Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

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A Comprehensive Overview of Globally Approved JAK Inhibitors

The Janus kinase (JAK) family of nonreceptor protein-tyrosine kinases consists of JAK1, JAK2, JAK3, and TYK2 (Tyrosine Kinase 2). Each of these proteins contains a JAK homology pseudokinase (JH2) domain that interacts with and regulates the activity of the adjacent protein kinase domain (JH1). The Janus kinase family is regulated by numerous cytokines including interferons, interleukins, and hormones such as erythropoietin and thrombopoietin. Ligand binding to cytokine receptors leads to the activation of associated Janus kinases, which then catalyze the phosphorylation of the receptors. The SH2 domain of signal transducers and activators of transcription (STAT) binds to the cytokine receptor phosphotyrosines thereby promoting STAT phosphorylation and activation by the Janus kinases. STAT dimers are then translocated into the nucleus where they participate in the regulation and expression of dozens of proteins. JAK1/3 signaling participates in the pathogenesis of inflammatory disorders while JAK1/2 signaling contributes to the development of myeloproliferative neoplasms as well as several malignancies including leukemias and lymphomas. An activating JAK2 V617F mutation occurs in 95% of people with polycythemia vera and about 50% of cases of myelofibrosis and essential thrombocythemia. Abrocitinib, ruxolitinib, and upadacitinib are JAK inhibitors that are FDA-approved for the treatment of atopic dermatitis. Baricitinib is used for the treatment of rheumatoid arthritis and covid 19. Tofacitinib and upadacitinib are JAK antagonists that are used for the treatment of rheumatoid arthritis and ulcerative colitis. Additionally, ruxolitinib is approved for the treatment of polycythemia vera while fedratinib, pacritinib, and ruxolitinib are approved for the treatment of myelofibrosis. 

Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders.

Ankylosing spondylitis (AS) is a seronegative, chronic inflammatory arthritis with high genetic burden. A strong association with HLA-B27 has long been established, but to date its contribution to disease aetiology remains unresolved. Recent insights through genome wide studies reveal an increasing array of immunogenetic risk variants extraneous to the HLA complex in AS cohorts. These genetic traits build a complex profile of disease causality, highlighting several molecular pathways associated with the condition. This and other evidence strongly implicates T-cell-driven pathology, revolving around the T helper 17 cell subset as an important contributor to disease. This prominence of the T helper 17 cell subset has presented the opportunity for therapeutic intervention through inhibition of interleukins 17 and 23 which drive T helper 17 activity. While targeting of interleukin 17 has proven effective, this success has not been replicated with interleukin 23 inhibition in AS patients. Evidence points to significant genetic diversity between AS patients which may, in part, explain the observed refractoriness among a proportion of patients. In this review we discuss the impact of genetics on our understanding of AS and its relationship with closely linked pathologies. We further explore how genetics can be used in the development of therapeutics and as a tool to assist in the diagnosis and management of patients. This evidence indicates that genetic profiling should play a role in the clinician's choice of therapy as part of a precision medicine strategy towards disease management. 

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The genetic backbone of ankylosing spondylitis: how knowledge of genetic susceptibility informs our understanding and management of disease

Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

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JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

An overview of how the treatment landscape of axial spondyloarthritis (axSpA) has shaped our understanding of the disease.Prior to the millennium, non-steroidal anti-inflammatory drugs (NSAIDs) were the only treatment for axSpA, yet only 30% of patients responded and many developed side effects. In 2003, the first biological disease-modifying drug (bDMARD) was licensed for axSpA which substantially improved outcomes in comparison to NSAIDs. In 2022, there are now several bDMARDs for axSpA; however, they too are not universally efficacious in treating axial inflammation and may have deleterious effects on extramusculoskeletal manifestations. Nevertheless, successful or not, each bDMARD gives invaluable insight into axSpA immunobiology. This review discusses how much we have learned from the use of bDMARDs in axSpA, how this has redefined our understanding of the disease, and how we might use this knowledge to develop new and better treatments for axSpA in the future. 

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Have Therapeutics Enhanced Our Knowledge of Axial Spondyloarthritis?

Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Ankylosing spondylitis, also known as radiographic axial spondyloarthritis, is a complex, immune-mediated inflammatory disorder most commonly involving the spine including the sacroiliac joints.Complex pathogenesis of axial spondyloarthritis involving genetic, environmental, and both innate and adaptive immune systems. Treatment options for ankylosing spondylitis. Pharmacologic properties, efficacy, and safety of tofacitinib, a JAK inhibitor. Data regarding efficacy of approved JAK inhibitors in the treatment of ankylosing spondylitis, including tofacitinib, upadacitinib, and filgotinib.Current treatment options of ankylosing spondylitis include NSAIDs, TNFi, and IL-17i. JAK inhibitors present a new class of therapy that has shown efficacy in the treatment of active ankylosing spondylitis in adults. While it has not been directly compared to alternative therapies, tofacitinib has been shown to be effective in both phase II and phase III trials for the treatment of ankylosing spondylitis. While these trials did not show any significant difference from placebo in terms of safety, the ORAL Surveillance study showed tofacitinib to be inferior to TNFi when comparing adverse events. Thus, tofacitinib presents a viable treatment option for the management of AS, however shared decision-making regarding risks and benefits will be important. 

Tofacitinib for the treatment of active ankylosing spondylitis in adults

Background/Objective This post hoc analysis assessed efficacy and safety of intravenous (IV) golimumab in ankylosing spondylitis (AS) patients with early disease (ED) versus late disease (LD). Methods The phase 3, double-blind, GO-ALIVE study randomized patients to IV golimumab 2 mg/kg at weeks 0 and 4 and then every 8 weeks through week 52, or placebo at weeks 0, 4, and 12 with crossover to IV golimumab at week 16. Clinical efficacy was assessed by ≥20% improvement in Assessment of Spondyloarthritis International Society response criteria (ASAS20), ≥50% improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI 50), and Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 (inactive disease). Using self-reported duration of inflammatory back pain (IBP), patients were grouped into quartiles: first = ED and fourth = LD. Descriptive statistics summarized efficacy and safety findings through 1 year. Results Early disease patients (n = 60) were ~10 years younger and had shorter median AS (IBP) symptom duration (2–3 years) versus LD patients (n = 52; 21–24 years). At week 16, numerically higher proportions of golimumab- than placebo-treated patients achieved ASAS20 (ED: 71% vs. 32%; LD: 67% vs. 21%), BASDAI 50 (ED: 40% vs. 12%; LD: 33% vs. 7%), and ASDAS <1.3 (ED: 17% vs. 4%; LD 8% vs. 0%) regardless of IBP duration. Efficacy was durable through 1 year of treatment; however, response rates were numerically higher in patients with ED versus LD. Through week 60, adverse events and serious adverse events, respectively, were reported by 46% and 3% of ED patients and 61% and 2% of LD patients. Conclusion Prompt diagnosis of AS and early treatment with IV golimumab may yield more robust improvements in disease activity. 

Olga Ioannou

Papers

Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Tofacitinib for the treatment of active ankylosing spondylitis in adults

Efficacy and Safety of Intravenous Golimumab in Ankylosing Spondylitis Patients With Early and Late Disease Through One Year of the GO-ALIVE Study

Efficacy and Safety of Intravenous Golimumab in Patients With Ankylosing Spondylitis and Complete Spinal Ankylosis