Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach.

The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK-STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.

Jakinibs of All Trades: Inhibiting Cytokine Signaling in Immune-Mediated Pathologies.

Over the last 25 years, inhibition of Janus kinases (JAKs) has been pursued as a modality for treating various immune and inflammatory disorders. While the clinical development of JAK inhibitors (jakinibs) began with the investigation of their use in allogeneic transplantation, their widest successful application came in autoimmune and allergic diseases. Multiple molecules have now been approved for diseases ranging from rheumatoid and juvenile arthritis to ulcerative colitis, atopic dermatitis, graft-versus-host-disease (GVHD) and other inflammatory pathologies in 80 countries around the world. Moreover, two jakinibs have also shown surprising efficacy in the treatment of hospitalized coronavirus disease-19 (COVID-19) patients, indicating additional roles for jakinibs in infectious diseases, cytokine storms and other hyperinflammatory syndromes. Jakinibs, as a class of pharmaceutics, continue to expand in clinical applications and with the development of more selective JAK-targeting and organ-selective delivery. Importantly, jakinib safety and pharmacokinetics have been investigated alongside clinical development, further cementing the potential benefits and limits of jakinib use. This review covers jakinibs that are approved or are under late phase investigation, focusing on clinical applications, pharmacokinetic and safety profiles, and future opportunities and challenges.

Clotting of Hemodialysis Access in Patients with COVID-19 in an Inner-City Hospital.

BACKGROUND: An increased incidence of thrombotic complications in patients with coronavirus disease 2019 (COVID-19) has been reported. Severe acute kidney injury (AKI) is one of the major clinical manifestations of COVID-19 with the need for renal replacement therapy. It was observed that hemodialysis (HD) accesses tended to thrombose more often in the COVID-19 population than in non-COVID-19 patients. We hypothesize that the hypercoagulable state of COVID-19 is associated with higher incidence of access clotting. METHOD: In this retrospective single-centered study at Kings County Hospital in New York City, 1,075 patients with COVID-19 were screened, and 174 patients who received HD from January 3, 2021 to May 15, 2020 were enrolled to examine the risk factors of dialysis access clotting in patients with COVID-19. RESULTS: Of the 174 patients, 109 (63%) were COVID-19 positive. 39 (22.6%) patients had dialysis access clotting at least once during their hospitalization, and they had significantly higher body mass index (BMI) (p = 0.001), higher rates of COVID-19 (p = 0.015), AKI (p < 0.001), higher platelet counts (p = 0.029), higher lactate dehydrogenase levels (p = 0.009), and lower albumin levels (p = 0.001) than those without access malfunctions. Low albumin levels (p = 0.008), AKI (p = 0.008), and high BMI (p = 0.018) were risk factors associated with HD access clotting among COVID-19 patients. CONCLUSION: Patients with COVID-19 who receive HD for AKI with high BMI are at a higher risk of clotting their HD access.