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COVID-19 and MIS-C
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Jordan E. Roberts, Mary Beth Son
Targeted immunomodulators have also played an important role in the treatment of acute COVID-19. Initial promising results for high-dose anakinra (anti-IL-1) were not replicated in a more recent trial, though the later study included more mildly ill patients, and anakinra was previously shown to have greater benefit in patients with more profound systemic inflammation (Pontali, Kyriazopoulou, CORIMUNO ANA-1). Canakinumab, an IL-1β monoclonal antibody, also failed to show a survival benefit (Carricchio). Tocilizumab, an anti-IL-6 monoclonal antibody, has also been widely used, and randomized studies have shown benefit in hospitalized adults (Rosas, REMAP-CAP, Strohbehn). More recently, JAK inhibitors have been used more broadly after studies showing benefit. Tofacitinib reduced risk of respiratory failure or death among hospitalized adults, and baricitinib, while not meeting primary disease progression end point, was associated with reduced mortality (Guimarães, Marconi). A study assessing baricitinib plus remdesivir found benefit from the combination therapy compared to remdesivir alone, especially among those patients receiving high-flow oxygen or noninvasive ventilation (Kalil).
Emerging Oral Treatments: Oral JAK Inhibitors for Alopecia Areata
Published in Rubina Alves, Ramon Grimalt, Techniques in the Evaluation and Management of Hair Diseases, 2021
Jared Marc John, Rodney Sinclair
An important development was the discovery that blocking a common intracellular signal transduction pathway reversed AA in mice: the janus kinase – signal transducer and activator of transcription (JAK-STAT) pathway [6]. The JAKs are a family of four intracellular enzymes (JAK1, JAK2, JAK3, and tyrosine kinase 2, TYK2) that phosphorylate sites on various cytosolic receptors which then activate downstream STAT targets to promote DNA transcription and gene expression (Figure 11A.2) [8, 11]. Cell responses to IFN-γ and IL-15 are mediated through JAK1/2 and JAK1/3, respectively [2].
Etiopathogenesis
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Dario Didona, Biagio Didona, Giovanni Paolino, Raffaele Dante Caposiena Caro
The JAK-STAT signaling pathway is essential to transmit extracellular signals of several cytokines to the nucleus, including IL-12, IL-6, IL-17, IL-21, IL-23, and IFN-γ [22]. It mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK-STAT pathway contributes to numerous autoimmune diseases, including vitiligo [22]. Four members of the JAK family have been described: JAK1, JAK2, JAK3, and tyrosine kinase 2. Among these, JAK1 and JAK2 are directly involved in IFN-γ signaling, which activates STAT1 and thus induces the transcription of IFN-γ–induced genes, including CXCL10, which through its receptor CXCR3 recruits more autoreactive T cells to the epidermis, resulting in widespread melanocyte destruction [22].
JAK inhibitors in dermatology: the road travelled and path ahead, a narrative review
Published in Expert Review of Clinical Pharmacology, 2023
Aishwarya Muddebihal, Ananta Khurana, Kabir Sardana
Numerous cytokines signal via the tyrosine kinase pathway resulting in downstream effects. The JAK STAT pathway is physiologically required for hematopoiesis and immune development. Abnormal signaling of this pathway may result in immunodeficiency, inflammatory and autoimmune conditions, while inhibition of this pathway is therapeutic in various inflammatory and autoimmune disorders. Over the past few years there have been significant advances in the field of JAK inhibitor drugs, with newer drugs of the class being developed and robust clinical trials being undertaken to demonstrate their efficacy in varied conditions. Their development has revolutionized the treatment of various inflammatory and autoimmune dermatological conditions such as alopecia areata, atopic dermatitis and psoriatic arthritis, apart from non-dermatologic conditions such as rheumatoid arthritis, ulcerative colitis and myeloproliferative disorders. JAKinibs have given dermatologists significant alternatives in treating diseases recalcitrant to traditional drugs or when the latter are contraindicated. Oral administration, lower cost and a largely favorable side effect profile are few important areas where they score over biologics. The efficacy of JAK inhibitors has also been shown to be comparable to DMARDs and biologicals in certain conditions. Higher efficacy, with a better side effect profile, make them a more preferred treatment choice, over oral steroids and conventional immunosuppressives, in alopecia areata, atopic dermatitis, vitiligo and several other upcoming indications.
Pharmacotherapeutic advances for splenomegaly in myelofibrosis
Published in Expert Opinion on Pharmacotherapy, 2023
Douglas Tremblay, John Mascarenhas
Other JAK inhibitors have been evaluated in the front-line setting. Fedratinib, a JAK2/FLT3 inhibitor has been tested in the phase 3 JAKARTA study against placebo. Two-hundred and eighty-nine patients with intermediate-2 or high-risk disease were enrolled and randomized to either fedratinib 400 mg daily, 500 mg daily or placebo. The primary endpoint of SVR35% was achieved in 36% and 40% of patients in the 400 mg and 500 mg arms and in 7% of patients in the placebo arm at the end of 24 weeks [29]. The JAKARTA study was placed on a full clinical hold approximately 2 years after opening given concerns for cases of Wernicke encephalopathy. This clinical hold was eventually lifted after reanalysis of existing data suggested that this was a rare event [30]. However, the clinical hold limits the availability of long-term follow-up data. For instance, a post-hoc analysis showed a median duration of response in the fedratinib 400 mg arm was 18.2 months, although this was subject to censoring of patients at time of study termination [31].
Treatment update for vitiligo based on autoimmune inhibition and melanocyte protection
Published in Expert Opinion on Therapeutic Targets, 2023
Bo Xie, Yuqi Zhu, Yuqing Shen, Wen Xu, Xiuzu Song
It is well established that the IFN-γ signaling pathway, achieved through the JAK-STAT signaling, is at the core of the pathogenesis of vitiligo (Figure 1) [42]. According to existing literature, the expressions of JAK1 and JAK3 are elevated in lesional skin compared to normal control [43–45]. Thus, the stepwise over-expression of JAK1 and JAK3 strongly indicates their roles in vitiligo progression. In keratinocytes, IFN-γ activates the JAK1/2 dimer, thereby promoting the expression of CXCL9 and CXCL10, which further recruit CD8+ T cells to attack melanocytes [42]. JAK3 expression is mostly restricted to immune cells. JAK3 and its dimerization partner JAK1 regulate T cell and B cell development, natural killer cell proliferation, and exert other immune regulation effects [46].