Determining Treatment-related Impacts of Peficitinib on Alopecia Mackenzie Tabler Department of Biological and Environmental Sciences

Introduction Methodologies

• Though the immune system is known as the disease fighting method of the body, there are some cases when the immune response unintentionally causes damage to tissues, this is called an autoimmune disease [3].

• Approximately 50 million people are affected by different autoimmune diseases [1].

• Autoimmune diseases affect almost every organ and tissue in the human body, making them extremely difficult to research, in some cases it is nearly impossible [7].

Alopecia Areata

• Alopecia results in partial or complete hair loss on different areas of the body where hair Potential Pitfalls normally grows.

• When an individual has alopecia, the body’s immune system’s T-cell lymphocytes mistakenly attack healthy hair follicles, causing them to fall out, usually transpiring in a • One potentially serious drawback of this patchy, thinning, or dispersed pattern [8]. research could be the possible adverse effects of this drug, which could be as serious as liver damage [2]. • The immense psychological impact that this disease can have on an individual • Though unlikely, if these were to occur, it can affect a person’s everyday life. could hinder the results of this study. • Lack of recognition and awareness of alopecia is a major setback in research and discovery of treatments. Conclusions Figure 1: Presenting that peficitinib has a greater inhibition compared to

Janus Kinase Inhibitors

• JAK inhibitors (JAK1, JAK2, JAK3, and TYK2) are protein tyrosine kinases that eliminate IFN indicators, which prevents the progression of alopecia [11].

• , tofacitinib, and

• Peficitinib is currently in clinical trials for • Peficitinib, as an inhibitor of all Janus kinases, should have a similar, if not better reaction rheumatoid arthritis (RA), and appears to be in patients since it deals with not only JAK3 inhibition, but the others as well. effective and safe for those patients [9]. • Other JAK inhibitors that are used for RA also have success in treating alopecia.

• Researchers of peficitinib on rheumatoid arthritis (RA) found that inhibiting JAK3 Specific Aim weakened TLR4-mediated activity in anti-inflammatory IL-10, and enhanced generation of pro-inflammatory [9].

• My proposal is based on the studies that have been completed on JAK inhibitors ruxolitinib and tofacitinib. References

• JAK3 inhibitors are known to be the greatest possible 1. AARDA. 2018. Autoimmune Disease Statistics. American Autoimmune Related Diseases Association [Internet]. Available from https://www.aarda.org/news-information/statistics/#1488234345468-3bf2d325-1052 treatments for autoimmune diseases because it focuses 2. Crispin MK, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, Chen JC, Cerise JE, Jabbari A, Winge MC, Marinkovich MP. 2016. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia [4] areata. JCI insight, 1(15). on lymphocytes . 3. Fairweather D, Root‐Bernstein R. 2007. Autoimmune disease: mechanisms. eLS. 4. Furumoto Y, Gadina M. 2013. The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders. BioDrugs, 27(5): 431-438. 5. Ito M, YamazShirakamiaki S, Yamagami K, Kuno M, Morita Y, Okuma K, Nakamura K, Chida N, Inami M, Inoue T. 2017. A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. Journal of pharmacological sciences, 133(1): 25-33. 6. Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, Furniss M, Vaughan R, Christiano AM, Clynes R. 2016. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI insight, 1(15). 7. Marrack P, Kappler J, Kotzin BL. 2001. Autoimmune disease: why and where itoccurs. Nature medicine, 7(8): 899. For my research, I wish to identify the impacts of peficitinib on alopecia areata patients by 8. Petukhova L, Duvic M, Hordinsky M, Norris D, Price V, Shimomura Y, Kim H, Singh P, Lee A, Chen WV, Meyer KC. 2010. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature, 466(7302): 113. determining treatment-related stimulation of inflammatory cytokines, such as TLR4-mediated 9. Walsh N. 2015. New JAK Inhibitor Succeeds Versus Placebo in RA- Once-daily oral peficitinib met 12-week endpoint in phase IIb study. MEDPAGE TODAY [Internet]. Available from https://www.medpagetoday.com/rheumatology/arthritis/55381 interleukin production, and activation of response genes with gene expression profiling. 10. Wang H, Brown J, Gao S, Liang S, Jotwani R, Zhou H, Suttles J, Scott DA, Lamont RJ. 2013. The role of JAK-3 in regulating TLR-mediated production in innate immune cells. The Journal of Immunology, 191(3): 1164-1174. 11. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, De Jong A, Harel S, DeStefano GM, Rothman L, Singh P. 2014. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature medicine, 20(9): 1043.