Previously published results of a retrospective analysis showed that switching to levilimab from other interleukin 6 receptor inhibitor (iIL6R) allows maintaining the achieved effect, and in some cases, increasing the effectiveness of treatment. This article presents the results of an extended observation period.The aim – to evaluate the efficacy, safety and retention rate of levilimab in patients with rheumatoid arthritis (RA) during one year of observation.Materials and methods. A retrospective analysis of data from the Moscow register of RA patients. The analyzed sample included RA patients who received levilimab 162 mg weekly after switching from other iIL6R (tocilizumab and sarilumab). Patient retention rate on levilimab therapy was assessed during 52 weeks of observation. The efficacy was evaluated at months 3, 6, 9 and 12 of levilimab therapy by the following parameters: laboratory markers of inflammation (C-reactive protein (CRP), erythrocyte sedimentation rate), assessment of the number of swollen (SJC) and painful (PJC) joints, assessment of the patient’s global assessment (PGA) by visual analogue scale (VAS), and DAS28-CRP (Disease Activity Score 28 with CPR).Results. 141 patients were included in analysis, the majority of patients were female (89%), the mean age was 57.8 years. The mean duration of levilimab therapy was 12.2±4.4 months. After 12 months of treatment, 87.5% [95% confidence interval: 82.1; 93.2] of patients continued levilimab therapy. Retention rate of levilimab therapy remained high in the levilimab monotherapy and combination therapy subgroups, and when prescribed as second or following biologic disease-modifying antirheumatic drugs (DMARDs). The mean DAS28-CRP, CRP level, TJC, SJC, and PGA by VAS were low at the time of initiation of levilimab therapy and remained stable during the year of therapy.Conclusions. Levilimab had high patient retention in therapy when used both as monotherapy and in combination with conventional synthetic DMARDs, as well as when prescribed in second and following lines of biologic DMARDs.

Baricitinib (BARI) is widely used in rheumatoid arthritis (RA); however, real-world data on its place in therapy and efficacy in patients with difficult-to-treat (D2T) RA are limited. Objective: to assess the clinical and demographic characteristics of patients with RA, including those in the D2T RA subgroup, the outcomes of BARI use in routine practice across different lines of therapy (LT) and switching strategies, as well as its steroid-sparing effect. Material and methods. A retrospective analysis was performed of patients included in the Moscow registry of immune-mediated inflammatory/autoimmune diseases who were followed up from 19.08.2021 to 26.12.2024 and were prescribed BARI. Data from three visits (V1–V3) with a 6-month interval were analyzed. Study endpoints were changes in DAS28-ESR/CRP, CDAI/SDAI, tender joint count (TJC) and swollen joint count (SJC), patient and physician global assessment of disease activity; the proportion of patients in remission and with low disease activity; the number of patients receiving glucocorticoids (GCs) and methotrexate (MTX), as well as GCs and MTX doses. Current therapy at the time of the study and prior therapy were analyzed; a separate analysis was performed for the D2T RA subgroup. Results and discussion. The study included 188 patients (82% women); mean age was 56.0±12.1 years; median RA duration was 11 (7–18) years. The mean follow-up duration was 12.6 (2.3–29.7) months. The intervals between visits averaged 6.5 months. The D2T RA subgroup included 17 (9%) patients. BARI was prescribed as 1st LT in 62.2% of patients, as 2nd LT in 14.9%, and as 3rd LT in 22.9%; 62.2% of patients had not previously received biologic DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs), whereas 37.8% were switched to BARI from bDMARDs or tsDMARDs. By V3, with BARI used as 1st LT, the median DAS28-ESR decreased from 3.4 to 3.1 (-8.8%; p<0.05); as 2 ^nd LT, from 3.3 to 2.9 (-12.1%); and as 3rd LT, from 4.1 to 2.9 (-29.3%); the median DAS28-CRP decreased by 6.9%, 6.9%, and 24.1%, respectively. The greatest reduction in activity indices was observed after switching from interleukin-6 inhibitors (IL-6i): the median DAS28-ESR decreased from 4.02 to 2.99 (-25.6%; p=0.0174) and CDAI from 14.47 to 10.88 (-24.8%). The smallest decrease in indices was recorded after prior therapy with Janus kinase inhibitors (JAKi). In such patients, DAS28-ESR decreased on average by 3.0%, while CDAI increased by 9.1%. In the D2T RA group, a significant reduction in SJC (-74.1%) and TJC (-59.6%) was noted (p<0.05), with a clinically noticeable but statistically non-significant decrease in DAS28-ESR (-18.3%), DAS28-CRP (-23.8%), CDAI (-34.6%), and SDAI (-39.4%). By V3, in 52.1% of patients (p<0.05) it was possible to reduce the GCs dose (21.7%) or discontinue GCs completely (30.4%); the MTX dose and the proportion of patients receiving it also decreased. Conclusion. In real-world practice, BARI therapy provided a reduction in RA activity across different LT and demonstrated a steroid-sparing effect. Even in patients with D2T RA, a clinically meaningful decrease in arthritis activity was observed. The most favorable switching outcomes were noted in patients previously treated with IL-6i, whereas in patients who had used JAKi, the effect of BARI was limited, which is associated with a change in the mechanism of action when another drug is prescribed. These findings require confirmation in prospective studies.

Genetic determinants of response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) remain insufficiently characterized. We developed a targeted sequencing panel of candidate immunogenetic variants identified through a literature review and evaluated associations with response to TNF-α inhibitors, response to IL-6 inhibitors, and difficult-to-treat RA (D2TRA). Whole-blood DNA was sequenced using custom hybridization capture on a DNBSEQ-G400 platform (2 × 150 bp). Reads were aligned to hg38 using BWA-MEM, and variants were called with GATK HaplotypeCaller. After quality control, the D2TRA analysis included 154 patients (59 D2TRA and 95 non-D2TRA); drug-response analyses included 66 anti-TNF patients (26 responders, 40 non-responders) and 69 anti-IL-6 patients (29 responders, 40 non-responders). Treatment-response associations were assessed using unadjusted allelic chi-square tests with multiple-testing correction; D2TRA was analyzed using logistic regression adjusted for age, sex, and body mass index. For IL-6 inhibitor response, rs11656130/MAP2K6 (p = 0.0163; FDR = 0.3704) and rs4910008/GALNT18 (p = 0.0212; FDR = 0.3704) were identified, while rs7767069/LINC02549 was associated with TNF-α inhibitor response (p = 0.0171; FDR = 0.5968). For D2TRA, rs1813443 in CNTN5 (OR = 1.85, p = 0.017) and rs12081765, an intergenic variant near LMX1A/RXRG (OR = 0.59, p = 0.028), were nominally associated; neither association remained significant after multiple-testing correction. With the current sample sizes, the study could detect only large genetic effects, and was underpowered for these after Bonferroni correction (α = 0.00143). The findings highlight the limited reproducibility of candidate pharmacogenetic markers in RA and provide a targeted panel and analytical framework for larger replication studies.

Background/Objectives: Difficult-to-treat rheumatoid arthritis (D2T-RA) affects approximately 11.7% of patients. Real-world data on treatment trajectories, biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), and adverse events (AEs) remain limited. This study evaluated treatment patterns, line survival, and AEs in D2T-RA. Methods: This retrospective study included 97 D2T-RA patients. Treatment-line survival was assessed using Kaplan–Meier analysis with log-rank tests and a cluster-robust Cox proportional hazards model. Generalized estimating equation models (GEE) identified factors associated with AEs. Cluster analysis (K-modes, MCA followed by K-means, and hierarchical clustering) was performed to identify treatment patterns. Results: A median time to first prescription of b/tsDMARDs was 1369 days (IQR 852–2557). Inefficacy was the most common reason for switching (65.8%); csDMARD/GCs were discontinued for inefficacy more frequently than b/tsDMARD (70.1% vs. 61.3%). Among 470 b/tsDMARD-containing treatment lines, interleukin-6 (IL-6) inhibitors were most common (127 lines, 27.0%), followed by tumor necrosis factor-α (TNF-α) inhibitors (109 lines, 23.2%), Janus kinase (JAK) inhibitors (89 lines, 18.9%), rituximab (82 lines, 17.4%), and abatacept (61 lines, 13.0%). The agents used included tocilizumab, levilimab, sarilumab, and olokizumab; adalimumab, etanercept, infliximab, golimumab, and certolizumab pegol; and tofacitinib, baricitinib, and upadacitinib. In adjusted GEE models, treatment type was not a significant predictor of AE occurrence (OR 0.93, 95% CI 0.63–1.36); line number and female sex were independently associated with AEs, and a previous AE increased the risk of AE on the current line (OR 1.72, 95% CI 1.13–2.60; p = 0.011). TNF-α inhibitors were prescribed without concomitant methotrexate in 59 of 109 treatment lines (54.1%). At the final treatment line, lower disease activity was observed with abatacept, levilimab, and olokizumab, whereas higher values were observed with rituximab and etanercept; between-treatment differences were significant for DAS28-ESR (p = 0.0269), but not for CDAI, SDAI, or DAS28-CRP. Cluster analysis identified three exploratory treatment patterns, differing primarily in the use of tsDMARDs and hydroxychloroquine. Conclusions: D2T-RA is characterized by multiple treatment lines and frequent switching due to inefficacy, particularly for csDMARD/GC therapy. Among the targeted therapies evaluated, IL-6 inhibitors and abatacept were associated with lower disease activity at the final treatment line, whereas rituximab and etanercept were associated with higher values; these exploratory observations do not establish comparative effectiveness. The frequent use of TNF-α inhibitors without concomitant methotrexate highlights a potential target for treatment optimization. A history of AEs may help identify patients requiring closer safety monitoring.

The growing demand for biological disease-modifying antirheumatic drugs (bDMARDs) and their high cost put a heavy burden on the healthcare budget, thereby limiting the availability of treatment for patients. The introduction of bDMARDs biosimilars into clinical practice has made it possible to expand the availability of therapy for a larger number of patients. Our analysis of the use of the biosimilar etanercept Erelzi in 103 patients with rheumatoid arthritis showed that the drug is highly effective in the treatment of rheumatoid arthritis. It can be used both in bionaive patients with the ineffectiveness of basic therapy, and in the case of medical switching from other biologics (including tumor necrosis factor alpha inhibitors (iTNF)) and targeted synthetic basic anti-inflammatory drugs (tsDMARDs), as well as when non-medical switching is necessary. The biosimilar of etanercept Erelzi has optimal cost of treatment course and the lowest cost-effectiveness value, which means that its use will not affect the budget and will make highly effective therapy available to more patients.