Session Information
Date: Tuesday, November 14, 2023
Title: (1945–1972) Muscle Biology, Myositis & Myopathies – Basic & Clinical Science Poster III
Session Type: Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Dysregulation of the interferon (IFN) pathway plays a major role in the pathophysiology of autoimmune myositis. Upregulation of type 1 IFN stimulated genes (an IFN ‘signature’) is present in myositis patients and this signature is related to disease severity. The JAK family of tyrosine kinases, which mediate interferon signaling through the signal transducer and activators of transcription (STAT), have thus become therapeutic targets for treating myositis as well as other autoimmune diseases. Therefore, we investigated the effects of two JAK-STAT inhibitors, baricitinib and tofacitinib, on development of the disease process in the major histocompatibility complex (MHC) class I transgenic mouse model, which exhibits features very similar to human myositis, including an upregulation of type 1 IFN stimulated genes.
Methods: Myositis was induced in 21-day old female mice by removal of doxycycline. Mice were randomized into 4 groups (n=12/group); myositis no treatment, myositis + baricitinib, myositis + tofacitinib, and control. Baricitinib and tofacitinib were administered daily as a cherry syrup oral suspension at 10 mg/kg and 20 mg/kg body weight respectively for six weeks. Treatment groups were evaluated based on survival time, body weight, muscle strength and function (GSM, in vitro torque and treadmill exhaustion), histologic disease severity and expression levels of the type 1 IFN stimulated genes (ISG) Mx1, IFIT1, IRF7, and ISG15. Data were collected in a blinded fashion.
Results: Myositis mice had significantly reduced weight gain, muscle function and strength, and inflammation in the quadricep muscle compared to controls. Tofacitinib treatment resulted in significant improvement in survival of myositis mice, with 55% surviving to the end of the study compared to 27% for the myositis and baricitinib treatment groups. Expression levels of the type 1 interferon genes Mx1, IFIT1, IRF7, and ISG15, which were significantly elevated in myositis mice, were noticeably decreased in skeletal muscle of both baricitinib and tofacitinib treated mice. However, significant reductions in IFIT1 (p = 0.03) and IRF7 (p = 0.04) expression were observed only in the tofacitinib treated group. Neither tofacitinib nor baricitinib treatment resulted in significant functional improvement.
Conclusion: Overall, we observed that treatment with tofacitinib significantly improved survival and lowered the IFN signature, but this did not translate to functional improvement. Furthermore, baricitinib did not significantly improve any of the measures tested.While both tofacitinib and baricitinib interfere with the JAK1 pathway, tofacitinib additionally interferes with the JAK3 pathway which is involved in signal transduction of the γc family of cytokines. This difference could explain the increased efficacy of tofacitinib in this study.
To cite this abstract in AMA style:
Spathis R, Narvesen S, Robles Kuriplach D, Huang K, Sundar T, Shulman D, Bagley E, Nagaraju K, Morales M. Effect of JAK-STAT Inhibition by Baricitinib and Tofacitinib on Disease Phenotype in a Mouse Model of Myositis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/effect-of-jak-stat-inhibition-by-baricitinib-and-tofacitinib-on-disease-phenotype-in-a-mouse-model-of-myositis/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-jak-stat-inhibition-by-baricitinib-and-tofacitinib-on-disease-phenotype-in-a-mouse-model-of-myositis/