イグラチモドについて
Abstract
Background: Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies have found that IGU has certain advantages in improving lung function and shows great potential for pulmonary fibrosis therapy. However, the specific mechanism is not clear. This study was designed to observe and investigate the therapeutic effects of IGU on bleomycin-induced pulmonary fibrosis and further investigate its underlying mechanism.
Methods: A mouse model of pulmonary fibrosis was induced by intratracheal injection of bleomycin (BLM). Model mice were randomly assigned to receive different concentrations of IGU. A TGF-β (T)-induced A549 epithelial-mesenchymal transition (EMT) cell model was utilized to investigate the effects of IGU on EMT in vitro. The NLRP3 inflammasome was activated by the costimulation of LPS+ATP (LA) to evaluate the effects of IGU in vitro.
Results: We found that IGU resulted in favourable therapeutic outcomes by affecting inflammatory infiltration and collagen deposition. Additionally, the markers of the BLM-mediated EMT phenotype and NLRP3-activated phenotype in the lung were also attenuated after IGU administration. In vitro experiments, the results confirmed its anti-EMT and anti-NLRP3 inflammasome activation effects.We then found that the anti-lung fibrosis effect of IGU was accompanied by a decrease in reactive oxygen species (ROS) production.
Conclusion: IGU can inhibit the EMT process and NLRP3 inflammasome activation and reduce ROS production to ameliorate pulmonary fibrosis, which may provide new insights into the further application of IGU in interstitial pulmonary fibrosis.
Keywords: EMT; Iguratimod; NLRP3; Pulmonary fibrosis; ROS.
Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease with an unclear pathogenesis, and there is currently no approved drug for the treatment of this disease. Iguratimod, as a novel clinical anti-rheumatic drug in China and Japan, has shown remarkable efficacy in improving the symptoms of patients with pSS in clinical studies. In this study we investigated the mechanisms underlying the therapeutic effect of iguratimod in the treatment of pSS. Experimental Sjögren's syndrome (ESS) model was established in female mice by immunizing with salivary gland protein. After immunization, ESS mice were orally treated with iguratimod (10, 30, 100 mg·kg-1·d-1) or hydroxychloroquine (50 mg·kg-1·d-1) for 70 days. We showed that iguratimod administration dose-dependently increased saliva secretion, and ameliorated ESS development by predominantly inhibiting B cells activation and plasma cell differentiation. Iguratimod (30 and 100 mg·kg-1·d-1) was more effective than hydroxychloroquine (50 mg·kg-1·d-1). When the potential target of iguratimod was searched, we found that iguratimod bound to TEC kinase and promoted its degradation through the autophagy-lysosome pathway in BAFF-activated B cells, thereby directly inhibiting TEC-regulated B cells function, suggesting that the action mode of iguratimod on TEC was different from that of conventional kinase inhibitors. In addition, we found a crucial role of TEC overexpression in plasma cells of patients with pSS. Together, we demonstrate that iguratimod effectively ameliorates ESS via its unique suppression of TEC function, which will be helpful for its clinical application. Targeting TEC kinase, a new regulatory factor for B cells, may be a promising therapeutic option.
Autoimmune diseases are affected by complex pathophysiology involving multiple cell types, cytokines, antibodies and mimicking factors. Different drugs are used to improve these autoimmune responses, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and small molecule drugs (DMARDs), which are prevalent clinically in the treatment of rheumatoid arthritis (RA), etc. However, low cost-effectiveness, reduced efficacy, adverse effects, and patient non-response are unattractive factors driving the development of new drugs such as iguratimod. As a new disease-modifying antirheumatic drug, iguratimod has pharmacological activities such as regulating autoimmune disorders, inflammatory cytokines, regulating immune cell activation, differentiation and proliferation, improving bone metabolism, and inhibiting fibrosis. In recent years, clinical studies have found that iguratimod is effective in the treatment of RA, SLE, IGG4-RD, Sjogren 's syndrome, ankylosing spondylitis, interstitial lung disease, and other autoimmune diseases and rheumatic diseases. The amount of basic and clinical research on other autoimmune diseases is also increasing. Therefore, this review systematically reviews the latest relevant literature in recent years, reviews the research results in recent years, and summarizes the research progress of iguratimod in the treatment of related diseases. This review highlights the role of iguratimod in the protection of autoimmune and rheumatic bone and related immune diseases. It is believed that iguratimod's unique mode of action and its favorable patient response compared to other DMARDs make it a suitable antirheumatic and bone protective agent in the future.
イグラチモドに係る調査結果
製品概要
販売名：コルベット錠 25mg（富山化学工業株式会社）
ケアラム錠 25mg（エーザイ株式会社）
成分名：イグラチモド
効能・効果：関節リウマチ
使用患者数：2660 人（2012 年 9 月 12 日～2013 年 5 月 10 日）
概要
イグラチモドについては、ラットにおいてワルファリンとの併用によりワルファリン
の作用が増強したデータが示されたことから、承認時より国内添付文書の「併用注意」
の項にてワルファリンとの相互作用について注意喚起を行っている。2012 年 12 月、イ
グラチモドとワルファリンを併用し出血事象またはPT-INR増加を発現した国内症例が
3 例集積したことから、製造販売業者に対して医療従事者向け資材及び患者向け資材の
配布による情報提供を指示した。この時点では、国内においてワルファリン併用症例に
おける死亡症例はなかった。
その後、2013 年 5 月 7 日に、肺胞出血による死亡例の FAX 報告が、製造販売業者よ
り提出された。10 日に追加情報が提出され、定期的な血液凝固能検査が行われていた
にもかかわらず、重篤な転帰を防止することができなかったことが判明。なお、2012
年 9 月 12 日（販売開始）～2013 年 5 月 14 日に当局報告されたイグラチモドとワルフ
ァリンを併用し出血事象または PT-INR 増加を発現した症例は、9 例（うち重篤 3 例【死
亡 1 例を含む】）。イグラチモドについて検討した結果、機構は、イグラチモドの国内
添付文書においてワルファリンを併用禁忌にすることが妥当であり、緊急案件に該当す
ると判断した。また、それに伴い、ワルファリンの国内添付文書においてもイグラチモ
ドとの相互作用について注意喚起が必要であると判断した。
調査結果
専門家の意見も聴取し、検討を行った結果、機構は、以下の理由により、本件が緊急
案件に該当すると判断した。
・ イグラチモドとワルファリンを併用し重篤な出血事象を発現した症例が 3 例（う
ち死亡 1 例）集積し、イグラチモドとワルファリンの相互作用により肺胞出血を発
現し死亡に至った可能性が否定できない症例があること。
・ 死亡症例については、2012 年 12 月の注意喚起を受け、定期的な血液凝固能検査
が行われていたにも関わらず、重篤な転帰に至った症例であること。
・ 算出したワルファリン併用症例における出血事象または PT-INR 増加の推定発現率
は 31.0%であり、高頻度と考えられること。
以上より、イグラチモドとワルファリンとの併用により重篤な出血事象を発現し死亡
に至った症例が報告されていることを周知するとともに、更なる注意喚起の必要がある
と判断した
iguratimod attenuates severe acute oancreatitis by inhiting the NLRP3 inflammasome and NFKB pathway
Severe acute pancreatitis (SAP) is an acute abdominal disease that can develop locally to the multiple organs. It is characterized by pancreatic tissue self-digestion, and the rapid release of inflammatory cytokines, which play a dominant role in local or even systemic inflammation. In this study, we investigate the protective effect of T-614 against SAP induced by cerulein plus LPS in mice. Biochemical markers associated with pancreatitis in serum such as inflammatory cytokines, amylase and lipase activities were measured. Related proteins of NLRP3 inflammasome and NF-κB signaling pathway were evaluated by western blotting. Hematoxylin-eosin staining (HE) and immunohistochemistry (IHC) were used to evaluate changes of inflammation in pancreatic tissue. T-614 significantly alleviated the elevation markers of pancreatitis and suppresses the pancreatic tissue damage, including histopathological and molecular manifestations. In conclusion, T-614 plays a protective role in experimental SAP mice model via anti-inflammatory effects.
Keywords: COX-2; Iguratimod; NF-κB pathway; NLRP3; Severe acute pancreatitis.
2024年11月20日 | カテゴリー：各種治療学, 関節リウマチ リウマチ外来, 膠原病, 免疫疾患 |
