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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors

Author(s): Felice Rivellese*, Antonio Lobasso, Letizia Barbieri, Bianca Liccardo, Amato de Paulis and Francesca Wanda Rossi*

Volume 26, Issue 16, 2019

Page: [2823 - 2843] Pages: 21

DOI: 10.2174/0929867325666180209145243

Price: $65

Open Access Journals Promotions 2
Abstract

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis.

Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA.

Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date.

Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA.

Keywords: Rheumatoid arthritis, janus kinase inhibitors, chronic disease, inflammation, drug free remission, hyperplasia.

[1]
Smolen, J.S.; Aletaha, D.; McInnes, I.B. Rheumatoid arthritis. Lancet, 2016, 388(10055), 2023-2038. [http://dx.doi.org/10.1016/S0140-6736(16)30173-8]. [PMID: 27156434].
[2]
Scott, D.L.; Wolfe, F.; Huizinga, T.W. Rheumatoid arthritis. Lancet, 2010, 376(9746), 1094-1108. [http://dx.doi.org/10.1016/S0140-6736(10)60826-4]. [PMID: 20870100].
[3]
Nam, J.L.; Takase-Minegishi, K.; Ramiro, S.; Chatzidionysiou, K.; Smolen, J.S.; van der Heijde, D.; Bijlsma, J.W.; Burmester, G.R.; Dougados, M.; Scholte-Voshaar, M.; van Vollenhoven, R.; Landewé, R. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis., 2017, 76(6), 1113-1136. [http://dx.doi.org/10.1136/annrheumdis-2016-210713]. [PMID: 28283512].
[4]
McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med., 2011, 365(23), 2205-2219. [http://dx.doi.org/10.1056/NEJMra1004965]. [PMID: 22150039].
[5]
Klein, K.; Gay, S. Epigenetics in rheumatoid arthritis. Curr. Opin. Rheumatol., 2015, 27(1), 76-82. [http://dx.doi.org/10.1097/BOR.0000000000000128]. [PMID: 25415526].
[6]
Blüml, S.; Bonelli, M.; Niederreiter, B.; Puchner, A.; Mayr, G.; Hayer, S.; Koenders, M.I.; van den Berg, W.B.; Smolen, J.; Redlich, K. Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum., 2011, 63(5), 1281-1288. [http://dx.doi.org/10.1002/art.30281]. [PMID: 21321928].
[7]
Baxter, D.; McInnes, I.B.; Kurowska-Stolarska, M. Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA. Immunol. Cell Biol., 2012, 90(3), 288-292. [http://dx.doi.org/10.1038/icb.2011.114]. [PMID: 22249200].
[8]
Millar, K.; Lloyd, S.M.; McLean, J.S.; Batty, G.D.; Burns, H.; Cavanagh, J.; Deans, K.A.; Ford, I.; McConnachie, A.; McGinty, A.; Mõttus, R.; Packard, C.J.; Sattar, N.; Shiels, P.G.; Velupillai, Y.N.; Tannahill, C. Personality, socio-economic status and inflammation: cross-sectional, population-based study. PLoS One, 2013, 8(3)e58256 [http://dx.doi.org/10.1371/journal.pone.0058256]. [PMID: 23516457].
[9]
Callahan, L.F.; Pincus, T. Education, self-care, and outcomes of rheumatic diseases: further challenges to the “biomedical model” paradigm. Arthritis Rheumatol., 2016, 68(1), 35-45. [PMID: 26331579].
[10]
Scher, J.U.; Littman, D.R.; Abramson, S.B. Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases. Arthritis Rheumatol., 2016, 68(1), 35-45. [http://dx.doi.org/10.1002/art.39259]. [PMID: 26331579].
[11]
Harre, U.; Georgess, D.; Bang, H.; Bozec, A.; Axmann, R.; Ossipova, E.; Jakobsson, P.J.; Baum, W.; Nimmerjahn, F.; Szarka, E.; Sarmay, G.; Krumbholz, G.; Neumann, E.; Toes, R.; Scherer, H.U.; Catrina, A.I.; Klareskog, L.; Jurdic, P.; Schett, G. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest., 2012, 122(5), 1791-1802. [http://dx.doi.org/10.1172/JCI60975]. [PMID: 22505457].
[12]
Krishnamurthy, A.; Joshua, V.; Haj Hensvold, A.; Jin, T.; Sun, M.; Vivar, N.; Ytterberg, A.J.; Engström, M.; Fernandes-Cerqueira, C.; Amara, K.; Magnusson, M.; Wigerblad, G.; Kato, J.; Jiménez-Andrade, J.M.; Tyson, K.; Rapecki, S.; Lundberg, K.; Catrina, S.B.; Jakobsson, P.J.; Svensson, C.; Malmström, V.; Klareskog, L.; Wähämaa, H.; Catrina, A.I. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis., 2016, 75(4), 721-729. [http://dx.doi.org/10.1136/annrheumdis-2015-208093]. [PMID: 26612338].
[13]
Ummarino, D. Rheumatoid arthritis: ACPA status influences RA development. Nat. Rev. Rheumatol., 2017, 13(8), 450. [PMID: 28660910].
[14]
Angelotti, F.; Parma, A.; Cafaro, G.; Capecchi, R.; Alunno, A.; Puxeddu, I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin. Exp. Rheumatol., 2017, 35(3), 368-378. [PMID: 28631608].
[15]
Paul, B.J.; Kandy, H.I.; Krishnan, V. Pre-rheumatoid arthritis and its prevention. Eur. J. Rheumatol., 2017, 4(2), 161-165. [http://dx.doi.org/10.5152/eurjrheum.2017.16006]. [PMID: 28638695].
[16]
Müller-Ladner, U.; Kriegsmann, J.; Franklin, B.N.; Matsumoto, S.; Geiler, T.; Gay, R.E.; Gay, S. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol., 1996, 149(5), 1607-1615. [PMID: 8909250].
[17]
Rivellese, F.; Nerviani, A.; Rossi, F.W.; Marone, G.; Matucci-Cerinic, M.; de Paulis, A.; Pitzalis, C. Mast cells in rheumatoid arthritis: friends or foes? Autoimmun. Rev., 2017, 16(6), 557-563. [http://dx.doi.org/10.1016/j.autrev.2017.04.001]. [PMID: 28411167].
[18]
Pitzalis, C.; Kelly, S.; Humby, F. New learnings on the pathophysiology of RA from synovial biopsies. Curr. Opin. Rheumatol., 2013, 25(3), 334-344. [http://dx.doi.org/10.1097/BOR.0b013e32835fd8eb]. [PMID: 23492740].
[19]
Feldmann, M.; Maini, S.R. Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol. Rev., 2008, 223, 7-19.http://www.sciencedirect. com/science/article/pii/S0140673616301738?via%3Dihub [http://dx.doi.org/10.1111/j.1600-065X.2008.00626.x].
[20]
O’Shea, J.J.; Laurence, A.; McInnes, I.B. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat. Rev. Rheumatol., 2013, 9(3), 173-182. [http://dx.doi.org/10.1038/nrrheum.2013.7]. [PMID: 23419429].
[21]
Malemud, C.J. Negative Regulators of JAK/STAT Signaling in Rheumatoid Arthritis and Osteoarthritis. Int. J. Mol. Sci., 2017, 18(3)E484 [http://dx.doi.org/10.3390/ijms18030484]. [PMID: 28245561].
[22]
Roskoski, R. Jr Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol. Res., 2016, 111, 784-803. [http://dx.doi.org/10.1016/j.phrs.2016.07.038]. [PMID: 27473820].
[23]
Janku, F. Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients. Cancer Treat. Rev., 2017, 59, 93-101. [http://dx.doi.org/10.1016/j.ctrv.2017.07.005]. [PMID: 28779636].
[24]
Winthrop, K.L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol., 2017, 13(4), 234-243. [http://dx.doi.org/10.1038/nrrheum.2017.23]. [PMID: 28250461].
[25]
Rawlings, J.S.; Rosler, K.M.; Harrison, D.A. The JAK/STAT signaling pathway. J. Cell Sci., 2004, 117(Pt 8), 1281-1283. [http://dx.doi.org/10.1242/jcs.00963]. [PMID: 15020666].
[26]
Villarino, A.V.; Kanno, Y.; O’Shea, J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol., 2017, 18(4), 374-384. [http://dx.doi.org/10.1038/ni.3691]. [PMID: 28323260].
[27]
Yamaoka, K.; Saharinen, P.; Pesu, M.; Holt, V.E., III; Silvennoinen, O.; O’Shea, J.J. The Janus kinases (JAKs). Genome Biol., 2004, 5(12), 253. [http://dx.doi.org/10.1186/gb-2004-5-12-253]. [PMID: 15575979].
[28]
O’Shea, J.J.; Schwartz, D.M.; Villarino, A.V.; Gadina, M.; McInnes, I.B.; Laurence, A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med., 2015, 66, 311-328. [http://dx.doi.org/10.1146/annurev-med-051113-024537]. [PMID: 25587654].
[29]
Macchi, P.; Villa, A.; Giliani, S.; Sacco, M.G.; Frattini, A.; Porta, F.; Ugazio, A.G.; Johnston, J.A.; Candotti, F.; O’Shea, J.J. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature, 1995, 377(6544), 65-68. [http://dx.doi.org/10.1038/377065a0]. [PMID: 7659163].
[30]
van der Heijde, D.; Tanaka, Y.; Fleischmann, R.; Keystone, E.; Kremer, J.; Zerbini, C.; Cardiel, M.H.; Cohen, S.; Nash, P.; Song, Y.W.; Tegzová, D.; Wyman, B.T.; Gruben, D.; Benda, B.; Wallenstein, G.; Krishnaswami, S.; Zwillich, S.H.; Bradley, J.D.; Connell, C.A. 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), 559-570. [http://dx.doi.org/10.1002/art.37816]. [PMID: 23348607].
[31]
Lee, E.B.; Fleischmann, R.; Hall, S.; Wilkinson, B.; Bradley, J.D.; Gruben, D.; Koncz, T.; Krishnaswami, S.; Wallenstein, G.V.; Zang, C.; Zwillich, S.H.; van Vollenhoven, R.F. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med., 2014, 370(25), 2377-2386. [http://dx.doi.org/10.1056/NEJMoa1310476]. [PMID: 24941177].
[32]
Meyer, D.M.; Jesson, M.I.; Li, X.; Elrick, M.M.; Funckes-Shippy, C.L.; Warner, J.D.; Gross, C.J.; Dowty, M.E.; Ramaiah, S.K.; Hirsch, J.L.; Saabye, M.J.; Barks, J.L.; Kishore, N.; Morris, D.L. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J. Inflamm. (Lond.), 2010, 7, 41. [http://dx.doi.org/10.1186/1476-9255-7-41]. [PMID: 20701804].
[33]
Riese, R.J.; Krishnaswami, S.; Kremer, J. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract. Res. Clin. Rheumatol., 2010, 24(4), 513-526. [http://dx.doi.org/10.1016/j.berh.2010.02.003]. [PMID: 20732649].
[34]
Migita, K.; Izumi, Y.; Torigoshi, T.; Satomura, K.; Izumi, M.; Nishino, Y.; Jiuchi, Y.; Nakamura, M.; Kozuru, H.; Nonaka, F.; Eguchi, K.; Kawakami, A.; Motokawa, S. Inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway in rheumatoid synovial fibroblasts using small molecule compounds. Clin. Exp. Immunol., 2013, 174(3), 356-363. [http://dx.doi.org/10.1111/cei.12190]. [PMID: 23968543].
[35]
Rizzi, M.; Lorenzetti, R.; Fischer, K.; Staniek, J.; Janowska, I.; Troilo, A.; Strohmeier, V.; Erlacher, M.; Kunze, M.; Bannert, B.; Kyburz, D.; Voll, R.E.; Venhoff, N.; Thiel, J. Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J. Autoimmun., 2017, 77, 55-66. [http://dx.doi.org/10.1016/j.jaut.2016.10.005]. [PMID: 27793425].
[36]
Yarilina, A.; Xu, K.; Chan, C.; Ivashkiv, L.B. Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum., 2012, 64(12), 3856-3866. [http://dx.doi.org/10.1002/art.37691]. [PMID: 22941906].
[37]
Afrin, L.B.; Fox, R.W.; Zito, S.L.; Choe, L.; Glover, S.C. Successful targeted treatment of mast cell activation syndrome with tofacitinib. Eur. J. Haematol., 2017, 99(2), 190-193. [http://dx.doi.org/10.1111/ejh.12893]. [PMID: 28382662].
[38]
Suurmond, J.; Rivellese, F.; Dorjée, A.L.; Bakker, A.M.; Rombouts, Y.J.; Rispens, T.; Wolbink, G.; Zaldumbide, A.; Hoeben, R.C.; Huizinga, T.W.; Toes, R.E. Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated protein antibodies. Ann. Rheum. Dis., 2015, 74(10), 1915-1923. [http://dx.doi.org/10.1136/annrheumdis-2014-205562]. [PMID: 24818634].
[39]
Rivellese, F.; Suurmond, J.; Habets, K.; Dorjée, A.L.; Ramamoorthi, N.; Townsend, M.J. et al Ability of Interleukin-33- and Immune Complex-Triggered Activation of Human Mast Cells to Down-Regulate Monocyte-Mediated Immune Responses. Arthritis Rheumatol., 2015, 67(9), 2343-53.
[40]
Murakami, K.; Kobayashi, Y.; Uehara, S.; Suzuki, T.; Koide, M.; Yamashita, T.; Nakamura, M.; Takahashi, N.; Kato, H.; Udagawa, N.; Nakamura, Y.A. Jak1/2 inhibitor, baricitinib, inhibits osteoclastogenesis by suppressing RANKL expression in osteoblasts in vitro. PLoS One, 2017, 12(7)e0181126 [http://dx.doi.org/10.1371/journal.pone.0181126]. [PMID: 28708884].
[41]
Fleischmann, R.; Cutolo, M.; Genovese, M.C.; Lee, E.B.; Kanik, K.S.; Sadis, S.; Connell, C.A.; Gruben, D.; Krishnaswami, S.; Wallenstein, G.; Wilkinson, B.E.; Zwillich, S.H. 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), 617-629. [http://dx.doi.org/10.1002/art.33383]. [PMID: 21952978].
[42]
Singh, J.A.; Saag, K.G.; Bridges, S.L., Jr; Akl, E.A.; Bannuru, R.R.; Sullivan, M.C.; Vaysbrot, E.; McNaughton, C.; Osani, M.; Shmerling, R.H.; Curtis, J.R.; Furst, D.E.; Parks, D.; Kavanaugh, A.; O’Dell, J.; King, C.; Leong, A.; Matteson, E.L.; Schousboe, J.T.; Drevlow, B.; Ginsberg, S.; Grober, J.; St Clair, E.W.; Tindall, E.; Miller, A.S.; McAlindon, T. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol., 2016, 68(1), 1-26. [http://dx.doi.org/10.1002/art.39480]. [PMID: 26545940].
[43]
van Vollenhoven, R.F.; Fleischmann, R.; Cohen, S.; Lee, E.B.; García Meijide, J.A.; Wagner, S.; Forejtova, S.; Zwillich, S.H.; Gruben, D.; Koncz, T.; Wallenstein, G.V.; Krishnaswami, S.; Bradley, J.D.; Wilkinson, B. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med., 2012, 367(6), 508-519. [http://dx.doi.org/10.1056/NEJMoa1112072]. [PMID: 22873531].
[44]
Fleischmann, R.; Kremer, J.; Cush, J.; Schulze-Koops, H.; Connell, C.A.; Bradley, J.D.; Gruben, D.; Wallenstein, G.V.; Zwillich, S.H.; Kanik, K.S. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med., 2012, 367(6), 495-507. [http://dx.doi.org/10.1056/NEJMoa1109071]. [PMID: 22873530].
[45]
Burmester, G.R.; Pope, J.E. Novel treatment strategies in rheumatoid arthritis. Lancet, 2017, 389(10086), 2338-2348. [http://dx.doi.org/10.1016/S0140-6736(17)31491-5]. [PMID: 28612748].
[46]
Smolen, J.S.; Landewé, 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, C.D.; 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, J.E.; Hazes, J.M.W.; Huizinga, T.; Jani, M.; Karateev, D.; Kouloumas, M.; Kvien, T.; Li, Z.; Mariette, X.; McInnes, I.; Mysler, E.; Nash, P.; Pavelka, K.; Poór, G.; Richez, C.; van Riel, P.; Rubbert-Roth, A.; Saag, K.; da Silva, J.; Stamm, T.; Takeuchi, T.; Westhovens, R.; de Wit, M.; van der Heijde, D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis., 2017, 76(6), 960-977. [http://dx.doi.org/10.1136/annrheumdis-2016-210715]. [PMID: 28264816].
[47]
Baker, K.F.; Isaacs, J.D. Brief Report: Remission Rates With Tofacitinib Treatment in Rheumatoid Arthritis: A Comparison of Various Remission Criteria. Arthritis Rheumatol., 2017, 69(4), 728-734.
[48]
Smolen, J.S.; Aletaha, D.; Gruben, D.; Zwillich, S.H.; Krishnaswami, S.; Mebus, C. Brief Report: Remission Rates With Tofacitinib Treatment in Rheumatoid Arthritis: A Comparison of Various Remission Criteria. Arthritis Rheumatol., 2017, 69(4), 728-734. [http://dx.doi.org/10.1002/art.39996]. [PMID: 27907269].
[49]
Burmester, G.R.; Blanco, R.; Charles-Schoeman, C.; Wollenhaupt, J.; Zerbini, C.; Benda, B.; Gruben, D.; Wallenstein, G.; Krishnaswami, S.; Zwillich, S.H.; Koncz, T.; Soma, K.; Bradley, J.; Mebus, C. 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), 451-460. [http://dx.doi.org/10.1016/S0140-6736(12)61424-X]. [PMID: 23294500].
[50]
Vieira, M.C.; Zwillich, S.H.; Jansen, J.P.; Smiechowski, B.; Spurden, D.; Wallenstein, G.V. Tofacitinib Versus Biologic Treatments in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Tumor Necrosis Factor Inhibitors: Results From a Network Meta-analysis. Clin. Ther., 2016, 38(12), 2628-2641.e5. [http://dx.doi.org/10.1016/j.clinthera.2016.11.004]. [PMID: 27889300].
[51]
Park, S.K.; Lee, M.Y.; Jang, E.J.; Kim, H.L.; Ha, D.M.; Lee, E.K. A comparison of discontinuation rates of tofacitinib and biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: a systematic review and Bayesian network meta-analysis. Clin. Exp. Rheumatol., 2017, 35(4), 689-699. [PMID: 28079510].
[52]
Keystone, E.C.; Taylor, P.C.; Drescher, E.; Schlichting, D.E.; Beattie, S.D.; Berclaz, P.Y.; Lee, C.H.; Fidelus-Gort, R.K.; Luchi, M.E.; Rooney, T.P.; Macias, W.L.; Genovese, M.C. 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), 333-340. [http://dx.doi.org/10.1136/annrheumdis-2014-206478]. [PMID: 25431052].
[53]
Genovese, M.C.; Kremer, J.; Zamani, O.; Ludivico, C.; Krogulec, M.; Xie, L.; Beattie, S.D.; Koch, A.E.; Cardillo, T.E.; Rooney, T.P.; Macias, W.L.; de Bono, S.; Schlichting, D.E.; Smolen, J.S. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N. Engl. J. Med., 2016, 374(13), 1243-1252. [http://dx.doi.org/10.1056/NEJMoa1507247]. [PMID: 27028914].
[54]
Dougados, M.; van der Heijde, D.; Chen, Y.C.; Greenwald, M.; Drescher, E.; Liu, J.; Beattie, S.; Witt, S.; de la Torre, I.; Gaich, C.; Rooney, T.; Schlichting, D.; de Bono, S.; Emery, P. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann. Rheum. Dis., 2017, 76(1), 88-95. [http://dx.doi.org/10.1136/annrheumdis-2016-210094]. [PMID: 27689735].
[55]
Fleischmann, R.; Schiff, M.; van der Heijde, D.; Ramos-Remus, C.; Spindler, A.; Stanislav, M.; Zerbini, C.A.; Gurbuz, S.; Dickson, C.; de Bono, S.; Schlichting, D.; Beattie, S.; Kuo, W.L.; Rooney, T.; Macias, W.; Takeuchi, T. Baricitinib, Methotrexate, or Combination in Patients With Rheumatoid Arthritis and No or Limited Prior Disease-Modifying Antirheumatic Drug Treatment. Arthritis Rheumatol., 2017, 69(3), 506-517. [http://dx.doi.org/10.1002/art.39953]. [PMID: 27723271].
[56]
Taylor, P.C.; Keystone, E.C.; van der Heijde, D.; Tanaka, Y. Baricitinib versus placebo or adalimumab in patients with active rheumatoid arthritis and an inadequate response to background methotrexate therapy: results of a phase 3 study. Arthritis Rheumatol., 2015, 67(Suppl. 10), 3927-3931.
[57]
Takeuchi, T.; Genovese, M.; Xie, L.; Issa, M.; Pinto Correia, A.L.; Rooney, T. Baricitinib dose step down following disease control in patients with rheumatoid arthritis. Ann. Rheum. Dis., 2016, 75(Suppl. 2), 144. [http://dx.doi.org/10.1136/annrheumdis-2016-eular.1610].
[58]
Banerjee, S.; Biehl, A.; Gadina, M.; Hasni, S.; Schwartz, D.M. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs, 2017, 77(5), 521-546. [http://dx.doi.org/10.1007/s40265-017-0701-9]. [PMID: 28255960].
[59]
Namour, F. Author’s Reply to Srinivas: “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection. Clin. Pharmacokinet., 2015, 54(12), 1297-1298. [http://dx.doi.org/10.1007/s40262-015-0336-5]. [PMID: 26482170].
[60]
Namour, F.; Galien, R.; Gheyle, L.; Vanhoutte, F.; Vayssière, B.; Van der Aa, A. Once Daily High Dose Regimens of GLPG0634 in Healthy Volunteers Are Safe and Provide Continuous Inhibition of JAK1 but not JAK2. Arthritis Rheum., 2012, 64(Suppl. 10), 1331.
[61]
Vanhoutte, F.; Mazur, M.; Van der Aa, A.; van’t Klooster, G.; Wigerinck, P.; Galapagos, N.V. Selective JAK1 Inhibition in the Treatment of Rheumatoid rArthritis: Proof of Concept with GLPG0634. Arthritis Rheum., 2012, 64(Suppl. 10), 2489. [PMID: 22421978].
[62]
Tasset, C.; Harrison, P.; Van der Aa, A. 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. Arthritis Rheum., 2013, 65(Suppl. 10), 2381.
[63]
Westhovens, R.; Taylor, P.C.; Alten, R.; Pavlova, D.; Enríquez-Sosa, F.; Mazur, M.; Greenwald, M.; Van der Aa, A.; Vanhoutte, F.; Tasset, C.; Harrison, P. 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., 2017, 76(6), 998-1008. [http://dx.doi.org/10.1136/annrheumdis-2016-210104]. [PMID: 27993829].
[64]
Kavanaugh, A.; Kremer, J.; Ponce, L.; Cseuz, R.; Reshetko, O.V.; Stanislavchuk, M.; Greenwald, M.; Van der Aa, A.; Vanhoutte, F.; Tasset, C.; Harrison, P. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann. Rheum. Dis., 2017, 76(6), 1009-1019. [http://dx.doi.org/10.1136/annrheumdis-2016-210105]. [PMID: 27993828].
[65]
Smolen, J.; Genovese, M.; Takeuchi, T.; Hyslop, D.; Macias, W.L.; al Rooneyet, T.P. al Safety profile of baricitinib in patients with active RA: an integrated analysis. Ann. Rheum. Dis., 2016, 75(Suppl. 2), 243-244. [http://dx.doi.org/10.1136/annrheumdis-2016-eular.1612].
[66]
Winthrop, K.L.; Yamanaka, H.; Valdez, H.; Mortensen, E.; Chew, R.; Krishnaswami, S.; Kawabata, T.; Riese, R. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol., 2014, 66(10), 2675-2684. [http://dx.doi.org/10.1002/art.38745]. [PMID: 24943354].
[67]
Curtis, J.R.; Lee, E.B.; Kaplan, I.V.; Kwok, K.; Geier, J.; Benda, B.; Soma, K.; Wang, L.; Riese, R. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann. Rheum. Dis., 2016, 75(5), 831-841. [http://dx.doi.org/10.1136/annrheumdis-2014-205847]. [PMID: 25902789].
[68]
Breccia, M. Efficacy and safety of ruxolitinib in intermediate-1 IPSS risk myelofibrosis patients: Results from an independent study. Palandri F1, Tiribelli M2, Benevolo G3, Tieghi A4, Cavazzini F5. Hematol. Oncol., 2018, 36(1), 285-290. [http://dx.doi.org/10.1002/hon.2429].
[69]
Damsky, W.; King, B.A. JAK inhibitors in dermatology: the promise of a new drug class. J. Am. Acad. Dermatol., 2017, 76(4), 736-744. [http://dx.doi.org/10.1016/j.jaad.2016.12.005]. [PMID: 28139263].
[70]
Furumoto, Y.; Smith, C.K.; Blanco, L.; Zhao, W.; Brooks, S.R.; Thacker, S.G.; Abdalrahman, Z.; Sciumè, G.; Tsai, W.L.; Trier, A.M.; Nunez, L.; Mast, L.; Hoffmann, V.; Remaley, A.T.; O’Shea, J.J.; Kaplan, M.J.; Gadina, M. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol., 2017, 69(1), 148-160. [http://dx.doi.org/10.1002/art.39818]. [PMID: 27429362].
[71]
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. JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation. BMC Immunol., 2017, 18(1), 41. [http://dx.doi.org/10.1186/s12865-017-0225-9]. [PMID: 28830352].

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