JAK Inhibitors: Prospects in Connective Tissue Diseases

Abstract

The dysregulation of the JAK–STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous JAK inhibitors are currently being tested in phase II and III trials for the treatment of various autoimmune inflammatory diseases. In this narrative review, we elucidate the involvement of the JAK–STAT signaling pathway in the pathogenesis of connective tissue diseases (CTDs). We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren’s syndrome, and vasculitis, based on laboratory and clinical research findings. JAK inhibitors have great potential for the treatment of various CTDs by reducing multiple cytokine production and suppressing inflammation, with the advantages of rapid onset in an oral formulation and decreased corticosteroid dependence and the associated adverse events, especially in refractory cases. We also highlight the safety of novel JAK inhibitors, which can cause opportunistic infections, especially viral infections. Being a very recent therapeutic option, information regarding the safety of JAK inhibitors during pregnancy and for pediatric use is limited. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Mok CC (2019) The Jakinibs in systemic lupus erythematosus: progress and prospects. Expert Opin Investig Drugs 28(1):85–92. https://doi.org/10.1080/13543784.2019.1551358

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Choy EH (2019) Clinical significance of Janus Kinase inhibitor selectivity. Rheumatology 58(6):953–962. https://doi.org/10.1093/rheumatology/key339

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Gadina M, Johnson C, Schwartz D, Bonelli M, Hasni S, Kanno Y, Changelian P, Laurence A, O'Shea JJ (2018) Translational and clinical advances in JAK-STAT biology: the present and future of jakinibs. J Leukoc Biol 104(3):499–514. https://doi.org/10.1002/JLB.5RI0218-084R

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ (2018) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17(1):78. https://doi.org/10.1038/nrd.2017.267

    CAS  Article  Google Scholar 

  5. 5.

    O'Shea JJ, Gadina M (2019) Selective Janus kinase inhibitors come of age. Nat Rev Rheumatol 15(2):74–75. https://doi.org/10.1038/s41584-018-0155-9

    Article  PubMed  Google Scholar 

  6. 6.

    Baker KF, Isaacs JD (2017) Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2017-211555

  7. 7.

    Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes J, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-Roth A, Saag K, Da SJ, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76(6):960–977. https://doi.org/10.1136/annrheumdis-2016-210715

    Article  PubMed  Google Scholar 

  8. 8.

    Singh JA, Saag KG, Bridges SJ, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, St CE, Tindall E, Miller AS, McAlindon T (2016) 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Care Res 68(1):1–25. https://doi.org/10.1002/acr.22783

    Article  Google Scholar 

  9. 9.

    Markham A (2017) Baricitinib: first global approval. Drugs 77(6):697–704. https://doi.org/10.1007/s40265-017-0723-3

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Clark JD, Flanagan ME, Telliez JB (2014) Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem 57(12):5023–5038. https://doi.org/10.1021/jm401490p

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Duggan S, Keam SJ (2019) Upadacitinib: first approval. Drugs. https://doi.org/10.1007/s40265-019-01211-z

  12. 12.

    Markham A, Keam SJ (2019) Peficitinib: first global approval. Drugs 79(8):887–891. https://doi.org/10.1007/s40265-019-01131-y

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Ikeda K, Hayakawa K, Fujishiro M, Kawasaki M, Hirai T, Tsushima H, Miyashita T, Suzuki S, Morimoto S, Tamura N, Takamori K, Ogawa H, Sekigawa I (2017) JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation. BMC Immunol 18(1). https://doi.org/10.1186/s12865-017-0225-9

  14. 14.

    Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, Zarzour A, Sciumè G, Tsai WL, Trier AM, Nunez L, Mast L, Hoffmann V, Remaley AT, O'Shea JJ, Kaplan MJ, Gadina M (2017) Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheum 69(1):148–160. https://doi.org/10.1002/art.39818

    CAS  Article  Google Scholar 

  15. 15.

    Ripoll E, de Ramon L, Draibe BJ, Merino A, Bolanos N, Goma M, Cruzado JM, Grinyo JM, Torras J (2016) JAK3-STAT pathway blocking benefits in experimental lupus nephritis. Arthritis Res Ther 18(1):134. https://doi.org/10.1186/s13075-016-1034-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Yamamoto M, Yokoyama Y, Shimizu Y, Yajima H, Sakurai N, Suzuki C, Naishiro Y, Takahashi H (2016) Tofacitinib can decrease anti-DNA antibody titers in inactive systemic lupus erythematosus complicated by rheumatoid arthritis. Mod Rheumatol 26(4):633–634. https://doi.org/10.3109/14397595.2015.1069473

    Article  PubMed  Google Scholar 

  17. 17.

    You H, Zhang G, Wang Q, Zhang S, Zhao J, Tian X, Li H, Li M, Zeng X (2019) Successful treatment of arthritis and rash with tofacitinib in systemic lupus erythematosus: the experience from a single centre. Ann Rheum Dis 78(10):1441–1443. https://doi.org/10.1136/annrheumdis-2019-215455

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Chan ES, Herlitz LC, Jabbari A (2015) Ruxolitinib attenuates cutaneous lupus development in a mouse lupus model. J Invest Dermatol 135(7):1912–1915. https://doi.org/10.1038/jid.2015.107

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    de la Varga MR, Rodriguez-Bayona B, Anez GA, Medina VF, Perez VJ, Brieva JA, Rodriguez C (2017) Clinical relevance of circulating anti-ENA and anti-dsDNA secreting cells from SLE patients and their dependence on STAT-3 activation. Eur J Immunol 47(7):1211–1219. https://doi.org/10.1002/eji.201646872

    CAS  Article  Google Scholar 

  20. 20.

    Klaeschen AS, Wolf D, Brossart P, Bieber T, Wenzel J (2017) JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus. Exp Dermatol 26(8):728–730. https://doi.org/10.1111/exd.13253

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Wenzel J, van Holt N, Maier J, Vonnahme M, Bieber T, Wolf D (2016) JAK1/2 inhibitor ruxolitinib controls a case of chilblain lupus erythematosus. J Invest Dermatol 136(6):1281–1283. https://doi.org/10.1016/j.jid.2016.02.015

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Ladislau L, Suarez-Calvet X, Toquet S, Landon-Cardinal O, Amelin D, Depp M, Rodero MP, Hathazi D, Duffy D, Bondet V, Preusse C, Bienvenu B, Rozenberg F, Roos A, Benjamim CF, Gallardo E, Illa I, Mouly V, Stenzel W, Butler-Browne G, Benveniste O, Allenbach Y (2018) JAK inhibitor improves type I interferon induced damage: proof of concept in dermatomyositis. Brain 141(6):1609–1621. https://doi.org/10.1093/brain/awy105

    Article  PubMed  Google Scholar 

  23. 23.

    Hornung T, Janzen V, Heidgen FJ, Wolf D, Bieber T, Wenzel J (2014) Remission of recalcitrant dermatomyositis treated with ruxolitinib. N Engl J Med 371(26):2537–2538. https://doi.org/10.1056/NEJMc1412997

    Article  PubMed  Google Scholar 

  24. 24.

    Aeschlimann FA, Frémond M, Duffy D, Rice GI, Charuel J, Bondet V, Saire E, Neven B, Bodemer C, Balu L, Gitiaux C, Crow YJ, Bader-Meunier B (2018) A child with severe juvenile dermatomyositis treated with ruxolitinib. Brain 141(11):e80. https://doi.org/10.1093/brain/awy255

    Article  PubMed  Google Scholar 

  25. 25.

    Wang K, Zhao J, Chen Z, Li T, Tan X, Zheng Y, Gu L, Guo L, Sun F, Wang H, Li J, Wang X, Riemekasten G, Ye S (2019) CD4+CXCR4+ T cells as a novel prognostic biomarker in patients with idiopathic inflammatory myopathy-associated interstitial lung disease. Rheumatology (Oxford) 58(3):557. https://doi.org/10.1093/rheumatology/key425

    Article  Google Scholar 

  26. 26.

    Kurasawa K, Arai S, Namiki Y, Tanaka A, Takamura Y, Owada T, Arima M, Maezawa R (2018) Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis. Rheumatology (Oxford) 57(12):2114–2119. https://doi.org/10.1093/rheumatology/key188

    CAS  Article  Google Scholar 

  27. 27.

    Chen Z, Wang X, Ye S (2019) Tofacitinib in amyopathic dermatomyositis-associated interstitial lung disease. N Engl J Med 381(3):291–293. https://doi.org/10.1056/NEJMc1900045

    Article  PubMed  Google Scholar 

  28. 28.

    Papadopoulou C, Hong Y, Omoyinmi E, Brogan PA, Eleftheriou D (2019) Janus kinase 1/2 inhibition with baricitinib in the treatment of juvenile dermatomyositis. Brain 142(3):e8. https://doi.org/10.1093/brain/awz005

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Kurtzman DJ, Wright NA, Lin J, Femia AN, Merola JF, Patel M, Vleugels RA (2016) Tofacitinib citrate for refractory cutaneous dermatomyositis: an alternative treatment. JAMA Dermatol 152(8):944–945. https://doi.org/10.1001/jamadermatol.2016.0866

    Article  PubMed  Google Scholar 

  30. 30.

    Paik JJ, Christopher-Stine L (2017) A case of refractory dermatomyositis responsive to tofacitinib. Semin Arthritis Rheum 46(4):e19. https://doi.org/10.1016/j.semarthrit.2016.08.009

    Article  PubMed  Google Scholar 

  31. 31.

    Siamak Moghadam-Kia DCRA (2019) Management of refractory cutaneous dermatomyositis: potential role of Janus kinase inhibition with tofacitinib. Rheumatology. https://doi.org/10.1093/rheumatology/key366

  32. 32.

    Wendel S, Venhoff N, Frye BC, May AM, Agarwal P, Rizzi M, Voll RE, Thiel J (2019) Successful treatment of extensive calcifications and acute pulmonary involvement in dermatomyositis with the Janus-kinase inhibitor tofacitinib – a report of two cases. J Autoimmun 100:131–136. https://doi.org/10.1016/j.jaut.2019.03.003

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Babaoglu H, Varan O, Atas N, Satis H, Salman R, Tufan A (2018) Tofacitinib for the treatment of refractory polymyositis. J Clin Rheumatol. https://doi.org/10.1097/RHU.0000000000000807

  34. 34.

    Komai T, Shoda H, Hanata N, Fujio K (2018) Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis. Scand J Rheumatol 47(6):505–506. https://doi.org/10.1080/03009742.2017.1387673

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Dees C, Tomcik M, Palumbo-Zerr K, Distler A, Beyer C, Lang V, Horn A, Zerr P, Zwerina J, Gelse K, Distler O, Schett G, Distler JH (2012) JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor beta in systemic sclerosis. Arthritis Rheum 64(9):3006–3015. https://doi.org/10.1002/art.34500

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Lee J, Lee J, Kwok SK, Baek S, Jang SG, Hong SM, Min JW, Choi SS, Lee J, Cho ML, Park SH (2018) JAK-1 inhibition suppresses interferon-induced BAFF production in human salivary gland: potential therapeutic strategy for primary Sjogren’s syndrome. Arthritis Rheum 70(12):2057–2066. https://doi.org/10.1002/art.40589

    CAS  Article  Google Scholar 

  37. 37.

    Zhang H, Watanabe R, Berry GJ, Tian L, Goronzy JJ, Weyand CM (2018) Inhibition of JAK-STAT signaling suppresses pathogenic immune responses in medium and large vessel vasculitis. Circulation 137(18):1934–1948. https://doi.org/10.1161/CIRCULATIONAHA.117.030423

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Rimar D, Alpert A, Starosvetsky E, Rosner I, Slobodin G, Rozenbaum M, Kaly L, Boulman N, Awisat A, Ginsberg S, Zilber K, Shen-Orr SS (2016) Tofacitinib for polyarteritis nodosa: a tailored therapy. Ann Rheum Dis 75(12):2214–2216. https://doi.org/10.1136/annrheumdis-2016-209330

    Article  PubMed  Google Scholar 

  39. 39.

    Meshkov AD, Novikov PI, Zhilyaev EV, Ilevsky I, Moiseev SV (2019) Tofacitinib in steroid-dependent relapsing polychondritis. Ann Rheum Dis 78(7):e72. https://doi.org/10.1136/annrheumdis-2018-213554

    Article  PubMed  Google Scholar 

  40. 40.

    McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365(23):2205–2219. https://doi.org/10.1056/NEJMra1004965

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Guimaraes PM, Scavuzzi BM, Stadtlober NP, Franchi SL, Lozovoy M, Iriyoda T, Costa NT, Reiche E, Maes M, Dichi I, Simao A (2017) Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles. Immunol Cell Biol 95(9):824–831. https://doi.org/10.1038/icb.2017.53

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Lundberg MZAI (2011) Pathogenesis, classification and treatment of inflammatory myopathies. Nat Rev Rheumatol 7(5):293–306

    Google Scholar 

  43. 43.

    Raja J, Denton CP (2015) Cytokines in the immunopathology of systemic sclerosis. Semin Immunopathol 37(5):543–557. https://doi.org/10.1007/s00281-015-0511-7

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Psianou K, Panagoulias I, Papanastasiou AD, de Lastic A, Rodi M, Spantidea PI, Degn SE, Georgiou P, Mouzaki A (2018) Clinical and immunological parameters of Sjögren’s syndrome. Autoimmun Rev 17(10):1053–1064. https://doi.org/10.1016/j.autrev.2018.05.005

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Burja B, Kuret T, Sodin-Semrl S, Lakota K, Rotar Ž, Ješe R, Mrak-Poljšak K, Žigon P, Thallinger GG, Feichtinger J, Čučnik S, Tomšič M, Praprotnik S, Hočevar A (2018) A concise review of significantly modified serological biomarkers in giant cell arteritis, as detected by different methods. Autoimmun Rev 17(2):188–194. https://doi.org/10.1016/j.autrev.2017.11.022

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Nakazawa D, Masuda S, Tomaru U, Ishizu A (2019) Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol 15(2):91–101. https://doi.org/10.1038/s41584-018-0145-y

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Laurent Arnaud AMJH (2014) Pathogenesis of relapsing polychondritis: a 2013 update. Autoimmun Rev 13(2):90–95. https://doi.org/10.1016/j.autrev.2013.07.005

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Lauper K, Mongin D, Iannone F, Kristianslund EK, Kvien TK, Nordstrom DC, Pavelka K, Pombo-Suarez M, Rotar Z, Santos MJ, Codreanu C, Lukina G, Gale SL, John M, Luder Y, Courvoisier DS, Gabay C (2019) Comparative effectiveness of TNF inhibitors and tocilizumab with and without conventional synthetic disease-modifying antirheumatic drugs in a pan-European observational cohort of bio-naive patients with rheumatoid arthritis. Semin Arthritis Rheum. https://doi.org/10.1016/j.semarthrit.2019.06.020

  49. 49.

    Winthrop KL (2017) The emerging safety profile of JAK inhibitors in rheumatic disease. NAT REV. Rheumatol 13(5):320. https://doi.org/10.1038/nrrheum.2017.23

    CAS  Article  Google Scholar 

  50. 50.

    Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K (2010) Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 184(9):5298–5307. https://doi.org/10.4049/jimmunol.0902819

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC (2015) Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 74(2):333–340. https://doi.org/10.1136/annrheumdis-2014-206478

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Tanaka Y, Takeuchi T, Tanaka S, Kawakami A, Iwasaki M, Song YW, Chen YH, Wei JC, Lee SH, Rokuda M, Izutsu H, Ushijima S, Kaneko Y, Akazawa R, Shiomi T, Yamada E (2019) Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3). Ann Rheum Dis 78(10):1320–1332. https://doi.org/10.1136/annrheumdis-2019-215163

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y (2016) 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 75(6):1057–1064. https://doi.org/10.1136/annrheumdis-2015-208279

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C, Harrison P (2017) Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 76(6):998–1008. https://doi.org/10.1136/annrheumdis-2016-210104

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Quintas-Cardama A, Kantarjian H, Cortes J, Verstovsek S (2011) Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov 10(2):127–140. https://doi.org/10.1038/nrd3264

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Genovese MC, van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N (2016) VX-509 (Decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 68(1):46–55. https://doi.org/10.1002/art.39473

    CAS  Article  Google Scholar 

  57. 57.

    Kawasaki M, Fujishiro M, Yamaguchi A, Nozawa K, Kaneko H, Takasaki Y, Takamori K, Ogawa H, Sekigawa I (2011) Possible role of the JAK/STAT pathways in the regulation of T cell-interferon related genes in systemic lupus erythematosus. Lupus 20(12):1231–1239. https://doi.org/10.1177/0961203311409963

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Goropevsek A, Gorenjak M, Gradisnik S, Dai K, Holc I, Hojs R, Krajnc I, Pahor A, Avcin T (2017) Increased levels of STAT1 protein in blood CD4 T cells from systemic lupus erythematosus patients are associated with perturbed homeostasis of activated CD45RA(−)FOXP3(hi) regulatory subset and follow-up disease severity. J Interf Cytokine Res 37(6):254–268. https://doi.org/10.1089/jir.2016.0040

    CAS  Article  Google Scholar 

  59. 59.

    Kubo S, Yamaoka K, Kondo M, Yamagata K, Zhao J, Iwata S, Tanaka Y (2014) The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells. Ann Rheum Dis 73(12):2192–2198. https://doi.org/10.1136/annrheumdis-2013-203756

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Kubo S, Nakayamada S, Sakata K, Kitanaga Y, Ma X, Lee S, Ishii A, Yamagata K, Nakano K, Tanaka Y (2018) Janus kinase inhibitor baricitinib modulates human innate and adaptive immune system. Front Immunol 9(1510). https://doi.org/10.3389/fimmu.2018.01510

  61. 61.

    Braunstein I, Klein R, Okawa J, Werth VP (2012) The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br J Dermatol 166(5):971–975. https://doi.org/10.1111/j.1365-2133.2012.10825.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wallace DJ, Furie RA, Tanaka Y, Kalunian KC, Mosca M, Petri MA, Dorner T, Cardiel MH, Bruce IN, Gomez E, Carmack T, DeLozier AM, Janes JM, Linnik MD, de Bono S, Silk ME, Hoffman RW (2018) Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392(10143):222–231. https://doi.org/10.1016/S0140-6736(18)31363-1

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Dorner T, Furie R (2019) Novel paradigms in systemic lupus erythematosus. Lancet 393(10188):2344–2358. https://doi.org/10.1016/S0140-6736(19)30546-X

    Article  PubMed  Google Scholar 

  64. 64.

    Furie R, Werth VP, Merola JF, Stevenson L, Reynolds TL, Naik H, Wang W, Christmann R, Gardet A, Pellerin A, Hamann S, Auluck P, Barbey C, Gulati P, Rabah D, Franchimont N (2019) Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus. J Clin Invest 129(3):1359–1371. https://doi.org/10.1172/JCI124466

    Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Kahl L, Patel J, Layton M, Binks M, Hicks K, Leon G, Hachulla E, Machado D, Staumont-Salle D, Dickson M, Condreay L, Schifano L, Zamuner S, van Vollenhoven RF (2016) Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus. Lupus 25(13):1420–1430. https://doi.org/10.1177/0961203316640910

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    J. K. Presto LGOR (2018) Computerized planimetry to assess clinical responsiveness in a phase II randomized trial of topical R333 for discoid lupus erythematosus. Br J Dermatol. https://doi.org/10.1111/bjd.16337

  67. 67.

    Kato M, Ikeda K, Kageyama T, Kasuya T, Kumagai T, Furuya H, Furuta S, Tamachi T, Suto A, Suzuki K, Nakajima H (2019) Successful treatment for refractory interstitial lung disease and pneumomediastinum with multidisciplinary therapy including tofacitinib in a patient with anti-MDA5 antibody-positive dermatomyositis. J Clin Rheumatol. https://doi.org/10.1097/RHU.0000000000000984

  68. 68.

    van Vollenhoven RF, Layton M, Kahl L, Schifano L, Hachulla E, Machado D, Staumont-Salle D, Patel J (2015) DRESS syndrome and reversible liver function abnormalities in patients with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. Lupus 24(6):648–649. https://doi.org/10.1177/0961203315573347

    Article  PubMed  Google Scholar 

  69. 69.

    Greenberg SA (2014) Sustained autoimmune mechanisms in dermatomyositis. J Pathol 233(3):215–216. https://doi.org/10.1002/path.4355

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Moneta GM, Pires Marafon D, Marasco E, Rosina S, Verardo M, Fiorillo C, Minetti C, Bracci Laudiero L, Ravelli A, De Benedetti F, Nicolai R (2019) Muscle expression of type I and type II interferons is increased in juvenile dermatomyositis and related to clinical and histologic features. Arthritis Rheum 71(6):1011–1021. https://doi.org/10.1002/art.40800

    CAS  Article  Google Scholar 

  71. 71.

    Pinal-Fernandez I, Casal-Dominguez M, Derfoul A, Pak K, Plotz P, Miller FW, Milisenda JC, Grau-Junyent JM, Selva-O'Callaghan A, Paik J, Albayda J, Christopher-Stine L, Lloyd TE, Corse AM, Mammen AL (2019) Identification of distinctive interferon gene signatures in different types of myositis. Neurology 93(12):e1193–e1204. https://doi.org/10.1212/WNL.0000000000008128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Denton CP, Khanna D (2017) Systemic sclerosis. Lancet 390(10103):1685–1699. https://doi.org/10.1016/S0140-6736(17)30933-9

    Article  PubMed  Google Scholar 

  73. 73.

    Cao XY, Zhao JL, Hou Y, Wang FD, Lu ZH (2019) Janus kinase inhibitor tofacitinib is a potential therapeutic option for refractory eosinophilic fasciitis. Clin Exp Rheumatol

  74. 74.

    Kim SR, Charos A, Damsky W, Heald P, Girardi M, King BA (2018) Treatment of generalized deep morphea and eosinophilic fasciitis with the Janus kinase inhibitor tofacitinib. JAAD Case Rep 4(5):443–445. https://doi.org/10.1016/j.jdcr.2017.12.003

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Ciccia F, Rizzo A, Guggino G, Cavazza A, Alessandro R, Maugeri R, Cannizzaro A, Boiardi L, Iacopino DG, Salvarani C, Triolo G (2015) Difference in the expression of IL-9 and IL-17 correlates with different histological pattern of vascular wall injury in giant cell arteritis. Rheumatology (Oxford) 54(9):1596–1604. https://doi.org/10.1093/rheumatology/kev102

    CAS  Article  Google Scholar 

  76. 76.

    Genovese MC, Rubbert-Roth A, Smolen JS, Kremer J, Khraishi M, Gomez-Reino J, Sebba A, Pilson R, Williams S, Van Vollenhoven R (2013) Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol 40(6):768–780. https://doi.org/10.3899/jrheum.120687

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Smolen JS, Genovese MC, Takeuchi T, Hyslop DL, Macias WL, Rooney T, Chen L, Dickson CL, Riddle CJ, Cardillo TE, Ishii T, Winthrop KL (2019) Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J Rheumatol 46(1):7–18. https://doi.org/10.3899/jrheum.171361

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Curtis JR, Xie F, Yang S, Bernatsky S, Chen L, Yun H, Winthrop K (2018) Herpes zoster in tofacitinib: risk is further increased with glucocorticoids but not methotrexate. Arthritis Care Res. https://doi.org/10.1002/acr.23769

  79. 79.

    Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z (2019) Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Ann Rheum Dis 78(8):1048–1054. https://doi.org/10.1136/annrheumdis-2018-214846

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, Issa M, Salinas CA, Saifan C, Zhang X, Cardoso A, Gonzalez-Gay MA, Takeuchi T (2019) Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheum 71(7):1042–1055. https://doi.org/10.1002/art.40841

    CAS  Article  Google Scholar 

  81. 81.

    Clowse MEB, Feldman SR, Isaacs JD, Kimball AB, Strand V, Warren RB, Xibillé D, Chen Y, Frazier D, Geier J, Proulx J, Marren A (2016) Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf 39(8):755–762. https://doi.org/10.1007/s40264-016-0431-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Götestam Skorpen C, Hoeltzenbein M, Tincani A, Fischer-Betz R, Elefant E, Chambers C, Da Silva J, Nelson-Piercy C, Cetin I, Costedoat-Chalumeau N, Dolhain R, Förger F, Khamashta M, Ruiz-Irastorza G, Zink A, Vencovsky J, Cutolo M, Caeyers N, Zumbühl C, Østensen M (2016) The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis 75(5):795–810. https://doi.org/10.1136/annrheumdis-2015-208840

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the Chinese National Key Research R&D Program (grant number 2017YFC0907600, 2008BAI59B02, Chinese National High Technology Research and Development Program, Ministry of Science and Technology (grant number 2012AA02A513), CAMS Innovation Fund for Medical Sciences (grant number CIFMS2019-I2M-2-008) and the Fundamental Research Funds for CAMS&PUMC (grant number 2019PT330004).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Mengtao Li.

Ethics declarations

Competing Interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

You, H., Xu, D., Zhao, J. et al. JAK Inhibitors: Prospects in Connective Tissue Diseases. Clinic Rev Allerg Immunol 59, 334–351 (2020). https://doi.org/10.1007/s12016-020-08786-6

Download citation

Keywords

  • DMARDs (biologic)
  • JAK inhibitor
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Dermatomyositis
  • Systemic sclerosis