We report the long-term safety of upadacitinib (oral, selective, and reversible Janus kinase inhibitor) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-axSpA), atopic dermatitis (AD), Crohn’s disease (CD), and ulcerative colitis (UC). Data were analyzed from 16 studies (data cutoff August 15, 2024). Each treatment group was pooled across studies within each indication. Active comparator arms included adalimumab (RA/PsA) and methotrexate (RA). Treatment-emergent adverse events (TEAEs) were reported as exposure-adjusted incidence rates per 100 patient-years (n/100 PY). This analysis included 8632 (RA, n = 3209; PsA, n = 907; AS, n = 596; nr-axSpA, n = 286; AD, n = 2683; CD, n = 450; UC, n = 501) upadacitinib-treated patients over 27,164.2 patient-years (range 199.4–12,315.8 PY across indications). Rates (n/100 PY) of any TEAEs ranged from 112.0 (AS) to 401.1 (RA). Most frequently reported TEAEs included COVID-19, upper respiratory tract infection, nasopharyngitis, herpes zoster, urinary tract infection, and acne (primarily patients with AD). Serious TEAEs ranged from 4.5 (AD) to 11.0 (UC), and those leading to discontinuation ranged from 2.9 (AS) to 8.3 (UC). TEAEs leading to death ranged from 0 (nr-axSpA, UC) to 0.7 (RA). Among upadacitinib-treated patients across indications, rates of adverse events of special interest ranged from 1.3 to 4.6 (serious infection), 2.4–6.6 (herpes zoster), 0.2–0.9 (malignancy excluding nonmelanoma skin cancer [NMSC]), 0–1.4 (NMSC), 0–0.5 (major adverse cardiovascular event [MACE]), 0–0.9 (venous thromboembolism [VTE]), and 0–9.2 (elevated creatine kinase). In RA and PsA, herpes zoster, NMSC, and elevated creatine kinase rates were numerically higher with upadacitinib vs active comparators. Serious infection, herpes zoster, malignancy (excluding NMSC), NMSC, MACE, and VTE rates remained stable over time. This descriptive analysis indicates a long-term safety profile of upadacitinib consistent with previous reports, further supporting long-term treatment of chronic diseases with upadacitinib. Variations in TEAE rates across indications likely reflected differences in populations and underlying comorbidities. ClinicalTrials.gov identifiers NCT02675426, NCT02706951, NCT02706847, NCT02629159, NCT02706873, NCT03086343, NCT03104374, NCT03104400, NCT03178487, NCT04169373, NCT03569293, NCT03568318, NCT03607422, NCT03345823, NCT02819635.

RA-BE-REAL is a 3-year, multinational, prospective, observational study of adult patients with rheumatoid arthritis (RA) evaluating time to discontinuation of initial RA treatment along with patient baseline characteristics. This study’s primary objective was to assess the time to discontinuation of initial baricitinib, any other targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD), or any biologic disease-modifying anti-rheumatic drug (bDMARD) treatment for all causes (excluding sustained clinical response) over 24 months in a European population. Patients initiated treatment with baricitinib (cohort A) or any bDMARD or tsDMARD (cohort B) for the first time. This study’s primary objective was to assess the time to discontinuation of initial baricitinib, any other targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD), or any biologic disease-modifying anti-rheumatic drug (bDMARD) treatment for all causes (excluding sustained clinical response) over 24 months in a European population. Comparative effectiveness analyses, over 24 months, included time to treatment discontinuation for all causes (excluding sustained clinical response), percentage of patients achieving Clinical Disease Activity Index (CDAI) remission or low disease activity (LDA), as well as mean changes from baseline for CDAI, pain visual analogue scale, and the Health Assessment Questionnaire-Disability Index (HAQ-DI). For this European subpopulation, comparative analyses were performed using a frequentist model averaging (FMA) framework based on a data-driven machine learning causal inference approach to compare time to discontinuation, effectiveness, rates of remission or LDA, and patient-reported outcomes over 24 months comparing baricitinib with TNFi, as well as non-TNFi and tsDMARD grouped as other mechanism of action (OMA) drugs. In the European sample of RA-BE-REAL, patients with RA treated with baricitinib experienced fewer discontinuations in comparison to those treated with tumour necrosis factor inhibitors or OMA. Overall, patients naïve to b/tsDMARDs achieved a higher rate of LDA and remission compared with experienced patients. A significantly greater proportion of patients treated with baricitinib achieved LDA compared with b/tsDMARDs. This real-world data can better inform clinicians about baricitinib effectiveness and drug survival when prescribing treatment for patients with RA across different subpopulations.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease whose therapeutic management has improved significantly through early diagnosis, treat-to-target strategies, and the use of biologic (bDMARDs) and targeted synthetic (tsDMARDs) disease-modifying drugs. Nevertheless, a relevant proportion of patients remain in a difficult-to-treat state (difficult-to-treat RA), failing to achieve remission or low disease activity despite modern therapies. This article analyses new immunomodulatory therapeutic approaches with the aim of closing this treatment gap. A central new concept is the modulation of inhibitory immune checkpoints. The PD-1 agonist rosnilimab demonstrated significant clinical improvements with a favourable safety profile in a phase 2b study in moderate-to-severe RA. In contrast to classic cytokine blockades, rosnilimab aims to restore T-cell homeostasis by depleting pathogenic PD-1 high T cells and inducing regulatory T cells. A related agent, peresolimab, confirmed the principle of PD-1 agonism, but was not developed further. Other immunological targets, such as BTLA or CD122, are currently undergoing preclinical testing. Bispecific antibodies (bsAbs) represent another innovative field of therapy. Two main approaches are being pursued: (1) dual cytokine blockade - for example against TNF and IL-17A (ABT-122) or TNF and IL-6 (V5-3) - aimed at achieving synergistic effects in the presence of redundant inflammatory activity; (2) T-cell engagers that target cytotoxic T cells against autoreactive B cells (e. g. CD19xCD3, blinatumomab) or plasma cells (BCMAxCD3, teclistamab). Initial clinical data indicate significant reductions in both disease activity and pathogenic autoantibodies. Other bispecific molecules, such as imvotamab (CD20xCD3), are currently under clinical investigation. Antibody-glucocorticoid conjugates also represent a promising therapeutic approach. CAR T-cell therapy is currently the most intensive form of therapy. Case reports show that RA patients can achieve drug-free remission for more than a year after anti-CD19 or CD20/CAR T cell therapy, which was originally developed for malignant diseases. In addition to B cells, synovial fibroblasts (FAP-positive cells) are increasingly recognised as potential target structures. In preclinical models, FAP CAR T cells achieved targeted depletion of pro-inflammatory stromal cells and induced remission of arthritis. In addition, regulatory CAR T cells (CAR-Tregs) are being explored as a novel strategy for local immunosuppression in joints. These new therapies differ fundamentally in their target, mechanism of action, and mode of application. While PD-1 agonists represent an evolution of biological therapies, bispecific antibodies offer greater targeting precision, and CAR T cells hold the potential for curative effects. However, costs, complexity and potential side-effects are key challenges. Alongside clinical development, predictive biomarkers are crucial to enable personalised treatment decisions. RA therapy is therefore facing a potential paradigm shift: from predominantly symptom-controlling approaches towards immunologically targeted and potentially curative interventions. The next few years will show which of these innovative strategies will make their way into clinical practice, with the long-term goal of achieving remission or cure for all patients.

BACKGROUND:CT-P47 is a candidate tocilizumab biosimilar that is currently in clinical development. We assessed the usability of CT-P47 self-administration via auto-injector (AI) in patients with rheumatoid arthritis (RA). RESEARCH DESIGN AND METHODS:This was a 12-week, single-arm, open-label, multiple-dose, Phase 3 study. Patients self-injected CT-P47 (162 mg/0.9 mL) via AI at Weeks 0 and 2, and then every other week via pre-filled syringe (PFS) from Week 4 through Week 10. The primary endpoint was POST-Self-Injection Assessment Questionnaire (SIAQ) at Week 2. Efficacy, safety, and immunogenicity were also assessed. RESULTS:Thirty-three patients were enrolled. Mean scores for all POST-SIAQ domains at Week 2 exceeded 8, except for 'self-confidence' (7.11) and 'satisfaction with self-injection' (7.98), indicating positive patient experiences with CT-P47 AI. Furthermore, an observer-completed checklist found that all patients successfully followed the required steps for self-injection. Efficacy, assessed by Disease Activity Score in 28 joints and its components, showed improvements from baseline to Week 12. No new safety signals were observed; the most common adverse events were leukopenia, neutropenia, and injection-site reaction, each occurring in 3 (9.1%) patients. CONCLUSIONS:CT-P47 self-administered using an AI showed successful usability in patients with moderate-to-severe RA. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05725434.

BACKGROUND:Rheumatoid arthritis is an inflammatory disease frequently treated with TNF inhibitors. Little is known about predictors of response to TNF inhibitors. Because clinical response in rheumatoid arthritis is measured by composite scores containing subjective patient-orientated domains (eg, pain and global disease perception), we hypothesised that patients with high disease representation in the CNS might respond better to TNF inhibitors than patients with less CNS disease representation. METHODS:We did a phase 3, multicentre, double-blind, placebo-controlled, parallel-group randomised trial in patients with active rheumatoid arthritis at six rheumatology centres across Germany, Portugal, and Serbia. All patients had a functional MRI (fMRI) brain scan at baseline to measure CNS pain activation. Patients (aged ≥18 years) with active rheumatoid arthritis who have active disease despite the use of at least one conventional synthetic disease-modifying antirheumatic drug were stratified according to fMRI (high volume or low volume) and were randomly assigned 2:1 using a randomisation list generated by a study statistician to treatment with the TNF inhibitor certolizumab pegol (400 mg subcutaneously on weeks 0, 2, and 4, and 200 mg once every 2 weeks for maximum 24 weeks) or placebo. Patients and clinicians were masked to allocation. The primary outcome was the proportion of patients reaching low disease activity (Disease Activity Score in 28 joints ≤3·2) at week 12, analysed in the intention-to-treat population. There was no lived experience involvement in study design. The study was registered with EudraCT (2013-000337-13) and ClinicalTrials.gov (NCT01864265). FINDINGS:Between Sept 3, 2013, and Jan 10, 2020, 148 patients with rheumatoid arthritis were screened and 139 (99 [71%] women and 40 [29%] men) were randomly assigned to the high-volume certolizumab pegol group (n=49), the low-volume certolizumab pegol group (n=43), or the placebo group (n=47). Low disease activity was reached by 28 (57%) in the high-volume certolizumab pegol group, 19 (44%) in the low-volume certolizumab pegol group, and 12 (26%) in the placebo group at week 12. Response in the high-volume certolizumab pegol group was significantly different (p=0·0017) to the placebo group, but not the low-volume certolizumab pegol group (p=0·063). There were 25 treatment-related adverse events: 22 in the certolizumab pegol groups and three in the placebo group. INTERPRETATION:High disease-associated fMRI CNS pain activation might predict clinical response of patients with rheumatoid arthritis to TNF inhibitor treatment. FUNDING:UCB Biopharma.

Background: Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory disease that affects the intertriginous skin sites, especially axillary, inguinal, and perianal [1]. In recent studies, a higher prevalence of spondyloarthritis (SpA) in the HS population than in the general population (with 1%) was presented, however, the reported prevalence rates demonstrated a wide range of 2.3%-28.2% (2, 3). Furthermore, the studies mainly referred to axial SpA in association with HS [2-4]. One recent study described an association between peripheral SpA (pSpA) features such as peripheral arthritis, enthesitis, and dactylitis with HS, but the self-reporting design of this study was a limitation [5]. Objectives: To investigate the prevalence of pSpA features both clinically and by the detection of synovitis, tenosynovitis and enthesitis by musculoskeletal ultrasound (MSUS) in B-mode (GS) and power Doppler (PD), and by fluorescence optical imaging (FOI). Methods: Adult HS patients presenting at the outpatient department of Dermatology (HS diagnosed by a dermatologist) with musculoskeletal symptoms suspicious for pSpA have been included in this monocenter study. Patients were examined by a rheumatologist for tender and swollen joints (TJC-68; SJC-66). The laboratory parameters CRP, ESR, and HLA-B27 were evaluated. MSUS was performed for the detection of synovitis and tenosynovitis (both wrists, MCP and (P)IP1-5, knees, MTP1-5) in GS and PD (each 0-3), and enthesitis (both common flexor and extensor tendons, quadriceps and patellar tendons, and Achilles tendons) in PD (0-3). FOI of both hands was done by the Xiralite method in a standardized manner using PrimaVista Mode (PVM) and three predefined phases (p1-p3). Results: In total, 25 HS patients with a disease duration of 8.5±8.4 years were included (72% female, mean age 47.3±9.6, mean BMI (kg/m2) 31.8±6.1). They clinically presented with a mean TJC-68 of 7.6±7.0 and a mean SJC-66 of 0.4±1.2. CRP (normal <5.0 mg/l) and ESR (normal <20 mm/h) showed mean values of 7.2±9.2 mg/l and 19.1±14.5 mm/h. Five patients (21%) were positive for HLA B27. Mean sum scores for synovitis and tenosynovitis by MSUS were as follows: GS-synovitis 11.1±6.3, PD-synovitis 0.5±0.9, GS-tenosynovitis 0.8±1.7, PD-tenosynovitis 0.2±0.6. Six HS patients (24%) presented with PD positive enthesitis of at least one enthesis. Mean sum scores by FOI were as follows: PVM 10.2±9.0, p1 1.1±2.7, p2 12.2±11.8, p3 0.7±1.1. Conclusion: This is the first study that objectively investigates the prevalence of pSpA features such as peripheral arthritis and enthesitis in a monocenter HS cohort. All imaging scores presented elevated values, so that an association between HS and pSpA could be strongly assumed. REFERENCES: [1] Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012; 366: 158-64[2] Richette P, Molto A, Viguier M, et al. Hidradenitis suppurativa associated with spondyloarthritis - results from a multicenter national prospective study. J Rheumatol. 2014;41(3):490-494.[3] Fauconier M, Reguiai Z, Barbe C, et al. Association between hidradenitis suppurativa and spondyloarthritis. Joint Bone Spine. 2017. pii: S1297-S1319X(17)30164-1.[4] Schneider-Burrus S, Witte-Händel E, Christou D, Rigoni B, Sabat R, Diederichs G. High Prevalence of Back Pain and Axial Spondyloarthropathy in Patients with Hidradenitis Suppurativa. Dermatology 2016;232:606–612.[5] Rondags A, van Straalen KR, Arends S, et al. High prevalence of clinical spondyloarthritis features in patients with hidradenitis suppurativa. J Am Acad Dermatol 2019 Feb;80(2):551-554.e1. Acknowledgements: This study was partially supported by Novartis Pharma GmbH. Novartis Pharma GmbH did not have any influence on the study design, data analysis, or writing of the abstract. Disclosure of Interests: Sarah Ohrndorf Novartis; Janssen; Mylan, Speakers’ honoraria or travel expense reimbursements by: • AbbVie, Amgen, BMS, Galapagos, Janssen, Mylan, Novartis, UCB, Novartis; GSK; AbbVie, Jens Klotsche: None declared, Tereza Jakovljevicova: None declared, Gabriela Schmittat: None declared, Gerd R. Burmester: None declared, Gerhard Krönke: None declared, Georgios Kokolakis: None declared.

To assess radiographic progression in certolizumab pegol (CZP)+methotrexate (MTX) vs placebo (PBO)+MTX-treated patients (pts) with rheumatoid arthritis (RA), stratified by rheumatoid factor (RF) level, in the C-EARLY ( NCT01519791 ) and C-OPERA ( NCT01451203 ) phase 3 randomized trials. A pooled analysis of pts with early (≤1 year active disease) moderate-to-severe RA with poor prognostic factors in the C-EARLY and C-OPERA trials is presented (full analysis set). At Week (Wk)24, PBO-treated non-responders could switch to CZP for the remaining 28 wks (early escapers). Pts were stratified by baseline (BL) RF level (low: <200 IU/mL; high: ≥200 IU/mL), per published strata.[1,2] Change from BL in modified total Sharp score (mTSS) and proportions of pts experiencing minimum clinically important difference (worsening) of mTSS (>5) at Wk24 and Wk52 are reported. 813 CZP-treated (low RF: N=571; high RF: N=242) and 367 PBO-treated (low RF: N=242; high RF: N=125) pts with BL RF measurements were included; 56 PBO-treated pts were early escapers. BL characteristics were similar between CZP- and PBO-treated pts within each RF stratification. However, pts with high RF had more severe disease at BL than those with low RF, with higher mean C-reactive protein, anti-citrullinated protein antibodies, mTSS, and erosion scores. By Wk52, mean mTSS increased from BL in PBO-treated pts with both high RF (change from BL [CfB]: 2.36±6.20) and low RF (CfB: 1.37±3.43) but was comparable in CZP-treated pts (high RF, CfB: 0.28±2.63; low RF, CfB: 0.14±3.11). The proportion of pts with meaningfully worsening radiographic progression was higher in PBO-treated pts with high RF compared to low RF at both Wk24 (6.48% vs 2.84%) and Wk52 (17.59% vs 10.43%) (Figure). By contrast, a smaller proportion of CZP-treated pts experienced meaningful worsening and this was similar between pts with high and low RF (Wk24: 0.00% vs 1.05%; Wk52: 5.29% vs 3.14%, respectively). Figure. Individual pt CfB in mTSS at Wk24 and Wk52, stratified by baseline RF level (low [<200 IU/mL] vs high [≥200 IU/mL]) Pts with high BL RF levels had more severe RA and BL radiographic damage than those with low RF. Worsening radiographic damage was observed in PBO-treated pts, with slightly greater progression in high RF pts than low RF. In contrast, irrespective of BL RF levels, CZP-treated pts demonstrated consistently lower radiographic progression, suggesting RF does not adversely influence radiographic response to CZP. Previously submitted to: ACR 2024. [1.] Vastesaeger N. Rheumatology (Oxford) 2009;48:1114-21; [2.] Smolen J. Arthritis Rheumatol 2023;75(suppl 9).

Background: Real-world evidence provides insights into treatment effectiveness, safety and PROs beyond clinical trials. FILOSOPHY (NCT04871919) and PARROTFISH (NCT05323591) are prospective, observational Phase 4 studies ongoing in Europe and France. Objectives: To report baseline characteristics, PROs, effectiveness and safety based on pooled data from the first 1,177 patients treated with filgotinib for up to 18 months. Methods: FILOSOPHY and PARROTFISH will enroll approximately 1,500 patients aged ≥18 years with moderate to severe active RA, who are prescribed filgotinib for the first time and as per the product label1 in daily practice.At Week 1, 2 and 3 and Month 1, 3, 6, 9, 12, 15 and 18, pain (visual analog scale [VAS]), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, work productivity (Work Productivity and Activity Impairment questionnaire) and Rheumatoid Arthritis Impact of Disease (RAID) score were electronically assessed. The proportion of patients with a clinically meaningful change from baseline in VAS pain (reduction of ≥10 mm) and FACIT-Fatigue score (increase of ≥4) was assessed in advanced therapy (AT)-naïve and AT-experienced patients.At Month 1, 3, 6, 12 and 18, Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire–Disability Index (HAQ-DI) were assessed. The proportion of patients achieving DAS28-CRP of ≤2.6 or ≤3.2 and CDAI of ≤2.8 or ≤10 was determined.Treatment-emergent adverse events (TEAEs) on study were recorded. Results: As of July 2023, 1,177 patients had been treated, with a median follow-up of 322 days; baseline characteristics are shown in Table 1. 50.8% of patients received filgotinib monotherapy; 48.8% received filgotinib in combination with conventional synthetic disease-modifying antirheumatic drugs. 91.6% received filgotinib 200 mg; 8.4% received filgotinib 100 mg. 37.6% of patients were AT naïve; 62.4% were AT experienced. Pain and fatigue improved as early as Week 1. At Week 1, 39.2% and 46.6% of AT-naïve and AT-experienced patients, respectively, had a clinically meaningful improvement in VAS pain, and 42.9% and 44.4%, respectively, had a clinically meaningful improvement in FACIT-Fatigue score. Clinically meaningful changes were observed in patients followed up to Month 18 (Figure 1A and B). Work productivity and daily activity impairment improved from Week 1; improvements were observed in patients followed up to Month 18 (Figure 1C). Most patients initially had moderate to high disease activity. Improvements were seen as early as Month 1. By Month 18, DAS28-CRP of ≤2.6 was reported by 60.3% (82/136) while DAS28-CRP of >2.6 and ≤3.2 was reported by 15.4% (21/136) of patients; CDAI scores of ≤2.8 were reported by 36.8% (57/155) while scores of >2.8 and ≤10 were reported by 34.2% (53/155) of patients. Median (interquartile range) HAQ-DI was 1.4 (0.8, 1.8) at baseline (N=213), 0.8 (0.3, 1.4) at Month 1 (N=149) and 0.8 (0.3, 1.5) at Month 6 (N=97). Median (IQR) RAID score was 6.6 (5.0, 7.6) at baseline (N=142), 5.8 (4.1, 6.9) at Week 1 (N=300) and 3.9 (2.2, 6.0) at Month 6 (N=220). 618 patients (52.5%) had TEAEs on study, leading to treatment discontinuation in 91 (7.7%) cases. There were 6 deaths, 1 of which was considered related to study treatment (pneumonia and pulmonary embolism). TEAEs included COVID-19 (n=106), herpes zoster (n=16), fractures (n=20), opportunistic infections (n=3), stroke (n=6), transient ischemic attack (n=5), unstable angina (n=7), malignant/unspecified tumor (n=7) and pulmonary embolism (n=2). Conclusion: Interim data from patients treated with filgotinib in routine practice show pain, fatigue, work productivity and RAID score improved as early as Week 1. DAS28-CRP, CDAI and HAQ-DI improved as early as Month 1, the first timepoint these endpoints were assessed. Improvements were maintained up to Month 18 (Month 6 for RAID and HAQ-DI). Longer-term follow-up and completion of the studies will allow further evaluation of effectiveness and safety. REFERENCES: [1] Jyseleca SmPC. Galapagos NV, May 2022 Acknowledgements: We thank the physicians and patients who participated in this study. The study was funded by Galapagos NV (Mechelen, Belgium). Medical writing support was provided by Debbie Sherwood, BSc, CMPP (Aspire Scientific, Bollington, UK), and funded by Galapagos NV. Publication coordination was provided by Jo-Ann E. West, MSc, a consultant funded by Galapagos NV. Disclosure of Interests: Jérôme Avouac AbbVie, AstraZeneca, Biogen, BMS, Eli Lilly, Fresenius Kabi, Galapagos, MSD, Novartis, Pfizer, Sandoz and Sanofi, AbbVie, Fresenius Kabi, Galapagos and Sanofi, BMS, Fresenius Kabi, Galapagos, Novartis and Pfizer, Gerd R. Burmester AbbVie, BMS, Eli Lilly, Galapagos, MSD and Pfizer, AbbVie, BMS, Eli Lilly, Galapagos, MSD and Pfizer, Roberto F. Caporali AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer and UCB, AbbVie, Accord, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, Novartis, Pfizer and UCB, Thomas P. A. Debray Biogen, Daiichi Sankyo, Galapagos and Gilead, Francesco De Leonardis Galapagos, Galapagos, James Galloway AbbVie, Eli Lilly, Galapagos, Janssen, Pfizer and UCB, AbbVie, Eli Lilly, Galapagos, Janssen and Pfizer, AstraZeneca, Janssen and Pfizer, Neil Betteridge Amgen, ASIF, Edwards Lifesciences, Eli Lilly, EULAR Global Alliance for Musculoskeletal Health, Global Alliance for Patient Access, Grünenthal, Heart Valve Voice, Pfizer and Sanofi Genzyme, Karen Bevers Galapagos, Susana Romero-Yuste AbbVie, Biogen, BMS, Eli Lilly and Pfizer, Eli Lilly and Sanofi, Eli Lilly and MSD, Monia Zignani Galapagos, Galapagos, Patrick Verschueren Eli Lilly and Galapagos, AbbVie, Eli Lilly and Galapagos, Galapagos and Pfizer.

CT-P47 is a candidate biosimilar of tocilizumab. This 12-week, randomized, double-blind, parallel-design, phase 1 study aimed to demonstrate pharmacokinetic (PK) equivalence of CT-P47 and reference tocilizumab. Participants were healthy Japanese adults aged 18-55 years. Participants were randomized (1:1:1) to receive a single intravenous dose (8 mg/kg) of CT-P47, EU-approved tocilizumab (EU-tocilizumab), or US-licensed tocilizumab (US-tocilizumab). Primary PK endpoints were area under the concentration-time curve (AUC) from time zero to infinity, AUC from time zero to the last quantifiable concentration, and maximum serum concentration. Additional PK variables, safety, and immunogenicity were evaluated. The study was conducted from January 20 to May 26, 2023, in three centers in Japan. In total, 133 male participants were randomized (n = 45 to CT-P47, n = 44 to EU-tocilizumab, and n = 44 to US-tocilizumab). For all primary PK variables, 90% confidence intervals of the ratio of geometric least squares means were within the predefined equivalence margin of 0.80-1.25. Secondary PK variables were similar across groups. The most common treatment-emergent adverse event (TEAE) was neutrophil count decreased, occurring in 15 (33.3%), 13 (30.2%), and 12 (27.3%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively. There were no serious TEAEs, deaths, or study drug discontinuations due to TEAEs. Few participants were anti-drug antibody (ADA)- or neutralizing antibody (NAb)-positive. At the end of study, four (8.9%), one (2.3%), and two (4.5%) participants in the CT-P47, EU-tocilizumab, and US-tocilizumab groups, respectively, were ADA-positive; two (4.4%), zero (0%), and one (2.3%) in the respective groups were NAb-positive. CT-P47 demonstrated PK equivalence and comparable safety to EU- and US-tocilizumab.

Background: CT-P47 is a recombinant humanized monoclonal antibody developed as a proposed biosimilar of tocilizumab. Here we report the study results from a comparative clinical trial. Objectives: The purpose of this study was to compare the efficacy and safety of CT-P47 with reference tocilizumab (ref-tocilizumab) in patients with active moderate-to-severe rheumatoid arthritis (RA). Methods: Patients with moderate-to-severe RA who had inadequate response to ≥1 disease-modifying antirheumatic drugs were randomized 1:1 to receive 8 mg/kg of CT-P47 or ref-tocilizumab every 4 weeks up to Week 20. Prior to dosing at Week 24, patients in ref-tocilizumab group were re-randomized either to continue with ref-tocilizumab or undergo transition to CT-P47. Patients initially assigned to CT-P47 continued CT-P47 treatment until Week 48. The primary endpoint was mean change from baseline of disease activity score 28 (DAS28) (erythrocyte segmentation rate [ESR]) at two timepoints of Week 12 and Week 24 considering different regulatory requirement. Additional efficacy, PK and safety including immunogenicity were also evaluated. Results: 471 randomized patients initiated treatment (CT-P47 in 234; ref-tocilizumab in 237). Baseline characteristics were similar between groups. The least squares mean (standard error) change from baseline of DAS28 (ESR) by analysis of covariate (ANCOVA) was -3.01 (0.121) and -3.00 (0.120) at Week 12 and by ANCOVA with multiple imputation was -3.77 (0.120) and -3.67 (0.118) at Week 24 for CT-P47 and ref-tocilizumab, respectively. The confidence intervals (CIs) of treatment difference were entirely within the predefined equivalence margins of Week 12: ±0.6 (95% CI: -0.01 [-0.26 to 0.24]) and Week 24: -0.6 to 0.5 (90% CI: -0.10 [-0.30 to 0.10]). Secondary efficacy endpoints up to Week 24 showed gradual improvement and were also similar between groups (Table 1) and maintained with slight improvement from Weeks 24 to 32.Mean serum concentration was similar between groups up to Week 32 (Week 24: CT-P47; 14.63 μg/mL vs ref-tocilizumab; 15.14 μg/mL).Up to Week 24 predose, 375 patients (CT-P47: 80.3% vs. ref-tocilizumab: 78.9%) experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAE was upper respiratory tract infection (21.4%) in the CT-P47 and alanine aminotransferase increased (20.3%) in the ref-tocilizumab. Similar proportions of patients in both groups experienced at least 1 serious TEAE, TEAE classified as hypersensitivity reactions, hepatic event, and hemorrhage. From Weeks 24 to 32, the proportion of patients in overall TEAEs were also similar among groups (Table 2).Up to Week 32, the proportion of patients who had at least 1 anti-drug antibody positive result at post-treatment was similar between groups (CT-P47: 5.1% vs. ref-tocilizumab: 5.5%), and 4.7% in CT-P47 and 4.2% in ref-tocilizumab also had at least 1 neutralizing antibody positive result at post-treatment. Conclusion: The results demonstrated that CT-P47 was equivalent to ref-tocilizumab as measured by the DAS28 (ESR). Also, efficacy, PK, safety and immunogenicity profiles were comparable among groups after Week 24 up to Week 32. Thus, this study supports the biosimilarity of CT-P47 to ref-tocilizumab and clinical evidence for switching from ref-tocilizumab to CT-P47. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Josef S. Smolen Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Amgen, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche, Jakub Trefler: None declared, Artur Racewicz: None declared, Janusz Jaworski: None declared, Agnieszka Zielinska: None declared, Marek Krogulec: None declared, Sławomir Jeka Abbvie, Amgen, Celgene, Lilly, Novartis, Roche, Sandoz, Sobi, UCB,Rafał Wojciechowski Eli Lilly, Novartis, UCB, Janssen, Katarzyna Kolossa: None declared, Anna Dudek: None declared, Magdalena Krajewska-Włodarczyk: None declared, Paweł Hrycaj: None declared, Piotr Adrian Klimiuk: None declared, Gerd R. Burmester Chugai, Fresenius, Sanofi, Celltrion, Fresenius, Sanofi, Sung Hyun Kim Celltrion, Inc., YunJu Bae Celltrion, Inc., Dabee Jeon Celltrion, Inc., GoEun Yang Celltrion, Inc., YooBin Jung Celltrion, Inc., JiWoo Hong Celltrion, Inc., Edward Keystone AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, AbbVie, Celltrion, GSK Pharmaceuticals, Lilly Pharmaceuticals, Pfizer Pharmaceuticals, Sandoz, Samsung Bioepsis Table 1Secondary Efficacy Results at Week 24 (ITT Set)CT-P47N=234Ref-TocilizumabN=237DAS28 (CRP), mean CFB (SD)-3.0 (1.08)-2.9 (1.20)ACR20, n (%)199 (85.0)189 (79.7)ACR50, n (%)142 (60.7)146 (61.6)ACR70, n (%)100 (42.7)99 (41.8)CDAI, remission rate, n (%)59 (25.2)57 (24.1)SDAI, remission rate, n (%)63 (26.9)60 (25.3)EULAR response (ESR) (good to moderate), n (%)218 (93.2)217 (91.6)ACR/EULAR remission (Boolean-definition), n (%)44 (18.8)40 (16.9)Abbreviations: ACR, American college of Rheumatology; CDAI, clinical disease activity index; CFB, change from baseline; DAS28, Disease Activity Score 28; EULAR, European Alliance of Associations for Rheumatology; ITT, intent-to-treat; SD, standard deviation; SDAI, simplified disease activity index.

BACKGROUND:Potential associations between targeted therapies and a new cancer in patients with inflammatory arthritis (IA) and a previous malignancy are a frequent concern in daily rheumatology practice. OBJECTIVES:To develop points to consider (PTC) to assist rheumatologists when initiating a targeted therapy in the context of a previous malignancy. METHODS:Following EULAR standardised operating procedures, a task force met to define the research questions for a systematic literature review and to formulate the overarching principles (OPs) and the PTC. RESULTS:The group formulated five OPs; seven PTC were formulated concerning the initiation of targeted therapies in patients with active IA and a previous malignancy in remission and one PTC concerning patients with active IA who were not in cancer remission. Major themes included (a) the need to assess the individualised risk of cancer recurrence based on the characteristics of the patient, cancer and the underlying disease; (b) the importance of engaging with specialists caring for cancer and defining treatment based on a shared decision between the patient and the rheumatologist; (c) the value of initiating without delay an appropriate targeted therapy for the treatment of the IA in patients in remission of their cancer; (d) the proposal to use Janus kinase inhibitors and abatacept with caution and in the absence of therapeutic alternatives, based on the absence of any data concerning their use in the context of previous malignancy. CONCLUSION:The 2024 EULAR points to consider provide guidance on the management of targeted therapies in patients with IA and a previous malignancy.

Abstract Background Patients with rheumatoid arthritis (RA) are at risk of developing interstitial lung disease (ILD), which is associated with high mortality. Screening tools based on risk factors are needed to decide which patients with RA should be screened for ILD using high-resolution computed tomography (HRCT). The ANCHOR-RA study is a multi-national cross-sectional study that will develop a multivariable model for prediction of RA-ILD, which can be used to inform screening for RA-ILD in clinical practice. Methods Investigators will enrol consecutive patients with RA who have ≥ 2 of the following risk factors for RA-ILD: male; current or previous smoker; age ≥ 60 years at RA diagnosis; high-positive rheumatoid factor and/or anti-cyclic citrullinated peptide (titre > 3 x upper limit of normal); presence or history of certain extra-articular manifestations of RA (vasculitis, Felty’s syndrome, secondary Sjögren’s syndrome, cutaneous rheumatoid nodules, serositis, and/or scleritis/uveitis); high RA disease activity in the prior 12 months. Patients previously identified as having ILD, or who have had a CT scan in the prior 2 years, will not be eligible. Participants will undergo an HRCT scan at their local site, which will be assessed centrally by two expert radiologists. Data will be collected prospectively on demographic and RA-related characteristics, patient-reported outcomes, comorbidities and pulmonary function. The primary outcomes will be the development of a probability score for RA-ILD, based on a multivariable model incorporating potential risk factors commonly assessed in clinical practice, and an estimate of the prevalence of RA-ILD in the study population. It is planned that 1200 participants will be enrolled at approximately 30 sites in the USA, UK, Germany, France, Italy, Spain. Discussion Data from the ANCHOR-RA study will add to the body of evidence to support recommendations for screening for RA-ILD to improve detection of this important complication of RA and enable early intervention. Trial registration clinicaltrials.gov NCT05855109 (submission date: 3 May 2023).