Knee SxOA was associated with an increased risk of all-cause mortality among the residents in the rural areas of China.
To investigate the effects of altered collagen II (CII) peptide ligands in collagen-induced arthritis (CIA), CIA rats were subcutaneously injected with an altered CII263-272 peptide ligand (APL, 100, 10, and 1 microg/dose, six dose each, twice a week), which had been identified by us as an inhibitory effect on CII-specific T-cell activation in vitro in rheumatoid arthritis (RA). Clinical, radiographic, and histologic scores were evaluated. Serum level of interferon (IFN)-gamma was assessed by enzyme-linked immunosorbent assay, and the numbers of interleukin (IL)-4-producing cells in vitro in memory responses to the APL were determined by enzyme-linked immunospot. The results showed significantly reduced arthritis scores in CIA rats treated with 100 microg/dose of APL compared with those treated with phosphate buffered solution (PBS) and control peptide. The mean radiographic and histologic scores were also markedly lower in APL-treated CIA rats. On day 35 after immunization, a significantly lower level of IFN-gamma in serum was found in APL-treated rats, accompanied by increased numbers of IL-4-producing cells, indicating that APL treatment skewed the T helper (Th)1/Th2 balance toward Th2-type response in vivo. Altered CII263-272 peptide ligand immunization induces inhibition of CIA through a shift toward Th2-type response, suggesting that altered CII peptide might be a potential therapeutic target for RA.
BackgroundOrelabrutinib is an oral, highly-selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Orelabrutinib has been approved for the treatment of B cell malignancies in China. Two distinct lupus animal models showed significant efficacy of orelabrutinib in reducing disease activity, which supported the clinical development of orelabrutinib in Systemic Lupus Erythematosus (SLE).ObjectivesThis phase Ib/IIa, randomized, double-blind, placebo-controlled, dose-finding study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy and biomarkers of orelabrutinib in patients with mild to moderate SLE who received standard of care (SoC) therapy.MethodsPatients diagnosed with SLE by the ACR classification criteria for ≥ 6 months, who had a SLEDAI-2K score ≥5 at screening, and were autoantibody-positive, were randomized 1:1:1:1 to receive oral orelabrutinib at 50mg, 80mg, 100mg or placebo once daily for 12 weeks, respectively.ResultsThis study randomized 60 patients with 55 patients who completed 12-week treatment. Age at baseline was 33.7±9.8 years and 96.7% were female. Baseline disease characteristics were generally balanced across treatment groups. Adverse events (AEs) were reported in 80%, 93.3% and 100% of orelabrutinib treated patients at doses of 50mg, 80mg and 100mg QD respectively versus 85.5% in placebo group. AEs were mostly mild or moderate. Treatment-related SAEs were reported in 3 patients treated with orelabrutinib, only 1 of which was grade 3. No deaths were reported. The plasma exposure of orelabrutinib (AUC and Cmax) was proportionally increased with doses. Nearly complete BTK occupancy was achieved at all dose levels, and the occupancy lasted for 24 hours without any decrease compared to that at 4 hour post-dosing. In all evaluable patients, the SLE Response Index (SRI)-4 response rates at week 12 were 50.0%, 61.5% and 64.3% in patients treated with orelabrutinib at 50mg (n=14), 80mg (n=13) and 100mg (n=14) respectively, compared with 35.7% in patients treated with placebo (n=14), which indicated the trend of dose-dependent improvement. Among the subgroup of patients with SLEDAI-2K≥8 at screening, SRI-4 response occurred in 70%, 70% and 66.7% of patients treated with orelabrutinib at 50mg (n=10), 80mg (n=10) and 100mg (n=9), respectively, compared with 30% who received placebo (n=10). Trends of reduced proteinuria, anti-dsDNA and IgG, total B cells and increased complements C4 were also observed following orelabrutinib treatment.ConclusionOrelabrutinib was generally safe and well tolerated in patients with SLE. Preliminary results also suggested encouraging efficacy which supports further development of orelabrutinib in larger and longer trials for SLE.Table 1.Efficacy results at week 12.All Evaluable PatientsPlaceboOrelabrutinibOrelabrutinibOrelabrutinib50 mg80 mg100 mgN=5514141314SRI-4 response, n (%)5 (35.7%)7 (50.0%)8 (61.5%)9 (64.3%)Treatment difference vs. PBO (%)14.3%25.8%28.6%SLEDAI-2K≥8, N=391010109SRI-4 response, n (%)3 (30.0%)7 (70.0%)7 (70.0%)6 (66.7%)Treatment difference vs. PBO (%)40.0%40.0%36.7%Note: All evaluable patients at week 12 efficacy data were included in the efficacy analysis.Figure 1.SRI-4 response rates at week 12.Disclosure of InterestsRu Li: None declared, Xiaoxia Zhu: None declared, Shengyun Liu: None declared, Xiao Zhang: None declared, Changhao Xie: None declared, Zili Fu: None declared, Anbin Huang: None declared, Lingyun Sun: None declared, Dongzhou Liu: None declared, Jinxia Zhao: None declared, Lin Wu: None declared, Zhoushuai Qin Employee of: InnoCare Pharma Limited., Sichen Li Employee of: InnoCare pharma Limited., Yaorong Liu Employee of: InnoCare pharma Limited., Zhanguo Li: None declared
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.