Objectives: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations.

Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-toseverely active rheumatoid arthritis (RA). Baricitinib's safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies). Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose. Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable. Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database.

ABSTRACT. The ICR-derived glomerulonephritis (ICGN) mouse is a novel inbred mouse strain with a hereditary nephrotic syndrome, considered to be a good model of human idiopathic nephrotic syndrome and develops proteinuria, hypoproteinemia and anemia. In the present study, we compared the cell kinetics in the kidneys of ICGN mice with age-matched ICR mice as normal controls. The proliferating cells were visualized by 5-bromo-2'-deoxyuridine labeling, and apoptotic cells were determined by terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end-labeling. Many proliferating epithelial cells of renal tubules, glomerular mesangial cells and tublointerstitial fibroblast-like cells were observed in the kidneys of ICGN mice, but no proliferating cells were seen in the kidneys of ICR mice. Apoptotic cells had round nuclei, and were observed only in the tubulointerstitium in the kidneys of ICGN mice but not in that of controls. The proliferation of renal tubular epithelial cells may represent a compensatory response, and that of mesangial and fibroblast-like cells may play a pathogenic role in nephrotic syndrome. Apoptosis in tubulointerstitial cells with round nuclei may have been erythropoietin-producing cells, and probably caused anemia. KEY WORDS: apoptotic cell, hereditary nephrotic mouse (ICGN), kidney, proliferating cell.J. Vet. Med. Sci. 63 (7): [781][782][783][784][785][786][787] 2001 The ICR-derived glomerulonephritis (ICGN) mouse is a novel inbred mouse strain with a hereditary nephrotic syndrome of unknown etiology, and considered to be a good model of human idiopathic nephrotic syndrome. ICGN mice show proteinuria at a young age, later develop hypoproteinemia, hyperlipemia and anemia, and approximately 40% of them fall into severe systemic edema [17][18][19][20][21][22]. Our previous studies [28,29] showed that many kinds of extracellular matrix (ECM) components, both basement membrane and interstitial components, abnormally accumulated in glomeruli and tubulointerstitium of ICGN mouse kidneys. We also reported that the progression of fibrotic degeneration in ICGN mouse kidneys may be caused by overproduction of ECM components, inhibition of ECM breakdown, and decreased activities of matrix metalloproteinases [30]. However, the cell kinetics about which types of cells proliferate and/or die in ICGN mouse kidneys have not been investigated. To understand the pathogenic mechanism of nephrotic and fibrogenic degeneration in the kidneys of ICGN mice, it is essential to clarify the timedependent changes in the cell kinetics of their kidneys. In the present study, we compared the cell kinetics in the kidneys of ICGN mice with age-matched ICR mice as normal controls. The proliferating cells were visualized by 5-bromo-2'-deoxyuridine (BrdU) labeling, and apoptotic cells were histochemically determined by terminal deoxynucleotidyl transferase (TdT)-mediated biotinylated deoxyuridine triphosphate nick end-labeling (TUNEL). MATERIALS AND METHODS Animals and tissue preparation:Nep...

Imatinib and nilotinib are inhibitors that selectively target a set of protein tyrosine kinases, including abelson kinase (Abl), together with the chimeric oncoprotein, breakpoint cluster region-abelson kinase (Bcr-Abl), as well as stem cell factor receptor (KIT), platelet-derived growth factor receptor (PDGFR), discoidin domain receptor (DDR), and colony stimulating factor-1 receptor (CSF-1R). The aim of the present study was to investigate whether imatinib or nilotinib was effective against arthritis in the glucose-6-phosphate isomerase (GPI)-induced arthritis mouse model. Imatinib or nilotinib was administered orally to the arthritic mice at different time points. Efficacy was evaluated by visual scoring and by determining the production of anti-GPI antibody. Splenocytes from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro, and cytokine levels in the culture supernatants were analyzed. To investigate the effects of imatinib and nilotinib on T-cell proliferation, lymph node cells from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro. Interleukin (IL)-17 mRNA expression in the arthritic ankle joints from the onset of arthritis was analyzed by real-time polymerase chain reaction (PCR). The administration of imatinib from day 0 showed suppression of arthritis (P < 0.05), the administration of nilotinib from day 0 resulted in pronounced suppression of arthritis (P < 0.01), and that from day 7 showed significant inhibition of the progression of arthritis (P < 0.05). A reduction in anti-GPI antibodies was correlated with the therapeutic efficacy of imatinib, but not with that of nilotinib. Imatinib dose-dependently inhibited tumor necrosis factor (TNF)-α, IL-6, interferon (IFN)-γ, and IL-17 production by splenocytes in vitro, while nilotinib inhibited only IL-17 and IFN-γ production in a dose-dependent fashion. Imatinib at 3 μM exerted a mild antiproliferative effect on CD4+ T cells (P < 0.05), whereas imatinib at 10 μM and nilotinib at 3 and 10 μM demonstrated a marked antiproliferative effect (P < 0.01). The IL17 gene expression level on day 7 tended to be higher than that on day 14. These findings suggest that imatinib and nilotinib could prevent autoimmune arthritis, essentially via distinct mechanisms, in that imatinib inhibits both inflammatory and T-cell-derived cytokine production, whereas nilotinib suppresses T-cell-derived cytokine production. Imatinib and nilotinib could have therapeutic potential for rheumatoid arthritis (RA) and other inflammatory diseases.