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Myositis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Tofacitinib, a Janus kinase inhibitor, has been used for the treatment of inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis) and ulcerative colitis. There has been in vitro and clinical data suggesting the efficacy of JAK-STAT inhibitor through targeting the IFN pathway,97 most interestingly in the recalcitrant anti-MDA-5 + ILD cases.86, 98 A pilot, open-label, single-center clinical trial of ten patients with refractory DM has been completed, and all patients met the primary outcome.99 Currently, a single-arm, open-label pilot study is recruiting patients in China with anti-MDA5 + DM with a focus on lung disease outcome, and a multicenter, phase 3, double-blind, randomized, placebo-controlled trial in France will examine the efficacy of baricitnib (JAK1 inhibitor).
Psoriasis
Published in Nilton Di Chiacchio, Antonella Tosti, Therapies for Nail Disorders, 2020
Stamatis Gregoriou, Eftychia Platsidaki, Dimitris Rigopoulos
Tofacitinib is an oral Janus kinase inhibitor. A randomized, controlled phase 3 study evaluated the efficacy and safety of tofacitinib in patients with moderate-to-severe plaque psoriasis and nail psoriasis. At week 16, significantly more patients receiving tofacitinib 5 mg and tofacitinib 10 mg versus placebo twice daily achieved NAPSI 50 (32.8%, 44.2% vs. 12.0%), NAPSI 75 (16.9%, 28.1% vs. 6.8%), and NAPSI 100 (10.3%, 18.2% vs. 5.1%), respectively.64 In subgroup analyses from a randomized, placebo-controlled phase 3 trial, reductions from baseline in NAPSI score were observed at week 16 with both tofacitinib 5 and 10 mg twice daily versus placebo. NAPSI scores continued to decrease through week 52 with both tofacitinib dose groups. By week 52, 22.2% and 47.6% of the patients who received tofacitinib 5 and 10 mg, respectively, achieved NAPSI 75.65 The most common adverse events related to laboratory parameter abnormalities were noted. Both studies showed that oral tofacitinib demonstrates efficacy on nail psoriasis, sustained over 52 weeks, with a manageable safety profile.
Gastrointestinal Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Gareth Davies, Chris Black, Keeley Fairbrass
Biological agents have transformed management of severe IBD. All agents down-regulate the inflammatory processes. Side effects include risk of infection and induction of autoimmune events including neurological. Antibodies may develop to these drugs, reducing or stopping the benefit: co-prescription of immunosuppressives can prevent such antibody formation. Assays are available to measure serum biological and antidrug antibody levels to help guide treatment. Cost is a major issue (in the order of £10 000 a year, over 10 times more than conventional therapies), and healthcare guidance typically follows a step-up approach, with biological drugs only being sanctioned when conventional therapies have failed. However, given longer-term savings (e.g. associated with fewer hospital admissions, reduced risk of surgery), for some high-risk IBD cases biological therapies may be recommended as an initial treatment. Generic competitors (called biosimilars) are now entering the market with significantly reduced costs. Screening is necessary prior to receiving biologics (TB [quanteferon and chest X-ray], varacella zoster IgG, hepatitis B and C, HIV).FBC, renal and liver function should be monitored at least 3-monthly.Examples: Infliximab: This is an anti-TNF agent, often first-line rescue in acute severe colitis, given by 2-weekly subcutaneous injection or IV infusion. Continued infusions may be needed every 8 weeks depending on response.Adalimumab: This is an anti-TNF therapy injected subcutaneously. It can be stored and administered by the patient at home.Vedolizumab: This is a gut-selective integrin blocker; fewer systemic side effects. It is administered intravenously.Ustekinumab: Recently approved for IBD if unresponsive to oral and anti-TNF therapies, this is an anti-interlukin agent. The first infusion is IV followed by subcutaneous injections.Tofacitinib: This is a JAK (Janus kinase) inhibitor, given orally twice daily. It is a small molecule thus less likely for drug antibodies to develop.
A review on qualifications and cost effectiveness of induced pluripotent stem cells (IPSCs)-induced cardiomyocytes in drug screening tests
Published in Archives of Physiology and Biochemistry, 2023
Golrokh Malihi, Vahid Nikoui, Elliot L. Elson
Therefore, numerous investigators have set up experimental trials to prove this concept (Jayawardena et al.2012). The group directed reprogramming of fibroblasts to cardiomyocytes in-vitro from different miRNAs that were characterised by their numbers: 1, 133, 208, 499. Analysis of miRNA of myocardial tissue was performed that showed the same above positive results regarding cardiomyocyte maturation. Reprogramming was further enhanced upon addition of a Janus kinase inhibitor (JAK inhibitor) which may be due to suppression of pluripotency signalling pathways (Efe et al.2011). This study demonstrated that miR-1 facilitated electrophysiological maturation, whereas mir-499 transduction could significantly increase the yield of ventricular subtypes without changing the electrophysiology (Fu et al.2011).
Network pharmacology and in vivo experiment-based strategy to investigate mechanisms of JingFangFuZiLiZhong formula for ulcerative colitis
Published in Annals of Medicine, 2022
Mengyuan Wang, Jianan Li, Yuzhang Yin, Liying Liu, Yifei Wang, Ying Qu, Yanqiu Hong, Shuangshuang Ji, Tao Zhang, Nan Wang, Jinlong Liu, Xu Cao, Xiaobin Zao, Shuxin Zhang
Next, we constructed the GO-BP, GO-CC, GO-MF, and KEGG enrichment analysis. The result revealed that the GO-CCs were particularly related to the vesicles, cytoplasm, and extracellular matrix, both relating to the exosomes. The previous study has shown that exosomes could mediate the functional transfer of genetic materials between immune cells like macrophages, Treg cells, and neutrophils, which affects immune response [41,42]. The GO-BPs mainly involved signal transductions, phosphorylations, gene expression, and metabolic processes. And, the GO-MFs were relevant to the binding functions, kinase activities, and hydrolase activity. These results showed that JFFZLZ could influence the expression of key genes, the process of signal transduction, and the production of metabolites in the pathogenesis of UC. In some clinical studies, tofacitinib, a small-molecule Janus kinase inhibitor affecting the process of the JAK-STAT pathway, was shown to have more effective efficacy in patients with moderately to severely active UC [43–46]. The KEGG enrichment revealed that MAPK, Chemokine signalling pathway, and Cytokine-cytokine receptor interaction played a critical role. Several reports had shown that inhibiting the signal transmission process of the MAPK signal pathway could improve the symptoms of diarrhoea, mucous, and haematochezia in UC model animals [47–49]. These results suggested that the treatment efficacy of JJFZLZ against UC was achieved through integrating multi-constituent, multi-target, and multi-pathway.
Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data
Published in Modern Rheumatology, 2019
Tsutomu Takeuchi, Hisashi Yamanaka, Kunihiro Yamaoka, Shoko Arai, Shigeyuki Toyoizumi, Ryan DeMasi, Yuri Fukuma, Tomohiro Hirose, Naonobu Sugiyama, Samuel H. Zwillich, Yoshiya Tanaka
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or in combination with csDMARDs, mainly MTX, in patients with moderately to severely active RA, has been demonstrated in global phase 2 [13–15] and phase 3 trials of up to 24 months’ duration [16–21], and in long-term extension studies with up to 114 months’ observation [22–24]. In Japan, the efficacy and safety of tofacitinib in patients with RA as monotherapy [25] and in combination with MTX [26] has been demonstrated in two randomized, 12-week, phase 2 studies (A3921040 [NCT00687193] and A3921039 [NCT00603512]), and in an LTE study (A3921041 [NCT00661661]) [24]. In addition, 118 Japanese patients were included in the global phase 3, 24-month randomized controlled trial ORAL Scan (A3921044 [NCT00847613]) [20]. Tofacitinib 5 mg BID administered as monotherapy or in combination with csDMARDs is approved in Japan for the treatment of patients with RA who have an inadequate response to at least one csDMARD or bDMARD [27]. The higher dose of 10 mg BID has not been approved for use in Japan for patients with RA.