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Janus Kinase Inhibitors

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Biologic and Systemic Agents in Dermatology

Abstract

To control gene expression, cytokines and other extracellular molecules utilize the Janus kinase (JAK) and signal transducers and activators of transcription (STAT). Dysregulation of the JAK-STAT pathway has been implicated in a myriad of inflammatory and hematologic disorders. Targeted JAK inhibitors (Jakinibs) are already in clinical use for rheumatoid arthritis, myelofibrosis, and polycythemia vera. These recent developments have spurred further interest in using Jakinibs to treat other cutaneous autoinflammatory disorders such as psoriasis, atopic dermatitis, and alopecia areata. While only two Jakinibs are currently FDA approved for human use, many new agents in this class are under investigation. Preliminary findings are promising, showing that Jakinibs have the potential to become a significant alternative medication class for cutaneous autoinflammatory disorders. This review will present an overview of this novel drug class, the mechanics of the signaling pathway, and clinical data in support of its therapeutic benefit.

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References

  1. Wilks AF. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989;86(5):1603–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. FDA. FDA approves Xeljanz for rheumatoid arthritis 2012 [updated Nov. 6, 2012]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm.

  3. FDA. FDA approves first drug to treat a rare bone marrow disease 2011 [updated Nov. 16, 2011]. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280102.htm.

  4. FDA. FDA approves Jakafi to treat patients with a chronic type of bone marrow disease 2014 [updated December 4, 2014]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425677.htm.

  5. FDA. NADA 141–345 APOQUEL Oclacitinib Tablet Dogs 2013 [updated May 14, 2013]. http://www.fda.gov/downloads/AnimalV.../UCM363901.pdf.

  6. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016;111:784–803.

    Article  CAS  PubMed  Google Scholar 

  8. Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, et al. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol. 2009;387(1):219–32.

    Article  CAS  PubMed  Google Scholar 

  9. Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A. 1994;91(14):6374–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella P, et al. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997;90(10):3996–4003.

    CAS  PubMed  Google Scholar 

  11. Chen M, Cheng A, Candotti F, Zhou YJ, Hymel A, Fasth A, et al. Complex effects of naturally occurring mutations in the JAK3 pseudokinase domain: evidence for interactions between the kinase and pseudokinase domains. Mol Cell Biol. 2000;20(3):947–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stark GR, Darnell JE Jr. The JAK-STAT pathway at twenty. Immunity. 2012;36(4):503–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell. 1998;93(5):827–39.

    Article  CAS  PubMed  Google Scholar 

  14. Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol. 2016;12(1):25–36.

    Article  CAS  PubMed  Google Scholar 

  15. Samadi A, Ahmad Nasrollahi S, Hashemi A, Nassiri Kashani M, Firooz A. Janus kinase (JAK) inhibitors for the treatment of skin and hair disorders: a review of literature. J Dermatolog Treat 2017:1–11.

    Google Scholar 

  16. Laurence A, Pesu M, Silvennoinen O, O’Shea J. JAK kinases in health and disease: an update. Open Rheumatol J. 2012;6:232–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285(1–2):1–24.

    Article  CAS  PubMed  Google Scholar 

  18. Bandaranayake RM, Ungureanu D, Shan Y, Shaw DE, Silvennoinen O, Hubbard SR. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat Struct Mol Biol. 2012;19(8):754–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054–61.

    Article  CAS  PubMed  Google Scholar 

  20. Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55.

    Article  CAS  PubMed  Google Scholar 

  21. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70.

    Article  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Lowes MA, Suarez-Farinas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014;32:227–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alves de Medeiros AK, Speeckaert R, Desmet E, Van Gele M, De Schepper S, Lambert J. JAK3 as an emerging target for topical treatment of inflammatory skin diseases. PLoS One. 2016;11(10):e0164080.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Andres RM, Hald A, Johansen C, Kragballe K, Iversen L. Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity. Exp Dermatol. 2013;22(5):323–8.

    Article  CAS  PubMed  Google Scholar 

  26. Hald A, Andres RM, Salskov-Iversen ML, Kjellerup RB, Iversen L, Johansen C. STAT1 expression and activation is increased in lesional psoriatic skin. Br J Dermatol. 2013;168(2):302–10.

    Article  CAS  PubMed  Google Scholar 

  27. Chang BY, Zhao F, He X, Ren H, Braselmann S, Taylor V, et al. JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice. J Immunol. 2009;183(3):2183–92.

    Article  CAS  PubMed  Google Scholar 

  28. Nakajima K. Critical role of the interleukin-23/T-helper 17 cell axis in the pathogenesis of psoriasis. J Dermatol. 2012;39(3):219–24.

    Article  CAS  PubMed  Google Scholar 

  29. Cho ML, Kang JW, Moon YM, Nam HJ, Jhun JY, Heo SB, et al. STAT3 and NF-kappaB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol. 2006;176(9):5652–61.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. DaVeiga SP. Epidemiology of atopic dermatitis: a review. Allergy Asthma Proc. 2012;33(3):227–34.

    Article  PubMed  Google Scholar 

  33. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003;361(9352):151–60.

    Article  PubMed  Google Scholar 

  34. O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542–50.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130–9.

    Article  PubMed  Google Scholar 

  36. Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013;2(3):e24137.

    PubMed  PubMed Central  Google Scholar 

  37. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. JAMA Dermatol. 2015;151(10):1110–2.

    Article  PubMed  Google Scholar 

  38. Klaeschen AS, Wenzel J. Upcoming therapeutic targets in cutaneous lupus erythematous. Expert Rev Clin Pharmacol. 2016:1–12.

    Google Scholar 

  39. Kurtzman DJ, Wright NA, Lin J, Femia AN, Merola JF, Patel M, et al. Tofacitinib citrate for refractory cutaneous dermatomyositis: an alternative treatment. JAMA Dermatol. 2016;152(8):944–5.

    Article  PubMed  Google Scholar 

  40. van de Kerkhof PC. An update on topical therapies for mild-moderate psoriasis. Dermatol Clin. 2015;33(1):73–7.

    Article  PubMed  Google Scholar 

  41. Dowty ME, Lin J, Ryder TF, Wang W, Walker GS, Vaz A, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. Drug Metab Dispos. 2014;42(4):759–73.

    Article  PubMed  Google Scholar 

  42. Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lindstrom TM, Robinson WH. A multitude of kinases—which are the best targets in treating rheumatoid arthritis? Rheum Dis Clin N Am. 2010;36(2):367–83.

    Article  Google Scholar 

  44. Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S, et al. The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis 2014;73(12):2192–2198.

    Google Scholar 

  45. Xeljanz. package insert. New York, NY: Pfizer Laboratories; 2016.

    Google Scholar 

  46. Clowse ME, Feldman SR, Isaacs JD, Kimball AB, Strand V, Warren RB, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39(8):755–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507.

    Article  CAS  PubMed  Google Scholar 

  48. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451–60.

    Article  CAS  PubMed  Google Scholar 

  49. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19.

    Article  PubMed  Google Scholar 

  50. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559–70.

    Article  PubMed  Google Scholar 

  51. Lee EB, Fleischmann RM, Hall S, van Vollenhoven RF, Bradley J, et al. Radiographic, clinical and functional comparison of tofacitinib monotherapy versus methotrexate in methotrexate-nave patients with rheumatoid arthritis. Arthritis Rheum. 2012;(S):64, 1049.

    Google Scholar 

  52. Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.

    Article  PubMed  Google Scholar 

  53. Conaghan PG, Ostergaard M, Bowes MA, Wu C, Fuerst T, van der Heijde D, et al. Effects of tofacitinib on MRI enpoints in methotrexate-naive early rheumatoid arthritis: a phase 2 MRI study with semi-quantitative and quantitative endpoints. Ann Rheum Dis. 2015;74(Suppl 2):738.

    Article  Google Scholar 

  54. Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials. Br J Dermatol. 2015;173(4):949–61.

    Article  CAS  PubMed  Google Scholar 

  55. Bachelez H, van de Kerkhof PCM, Strohal R, Kubanov A, Valenzuela F, Lee J-H, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet. 2015;386(9993):552–61.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  Google Scholar 

  57. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Ports WC, Khan S, Lan S, Lamba M, Bolduc C, Bissonnette R, et al. A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol. 2013;169(1):137–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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.

    Article  CAS  PubMed  Google Scholar 

  60. Cervantes F, Vannucchi AM, Kiladjian JJ, Al-Ali HK, Sirulnik A, Stalbovskaya V, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013;122(25):4047–53.

    Article  CAS  PubMed  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. Ortiz-Ibanez K, Alsina MM, Munoz-Santos C. Tofacitinib and other kinase inhibitors in the treatment of psoriasis. Actas Dermosifiliogr. 2013;104(4):304–10.

    Article  CAS  PubMed  Google Scholar 

  63. Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Identifier NCT02809976. Topical Ruxolitinib for the Treatment of Vitiligo [Internet]. https://clinicaltrials.gov/ct2/show/NCT02809976?term=Ruxolitinib&rank=11.

  65. Identifier NCT03011892. A study to evaluate the safety and efficacy of INCB018424 phosphate cream applied topically to adults with atopic dermatitis [Internet]. https://clinicaltrials.gov/ct2/show/NCT03011892?term=Ruxolitinib&rank=87.

  66. Identifier NCT02553330. A study with INCB018424 phosphate cream applied topically to subjects with alopecia areata (AA) [Internet]. https://clinicaltrials.gov/ct2/show/NCT02553330?term=Ruxolitinib&rank=92.

  67. Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74(2):333–40.

    Article  CAS  PubMed  Google Scholar 

  68. Smolen JS, Kremer JM, Gaich CL, DeLozier AM, Schlichting DE, Xie L, et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis. 2017;76(4):694–700.

    Article  PubMed  Google Scholar 

  69. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. OP0029-Baricitinib, an oral Janus Kinase (JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an inadequate response to TNF inhibitors: results of the phase 3 RA-beacon study. Ann Rheum Dis. 2015;74(S2):75–6.

    Google Scholar 

  70. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al. Baricitinib, an oral Janus Kinase (JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an inadequate response to cDMARD therapy: results of the phase 3 RA-BUILD Study. Ann Rheum Dis. 2015;74(S2)

    Google Scholar 

  71. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016;374(13):1243–52.

    Article  CAS  PubMed  Google Scholar 

  72. 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.

    Article  CAS  PubMed  Google Scholar 

  73. Identifier NCT02576938. A study of baricitinib (LY3009104) in participants with moderate-to-severe atopic dermatitis [Internet]. https://clinicaltrials.gov/ct2/show/NCT02576938?term=baricitinib+atopic+dermatitis&rank=1.

  74. Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016;75(6):1057–64.

    Article  CAS  PubMed  Google Scholar 

  75. Papp K, Pariser D, Catlin M, Wierz G, Ball G, Akinlade B, et al. A phase 2a randomized, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2015;173(3):767–76.

    Article  CAS  PubMed  Google Scholar 

  76. Bissonnette R, Luchi M, Fidelus-Gort R, Jackson S, Zhang H, Flores R, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. J Dermatolog Treat. 2016;27(4):332–8.

    Article  CAS  PubMed  Google Scholar 

  77. Identifier NCT02909569. Relieving chronic itch: oral medication (CIPS) [Internet]. https://clinicaltrials.gov/ct2/show/NCT02909569?term=INCB039110&rank=15.

  78. Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheum. 2016;68(12):2857–66.

    Article  CAS  Google Scholar 

  79. Identifier NCT02925117. A study to evaluate ABT-494 in adult subjects with moderate to severe atopic dermatitis [Internet]. https://clinicaltrials.gov/ct2/show/NCT02925117?term=ABt-494&rank=6.

  80. Identifier NCT02201524. Study to evaluate PF-04965842 in patients with moderate to severe psoriasis [Internet]. https://clinicaltrials.gov/ct2/show/results/NCT02201524?sect=X70156&term=PF-04965842&rank=1 - outcome1.

  81. Identifier NCT02780167. Study to evaluate Pf-04965842 in subjects with moderate to severe atopic dermatitis [Internet]. https://clinicaltrials.gov/ct2/show/NCT02780167.

  82. Ludbrook VJ, Hicks KJ, Hanrott KE, Patel JS, Binks MH, Wyres MR, et al. Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled phase IIa study. Br J Dermatol. 2016;174(5):985–95.

    Article  CAS  PubMed  Google Scholar 

  83. Identifier NCT00236119, Study of the efficacy, safety and tolerability of oral CEP-701 in patients with severe psoriasis [Internet]. https://clinicaltrials.gov/ct2/show/NCT00236119?term=lestaurtinib&rank=8.

  84. Wollenhaupt J, Silverfield J, Lee EB, Curtis JR, Wood SP, Soma K, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41(5):837–52.

    Article  CAS  PubMed  Google Scholar 

  85. Strober B, Buonanno M, Clark JD, Kawabata T, Tan H, Wolk R, et al. Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br J Dermatol. 2013;169(5):992–9.

    Article  CAS  PubMed  Google Scholar 

  86. Rao VU, Pavlov A, Klearman M, Musselman D, Giles JT, Bathon JM, et al. An evaluation of risk factors for major adverse cardiovascular events during tocilizumab therapy. Arthritis Rheum. 2015;67(2):372–80.

    Article  CAS  Google Scholar 

  87. Wu JJ, Strober BE, Hansen PR, Ahlehoff O, Egeberg A, Qureshi AA, et al. Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. J Am Acad Dermatol. 2016;75(5):897–905.

    Article  CAS  PubMed  Google Scholar 

  88. Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheum. 2014;66(10):2675–84.

    Article  CAS  Google Scholar 

  90. Sivaraman P, Cohen SB. Malignancy and Janus Kinase inhibition. Rheum Dis Clin N Am. 2017;43(1):79–93.

    Article  Google Scholar 

  91. Curtis JR, Lee EB, Kaplan IV, Kwok K, Geier J, Benda B, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis. 2016;75(5):831–41.

    Article  PubMed  Google Scholar 

  92. Woellner C, Schaffer AA, Puck JM, Renner ED, Knebel C, Holland SM, et al. The hyper IgE syndrome and mutations in TYK2. Immunity. 2007;26(5):535; author reply 6.

    Article  CAS  PubMed  Google Scholar 

  93. Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001;293(5528):300–3.

    Article  CAS  PubMed  Google Scholar 

  94. Kong XF, Ciancanelli M, Al-Hajjar S, Alsina L, Zumwalt T, Bustamante J, et al. A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood. 2010;116(26):5895–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(Suppl 2):ii111–5.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Hambleton S, Goodbourn S, Young DF, Dickinson P, Mohamad SM, Valappil M, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci U S A. 2013;110(8):3053–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–62.

    Article  CAS  PubMed  Google Scholar 

  98. Ellinghaus D, Ellinghaus E, Nair RP, Stuart PE, Esko T, Metspalu A, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Genet. 2012;90(4):636–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357(10):977–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Duetsch G, Illig T, Loesgen S, Rohde K, Klopp N, Herbon N, et al. STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Hum Mol Genet. 2002;11(6):613–21.

    Article  CAS  PubMed  Google Scholar 

  101. Farmer LJ, Ledeboer MW, Hoock T, Arnost MJ, Bethiel RS, Bennani YL, et al. Discovery of VX-509 (Decernotinib): a potent and selective Janus Kinase 3 inhibitor for the treatment of autoimmune diseases. J Med Chem. 2015;58(18):7195–216.

    Article  CAS  PubMed  Google Scholar 

  102. Quintas-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kim MK, Shin H, Park KS, Kim H, Park J, Kim K, et al. Benzimidazole derivatives as potent JAK1-selective inhibitors. J Med Chem. 2015;58(18):7596–602.

    Article  CAS  PubMed  Google Scholar 

  104. Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M. Oclacitinib (APOQUEL((R))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J Vet Pharmacol Ther. 2014;37(4):317–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Division of Dermatology, Dartmouth-Hitchcock, Concord, NH, 03301, USA

    Andrew Kim MD

  2. Department of Dermatology, University of Connecticut Health Center, 21 South Road, 2nd Floor, Farmington, CT, 06032, USA

    Bruce Strober MD, PhD

  3. Probity Medical Research, Waterloo, Ontario, Canada

    Bruce Strober MD, PhD

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  1. Andrew Kim MD
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  2. Bruce Strober MD, PhD
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Correspondence to Bruce Strober MD, PhD .

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  1. Division of Dermatology, David Geffen School of Medicine a UCLA, Los Angeles, California, USA

    Paul S. Yamauchi

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Kim, A., Strober, B. (2018). Janus Kinase Inhibitors. In: Yamauchi, P. (eds) Biologic and Systemic Agents in Dermatology. Springer, Cham. https://doi.org/10.1007/978-3-319-66884-0_19

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  • DOI: https://doi.org/10.1007/978-3-319-66884-0_19

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