Explore the vast range of titles available.

BackgroundAxial spondyloarthritis (axSpA) is a chronic rheumatic disease which requires optimal management and disease control. Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40) is a stringent efficacy outcome in clinical trials, while in clinical practice the focus is on the achievement of sustained remission or low disease activity (LDA) according to Ankylosing Spondylitis Disease Activity Score (ASDAS). Patients (pts) can experience loss of response in the long term and maintenance of response is an internationally recommended treatment target.[1]Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL‑17A. BKZ has demonstrated consistent and sustained clinical efficacy to Week (Wk) 52 in pts across the full spectrum of axSpA in the phase 3 studies BE MOBILE 1 and 2.[2]ObjectivesTo report the maintenance of stringent clinical responses through one year of treatment with BKZ in pts with non‑radiographic axSpA (nr-axSpA) and radiographic-axSpA (r‑axSpA, i.e., ankylosing spondylitis)[3] in phase 3 studies.MethodsIn BE MOBILE 1 (NCT03928704; nr-axSpA; pts met ASAS criteria for axSpA) and BE MOBILE 2 (NCT03928743; r‑axSpA; pts fulfilled ASAS and modified New York criteria for r-axSpA), pts were randomised to receive subcutaneous BKZ 160 mg every 4 wks (Q4W) or placebo (PBO) to Wk 16. From Wks 16−52, all pts received BKZ 160 mg Q4W.[4,5]ASAS40 and ASDAS <2.1 (LDA) or <1.3 (inactive disease [ID]) responses to Wk 52 were assessed among BKZ‑randomised pts who responded at Wk 16. Missing ASAS40 data were imputed using non-responder imputation (NRI), and multiple imputation (MI) was used for missing ASDAS data. MI was based on Markov Chain Monte Carlo (for intermittent missing data) followed by monotone regression (for monotone missing data). Observed case (OC) data are also reported. Wk 16 and Wk 52 responder rates for all BKZ-randomised pts are included for context (NRI or MI).The number of treatment-emergent adverse events (TEAEs) to Wk 52 are reported for pts who received ≥1 dose of BKZ, including pts who switched from PBO to BKZ at Wk 16.ResultsA total of 128 and 221 pts were randomised to BKZ 160 mg Q4W in BE MOBILE 1 and 2, respectively. At Wk 16, 47.7% and 44.8% of these pts achieved the primary endpoint, ASAS40, and this increased to 60.9% and 58.4% at Wk 52 (NRI, Figure 1). Of pts that achieved ASAS40 at Wk 16, 82.0% and 83.8% maintained this response at Wk 52 (NRI, Figure 1).ASDAS LDA was achieved by 46.1% and 44.8% of BKZ-randomised pts at Wk 16 of BE MOBILE 1 and 2, respectively; this increased to 61.6% and 57.1% at Wk 52 (MI, Figure 1). Of pts that achieved ASDAS LDA at Wk 16, 88.9% and 88.4% maintained this response at Wk 52 (MI, Figure 1).At Wk 16 of BE MOBILE 1 and 2, ASDAS ID was achieved by 18.8% and 16.4% of BKZ‑randomised pts, respectively; and this increased to 25.2% and 23.4% at Wk 52 (MI). Among Wk 16 ASDAS ID responders, ASDAS ID was maintained by 79.2% and 75.1% at Wk 24, 85.3% and 71.7% at Wk 36, and 88.0% and 58.7% at Wk 52 (MI).To Wk 52 of BE MOBILE 1 and 2, 183/244 (75.0%) and 249/330 (75.5%) pts reported ≥1 TEAE whilst receiving BKZ, respectively; 9 (3.7%) and 20 (6.1%) reported serious TEAEs.ConclusionDual inhibition of IL-17F and IL-17A with BKZ provided robust maintenance of stringent clinical responses from Wk 16 to Wk 52 across the full axSpA disease spectrum. This is consistent with previously reported observations of BKZ treatment over three years in pts with r-axSpA in the phase 2b study BE AGILE and its open-label extension.[6]References[1] Smolen J. Ann Rheum Dis 2018;77:3–17;[2] Baraliakos X. Arthritis Rheumatol 2022;74 (suppl 9);[3] Boel A. Ann Rheum Dis 2019;78:1545–9;[4] Deodhar A. Ann Rheum Dis 2022;81:772–3;[5] van der Heijde D. Ann Rheum Dis 2022;81:12–3;[6] Navarro-Compán V. Presented at EULAR 2022, POS0938.AcknowledgementsThis study was funded by UCB Pharma. Medical writing support was provided by Costello Medical, funded by UCB Pharma.Disclosure of InterestsFabian Proft Speakers bureau: AbbVie, Amgen, BMS, Celgene, Hexal, Janssen, MSD, Novartis, Pfizer, Roche and UCB Pharma, Consultant of: AbbVie, Amgen, BMS, Celgene, Hexal, Janssen, MSD, Novartis, Pfizer, Roche and UCB Pharma, Grant/research support from: Eli Lilly, Novartis and UCB Pharma, Désirée van der Heijde Consultant of: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer and UCB Pharma, Employee of: Director of Imaging Rheumatology BV, Xenofon Baraliakos Speakers bureau: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Paid instructor for: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, MSD, Novartis, Pfizer and UCB Pharma, Joerg Ermann Consultant of: Abbvie, Eli Lilly, Janssen, Novartis, Pfizer, Takeda and UCB Pharma, Grant/research support from: Abbvie, Boehringer Ingelheim, Novartis and Pfizer, Carmen Fleurinck Employee of: UCB Pharma, Ute Massow Employee of: UCB Pharma, Natasha de Peyrecave Employee of: UCB Pharma, Vanessa Taieb Employee of: UCB Pharma, Astrid van Tubergen Speakers bureau: Pfizer, Consultant of: Novartis, Pfizer and UCB Pharma, Grant/research support from: MSD, Novartis, Pfizer and UCB Pharma, Victoria Navarro-Compán Speakers bureau: AbbVie, Eli Lilly, Janssen, MSD, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Galapagos, Moonlake, MSD, Novartis, Pfizer and UCB Pharma, Grant/research support from: AbbVie and Novartis.

ObjectivesTo investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W).MethodsAdults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52.ResultsIn COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks.ConclusionThe significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab.Trial registration number NCT02696785/NCT02696798.

Key Points Immune cell profiling to provide prognostic information and predict treatment responses is not yet part of clinical rheumatology practice Novel technologies, including mass cytometry, RNA-seq and multiplexed functional assays, promise insight into the pathogenesis of rheumatic diseases with unprecedented detail and might lead to the discovery of new biomarkers Computational and statistical approaches for managing and analysing big data need to be refined to achieve the full potential of these assays Assay standardization and the definition of normal values are prerequisites for the introduction of high-dimensional cytometry, genome-wide gene expression analysis and multiplexed functional assays into clinical practice Immune cell profiling has the potential to improve outcomes in rheumatic diseases by providing mechanistic insight into the disease process in individual patients and guiding treatment decisions RNA sequencing and mass cytometry are exciting new technologies that could revolutionize the analysis of immune cells. In this article, these developments and parallel advances in the analysis of big data are reviewed with the aim of advancing biomarker discovery. Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies—big data—require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care.

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4 + CD25 + regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4 + CD25 + regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) α-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4 + CD25 + T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.

We have developed a multiplexed reverse phase protein (RPP) microarray platform for simultaneous monitoring of site-specific phosphorylation of numerous signaling proteins using nanogram amounts of lysates derived from stimulated living cells. We first show the application of RPP microarrays to the study of signaling kinetics and pathway delineation in Jurkat T lymphocytes. RPP microarrays were used to profile the phosphorylation state of 62 signaling components in Jurkat T cells stimulated through their membrane CD3 and CD28 receptors, identifying a previously unrecognized link between CD3 crosslinking and dephosphorylation of Raf-1 at Ser259. Finally, the potential of this technology to analyze rare primary cell populations is shown in a study of differential STAT protein phosphorylation in interleukin (IL)-2-stimulated CD4 + CD25 + regulatory T cells. RPP microarrays, prepared using simple procedures and standard microarray equipment, represent a powerful new tool for the study of signal transduction in both health and disease.

In this Overview, common themes of the accompanying News & Views on RA, SLE, IDDM, thyroiditis and MS are discussed. A unifying concept for the development of these and other autoimmune diseases should incorporate genetic predisposition, environmental factors and immune dysregulation.

OBJECTIVES To evaluate in vivo the contribution of tumour necrosis factor α (TNFα) to the chimeric transfer model of human rheumatoid arthritis synovial membrane into SCID mice (hu/mu SCID arthritis), systemic anti-TNFα treatment was performed and the clinical, serological, and histopathological effects of this treatment assessed. METHODS Animals were treated with the rat-antimouse TNFα monoclonal antibody V1q, starting on day 1 after hu/mu engraftment, twice weekly for 12 weeks. Joint swelling, serum concentrations of human and murine interleukin 6 (IL6), and serum amyloid P (SAP) were measured. Histopathological and immunohistochemical analyses of the joints were also performed at the end of treatment. RESULTS Neutralisation of murine TNFα induced the following effects: (a) reduction of extent and duration of the acute arthritis phase, with significant reduction of joint swelling at two weeks; (b) decrease of murine SAP concentrations after the first antibody administration; and (c) increase of murine IL6 in the serum. At the end of treatment, there was a significant reduction of the inflammatory infiltration in the engrafted joints. Because of the mild degree of joint erosion, no treatment effects could be demonstrated on the destructive process. CONCLUSION In the lymphocyte independent hu/mu SCID arthritis, anti-TNFα treatment reduces local and systemic signs of inflammation.

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4 super(+)CD25 super(+) regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4 super(+)CD25 super(+) regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) alpha -chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4 super(+)CD25 super(+) T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells.