Janus Kinase Enzyme (Jak) Inhibitors and Rheumatoid Arthritis: A Review of the Literature (original) (raw)
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Biomolecules, 2020
Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (up...
Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients?
BioMed Research International
The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated...
Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis
Rheumatology, 2019
Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA. Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3. Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patientreported outcomes as well as disease modification. Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX. An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016. In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.
PubMed, 2017
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. The introduction of a new class of disease-modifying anti-rheumatic drugs, which work by inhibiting the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway, has led to new possibilities for achieving remission of RA. Tofacitinib and baricitinib are both JAK/STAT inhibitors, which have shown efficacy in line with anti-tumour necrosis factor treatment. The side effects seem manageable, and up to now only increased risk of herpes zoster has raised consideration. JAK/STAT inhibitors create new possibilities for reaching low disease activity or remission for patients with RA.
Clinical perspectives of Janus Kinase Inhibitors: A review
Asian Journal of Pharmacy and Pharmacology
JAK inhibitors block cytokine mediated signalling via the JAK-STAT pathway, which plays an important role in immune regulation and growth. These 'small molecule' drugs are highly specific for blocking targets identified within cells that cause chronic inflammation. Rheumatoid arthritis (RA) is chronic autoimmune disorder characterized by severe destructive inflammation of the distal joints, particularly of the hands. The inflammation breaks down cartilage and bone, resulting in severe pain, stiffness, deformities, and disability. The inflammation can affect other areas as well, including the eyes, lungs, heart, or skin. RA can strike at any age but is more commonly seen in adulthood (Changelian et al., 2003). JAKs are intracellular enzymes that transmit signals from cytokines binding to receptors on the cell surface to signal transducers and activators of transcription (STATs), which drive pro-inflammatory cellular responses the JAK-STAT pathway. The JAK/STAT pathway: JAKs, named after the two-faced Roman God Janus, form a family consisting of four members: JAK1, JAK2, JAK3 and TYK2. They are all cytoplasmic tyrosine kinases able to phosphorylate tyrosine residues either on themselves (auto-phosphorylation) or on adjacent molecules (trans-phosphorylation), including the STATs. The latter is a family of transcription factors, acting downstream of JAKs and consisting of 7 members (O'Shea et al., 2013). Schematic representation of the various cytokines and their receptors signalling via the JAK/STAT Figure 1,. shows overview of the JAK-STAT signalling pathway. Binding of cytokines (yellow) to their receptors on the cell surface results in Janus kinase (JAK) activation and subsequent cross-phosphorylation of the receptors. Signal transducers and activators of transcription (STATs) then attach to the phosphorylated receptors, dimerize, and translocate to the nucleus where they drive the expression of proteins involved in inflammatory processes, including those leading to autoimmune diseases such as rheumatoid arthritis (Vashkiv and Hu, 2006). Methods The review of articles was done with articles published from 2003 to 2020 on JAK inhibitors which have clinical significance.
Annals of the Rheumatic Diseases, 2020
ObjectivesJanus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.MethodsExisting data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into considera...
Arthritis Research & Therapy, 2011
Introduction: Janus kinase 2 (JAK2) is involved in the downstream activation of signal transducer and activator of transcription 3 (STAT3) and STAT5 and is responsible for transducing signals for several proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis (RA), including interleukin (IL)-6, interferon γ (IFNγ) and IL-12. In this paper, we describe the efficacy profile of CEP-33779, a highly selective, orally active, small-molecule inhibitor of JAK2 evaluated in two mouse models of RA. Methods: Collagen antibody-induced arthritis (CAIA) and collagen type II (CII)-induced arthritis (CIA) were established before the oral administration of a small-molecule JAK2 inhibitor, CEP-33779, twice daily at 10 mg/kg, 30 mg/kg, 55 mg/kg or 100 mg/kg over a period of 4 to 8 weeks.
Janus kinase inhibitors in autoimmune diseases
Annals of the Rheumatic Diseases, 2013
Biological therapies directed at proinflammatory cytokines have irrevocably changed the landscape of treatment of rheumatoid arthritis (RA) and other autoimmune diseases. With the advances in our knowledge in cytokine signaling, the question emerges whether targeting intracellular signaling might also be a safe and efficacious strategy. Janus kinases or Jaks are critical for a large family of cytokines and the first Jak inhibitor has been approved by the FDA for the treatment of myelofibrosis. Late phase clinical trials have been completed for another Jakinib in RA. It is therefore timely to consider this new category of drugs and reflect on their potential roles, present and future, in the treatment of RA and related disorders. Role of Type I/II cytokines in RA and related diseases Cytokines are critical for host defense and immunoregulation, but also major players in the immunopathogenesis of autoimmune diseases. Practically, rheumatologists can adduce the success of recombinant cytokine receptors and monoclonal antibodies against cytokines as evidence for the immunopathological role of these factors 1 What the practicing physician may be less cognizant of is the complexity of cytokines and their diversity of their structure. Based on structure, several major families of cytokines can be recognized. Two major classes are the so-called Type I and Type II cytokine receptors. Type I receptors bind several interleukins (ILs), colony stimulating factors and hormones such erythropoietin, prolactin and growth hormone. Type II receptors bind interferons and IL-10 related cytokines. Genome wide association scans (GWAS) have identified a plethora of Single-Nucleotide Polymorphisms (SNPs) conferring genetic susceptibility in autoimmune diseases such as rheumatoid arthritis (RA), 2 psoriasis, 3 inflammatory bowel disease (IBD) 4 and ankylosing spondylitis 5. Polymorphisms of genes encoding type I cytokine receptors and their signaling elements are now firmly linked to various autoimmune diseases. For instance, IL-23R, IL12B, JAK2, and STAT3 polymorphisms are associated with IBD and psoriasis and IBD. STAT4 polymorphisms are associated with RA, systemic lupus erythematosus and Sjogren's syndrome. Other evidence of culpability of type I/II cytokines in autoimmunity comes from their detection in the context of disease. Rheumatoid arthritis, for instance, is