Rheumatoid arthritis (RA) is a systemic autoimmune disease currently with no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in at-risk populations prior to clinical onset is crucial to establishing effective prevention strategies. Here, we applied multimodal single-cell technologies (mass cytometry and CITE-Seq) to characterize the immunophenotypes in blood from at-risk individuals (ARIs) identified through the presence of serum antibodies against citrullinated protein antigens (ACPAs) and/or first-degree relative (FDR) status, as compared with patients with established RA and people in a healthy control group. We identified significant cell expansions in ARIs compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5lo naive B cell population was expanded in ACPA-positive FDRs. Further, we uncovered the molecular phenotype of the CCR2+CD4+ T cells, expressing high levels of Th17- and Th22-related signature transcripts including CCR6, IL23R, KLRB1, CD96, and IL22. Our integrated study provides a promising approach to identify targets to improve prevention strategy development for RA.
Introduction & Objectives: ORKA-001 is a novel half-life extended monoclonal antibody targeting IL-23p19 with similar potency and epitope binding to risankizumab. ORKA-001’s extended half-life has the potential to enable once-yearly dosing, increased efficacy, and extended off-treatment remission in psoriasis. Here, 24-week results of the First in Human (FIH) Phase 1 study of ORKA-001 in healthy volunteers are presented. Materials & Methods: This Phase 1, double-blinded, placebo-controlled, randomized FIH study evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) of ORKA-001 in 24 healthy adult volunteers. Participants were randomized 6:2 to receive a single subcutaneous (SC) dose of ORKA-001 or placebo across three ascending dose-level cohorts: 300 mg, 600 mg, and 1200 mg. Participants were admitted to a Clinical Research Unit, where they remained until Day 4 and then returned to the clinic for follow-up safety and PK assessments over one year. Results: Eight participants were dosed in each of the 3 cohorts: 6 with ORKA-001 and 2 with placebo. Baseline characteristics were typical of a healthy volunteer population. Half-life of ORKA-001 was approximately 100 days. Individual PK profiles showed no indication of anti-drug antibodies (ADAs). In an ex vivo assay, serum from subjects dosed with ORKA-001 potently inhibited IL-23-mediated STAT3 signaling for 24 weeks (study duration to date). The study remains blinded; however, no serious or severe adverse events (AEs) were reported, and no discontinuations occurred. AEs reported in >2 participants were headache, upper respiratory tract infection, and transient erythema at the injection site. All of these events were mild. No dose-dependent trends in AEs were observed. Conclusion: PK and PD results in this Phase 1 study of ORKA-001 support the potential for once-yearly dosing while maintaining trough antibody concentrations above approved IL-23 targeting antibodies like risankizumab. In addition, the PK profile supports evaluation of higher antibody exposures that may allow ORKA-001 to achieve higher rates of skin clearance than that of the current standard of care and long-term off-treatment remission in some patients. ORKA-001 was well-tolerated across all dose levels, with a favorable safety profile consistent with the IL-23p19 inhibitor class. These attributes are being further explored in an ongoing Phase 2a study, EVERLAST-A, which is evaluating efficacy and safety of ORKA-001 in adults with moderate-to-severe psoriasis.
Systemic Lupus Erythematosus (SLE) is a chronic, multisystem autoimmune disorder with a wide spectrum of clinical manifestations. Among its rare but severe complications is vasculitis, which results from immune complex deposition and subsequent inflammation of blood vessels, potentially leading to tissue ischemia and necrosis. This case details a 21-year-old female recently diagnosed with SLE, who presented with acute lupus vasculitis manifesting as painful blackish discoloration of the fingers. Despite prompt medical intervention, the severity of ischemia necessitated partial finger amputation. This case highlights the need for early recognition and aggressive treatment of vasculitic complications in SLE to prevent irreversible damage.
