Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

BACKGROUND Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). METHODS The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. RESULTS Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. CONCLUSIONS MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress

A Real-World Claims Database Study Assessing Long-Term Persistence with Golimumab Treatment in Patients with Rheumatoid Arthritis in Japan

Abstract Introduction The persistence of golimumab (GLM) treatment in Japanese patients with rheumatoid arthritis (RA) has been evaluated previously, but evidence of long-term real-world use is lacking. This study assessed the long-term persistence of GLM use, its influencing factors, and impact of prior medications in patients with RA in actual clinical practice in Japan. Methods This is a retrospective cohort study of patients with RA using data from a hospital insurance claims database in Japan. The identified patients were stratified as only GLM treatment (naïve), had one biological disease-modifying anti-rheumatic drug (bDMARD)/Janus kinase (JAK) inhibitor treatment prior to GLM [switch (1)] and had at least two bDMARDs/JAK prior to GLM treatment [switch (≥ 2)]. Patient characteristics were evaluated using descriptive statistics. Kaplan–Meier survival and Cox regression methods were used to analyze GLM persistence at 1, 3, 5, and 7 years and the associated factors. Treatment differences were compared using a log-rank test. Results GLM persistence rate in the naïve group was 58.8%, 32.1%, 21.4%, and 11.4% at 1, 3, 5, and 7 years, respectively. Overall persistence rates in the naïve group were higher than in switch groups. Higher GLM persistence was observed among patients aged 61–75 years and those concomitantly using methotrexate (MTX). Also, women were less likely to discontinue treatment compared to men. Higher Charlson Comorbidity Index score, initial GLM dose of 100 mg, and switch from bDMARDs/JAK inhibitor were related to a lower persistence rate. As a prior medication, infliximab showed the longest persistence for subsequent GLM, and using this as a reference, tocilizumab, sarilumab, and tofacitinib subgroups had significantly shorter persistence, respectively (p = 0.001, 0.025, 0.041). Conclusion This study presents the long-term real-world results for persistence of GLM and its potential determinants. These most recent and long-term observations demonstrated that GLM and other bDMARDs continue to benefit patients with RA in Japan

Successful embolization assisted by covered stents for a pseudoaneurysm following pancreatic surgery

Delayed intra-abdominal hemorrhage after pancreatic surgery is a potentially lethal complication. Transarterial coil embolization and/or the placing of an endovascular stent are minimally invasive and effective procedures. An artery that is extensively eroded and rendered friable due to operative skeletonization or postoperative inflammation sometimes contributes to delayed intra-abdominal hemorrhage or rebleeding after coil embolization. This report presents a case of successful management of postoperative hemorrhage in a-74-year-old Japanese male. He experienced bleeding from a pseudoaneurysm of the brittle hepatic artery following total pancreatectomy. Initially the pseudoaneurysm was successfully treated with covered coronary stent-grafts, but rebleeding occurred 1 mo later due to the brittleness of the artery. Rebleeding was definitively managed by the complete packing of the stent by coil embolization. He remains stable at 18 mo following the final embolization. A stent graft can be used for protecting a brittle artery to avoid injury by coil embolization

Impact of metastatic lymph node ratio in node-positive colorectal cancer

Colorectal cancer (CRC) is one of the most common malignant diseases in the world. Presently, the most widely used staging system for CRC is the tumor nodes metastasis classification system, which classifies patients into prognostic groups according to the depth of the primary tumor, presence of regional lymph node (LN) metastases, and evidence of distant metastatic spread. The number of LNs with confirmed metastasis is related to the severity of the disease, but this number depends on the number of LNs retrieved, which varies depending on patient age, tumor grade, surgical extent, and tumor site. Numerous studies and a recent structured review have demonstrated associated improvements in the survival of CRC patients with increasing numbers of LNs retrieved for examination. Hence, the impact of lymph node ratio (LNR), defined as the number of metastatic LNs divided by the number of LNs retrieved, has been investigated in various malignancies, including CRC. In this editorial, we review the literature demonstrating the clinicopathological significance of LNR in CRC patients. Some reports have indicated the advantage of considering the LNR compared to the number of LNs retrieved and/or LN status. When the LNR is taken into consideration for survival analysis, the number of LNs retrieved and/or the LN status is not always found to be a prognostic factor. The cut-off points for LNRs were proposed in numerous studies. However, optimal thresholds for LNRs have not yet received consensus. It is still unclear whether the LNR has more prognostic validity than N stage. For all these reasons, the potential advantages of LNRs in the staging system should be investigated in large prospective data sets