited by low statistical power, the findings suggest that continuation of IA during an infection is safe.

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.

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.

Background The REDO trial (REtreatment with Rituximab in RhEmatoid arthritis: Disease Outcome after Dose Optimisation) showed similar disease activity for retreatment with ultralow doses (200 mg and 500 mg per 6 months) compared with standard low-dose rituximab (RTX, 1000 mg per 6 months). We performed an observational extension study of the REDO trial to assess long-term effectiveness. Methods Patients from the REDO trial were followed from start of the trial to censoring in April 2021. RTX use was at the discretion of patient and rheumatologist using treat to target. The primary outcome was disease activity (disease activity score in 28 joints C-reactive protein (DAS28-CRP)), analysed using a longitudinal mixed model by original randomisation and time-varying RTX dose. The original DAS28-CRP non-inferiority (NI) margin of 0.6 was used. RTX dose and persistence, safety and radiological outcomes were also assessed. Findings Data from 126 of 142 REDO patients was collected from 15 December 2016, up to 30 April 2021. Drop-outs continued treatment elsewhere (n=3) or did not consent (n=13). Disease activity did not differ by original randomisation group: 1000 mg mean DAS28-CRP (95% CI) of 2.2 (2.0 to 2.5), 500 mg 2.3 (2.1 to 2.4) and 200 mg 2.4 (2.2 to 2.5). Lower time-varying RTX dose was associated with higher DAS28-CRP (0.22 (95% CI 0.05 to 0.40) higher for 200 mg/6 months compared with 1000 mg/6 months), but remained within the NI-margin. RTX persistence was 93%. Median RTX dose was 978 mg (IQR 684–1413) per year, and no association was found between RTX dose and adverse events or radiological damage. Interpretation Long-term use of ultralow doses of RTX is effective in patients with rheumatoid arthritis responding to standard dose RTX.