Objectives To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA). Methods A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019. Results 234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products. Conclusion This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR’s RA management recommendation.

https://ard.bmj.com/content/annrheumdis/79/6/744.full.pdf

Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis.

Objectives To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA). Methods This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022. Results Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission. Conclusion The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA.

Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis

To update the evidence on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) in patients with axial spondyloarthritis (axSpA) to inform the 2022 update of the Assessment of SpondyloArthritis international Society/European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axSpA.Systematic literature review (2016-2021) on efficacy and safety of bDMARDs in axSpA (radiographic axSpA (r-axSpA)/non-radiographic axSpA (nr-axSpA)). Eligible study designs included randomised controlled trials (RCTs), strategy trials and observational studies (the latter only for safety and extra-musculoskeletal manifestations). All relevant efficacy/safety outcomes were included.In total, 148 publications were included. Efficacy of golimumab and certolizumab was confirmed. Tumour necrosis factor inhibitor (TNFi) biosimilar-originator equivalence was demonstrated. RCT (n=15) data on efficacy of interleukin-17 inhibitors (IL-17i) demonstrated clinically relevant effects (risk ratio vs placebo to achieve ASAS40 response 1.3-15.3 (r-axSpA, n=9), 1.4-2.1 (nr-axSpA, n=2)). Efficacy of secukinumab/ixekizumab was demonstrated in TNFi-naïve and TNFi-inadequate responders. IL-23 and IL-12/23 inhibitors (risankizumab/ustekinumab) failed to show relevant benefits. Tapering of TNFi by spacing was non-inferior to standard-dose treatment. The first axSpA treat-to-target trial did not meet its primary endpoint, but showed improvements in secondary outcomes. No new risks were identified with TNFi use in observational studies (data lacking for IL-17i). Secukinumab (n=1) and etanercept (n=2) were associated with increased risk of uveitis in observational studies compared to monoclonal TNFi.New evidence supports the efficacy and safety of TNFi (originators/biosimilars) and IL-17i in r-axSpA and nr-axSpA, while IL-23i failed to show relevant effects. Observational studies are needed to confirm long-term IL-17i safety.CRD42021257588. 

/pdf/efficacy-and-safety-of-biological-dmards-a-systematic-1lfzrop2.pdf

Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis

https://doi.org/10.1016/j.intimp.2022.108536

An updated overview of recent advances, challenges, and clinical considerations of IL-6 signaling blockade in severe coronavirus disease 2019 (COVID-19)

Objectives The objective of this systematic review was to provide an overview of current developments and potentially available therapeutic options for spondyloarthritis (SpA) in the coming years. Methods We conducted a systematic review of 17 national and international clinical trial databases for all disease-modifying antirheumatic drugs (DMARDs) for SpA that are already marketed, in clinical development or withdrawn. The search was performed on February 2023 with the keywords “spondyloarthritis”, “ankylosing spondylitis” and “psoriatic arthritis”. For each molecule, we only considered the study at the most advanced stage of clinical development. Results Concerning axial SpA (axSpA), a total of 44 DMARDs were identified: 6 conventional synthetic DMARDs (csDMARDs), 27 biological DMARDs (bDMARDs) and 11 targeted synthetic DMARDs (tsDMARDs). Among the 18 targeted treatments (b+tsDMARDs) in current development, corresponding trials reached phase I (n=1), II (n=10) and III (n=7). Ten molecules are IL-17 inhibitors, two Janus kinase (JAK) inhibitors and two granulocyte-macrophage colony-stimulating factor inhibitors; four have another mode of action. Concerning psoriatic arthritis (PsA), 44 DMARDs were identified: 5 csDMARDs, 27 bDMARDs and 12 tsDMARDs. Among the 15 molecules in current development, corresponding trials reached phase II (n=8) and III (n=7). Six molecules are JAK inhibitors, six IL-17 inhibitors and one an IL-23 inhibitor; two have another mode of action. Conclusion This systematic review identified 18 and 15 molecules in clinical development for axSpA and PsA, respectively, which suggests a strengthening of the therapeutic arsenal in the coming years. However, with so many DMARDs but low target diversity, we will need to develop strategies or biomarkers to help clinicians make informed treatment decisions. 

The 2023 pipeline of disease-modifying antirheumatic drugs (DMARDs) in clinical development for spondyloarthritis (including psoriatic arthritis): a systematic review of trials

Background: Previously, the results of phase II AURORA clinical study of levilimab in subjects with active rheumatoid arthritis (RA) have been reported1. Here we report topline 24-weeks results of preliminary primary efficacy and safety analysis of phase 3 double-blind, placebo-controlled randomized clinical study (SOLAR). Objectives: To confirm that levilimab in combination with methotrexate is superior to placebo in combination with methotrexate in achieving ACR20 at week 12 and low disease activity (LDA) at week 24 in subjects with methotrexate (MTX) resistant active RA. Methods: The study is ongoing at 21 clinical sites in Russia and Belarus. All randomized subjects have completed 24 weeks of study between November 2019 and January 2021. 154 adults, aged ≥18 years with the diagnosis of RA (ACR 2010) for at least 24 weeks, and confirmed disease activity at screening despite treatment with MTX for the last 12 weeks (in a stable dose 15-25 mg/week, for at least 4 weeks) were randomly assigned (2:1) to receive either levilimab (162 mg, SC, QW) + MTX (n=102) or placebo + MTX (n=52). The randomization and treatment allocation were carried out by a central computer-based system. Subjects, caregivers, and those assessing the outcomes were blinded to group assignment. The hypothesis of superiority of levilimab over placebo was tested for two co-primary efficacy outcomes: proportion of subjects who achieved ACR20 at week 12 and proportion of subjects who achieved LDA of RA (DAS28-CRP For ethical reasons, subjects who haven’t achieved minimal clinical response at week 12 (≥20% reduction in the number of tender/swollen joints; 66/68) received rescue therapy at the discretion of the Investigator, and all subsequent efficacy assessments for those were considered missing. For the primary efficacy analysis, subjects with missing data due to study discontinuation or rescue therapy prescription were considered non-responders (non-responder imputation, NRI). Otherwise, the analysis was performed on observed cases. Safety was assessed through monitoring of adverse events (AEs). Results: The primary analysis was based on 149 randomized subjects (n=99 and n = 50) for ACR20 and 154 randomized subjects (n= 102 and n = 52) for LDA. 70/99 (71%) of subjects who received levilimab and 20/50 (40%) who received placebo achieved ACR20 response at week 12. The difference in proportion was 30% with a lower bound of 97.5% CI 12.8%; p=0.0003 (Pearson’s chi-squared test). 53/102 (52%) of subjects received levilimab and 3/52 (6%) received placebo achieved LDA at week 24. The difference in proportion was 46% with a lower bound of 97.5% CI 31.2 %; p The safety population included all subjects, who received investigational product (n=154). The most common adverse events (reported in ≥5% of subjects) in levilimab and placebo arms, respectively were: blood cholesterol increase (19% vs. 10%), ALT increase (11% vs. 8%), lymphocyte count decrease (9% vs. 8%), blood bilirubin increase (11% vs. 0%), blood triglycerides increase (9% vs. 2%), AST increase (7% vs. 4%), IGRA with M.tuberculosis antigen positive (5% vs. 6%), ANC decrease (8% vs. 0%). No deaths were occurred. Conclusion: The study confirmed superior efficacy of levilimab + MTX over placebo + MTX in subjects with MTX resistant active RA. No new safety signals were detected. Trial registration: Clinicaltrials.gov identifier NCT04397562 References: [1]Mazurov V, Zotkin E, Ilivanova E, et al. FRI0114 EFFICACY OF LEVILIMAB, NOVEL MONOCLONAL ANTI-IL-6 RECEPTOR ANTIBODY, IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS: 1-YEAR RESULTS OF PHASE 2 AURORA STUDY. Annals of the Rheumatic Diseases 2020;79:637-638. Acknowledgements: We thank all contributors to the SOLAR clinical trial Disclosure of Interests: V Mazurov: None declared, Maxim Korolev: None declared, Alena Kundzer: None declared, Nikolaj Soroka: None declared, Aleksander Kastanayan: None declared, Tatyana Povarova: None declared, Tatyana Plaksina: None declared, Olga Antipova: None declared, Diana Kretchikova: None declared, Svetlana Smakotina: None declared, Oksana Tciupa: None declared, Tatiana Raskina: None declared, Tatyana Kropotina: None declared, Olga Nesmeyanova: None declared, Tatiana Popova: None declared, Ekaterina Dokukina Employee of: JSC BIOCAD, Aleksandra Plotnikova Employee of: JSC BIOCAD, Anton Lutskii Employee of: JSC BIOCAD, Arina Zinkina-Orihan Employee of: JSC BIOCAD

https://ard.bmj.com/content/annrheumdis/80/Suppl_1/550.full.pdf

Pos0624 efficacy and safety of levilimab in combination with methotrexate in subjects with active rheumatoid arthritis: phase iii, double-blind, placebo-controlled, randomized trial

Background Equivalent efficacy of BCD-055 and infliximab (INF) innovator has been previously established (the primary endpoint: ACR20 at Wk14)1. Objectives The impact of BCD-055 and INF innovator on RA activity has been analysed within 14 week study period. DAS28-CRP(,4 CDAI and SDAI were evaluated. Additionally, safety data has been collected. Methods The study was conducted as international multicenter randomised double-blind placebo controlled study. The study enrolled 426 adults with active RA. Patients were randomised into 2 study arms in 2:1 ratio to receive BCD-055 or INF innovator in dose of 3 mg/kg. In the analysed period of the study, patients received the iv infusions on Wk0, Wk2, Wk6, Wk14. Results Efficacy: BCD-055 and INF innovator showed similar impact on RA activity: in both groups significant decline of DAS28-CRP(4 was observed (figure 1). This result corresponds to positive CDAI and SDAI dynamics (table 2). Medians of CDAI/SDAI on screening indicated high RA activity, while on Wk 14 – moderate activity. Analyses of inflammatory markers (ESR and C-reactive protein) revealed pronounced decline in ESR and CRP levels by Wk 2. No further elevation has been observed. Safety: No differences in safety profiles of BCD-055 and INF innovator has been shown. One of the most frequent AEs were arterial hypertension, anaemia, neutropenia and increase of transaminases. Number of patients with binding and neutralising antibodies also did not differ between groups. Babs were detected in 6.83% patients in BCD-055 arm and in 7.81% in INF innovator arm (p=0.888), Nab were observed in 1.61% and 0.78% patients in same arms (p=0.666). Conclusions Treatment with BCD-055 and INF innovator leads to significant decline in RA activity and inflammatory markers by Wk14, which corresponds with previous results of ACR20 assessment1. Both drugs are well tolerated with no differences in safety profiles. The frequency of ADA formation is also comparable. Reference [1] Denisov L, Gordeev I, Mazurov V, et al. FRI0208 Comparison of efficacy, safety and pharmacokinetics of infliximab biosimilar (BCD-055) and innovator infliximab Ann Rheum Dis2017;76:560–561. Disclosure of Interest A. Lila: None declared, L. Denisov: None declared, T. Plaksina: None declared, S. Smakotina: None declared, E. Kunder: None declared, N. Soroka: None declared, A. Kastanayan: None declared, O. Nesmeyanova: None declared, O. Antipova: None declared, E. Ilivanova: None declared, A. Eremeeva Employee of: JSC BIOCAD, E. Dokukina Employee of: JSC BIOCAD, E. Chernyaeva Employee of: JSC BIOCAD, R. Ivanov Employee of: JSC BIOCAD

https://ard.bmj.com/content/annrheumdis/77/Suppl_2/316.full.pdf

THU0193 Efficacy and safety of bcd-055 (INFLIXIMAB BIOSIMILAR) in rheumatoid arthritis. results of bcd-055–3/lira phase 3 clinical study

Netakimab (NTK) is a humanized monoclonal antibody targeting interleukin-17A. Objective . The main objective of BCD-085-5/ASTERA study was to prove superiority of NTK over placebo and assess its’ safety in patients with active AS. Subjects and methods . BCD-085-5/ASTERA was a double-blind, multicenter, randomized, placebo-controlled, phase III study, which included 228 adult patients with active AS, persisting despite active treatment with NSAIDs. AS was considered active at BASDAI score ≥ 4.0. Patients were blindly randomized (1:1) to receive subcutaneous injections of NTK (120 mg) or placebo at weeks 0, 1, 2 and then every other week up to week 14. Starting from week 16 all patients from NTK group and patients from placebo group not achieving ASAS20 were switched to open label 120 mg NTK s/c once every two weeks. The total duration of treatment with NTK was 3 years. Results . Higher proportion of patients had ASAS40 response at week 16 (primary endpoint) in NTK arm compared to placebo (40,4 vs 2,6%, р <0,0001, 95% CI [27,4%; 48,1%]). Spinal pain subsided and laboratory inflammation markers decreased within one week after the first NTK injection. NTK safety profile was comparable to that of placebo. The most common for NTK adverse events were neutropenia (7,0%) and ALT increase (6,1%). Conclusion . Subcutaneous NTK at 120 mg dose demonstrated superior efficacy vs placebo, with fast onset of response and favorable safety profile when used in patients with ankylosing spondylitis.

/pdf/efficacy-and-safety-of-netakimab-anti-il-17a-monoclonal-1kddj6ttna.pdf

Efficacy and safety of netakimab, anti-IL-17A monoclonal antibody, in patients with ankylosing spondylitis. Results of phase III international, multicenter, randomized double-blind clinical trial BCD-085-5/ASTERA

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Pos0624 efficacy and safety of levilimab in combination with methotrexate in subjects with active rheumatoid arthritis: phase iii, double-blind, placebo-controlled, randomized trial

THU0193 Efficacy and safety of bcd-055 (INFLIXIMAB BIOSIMILAR) in rheumatoid arthritis. results of bcd-055–3/lira phase 3 clinical study

Efficacy and safety of netakimab, anti-IL-17A monoclonal antibody, in patients with ankylosing spondylitis. Results of phase III international, multicenter, randomized double-blind clinical trial BCD-085-5/ASTERA