SKIN July 2023 Volume 7 Issue 4 (c) 2023 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 932 SHORT COMMUNICATION The JAK-Cytokine Interface – A Review and Update on Prospective Clinical Considerations David Hashemi, MD, MBA1, Neal Bhatia, MD2 1 Harvard Combined Dermatology Residency Training Program, Harvard Medical School, Boston, MA 2 Therapeutics Clinical Research, San Diego, CA Janus kinases (JAKs) are non-receptor tyrosine kinases that work together with signal transducers and activators of transcription (STAT) proteins to form the JAK/STAT pathway. Together, this pathway is responsible for mediating a wide range of downstream cytokines and growth factors, and inhibition of various components of this pathway has been a major area of research focus in recent years. Each of the major enzymes of the family – which include JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2) – or combinations of JAKs is responsible for its own set of most strongly-associated inflammatory mediators (Figure 1), and inhibition of specific JAKs or combination of JAKs can therefore also potentially allow for modulation of specific inflammatory factors and their associated conditions. This article will attempt to provide a concise review of the inflammatory factors affected by each JAK, and to support clinicians as they engage in the ever-growing body of research around the use of JAK inhibitors for potential treatment of these conditions. Atopic dermatitis represents one of the most studied, and consequently most targeted, conditions for JAK inhibition to date, with three FDA approvals of JAK inhibitors, two ABSTRACT Janus kinases (JAKs) are non-receptor tyrosine kinases that work together with signal transducers and activators of transcription (STAT) proteins to form the JAK/STAT pathway. Together, this pathway is responsible for mediating a wide range of downstream cytokines and growth factors, and inhibition of various components of this pathway has been a major area of research focus in recent years. Each of the major enzymes of the family – which include JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (TYK2) – or combinations of JAKs is responsible for its own set of most strongly-associated inflammatory mediators, and inhibition of specific JAKs or combination of JAKs can therefore also potentially allow for modulation of specific inflammatory factors and their associated conditions. To date, JAK inhibitors have particularly been studied in the treatment of atopic dermatitis (felt to be primarily driven by IL- 4, IL-13, and IL-5), psoriasis (IL-12/IL-23), alopecia areata (IL-2, IL-15, and IFN-γ), and vitiligo (IL-15 and IFN-γ), given that these factors can all be found downstream of specific JAK/STAT pathways as shown in Figure 1. By providing a concise review of the inflammatory factors affected by each JAK, this article aims to support clinicians as they engage in the ever- growing body of research around the use of JAK inhibitors for potential treatment of dermatologic conditions. SKIN July 2023 Volume 7 Issue 4 (c) 2023 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 933 Figure 1. Interactions between various cytokines and JAK1-3, TYK2, ITK, TEC, and BTK. systemic and one topical, for treatment of atopic dermatitis between 2021-2022. As shown in Figure 1, atopic dermatitis is classically mediated by IL-4 and IL-13 (downstream of JAK1/3 and JAK1/2 respectively) and IL-5 (downstream of JAK2)1. Early FDA approvals of JAK inhibitors for atopic dermatitis have emphasized the role of JAK1 inhibition, with topical ruxolitinib inhibiting JAK1/2 and oral upadacitinib and abrocitinib more selectively focusing on JAK11-2. With a number of selective JAK3 inhibitors in the pipeline, specifically focused on vitiligo and alopecia areata, future research may also evaluate whether selective JAK3 inhibition is also able to successfully treat atopic dermatitis via its inhibition of IL-4 while avoiding the broader set of cytokines and growth factors downstream of JAK1. Psoriasis is primarily mediated by the IL- 12/IL-23 pathway3, which as shown in Figure 1 is downstream of JAK2/TYK2. Through this lens, one can understand why deucravacitinib – a selective TYK2 inhibitor – demonstrates efficacy and has gained FDA approval for treatment of psoriasis4, and why less selective JAK inhibitors such as tofacitinib (which inhibits JAK1/2/3 and was FDA-approved for psoriatic arthritis5) demonstrated efficacy as well. However, as shown in Figure 1, both TYK2 and JAK1/2/3 also act on a very wide range of off-target SKIN July 2023 Volume 7 Issue 4 (c) 2023 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 934 downstream factors, raising the question of whether IL-12, IL-23, and/or IL-17 can be more selectively targeted in future generations of JAK inhibitors. Alopecia areata is driven by inflammation believed to be mediated by IL-2 and IL-15 (which is downstream of JAK1/3, as shown in Figure 1), as well as IFN-γ (downstream of JAK1/2)6. The first FDA-approved JAK inhibitor for alopecia areata was oral baricitinib7, which inhibits JAK1/2 and therefore likely impacts all of these factors. Vitiligo is also driven by IL-15 (downstream of JAK1/3) and IFN-γ (downstream of JAK1/2)8- 9, and like alopecia areata saw its first FDA approved JAK inhibitor in the form of a JAK1/2 inhibitor (topical ruxolitinib). More recently, there has been increasing research evaluating the potential for more targeted inhibition of JAK3 for alopecia areata and vitiligo, given it is still upstream of both IL-2 and IL-15 with fewer off-target factors than those downstream of JAK1/2. Interim results for ritlecitinib (a selective JAK3 inhibitor) in phase 3 alopecia areata studies10 and phase 2b vitiligo studies11 may potentially support this hypothesis, highlighting the potential promise of targeted inhibition aimed at specific cytokines of interest. In addition to these 4 initial dermatologic conditions for which JAK inhibitors have been approved to date, there have been a broad range of additional conditions reported for which JAK inhibition may hold promise12. By more specifically understanding which inflammatory mediators are downstream of each specific JAK, scientists and clinicians can aim to further optimize targeting of a given condition’s driving mediators, thereby maximizing impact while minimizing off-target effects and thus improving patient outcomes. Conflict of Interest Disclosures: Dr. Hashemi has completed an externship as Entrepreneur in Residence at Gore Range Capital. Dr. Bhatia has served as an advisor, consultant, and investigator for Abbvie, Almirall, Arcutis, Arena, Beiersdorf, Biofrontera, BMS, BI, Dermavant, Galderma, InCyte, ISDIN, J&J, LaRoche-Posay, Leo, Lilly, Novartis, Ortho, Pfizer, Regeneron, Sanofi, SunPharma, and Verrica. Funding: None Corresponding Author: Neal Bhatia, MD Therapeutics Clinical Research San Diego, CA Email: bhatiaharbor@gmail.com References: 1. Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov. 2022 Jan; 21(1):21-40. 2. Nezamololama N, Fieldhouse K, Metzger K, Gooderham M. Emerging systemic JAK inhibitors in the treatment of atopic dermatitis: a review of abrocitinib, baricitinib, and upadacitinib. Drugs Context. 2020 Nov 16; 9:2020-8-5. 3. Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis. J Immunol. 2018 Sep 15; 201(6):1605-1613. 4. Armstrong AW, Gooderham M, Warren RB, Papp KA, Strober B, Thaçi D, Morita A, Szepietowski JC, Imafuku S, Colston E, Throup J, Kundu S, Schoenfeld S, Linaberry M, Banerjee S, Blauvelt A. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J Am Acad Dermatol. 2023 Jan; 88(1):29-39. 5. Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of psoriasis and psoriatic arthritis. Expert Rev Clin Immunol. 2018 Sep; 14(9):719-730. 6. Lensing M, Jabbari A. An overview of JAK/STAT pathways and JAK inhibition in alopecia areata. Front Immunol. 2022 Aug 30; 13:955035. 7. King B, Ohyama M, Kwon O, Zlotogorski A, Ko J, Mesinkovska NA, Hordinsky M, Dutronc Y, Wu WS, McCollam J, Chiasserini C, Yu G, Stanley S, Holzwarth K, DeLozier AM, Sinclair R; BRAVE- AA Investigators. Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022 May 5; 386(18):1687-1699. SKIN July 2023 Volume 7 Issue 4 (c) 2023 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 935 8. Faraj S, Kemp EH, Gawkrodger DJ. Patho- immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors. Clin Exp Immunol. 2022 Jan 28; 207(1):27-43. 9. Richmond JM, Strassner JP, Zapata L Jr, Garg M, Riding RL, Refat MA, Fan X, Azzolino V, Tovar-Garza A, Tsurushita N, Pandya AG, Tso JY, Harris JE. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci Transl Med. 2018 Jul 18; 10(450):eaam7710. 10. Tsianakas A. Long-term safety and efficacy of ritlecitinib in adults and adolescents with alopecia areata: interim results from the ALLEGRO-LT phase 3, open-label trial. D3T01.1G, EADV Congress 2022, Milan, Italy, 7‒10 September. 11. Ezzedine K, Peeva E, Yamaguchi Y, Cox LA, Banerjee A, Han G, Hamzavi I, Ganesan AK, Picardo M, Thaçi D, Harris JE, Bae JM, Tsukamoto K, Sinclair R, Pandya AG, Sloan A, Yu D, Gandhi K, Vincent MS, King B. Efficacy and safety of oral ritlecitinib for the treatment of active nonsegmental vitiligo: A randomized phase 2b clinical trial. J Am Acad Dermatol. 2023 Feb; 88(2):395-403. 12. Howell MD, Kuo FI, Smith PA. Targeting the Janus Kinase Family in Autoimmune Skin Diseases. Front Immunol. 2019 Oct 9; 10:2342.