scholarly journals Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis

2018 ◽  
Vol 4 (11) ◽  
pp. eaat3834 ◽  
Author(s):  
Denis Tvorogov ◽  
Daniel Thomas ◽  
Nicholas P. D. Liau ◽  
Mara Dottore ◽  
Emma F. Barry ◽  
...  
Keyword(s):  
Drug Withdrawal ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Activation Loop ◽  
Type I ◽  
Type Ii ◽  
Jak Inhibitor ◽  
Janus Kinase Inhibitor ◽  
Life Threatening ◽  
Dose Dependent

Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn. We developed a time-dependent assay to mimic ruxolitinib withdrawal in primary JAK2V617Fand CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2V617Fsamples after drug washout. Accumulation of ruxolitinib-induced JAK2 phosphorylation was dose dependent and correlated with rebound signaling and the presence of a JAK2V617Fmutation. Ruxolitinib prevented dephosphorylation of a cryptic site involving Tyr1007/1008in JAK2 blocking ubiquitination and degradation. In contrast, a type II JAK inhibitor, CHZ868, did not induce JAK2 phosphorylation, was not associated with withdrawal signaling, and was superior in the eradication of flow-purified JAK2V617Fmutant CD34+progenitors after drug washout. Type I inhibitor–induced loop phosphorylation may act as a pathogenic signaling node released upon drug withdrawal, especially in JAK2V617Fpatients.

scholarly journals Topical Tofacitinib: A Janus Kinase Inhibitor for the Treatment of Vitiligo in an Adolescent Patient

2021 ◽  
pp. 190-194
Author(s):  
Sineida Berbert Ferreira ◽  
Rachel Berbert Ferreira ◽  
Afonso Cesar Neves Neto ◽  
Silvana Martins Caparroz Assef ◽  
Morton Scheinberg
Keyword(s):  
Case Report ◽  
Skin Disease ◽  
Kinase Inhibitor ◽  
Effective Therapy ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Adolescent Patient ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitor ◽  
History Of

Vitiligo is an autoimmune skin disease presenting with areas of depigmentation. Recent reports suggest that Janus kinase (JAK) inhibitors may be an effective therapy. In this case report, we show our experience with an adolescent patient with a long history of generalized and refractory vitiligo, for which treatment with topical tofacitinib, a JAK inhibitor, associated with phototherapy for 9 months, resulted in near complete repigmentation.

scholarly journals JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Lucas Walz ◽  
Avi J. Cohen ◽  
Andre P. Rebaza ◽  
James Vanchieri ◽  
Martin D. Slade ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Type I Interferon ◽  
Meta Analysis ◽  
Janus Kinase ◽  
Type I Interferons ◽  
Type I ◽  
Janus Kinase Inhibitor ◽  
Janus Kinase Inhibitors

Abstract Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 – 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 – 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 – 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 – 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 – 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

scholarly journals Calcification Induced by Type I Interferon in Human Aortic Valve Interstitial Cells Is Larger in Males and Blunted by a Janus Kinase Inhibitor

2018 ◽  
Vol 38 (9) ◽  
pp. 2148-2159 ◽  
Author(s):  
Iván Parra-Izquierdo ◽  
Irene Castaños-Mollor ◽  
Javier López ◽  
Cristina Gómez ◽  
J. Alberto San Román ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Kinase Inhibitor ◽  
Type I Interferon ◽  
Interstitial Cells ◽  
Janus Kinase ◽  
Type I ◽  
Janus Kinase Inhibitor ◽  
Valve Interstitial Cells ◽  
Human Aortic Valve

Successful management with Janus kinase inhibitor tofacitinib in refractory juvenile dermatomyositis: a pilot study and literature review

Rheumatology ◽  
2020 ◽  
Author(s):  
Zhongxun Yu ◽  
Lin Wang ◽  
Meiying Quan ◽  
Tiannan Zhang ◽  
Hongmei Song
Keyword(s):  
Pilot Study ◽  
Literature Review ◽  
Kinase Inhibitor ◽  
Immunosuppressive Agents ◽  
Janus Kinase ◽  
Muscle Disease ◽  
High Dose ◽  
Type I ◽  
Janus Kinase Inhibitor ◽  
Muscle Testing

Abstract Objectives JDM is a rare autoimmune inflammatory muscle disease with a pronounced IFN signature. Treatment for children with JDM has improved over the years with the use of steroids and immunosuppressive agents. However, there remains a subset of children who have refractory disease. Janus kinase and type I IFN signalling production are suspected to contribute to the pathogenesis of JDM. Our pilot study investigated the use of tofacitinib, a Janus kinase inhibitor, in refractory JDM cases to provide new therapeutic options for better treatment. Methods Refractory JDM was defined as patients who failed two or more steroid sparing agents or high-dose steroids. Tofacitinib was given to three refractory JDM patients with a dose of 5 mg twice per day for at least 6 months. Core set measures defined by Pediatric Rheumatology International Trials Organization were evaluated at month 0, 3 and 6 along with other systemic evaluations. A literature review was conducted to identify all the cases using Janus kinase inhibitors in JDM. Results All three subjects tolerated and responded well to tofacitinib with significant improvement in Child Myositis Assessment Scale, manual muscle testing-8, physician global disease activity and inflammatory indices without occurrence of severe adverse events. Conclusion This pilot study showed improvement of muscle strength, resolution of cutaneous lesions, increased daily quality of life and successful tapering of steroids when tofacitinib used in selected cases. Tofacitinib can be considered with caution when treating refractory JDM cases. Further randomized controlled trials are warranted to assess its efficacy in JDM.

scholarly journals Long‐term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis

2019 ◽  
Vol 47 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Hidemi Nakagawa ◽  
Osamu Nemoto ◽  
Atsuyuki Igarashi ◽  
Hidehisa Saeki ◽  
Ryusei Murata ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Adult Patients ◽  
Janus Kinase Inhibitor ◽  
Safety And Efficacy

scholarly journals Differential in vitro interactions of the Janus kinase inhibitor ruxolitinib with human SLC drug transporters

Xenobiotica ◽  
2021 ◽  
pp. 1-12
Author(s):  
Arnaud Bruyère ◽  
Marc Le Vée ◽  
Elodie Jouan ◽  
Stephanie Molez ◽  
Anne T. Nies ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Drug Transporters ◽  
Janus Kinase ◽  
Janus Kinase Inhibitor ◽  
In Vitro Interactions
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