The Janus Kinase Inhibitor Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction

Yasuko Furumoto¹, Carolyne K. Smith², Luz P. Blanco³, Wanxia L. Tsai⁴, Wenpu Zhao⁵, Victoria Hoffmann⁶, Seth Thacker⁷, Giuseppe Sciumè⁸, Leti Nuñez¹, Alan Remaley⁹, John J O'Shea¹⁰, Mariana Kaplan¹¹ and Massimo G. Gadina¹², ¹NIAMS NIH, Translational Immunology Section, Office of Science and Technology, Bethesda, MD, ²Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ³Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁴National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, ⁵NIAMS NIH, Systemic Autoimmunity Branch, Bethesda, MD, ⁶Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, ⁷NHLBI NIH, Lipoprotein Metabolism Section, Bethesda, MD, ⁸NIAMS NIH, Molecular Immunology and Inflammation Branch, Bethesda, MD, ⁹NHLBI, National Institutes of Health, Bethesda, MD, ¹⁰NIAMS NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ¹¹NIAMS/NIH, Bethesda, MD, ¹²Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Janus kinase (JAK), SLE and animal models

Session Information

Date: Tuesday, November 15, 2016

Title: Systemic Lupus Erythematosus – Animal Models - Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and on its associated vascular pathology remains to be characterized.

Methods: MRL/lprlupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular trap (NET) release, endothelium-dependent vasorelaxation and endothelial differentiation were compared in treated and untreated mice.

Results: Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NET formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies

Conclusion: Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.

Disclosure: Y. Furumoto, None; C. K. Smith, None; L. P. Blanco, None; W. L. Tsai, None; W. Zhao, None; V. Hoffmann, None; S. Thacker, None; G. Sciumè, None; L. Nuñez, None; A. Remaley, None; J. J. O'Shea, None; M. Kaplan, None; M. G. Gadina, None.

To cite this abstract in AMA style:

Furumoto Y, Smith CK, Blanco LP, Tsai WL, Zhao W, Hoffmann V, Thacker S, Sciumè G, Nuñez L, Remaley A, O'Shea JJ, Kaplan M, Gadina MG. The Janus Kinase Inhibitor Tofacitinib Ameliorates Murine Lupus and Its Associated Vascular Dysfunction [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/the-janus-kinase-inhibitor-tofacitinib-ameliorates-murine-lupus-and-its-associated-vascular-dysfunction/. Accessed .

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