JAK–STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects

O’Shea JJ, Kontzias A, Yamaoka K, et al. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(Suppl. 2):ii111–5. doi: 10.1136/annrheumdis-2012-202576 .

Kaul A, Gordon C, Crow MK, et al. Systemic lupus erythematosus. Nat Rev Dis Primers. 2016;2:16039. doi: 10.1038/nrdp.2016.39 .

Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Current Opin Chem Biol. 2016;32:29–33. doi: 10.1016/j.cbpa.2016.03.006 .

Hodge JA, Kawabata TT, Krishnaswami S, et al. The mechanism of action of tofacitinib: an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(2):318–28.

Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57(12):5023–38. doi: 10.1021/jm401490p .

Galluzzo M, D’Adamio S, Servoli S, et al. Tofacitinib for the treatment of psoriasis. Exp Opin Pharmacother. 2016;17(10):1421–33. doi: 10.1080/14656566.2016.1195812 .

Leonard WJ, O’Shea JJ. Jaks and STATs: biological implications. Ann Rev Immunol. 1998;16:293–322. doi: 10.1146/annurev.immunol.16.1.293 .

Walker JG, Ahern MJ, Coleman M, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rhem Dis. 2007;66(8):992–9. doi: 10.1136/ard.2006.060822 .

Isomaki P, Junttila I, Vidqvist KL, et al. The activity of JAK–STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels. Rheumatology. 2015;54(6):1103–13. doi: 10.1093/rheumatology/keu430 .

Hammaren HM, Ungureanu D, Grisouard J, et al. ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation. Proc Natl Acad Sci USA. 2015;112(15):4642–7. doi: 10.1073/pnas.1423201112 .

Ungureanu D, Wu J, Pekkala T, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat Struct Mol Biol. 2011;18(9):971–6. doi: 10.1038/nsmb.2099 .

Min X, Ungureanu D, Maxwell S, et al. Structural and functional characterization of the JH2 pseudokinase domain of JAK family tyrosine kinase 2 (TYK2). J Biol Chem. 2015;290(45):27261–70. doi: 10.1074/jbc.M115.672048 .

Babon JJ, Liau NP, Kershaw NJ. JAK1 Takes a FERM hold of type II cytokine receptors. Structure. 2016;24(6):840–2. doi: 10.1016/j.str.2016.05.007 .

Ferrao R, Wallweber HJ, Ho H, et al. The structural basis for class II cytokine receptor recognition by JAK1. Structure. 2016;24(6):897–905. doi: 10.1016/j.str.2016.03.023 .

Wallweber HJ, Tam C, Franke Y, et al. Structural basis of recognition of interferon-alpha receptor by tyrosine kinase 2. Nat Struct Mol Biol. 2014;21(5):443–8. doi: 10.1038/nsmb.2807 .

Vijayakrishnan L, Venkataramanan R, Gulati P. Treating inflammation with the Janus kinase inhibitor CP-690,550. Trends Pharmacol Sci. 2011;32(1):25–34. doi: 10.1016/j.tips.2010.10.004 .

Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Mol Biosyst. 2006;2(11):536–50. doi: 10.1039/b606246f .

Babon JJ, Lucet IS, Murphy JM, et al. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014;462(1):1–13. doi: 10.1042/BJ20140712 .

Lai PS, Rosa DA, Magdy Ali A, et al. A STAT inhibitor patent review: progress since 2011. Exp Opin Ther Pat. 2015;25(12):1397–421. doi: 10.1517/13543776.2015.1086749 .

Liongue C, Taznin T, Ward AC. Signaling via the CytoR/JAK/STAT/SOCS pathway: emergence during evolution. Mol Immunol. 2016;71:166–75. doi: 10.1016/j.molimm.2016.02.002 .

Sen M, Thomas SM, Kim S, et al. First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov. 2012;2(8):694–705. doi: 10.1158/2159-8290.CD-12-0191 .

Liongue C, Ward AC. Evolution of the JAK–STAT pathway. JAK–STAT. 2013;2(1):e22756. doi: 10.4161/jkst.22756 .

Brooks AJ, Dai W, O’Mara ML, et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science. 2014;344(6185):1249783. doi: 10.1126/science.1249783 .

Mavers M, Ruderman EM, Perlman H. Intracellular signal pathways: potential for therapies. Curr Rheumatol Rep. 2009;11(5):378–85.

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. doi: 10.1038/nrrheum.2015.167 .

Mao X, Ren Z, Parker GN, et al. Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell. 2005;17(6):761–71. doi: 10.1016/j.molcel.2005.02.021 .

O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013;368(2):161–70. doi: 10.1056/NEJMra1202117 .

Hofmann SR, Ettinger R, Zhou YJ, et al. Cytokines and their role in lymphoid development, differentiation and homeostasis. Curr Opin Allergy Clin Immunol. 2002;2(6):495–506. doi: 10.1097/01.all.0000044534.45448.bf .

Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ. Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol. 2015;194(1):21–7. doi: 10.4049/jimmunol.1401867 .

Morinobu A, Gadina M, Strober W, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci USA. 2002;99(19):12281–6. doi: 10.1073/pnas.182618999 .

Decker T. Emancipation from transcriptional latency: unphosphorylated STAT5 as guardian of hematopoietic differentiation. EMBO J. 2016;35(6):555–7. doi: 10.15252/embj.201693974 .

Mohr A, Chatain N, Domoszlai T, et al. Dynamics and non-canonical aspects of JAK/STAT signalling. Eur J Cell Biol. 2012;91(6–7):524–32. doi: 10.1016/j.ejcb.2011.09.005 .

O’Shea JJ, Schwartz DM, Villarino AV, et al. The JAK–STAT pathway: impact on human disease and therapeutic intervention. Ann Rev Med. 2015;66:311–28. doi: 10.1146/annurev-med-051113-024537 .

Basquiera AL, Soria NW, Ryser R, et al. Clinical significance of V617F mutation of the JAK2 gene in patients with chronic myeloproliferative disorders. Hematology. 2009;14(6):323–30. doi: 10.1179/102453309X12473408860226 .

Levine RL. JAK-mutant myeloproliferative neoplasms. Curr Top Microbiol Immunol. 2012;355:119–33. doi: 10.1007/82_2011_170 .

Jeong EG, Kim MS, Nam HK, et al. Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers. Clin Cancer Res. 2008;14(12):3716–21. doi: 10.1158/1078-0432.CCR-07-4839 .

Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2009;106(23):9414–8. doi: 10.1073/pnas.0811761106 .

Elliott NE, Cleveland SM, Grann V, et al. FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood. 2011;118(14):3911–21. doi: 10.1182/blood-2010-12-319467 .

Rodig SJ, Meraz MA, White JM, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93(3):373–83.

Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995;377(6544):65–8. doi: 10.1038/377065a0 .

Russell SM, Tayebi N, Nakajima H, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science. 1995;270(5237):797–800.

Sohn SJ, Barrett K, Van Abbema A, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol. 2013;191(5):2205–16. doi: 10.4049/jimmunol.1202859 .

Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28. doi: 10.1016/j.immuni.2012.03.016 .

Dupuis S, Dargemont C, Fieschi C, et al. Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science. 2001;293(5528):300–3. doi: 10.1126/science.1061154 .

Dupuis S, Jouanguy E, Al-Hajjar S, et al. Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet. 2003;33(3):388–91. doi: 10.1038/ng1097 .

Uzel G, Sampaio EP, Lawrence MG, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131(6):1611–23. doi: 10.1016/j.jaci.2012.11.054 .

Hambleton S, Goodbourn S, Young DF, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc Natl Acad Sci USA. 2013;110(8):3053–8. doi: 10.1073/pnas.1220098110 .

Dasgupta A, Chen KH, Tian L, Archer SL. Gone fission: an asymptomatic STAT2 mutation elongates mitochondria and causes human disease following viral infection. Brain. 2015;138(Pt 10):2802–6. doi: 10.1093/brain/awv237 .

Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264(5155):95–8.

Abroun S, Saki N, Ahmadvand M, et al. STATs: an old story, yet mesmerizing. Cell J. 2015;17(3):395–411.

Conti HR, Whibley N, Coleman BM, et al. Signaling through IL-17C/IL-17RE is dispensable for immunity to systemic, oral and cutaneous candidiasis. PloS One. 2015;10(4):e0122807. doi: 10.1371/journal.pone.0122807 .

Wolk K, Kunz S, Witte E, et al. IL-22 increases the innate immunity of tissues. Immunity. 2004;21(2):241–54. doi: 10.1016/j.immuni.2004.07.007 .

Freeman AF, Holland SM. The hyper-IgE syndromes. Immunol Allergy Clin North Am. 2008;28(2):277–91, viii. doi: 10.1016/j.iac.2008.01.005 .

Flanagan SE, Haapaniemi E, Russell MA, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Gen. 2014;46(8):812–4. doi: 10.1038/ng.3040 .

Milner JD, Vogel TP, Forbes L, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591–9. doi: 10.1182/blood-2014-09-602763 .

Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366(20):1905–13. doi: 10.1056/NEJMoa1114885 .

Wong AL, Soo RA, Tan DS, et al. Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. Ann Oncol. 2015;26(5):998–1005. doi: 10.1093/annonc/mdv026 .

Cohen AC, Nadeau KC, et al. Cutting edge: decreased accumulation and regulatory function of CD4 + CD25(high) T cells in human STAT5b deficiency. J Immunol. 2006;177(5):2770–4.

Kofoed EM, Hwa V, Little B, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003;349(12):1139–47. doi: 10.1056/NEJMoa022926 .

Sigurdsson S, Nordmark G, Goring HH, et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Gen. 2005;76(3):528–37. doi: 10.1086/428480 .

Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Gen. 2010;42(12):1118–25. doi: 10.1038/ng.717 .

Hu K, Hou S, Jiang Z, et al. JAK2 and STAT3 polymorphisms in a Han Chinese population with Behcet’s disease. Invest Ophthalmol Vis Sci. 2012;53(1):538–41. doi: 10.1167/iovs.11-8440 .

Ellinghaus D, Ellinghaus E, Nair RP, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am J Hum Gen. 2012;90(4):636–47. doi: 10.1016/j.ajhg.2012.02.020 .

Remmers EF, Plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357(10):977–86. doi: 10.1056/NEJMoa073003 .

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

Cacalano NA, Migone TS, Bazan F, et al. Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. EMBO J. 1999;18(6):1549–58. doi: 10.1093/emboj/18.6.1549 .

Pfizer receives positive CHMP opinion in europe for XELJANZ® (tofacitinib citrate) for the treatment of moderate to severe active rheumatoid arthritis receives positive CHMP opinion in Europe for XELJANZ® (tofacitinib citrate) for the treatment of moderate to severe active rheumatoid arthritis pfizer receives positive CHMP opinion in Europe for XELJANZ® (tofacitinib citrate) for the treatment of moderate to severe active rheumatoid arthritis receives positive CHMP opinion in Europe for xeljanz (tofacitinib citrate) for the treatment of moderate to severe active rheuamtoid arthritis. http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_receives_positive_chmp_opinion_in_europe_for_xeljanz_tofacitinib_citrate_for_the_treatment_of_moderate_to_severe_active_rheumatoid_arthritis. . Accessed 10 Feb 2017.

Changelian PS, Flanagan ME, Ball DJ, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302(5646):875–8. doi: 10.1126/science.1087061 .

Zerbini CA, Lomonte AB. Tofacitinib for the treatment of rheumatoid arthritis. Exp Rev Clin Immunol. 2012;8(4):319–31. doi: 10.1586/eci.12.19 .

Dowty ME, Lin J, Ryder TF, et al. The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a Janus kinase inhibitor, in humans. Drug Metab Dispos. 2014;42(4):759–73. doi: 10.1124/dmd.113.054940 .

Gupta P, Wang R, Kaplan I, et al. A phase 1 study to estimate the the effect of ketoconazole on the pharmacokinetics of tofacitinib (CP-690,550) in healthy volunteers [abstract no. P1-64]. Clin Pharmacol Ther. 2012;91(Suppl. 1):S31.

Chow V, Ni G, LaBadie R, Chan G. An open label study to estimate the effect of fluconazole on the pharmacokinetics of CP-690,550 in healthy adult subjects (Abstract). Clin Pharmacol Ther. 2008;83(Suppl 36):PI–93.

Xeljanz® [package insert]. New York: Pfizer Labs; 2016.

Lambda M, Wang R, Kaplan I, Salageanu J, Tarabar S, Krishnaswami S. The effect of rifampin on the pharmacokinetics of tofacitinib (CP-690,550) in healthy volunteers (Abstract no. PI-73). Clin Pharmacol Ther. 2012;91(Suppl 1):S35.

Gupta P, Alvey C, Wang R, et al. Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. Br J Clin Pharmacol. 2012;74(1):109–15. doi: 10.1111/j.1365-2125.2012.04168.x .

Lamba M, Wang R, Fletcher T, Alvey C, Kushner J, Stock TC. Extended-release once-daily formulation of tofacitinib: evaluation of pharmacokinetics compared with immediate-release tofacitinib and impact of food. J Clin Pharmacol. 2016;56(11):1362–71. doi: 10.1002/jcph.734 .

Ports WC, Khan S, Lan S, 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. doi: 10.1111/bjd.12266 .

Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60(7):1895–905. doi: 10.1002/art.24567 .

Tanaka Y, Suzuki M, Nakamura H, et al. Tofacitinib study I: phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res. 2011;63(8):1150–8. doi: 10.1002/acr.20494 .

Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64(4):970–81. doi: 10.1002/art.33419 .

Coombs JH, Bloom BJ, Breedveld FC, et al. Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2010;69(2):413–6. doi: 10.1136/ard.2009.108159 .

Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367(6):495–507. doi: 10.1056/NEJMoa1109071 .

Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64(3):617–29. doi: 10.1002/art.33383 .

Burmester GR, Blanco R, Charles-Schoeman C, 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. doi: 10.1016/S0140-6736(12)61424-X .

van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19. doi: 10.1056/NEJMoa1112072 .

Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159(4):253–61. doi: 10.7326/0003-4819-159-4-201308200-00006 .

van der Heijde D, Tanaka Y, Fleischmann R, 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. doi: 10.1002/art.37816 .

Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86. doi: 10.1056/NEJMoa1310476 .

Strand V, van Vollenhoven RF, Lee EB, Fleischmann R, Zwillich SH, Gruben D, et al. Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis. Rheumatology. 2016;55(6):1031–41. doi: 10.1093/rheumatology/kev442 .

Ostergaard M, Edmonds J, McQueen F, et al. An introduction to the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Ann Rheum Dis. 2005;64(Suppl. 1):i3–7. doi: 10.1136/ard.2004.031773 .

Conaghan PG, Ostergaard M, Bowes MA, Wu C, Fuerst T, van der Heijde D, et al. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis. 2016;75(6):1024–33. doi: 10.1136/annrheumdis-2015-208267 .

Wollenhaupt J, Silverfield J, Lee EB, 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. doi: 10.3899/jrheum.130683 .

Genovese MC, van Vollenhoven RF, Wilkinson B, et al. Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18:145. doi: 10.1186/s13075-016-1049-3 .

Coates LC, FitzGerald O, Helliwell PS, Paul C. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: is all inflammation the same? Semin Arthritis Rheum. 2016. doi: 10.1016/j.semarthrit.2016.05.012 .

Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol. 2009;129(9):2299–302. doi: 10.1038/jid.2009.25 .

Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167(3):668–77. doi: 10.1111/j.1365-2133.2012.11168.x .

Papp KA, Menter MA, Abe M, 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. doi: 10.1111/bjd.14018 .

Papp KA, Krueger JG, Feldman SR, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-term extension study. J Am Acad Dermatol. 2016. doi: 10.1016/j.jaad.2016.01.013 .

Bachelez H, van de Kerkhof PC, Strohal R, 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. doi: 10.1016/S0140-6736(14)62113-9 .

Caso F, Del Puente A, Peluso R, et al. Emerging drugs for psoriatic arthritis. Exp Opin Emerg Drugs. 2016;21(1):69–79. doi: 10.1517/14728214.2016.1146679 .

Danehy S. Pfizer announces positive top-line results from the first phase 3 trial of investigational tofacitinib in adults with psoriatic arthritis. 2016. http://www.businesswire.com/news/home/20160405005842/en/Pfizer-Announces-Positive-Top-Line-Results-Phase-3 . Accessed 1 May 2016.

Asahina A, Etoh T, Igarashi A, et al. Oral tofacitinib efficacy, safety and tolerability in Japanese patients with moderate to severe plaque psoriasis and psoriatic arthritis: a randomized, double-blind, phase 3 study. J Dermatol. 2016. doi: 10.1111/1346-8138.13258 .

Braun J, Kiltz U, Heldmann F, Baraliakos X. Emerging drugs for the treatment of axial and peripheral spondyloarthritis. Exp Opin Emerg Drugs. 2015;20(1):1–14. doi: 10.1517/14728214.2015.993378 .

Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5):329–42. doi: 10.1038/nri3661 .

Akiho H, Yokoyama A, Abe S, et al. Promising biological therapies for ulcerative colitis: a review of the literature. World J Gastrointest Pathophysiol. 2015;6(4):219–27. doi: 10.4291/wjgp.v6.i4.219 .

Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616–24. doi: 10.1056/NEJMoa1112168 .

Panes J, Su C, Bushmakin AG, Cappelleri JC, et al. Randomized trial of tofacitinib in active ulcerative colitis: analysis of efficacy based on patient-reported outcomes. BMC Gastroenterol. 2015;15:14. doi: 10.1186/s12876-015-0239-9 .

Pfizer (PFE)’s oral tofacitinib meets primary and key secondary endpoints in two late-stage trials. 2016. http://www.biospace.com/News/pfizers-oral-tofacitinib-meets-primary-and-key/412814 . Accessed 18 Mar 2016.

Nielsen OH, Seidelin JB, Ainsworth M, Coskun M. Will novel oral formulations change the management of inflammatory bowel disease? Exp Opin Invest Drugs. 2016. doi: 10.1517/13543784.2016.1165204 .

Sandborn WJ, Ghosh S, Panes J, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2014;12(9):1485–n93 e2. doi: 10.1016/j.cgh.2014.01.029 .

Panés J, Sandborn WJ, Schreiber S, et al., editors. OP021 Efficacy and safety of oral tofacitinib for induction therapy in patients with moderate-to-severe Crohns disease: results of a phase 2b randomised placebo-controlled trial. 11th Congress of European Crohns and Colitis Organization, 2016, Amsterdam.

D’Haens G, Higgins PDR, Colombel J-F, et al., editors. OP022 efficacy and safety of oral tofacitinib for maintenance therapy in patients with moderate-to-severe Crohns disease: results of a phase 2b randomised placebo-controlled trial. 11th Congress of European Crohn’s and Colitis Organization, 2016, Amsterdam.

Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10(2):127–40. doi: 10.1038/nrd3264 .

Deisseroth A, Kaminskas E, Grillo J, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212–7. doi: 10.1158/1078-0432.CCR-12-0653 .

Srdan Verstovsek M, Passamonti F, Rambaldi A, et al., editors. Long-term results from a phase II open-label study of ruxolitinib in patients with essential thrombocythemia refractory to or intolerant of hydroxyurea. 56th American Society of Hematology Annual Meeting and Exposition, 2014, San Francisco (CA).

FDA grants breakthrough therapy designation for Incyte’s ruxolitinib (Jakafi®) in acute graft-versus-host disease (GVHD). 2016. http://www.businesswire.com/news/home/20160623005540/en/FDA-Grants-Breakthrough-Therapy-Designation-Incyte%E2%80%99s-Ruxolitinib . Accessed 1 July 2016.

Shi JG, Chen X, Emm T, et al. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol. 2012;52(6):809–18. doi: 10.1177/0091270011405663 .

Shi JG, Fraczkiewicz G, Williams WV, Yeleswaram S. Predicting drug-drug interactions involving multiple mechanisms using physiologically based pharmacokinetic modeling: a case study with ruxolitinib. Clin Pharmacol Ther. 2015;97(2):177–85. doi: 10.1002/cpt.30 .

MacFarlane LA, Todd DJ. Kinase inhibitors: the next generation of therapies in the treatment of rheumatoid arthritis. Int J Rheum Dis. 2014;17(4):359–68. doi: 10.1111/1756-185X.12293 .

Wenzel J, van Holt N, Maier J, et al. JAK-1/2 inhibitor ruxolitinib controls a case of chilblain lupus erythematosus. J Invest Dermatol. 2016. doi: 10.1016/j.jid.2016.02.015 .

Hornung T, Janzen V, Heidgen FJ, et al. Remission of recalcitrant dermatomyositis treated with ruxolitinib. N Engl J Med. 2014;371(26):2537–8. doi: 10.1056/NEJMc1412997 .

Xing L, Dai Z, Jabbari A, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nature Med. 2014;20(9):1043–9. doi: 10.1038/nm.3645 .

Klaeschen AS, Wenzel J. Upcoming therapeutic targets in cutaneous lupus erythematous. Exp Rev Clin Pharmacol. 2016:1–12. doi: 10.1586/17512433.2016.1145543 .

Punwani N, Scherle P, Flores R, 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. doi: 10.1016/j.jaad.2011.12.018 .

Craiglow BG, Tavares D, King BA. Topical Ruxolitinib for the Treatment of Alopecia Universalis. JAMA Dermatol. 2016;152(4):490–1. doi: 10.1001/jamadermatol.2015.4445 .

Norman P. Selective JAK inhibitors in development for rheumatoid arthritis. Exp Opin Invest Drugs. 2014;23(8):1067–77. doi: 10.1517/13543784.2014.918604 .

Shi JG, Chen X, Lee F, et al. The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers. J Clin Pharmacol. 2014;54(12):1354–61. doi: 10.1002/jcph.354 .

Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rhem Dis. 2015;74(2):333–40. doi: 10.1136/annrheumdis-2014-206478 .

Tanaka Y, Emoto K, Cai Z, et al. Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J Rheumatol. 2016;43(3):504–11. doi: 10.3899/jrheum.150613 .

van Vollenhoven RF. Small molecular compounds in development for rheumatoid arthritis. Curr Opin Rheumatol. 2013;25(3):391–7. doi: 10.1097/BOR.0b013e32835fd828 .

Fleischmann R TT, Schlichting DE, Macias WL, et al. Baricitinib, methotrexate, or baricitinib plus methotrexate in patients with early rheumatoid arthritis who had received limited or no treatment with disease-modifying anti-rheumatic drugs (DMARDs): phase 3 trial results [abstract]. Arthritis Rheumatol. 2015;67(Suppl. 10).

Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243–52. doi: 10.1056/NEJMoa1507247 .

Dougados M, van der Heijde D, Chen Y-C, et al. LB0001 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(Suppl. 2):79.

Taylor PCKE, van der Heijde D, Tanaka Y, et al. Baricitinib versus placebo or adalimumab in patients with active rheumatoid arthritis (RA) and an inadequate response to background methotrexate therapy: results of a phase 3 study [abstract]. Arthritis Rheumatol. 2015;67(Suppl. 10):2015.

Walsh N. Swift response seen for baricitinib in RA: response by week four predicts subsequent low disease activity, remission. 2016.

Emery P, Gaich CL, DeLozier AM, et al. Patient-reported outcomes from a phase 3 study of baricitinib in patients with rheumatoid arthritis with inadequate response to conventional synthetic disease-modifying antirheumatic drugs. 2015 ACR/ARHP Annual Meeting, 29 Sep 2015, San Francisco (CA). Arthritis Rheumatol. 2015.

Papp K, Menter MA, Raman M, et al. A randomized phase 2b trial of baricitinib, an oral JAK1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis. Br J Dermatol. 2016. doi: 10.1111/bjd.14403 .

Montealegre AR, Brogan P, Berkun Y, et al. Preliminary response to Janus kinase inhibition with baricitinib in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE). 8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases. Pediatric Rheumatol. 2015.

Jabbari A, Dai Z, Xing L, et al. Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib. EBioMedicine. 2015;2(4):351–5. doi: 10.1016/j.ebiom.2015.02.015 .

Saridomichelakis MN, Olivry T. An update on the treatment of canine atopic dermatitis. Veterinary J. 2016;207:29–37. doi: 10.1016/j.tvjl.2015.09.016 .

Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. J Am Acad Dermatol. 2015;73(3):395–9. doi: 10.1016/j.jaad.2015.06.045 .

Strand V, Ahadieh S, French J, 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. doi: 10.1186/s13075-015-0880-2 .

Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(10):2675–84. doi: 10.1002/art.38745 .

Curtis JR, Xie F, Yun H, et al. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016. doi: 10.1136/annrheumdis-2016-209131 .

Busque S, Leventhal J, Brennan DC, et al. Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients. Am J Transplant. 2009;9(8):1936–45. doi: 10.1111/j.1600-6143.2009.02720.x .

Vincenti F, Tedesco Silva H, Busque S, et al. Randomized phase 2b trial of tofacitinib (CP-690,550) in de novo kidney transplant patients: efficacy, renal function and safety at 1 year. Am J Transplant. 2012;12(9):2446–56. doi: 10.1111/j.1600-6143.2012.04127.x .

Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N Engl J Med. 2013;369(2):197–8. doi: 10.1056/NEJMc1302135 .

Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases: elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25. doi: 10.1016/j.coi.2014.01.004 .

Vincenti F, Silva HT, Busque S, et al. Evaluation of the effect of tofacitinib exposure on outcomes in kidney transplant patients. Am J Transplant. 2015;15(6):1644–53. doi: 10.1111/ajt.13181 .

Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum. 2016. doi: 10.1016/j.semarthrit.2016.05.014 .

Scheller J, Garbers C, Rose-John S. Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol. 2014;26(1):2–12. doi: 10.1016/j.smim.2013.11.002 .

Wu JJ, Strober BE, Hansen PR, 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. doi: 10.1016/j.jaad.2016.06.012 .

Kume K, Amano K, Yamada S, et al. Tofacitinib improves arterial stiffness despite up-regulating serum cholesterol with chronic cardiovascular disease in methotrexate-resistant active rheumatoid arthritis patients: a cohort study. 2014 ACR/ARHP Annual Meeting, Boston (MA), 2014.

Charles-Schoeman C, Fleischmann R, Davignon J, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatol. 2015;67(3):616–25. doi: 10.1002/art.38974 .

Kremer JM, Kivitz AJ, Simon-Campos JA, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther. 2015;17:95. doi: 10.1186/s13075-015-0612-7 .

Mahajan S, Hogan JK, Shlyakhter D, et al. VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. J Pharmacol Exp Ther. 2015;353(2):405–14. doi: 10.1124/jpet.114.221176 .

Gadina M, Schwartz DM, O’Shea JJ. Editorial: decernotinib. A next-generation Jakinib. Arthritis Rheumatol. 2016;68(1):31–4. doi: 10.1002/art.39463 .

Huang JYJ, Yogaratnam J, Shen J. The effect of deuteration of VX-509 (Decernotinib) on drug–drug interactions (DDI) with midazolam. Ann Rheum Dis. 2015;74(Suppl. 2):740.

Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev. 1997;29(1–2):413–580.

Genovese MC, van Vollenhoven RF, Pacheco-Tena C, et al. VX-509 (decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):46–55. doi: 10.1002/art.39473 .

Hirota T, Ieiri I. Drug-drug interactions that interfere with statin metabolism. Exp Opin Drug Metab Toxicol. 2015;11(9):1435–47. doi: 10.1517/17425255.2015.1056149 .

Fleischmann RM, Damjanov NS, Kivitz AJ, et al. A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis. Arthritis Rheum. 2015;67(2):334–43. doi: 10.1002/art.38949 .

Genovese MC, Yang F, Ostergaard M, Kinnman N. Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Ann Rheum Dis. 2016;75(11):1979–83. doi: 10.1136/annrheumdis-2015-208901 .

Namour F, Desrivot J, Van der Aa A, et al. Clinical confirmation that the selective JAK1 inhibitor filgotinib (GLPG0634) has a low liability for drug-drug interactions. Drug Metab Lett. 2016;10(1):38–48.

Namour F, Diderichsen PM, Cox E, et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic modeling of filgotinib (GLPG0634), a selective JAK1 inhibitor, in support of phase IIB dose selection. Clin Pharmacokin. 2015;54(8):859–74. doi: 10.1007/s40262-015-0240-z .

Chantal Tasset PH, Annegret Van der Aa, Meuleners L, et al., editors. The JAK1-selective inhibitor GLPG0634 is safe and rapidly reduces disease activity in patients with moderate to severe rheumatoid arthritis; results of a 4-week dose ranging study. American College of Rheumatology Meeting, 2013.

Kavanaugh A, Ponce L, Cseuz R, Reshetko O, et al. Filgotinib (GLPG0634), an oral JAK1 selective inhibitor is effective as monotherapy in patients with active rheumatoid arthritis: results from a phase 2B dose ranging study [abstract]. Arthritis Rheuml. 2015;67(Suppl. 10).

Westhovens R, Alten R, Pavlova D, Enríquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P. Filgotinib (GLPG0634), an oral JAK1 selective inhibitor is effective in combination with methotrexate in patients with active rheumatoid arthritis: results from a phase 2B dose ranging study [abstract]. Arthritis Rheumatol. 2015;67(Suppl 10).

Efficacy and safety of GLPG0634 in subjects with active Crohn’s disease. 2016.

Vermeire S, Schreiber S, Petryka R, et al. Filgotinib (GLPG0634), an oral JAK1 selective inhibitor, induces clinical remission in patients with moderate-to-severe Crohn’s disease: results from the phase 2 FITZROY study interim analysis. Gastroenterology. 2016;150(4 Suppl. 1):S1267.

Galapagos. GLPG0778/555. Immuno and Inflammatory. http://www.glpg.com/glpg-0778-555 . 2016.

Voss J, Graff C, Schwartz A, et al. THU0127 pharmacodynamics of a novel JAK1 selective inhibitor in rat arthritis and anemia models and in healthy human subjects. EULAR 06.12.2014, Paris, France. Ann Rheum Dis. 2014;222.

Kremer JM, Emery P, Camp HS, et al. A phase 2b study of ABT-494, a selective JAK1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy. Arthritis Rheum. 2016. doi: 10.1002/art.39801 .

Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, et al. A randomized phase 2b study of ABT-494, a selective JAK1 inhibitor in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol. 2016;75(6):1024–33. doi: 10.1002/art.39808 .

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. doi: 10.1136/annrheumdis-2015-208279 .

Oda K, Cao YJ, Sawamoto T, et al. Human mass balance, metabolite profile and identification of metabolic enzymes of [(1)(4)C]ASP015K, a novel oral Janus kinase inhibitor. Xenobiotica. 2015;45(10):887–902. doi: 10.3109/00498254.2015.1026864 .

Yamazaki S, Inami M, Ito M, et al. ASP015K: a novel JAK inhibitor demonstrated potent efficacy in adjuvant-induced arthritis model in rats. Arthritis Rheum. 2012;64(Suppl. 10):2084.

Papp K, Pariser D, Catlin M, 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. doi: 10.1111/bjd.13745 .

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 2a study. Br J Dermatol. 2016;174(5):985–95. doi: 10.1111/bjd.14399 .

van Vollenhoven RF, Layton M, Kahl L, et al. DRESS syndrome and reversible liver function abnormalities in patients with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. Lupus. 2015;24(6):648–9. doi: 10.1177/0961203315573347 .

Kahl L, Patel J, Layton M, Binks M, Hicks K, Leon G, et al. Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus. 2016;25(13):1420–30. doi: 10.1177/0961203316640910 .

Bissonnette R, Luchi M, Fidelus-Gort 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 Dermatol Treat. 2016:1–7. doi: 10.3109/09546634.2015.1115819 .

Yiu ZZ, Warren RB. Novel oral therapies for psoriasis and psoriatic arthritis. Am J Clin Dermatol. 2016;17(3):191–200. doi: 10.1007/s40257-016-0179-3 .

Luchi M, Fidelus-Gort R, Douglas D, et al. A randomized, dose-ranging, placebo-controlled, 84-day study Of INCB039110, a selective Janus kinase-1 inhibitor, in patients with active rheumatoid arthritis [abstract]. Arthritis Rheum. 2013;65(Suppl. 10):1797.

Park JS, Kwok SK, Lim MA, et al. STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheum. 2014;66(4):918–29. doi: 10.1002/art.38305 .

Nowell MA, Richards PJ, Fielding CA, et al. Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 2006;54(7):2084–95. doi: 10.1002/art.21942 .

Shim SH, Sung MW, Park SW, Heo DS. Absence of STAT1 disturbs the anticancer effect induced by STAT3 inhibition in head and neck carcinoma cell lines. Int J Mol Med. 2009;23(6):805–10.

Yesylevskyy SO, Ramseyer C, Pudlo M, et al. Selective inhibition of STAT3 with respect to STAT1: insights from molecular dynamics and ensemble docking simulations. J Chem Info Model. 2016;56(8):1588–96. doi: 10.1021/acs.jcim.6b00198 .

Costa-Pereira AP, Tininini S, Strobl B, et al. Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc Natl Acad Sci USA. 2002;99(12):8043–7. doi: 10.1073/pnas.122236099 .

Okusaka T, Ueno H, Ikeda M, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res. 2015;45(13):1283–91. doi: 10.1111/hepr.12504 .

Ogura M, Uchida T, Terui Y, et al. Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci. 2015;106(7):896–901. doi: 10.1111/cas.12683 .

Mandal PK, Morlacchi P, Knight JM, et al. Targeting the Src homology 2 (SH2) domain of signal transducer and activator of transcription 6 (STAT6) with cell-permeable, phosphatase-stable phosphopeptide mimics potently inhibits Tyr641 phosphorylation and transcriptional activity. J Med Chem. 2015;58(22):8970–84. doi: 10.1021/acs.jmedchem.5b01321 .

Koo MY, Park J, Lim JM, et al. Selective inhibition of the function of tyrosine-phosphorylated STAT3 with a phosphorylation site-specific intrabody. Proc Natl Acad Sci USA. 2014;111(17):6269–74. doi: 10.1073/pnas.1316815111 .

Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, et al. Tofacitinib ameliorates murinelupus and its associated vascular dysfunction. Arthritis Rheum. 2016;69(1):148–60. doi: 10.1002/art.39818 .

Jabbari A, Nguyen N, Cerise JE, et al. Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers. Exp Dermatol. 2016;25(8):642–3. doi: 10.1111/exd.13060 .

Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol. 2016;74(2):370–1. doi: 10.1016/j.jaad.2015.09.073 .

Harel S, Higgins CA, Cerise JE, et al. Pharmacologic inhibition of JAK–STAT signaling promotes hair growth. Sci Adv. 2015;1(9):e1500973. doi: 10.1126/sciadv.1500973 .

O’Shea JJ, Kanno Y, Chan AC. In search of magic bullets: the golden age of immunotherapeutics. Cell. 2014;157(1):227–40. doi: 10.1016/j.cell.2014.03.010 .

Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, et al. Discovery of a JAK3-selective inhibitor: functional differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition. ACS Chem Biol. 2016;11(12):3442–51. doi: 10.1021/acschembio.6b00677 .

Wiegman CH, Adcock IM, Rothaul A, Main M, Morgan F. The Selective Pan-Janus Kinase (jak) Inhibitor Vr588 demonstrates potent anti-inflammatory activity in a murine chronic house dust mite (hdm) model of asthma (Abstract). J Aerosol Med Pulmonary Drug Delivery. 2015;28(3):A22–3.

Wu H, Yan S, Chen J, Luo X, Li P, Jia X, et al. JAK1-STAT3 blockade by JAK inhibitor SHR0302 attenuates inflammatory responses of adjuvant-induced arthritis rats and decreases Th17 and total B cells. Joint Bone Spine. 2016;83(5):525–32. doi: 10.1016/j.jbspin.2015.09.002 .

SHR 0302. Jiangsu Hengrui Medicine Co. http://adisinsight.springer.com/drugs/800042343 . Accessed 20 Feb 2017.

JTE 052. Originator: Japan Tobacco. http://adisinsight.springer.com/drugs/800035951 . Accessed 20 Feb 2017.