The signal transducer and activator of transcription (STAT) families and Janus kinase group (JAK) are important intracellular signalling components that affect more than 50 cytokines and growth elements. JAK inhibitors target distinct receptor-associated kinases, inhibiting the activation of inflammatory signals. With the expanding body of evidence supporting the use of targeted medicines, numerous JAK inhibitors, both topical and systemic, have been tested in the treatment of atopic dermatitis, with varying mechanisms of action, effectiveness, and safety. The efficacy and safety of JAK inhibitors used to treat inflammatory and atopic skin diseases are examined in this review study. Their application in the mentioned fields has been characterized by some excellent clinical responses, but wide variability in responses and some serious and even life-threatening side effects. While JAK inhibitors are now beneficial to many patients, further study is needed to better understand this complicated mechanism to improve treatment outcomes and minimize side effects.
1. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6(1):402.
2. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov. 2017;16(12):843-62.
3. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-7.
4. Rask-Andersen M, Zhang J, Fabbro D, Schiöth HB. Advances in kinase targeting: current clinical use and clinical trials. Trends Pharmacol Sci. 2014;35(11):604-20.
5. Herrera AF, Jacobsen ED. Ibrutinib for the treatment of mantle cell lymphoma. Clin Cancer Res. 2014;20(1):5365-71.
6. T Virtanen A, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: prospects in inflammatory and autoimmune diseases. BioDrugs. 2019;33(1):15-32.
7. Neis MM, Peters B, Dreuw A, Wenzel J, Bieber T, Mauch C, et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol. 2006;118(4):930-7.
8. Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol. 2021;85(4):863-72.
9. Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol. 2020;145(2):572-82.
10. Gong X, Chen X, Kuligowski ME, Liu X, Liu X, Cimino E, et al. Pharmacokinetics of ruxolitinib in patients with atopic dermatitis treated with ruxolitinib cream: data from phase II and III studies. Am J Clin Dermatol. 2021;22(4):555-66.
11. Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br J Dermatol. 2016;175(5):902-11.
12. Purohit VS, Ports WC, Wang C, Riley S. Systemic tofacitinib concentrations in adult patients with atopic dermatitis treated with 2% tofacitinib ointment and application to pediatric study planning. J Clin Pharmacol. 2019;59(6):811-20.
13. Bissonnette R, Maari C, Forman S, Bhatia N, Lee M, Fowler J, et al. The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study. Br J Dermatol. 2019;181(4):733-42.
14. Pavel AB, Song T, Kim HJ, Del Duca E, Krueger JG, Dubin C, et al. Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144(4):1011-24.
15. Radi G, Simonetti O, Rizzetto G, Diotallevi F, Molinelli E, Offidani A. Baricitinib: The first Jak inhibitor approved in Europe for the treatment of moderate to severe atopic dermatitis in adult patients. Healthcare (Basel). 2021;9(11):1575.
16. Guttman-Yassky E, Silverberg JI, Nemoto O, Forman SB, Wilke A, Prescilla R, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: A phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J Am Acad Dermatol. 2019;80(4):913-21.
17. Simpson EL, Lacour JP, Spelman L, Galimberti R, Eichenfield LF, Bissonnette R, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br J Dermatol. 2020;183(2):242-55.
18. Bieber T, Thyssen JP, Reich K, Simpson EL, Katoh N, Torrelo A, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-85.
19. Gooderham MJ, Forman SB, Bissonnette R, Beebe JS, Zhang W, Banfield C, et al. Efficacy and safety of oral Janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatol. 2019;155(12):1371-9.
20. Bieber T, Simpson EL, Silverberg JI, Thaçi D, Paul C, Pink AE, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N Engl J Med. 2021;384(12):1101-12.
21. Fadlalmola HA, Albadrani MS, Elhusein AM, Mohamedsalih WE, Swamy VDS, Mamanao DM. Effectiveness and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a systematic review and meta-analysis of randomized clinical trials. Dermatol Res Pract. 2021;2021:8382761.
22. Duggan S, Keam SJ. Upadacitinib: First Approval. Drugs. 2019;79(16):1819-28.
23. Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC, Papp KA, Reich K, et al. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;145(3):877-84.
24. Guttman-Yassky E, Teixeira HD, Simpson EL, Papp KA, Pangan AL, Blauvelt A, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomized controlled phase 3 trials. Lancet. 2021;397(10290):2151-68.
25. Reich K, Teixeira HD, de Bruin-Weller M, Bieber T, Soong W, Kabashima K, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397(10290):2169-81.
26. Blauvelt A, Teixeira HD, Simpson EL, Costanzo A, De Bruin-Weller M, Barbarot S, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157(9):1047-55.
27. Bissonnette R, Iversen L, Sofen H, Griffiths CE, Foley P, Romiti R, et al. Tofacitinib withdrawal and retreatment in moderate-to-severe chronic plaque psoriasis: a randomized controlled trial. Br J Dermatol. 2015;172(5):1395-406.
28. Chiricozzi A, Faleri S, Saraceno R, Bianchi L, Buonomo O, Chimenti S, et al. Tofacitinib for the treatment of moderate-to-severe psoriasis. Expert Rev Clin Immunol. 2015;11(4):443-55.
29. Bachelez H, van de Kerkhof PC, Strohal R, Kubanov A, Valenzuela F, Lee JH, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomized non-inferiority trial. Lancet. 2015;386(9993):552-61.
30. Papp KA, Menter MA, Raman M, Disch D, Schlichting DE, Gaich C, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2016;174(6):1266-76.
31. Punwani N, Scherle P, Flores R, Shi J, Liang J, Yeleswaram S, et al. Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. 2012;67(4):658-64.
32. Punwani N, Burn T, Scherle P, Flores R, Shi J, Collier P, et al. Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor. Br J Dermatol. 2015;173(4):989-97.
33. Meng J, Steinhoff M. Molecular mechanisms of pruritus. Curr Res Transl Med. 2016;64(4):203-6.
34. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20(9):1043-9.
35. Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017;76(1):22-8.
36. Scheinberg M, Ferreira SB. Reversal of alopecia universalis by tofacitinib: a case report. Ann Intern Med. 2016;165(10):750-1.
37. Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1(15):e89776.
38. Pieri L, Guglielmelli P, Vannucchi AM. Ruxolitinib-induced reversal of alopecia universalis in a patient with essential thrombocythemia. Am J Hematol. 2015;90(1):82-3.
39. Craiglow BG, Tavares D, King BA. Topical ruxolitinib for the treatment of alopecia universalis. JAMA Dermatol. 2016;152(4):490-1.
40. Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of alopecia areata and variants in adolescents. J Am Acad Dermatol. 2017;76(1):29-32.
41. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 2015;151(10):1110-2.
42. Koga T, Sato T, Umeda M, Fukui S, Horai Y, Kawashiri SY, et al. Successful treatment of palmoplantar pustulosis with rheumatoid arthritis, with tofacitinib: Impact of this JAK inhibitor on T-cell differentiation. Clin Immunol. 2016;173:147-8.
43. Damsky W, King BA. Idiopathic erythema multiforme: Evidence of underlying Janus kinase-signal transducer and activator of transcription activation and successful treatment with tofacitinib. JAAD Case Rep. 2016;2(6):502-4.
44. He H, Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an update. Am J Clin Dermatol. 2019;20(2):181-92.
45. Agboola F, Atlas SJ, Brouwer E, Carlson JJ, Hansen RN, Herron-Smith S, et al. JAK inhibitors and monoclonal antibodies for the treatment of atopic dermatitis: effectiveness and value. J Manag Care Spec Pharm. 2022;28(1):108-14.
46. FDA. FDA requires warnings about the increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions Washington DC, USA: United States Food and Drug Administration; 2021. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death#:~:text=FDA%20is%20requiring%20new%20and,treat%20certain%20serious%20inflammatory%20conditions.
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