The emerging role of Janus kinase inhibitors in the treatment of autoimmune and inflammatory diseases

Janus kinases inhibitors are molecules that target Janus kinases—signal transducers and activators of transcription (JAK/STAT). They inhibit this intracellular signal pathway, blocking the gene transcription of crucial proinflammatory cytokines that play a central role in the pathogenesis of many inflammatory and autoimmune diseases, including psoriasis. This process reduces psoriatic inflammation. The JAK inhibitors are divided into two generations. The first generation of JAK inhibitors blocks two or more different Janus kinases. The second generation is more specified and blocks only one type of Janus kinase and has less side effects than the first generation. Tofacitinib, ruxolitinib and baricitinib belong to first generation JAK inhibitors and decernotinib and filgotinib belong to second group. This narrative review summarizes the role of Janus kinase inhibitors in the therapy of psoriasis. Oral JAK inhibitors show promise for efficacy and safety in the treatment of psoriasis. Studies to date do not indicate that JAK inhibitors are superior to recent biologic drugs in terms of efficacy. However, JAK inhibitors, due to their lack of increased incidence of side effects compared to other biologic drugs, can be included in the psoriasis treatment algorithm because they are orally taken. Nevertheless, further studies are needed to evaluate long-term treatment effects with these drugs.

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2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-221366 ◽

2021 ◽

pp. annrheumdis-2021-221366

Author(s):

Alessia Alunno ◽

Aurélie Najm ◽

Pedro M Machado ◽

Heidi Bertheussen ◽

Gerd-Rüdiger R Burmester ◽

...

Keyword(s):

Kinase Inhibitors ◽

Task Force ◽

Inflammatory Diseases ◽

Janus Kinase ◽

Therapeutic Approaches ◽

Janus Kinase Inhibitors ◽

Immunosuppressed Patients ◽

Critical Patients ◽

Immunomodulatory Therapies ◽

Robust Evidence

ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

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Role of Janus Kinase inhibitors in rheumatoid arthritis treatment

Current Opinion in Rheumatology ◽

10.1097/bor.0000000000000792 ◽

2021 ◽

Vol 33 (3) ◽

pp. 300-306

Author(s):

Virginia Reddy ◽

Stanley Cohen

Keyword(s):

Rheumatoid Arthritis ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Janus Kinase Inhibitors ◽

Rheumatoid Arthritis Treatment

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The molecular regulation of Janus kinase (JAK) activation

Biochemical Journal ◽

10.1042/bj20140712 ◽

2014 ◽

Vol 462 (1) ◽

pp. 1-13 ◽

Cited By ~ 127

Author(s):

Jeffrey J. Babon ◽

Isabelle S. Lucet ◽

James M. Murphy ◽

Nicos A. Nicola ◽

Leila N. Varghese

Keyword(s):

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Sh2 Domain ◽

Janus Kinase ◽

Causative Role ◽

Tyrosine Kinase 2 ◽

Src Homology

The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haemopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the component FERM (4.1/ezrin/radixin/moesin)-SH2 (Src homology 2), pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain-containing proteins, SOCS (suppressors of cytokine signalling) proteins and LNK. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors.

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Pulmonary arterial hypertension in interferonophaties: a case report and a review of the literature

Pulmonary Circulation ◽

10.1177/2045894019869837 ◽

2019 ◽

Vol 9 (3) ◽

pp. 204589401986983 ◽

Cited By ~ 3

Author(s):

A. Trombetta ◽

S. Ghirardo ◽

S. Pastore ◽

A. Tesser ◽

E. Piscianz ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Lupus Erythematosus ◽

Kinase Inhibitors ◽

Janus Kinase ◽

Type I ◽

Systemic Lupus ◽

Janus Kinase Inhibitors ◽

Pulmonary Arterial

Background Pulmonary arterial hypertension consists in an increase of mean pulmonary arterial pressure (PAPm ≥ 25 mmHg), and may lead to right ventricular failure. Pulmonary arterial hypertension can arise in several disorders, encompassing inflammatory conditions and connective tissue diseases. The occurrence of pulmonary arterial hypertension has recently been reported in monogenic interferonopathies and in systemic lupus erythematosus, highlighting the pathogenic role of type I interferons and paving the way to therapies aimed at inhibiting interferon signaling. Case We describe a 17-year-old boy with DNase II deficiency, presenting a clinical picture with significant overlap with systemic lupus erythematosus. During treatment with the Janus kinase inhibitor ruxolitinib, he developed pulmonary arterial hypertension, raising the question whether it could represent a sign of insufficient disease control or a drug-related adverse event. The disease even worsened after drug withdrawal, but rapidly improved after starting the drug again at higher dosage. Summary and conclusion Pulmonary arterial hypertension can complicate type I interferonopathies. We propose that ruxolitinib was beneficial in this case, but the wider role of Janus kinase inhibitors for the treatment of pulmonary arterial hypertension is not clear. For this reason, a strict cardiologic evaluation must be part of the standard care of subjects with interferonopathies, especially when Janus kinase inhibitors are prescribed.

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