Publications
View and download slide summaries of the latest original articles focusing on cytokine signalling therapies within rheumatoid arthritis. All materials produced by the CSF team are subsequently reviewed and approved by individual Steering Committee members.
Anti-gm-csf Otilimab versus Sarilumab or Placebo in Patients with Rheumatoid Arthritis and Inadequate Response to Targeted Therapies: A Phase III Randomised Trial (contRAst 3)
Ann Rheum Dis. 2023 doi 10.1136/ard-2023-224449 Epub ahead of print
The ContRAst 3 study investigated otilimab, in RA patients with inadequate responses to multiple treatments. Otilimab did not significantly improve ACR20 versus placebo at Weeks 12 or 24. In addition, there we no significant improvements in secondary endpoints, including disease activity, disability, and pain.
Anti-GM-CSF Otilimab Versus Tofacitinib or Placebo in Patients With Active Rheumatoid Arthritis and an Inadequate Response to Conventional or Biologic DMARDs: Two Phase 3 Randomised Trials (contRAst 1 and contRAst 2)
Ann Rheum Dis 2023;0:1–11 doi 10.1136/ard-2023-224482
Fleischmann, et al investigated the safety and efficacy of otilimab versus tofacitinib and placebo in RA patients treated with MTX (contRAst 1) or csDMARDs (contRAst 2). They found that while otilimab achieved the primary endpoint of ACR20 versus placebo in Week 12, it did not demonstrate non-inferiority to tofacitinib.
Incidence, Prevalence, and Co-occurrence of Autoimmune Disorders Over Time and by Age, Sex, and Socioeconomic Status: A Population-based Cohort Study of 22 Million Individuals in the UK
Lancet. 2023; 401(10391):1878–1890 doi 10.1016/S0140-6736(23)00457-9
Incidence rates for autoimmune diseases increased between 2000 and 2019 in the UK, notably in coeliac disease, Sjogren's syndrome, and Graves' disease. Pernicious anaemia and Hashimoto's thyroiditis had the greatest decrease in incidence. These disorders affected about 10% of the population, with socioeconomic, seasonal, and regional variations observed.
Two Phase 3 Trials of Baricitinib for Alopecia Areata
N Engl J Med. 2022. Epub ahead of print doi: 10.1056/NEJMoa2110343
Phase 3 trials in patients with severe alopecia areata show that baricitinib is superior to placebo with respect to hair regrowth at 36 weeks.
Alopecia areata is characterised by nonscarring hair loss that can affect any hair-bearing site. Although mild cases of this emotionally- and psychosocially-distressing autoimmune disease may resolve within 12 months, more severe forms of the disease are unlikely to remit without treatment.
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Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach
Nat Rev Rheumatol. 2022 Jan 5:1–13. Epub ahead of print doi: 10.1038/s41584-021-00726-8
The development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders, to the extent that they could ultimately enable either complete withdrawal or avoidance of glucocorticoid use in some autoimmune diseases, and could have the potential to regulate any active factor inhibiting the transition to cure.In this review paper, Tanaka, et al. describe the progress in JAK-targetin...Keywords:
Safety, Tolerability, Pharmacokinetics, Target Occupancy, and QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers
Clin Transl Sci . 2020 Mar;13(2):325-336. doi: 10.1111/cts.12713. Epub 2019 Nov 29.
In this first in-human phase I, double-blind, placebo-controlled trial, the Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib was well-tolerated, showed linear and time-independent PK, induced long-lasting BTK inhibition, and was not associated with prolongation of QT/QTc interval in healthy subjects. Evobrutinib is an oral BTK inhibitor that has demonstrated efficacy in pre-clinical and autoimmune disease models. BTK is a key regulator of B cell receptor and Fc receptor signalling, and a rat...
Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models
J Immunol 2019;202:2888–2906. DOI: 10.4049/jimmunol.1800583
BTK is involved in both adaptive and innate immune responses and mediates signalling of several immune receptors of relevance to RA and SLE pathogenesis. Targeting BTK is a promising approach therefore for autoimmune disorders with aberrant B cell responses. Evobrutinib is a novel, highly specific, and irreversible BTK inhibitor. In vivo and animal models showed that evobrutinib modulated B cell and innate immune cell activation, was efficacious, and prevented joint damage. The potency of evobru...
JAK Inhibition as a Therapeutic Strategy for Immune and Inflammatory Diseases
Nat Rev Drug Discov 2017;16:843–62 DOI: 10.1038/nrd.2017.201
Janus kinases (JAKs) are essential mediators of downstream signaling pathways in many inflammatory and autoimmune diseases. This review summarizes current clinical data on first- and second-generation JAK inhibitors (jakinibs) and discusses their use for the treatment of immune and inflammatory conditions.First generation jakinibs such as tofacitinib, baricitinib, and ruxolitinib, non-selectively inhibit JAK-dependent pro-inflammatory cytokines, which are major contributors to immunopathology. T...
IL-6 stimulates intestinal epithelial proliferation and repair after injury
PLoS One. 2014 Dec 5;9(12):e114195. doi: 10.1371/journal.pone.0114195. eCollection 2014.
IL-6 is an inflammatory cytokine known to contribute to a number of autoimmune diseases such as RA. Therapies targeting the soluble IL-6 receptor have now become effective treatments for RA. However, one unforeseen, yet rare, potential complication of anti-IL-6 therapy is bowel perforation. Yet within the intestine, IL-6 protects intestinal epithelial cells from apoptosis during prolonged inflammation.The authors hypothesized that IL-6 may have beneficial properties in wound response/rep...
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Molecular pathways: Molecular basis for sensitivity and resistance to JAK inhibitors
Clin Cancer Research doi:10.1158/1078-0432.CCR-13-0279
Janus kinases (JAKs) mediate the regulation of a variety of cytokine signals with alterations in JAK1, JAK2, JAK3 and Tyk2 signalling contributing to many disease states including autoimmune diseases and haematological malignancies. Recently tofacitinib and ruxolitinib have been approved for treatment for rheumatoid arthritis and myelofibrosis respectively. Several JAK2 inhibitors, such as momelotinib and pacritinib, currently in development for myelofibrosis and the JAK1/2 inhibitor baricitinib...