Advertisement

JAK inhibitors in 2019, synthetic review in 10 points

      Highlights

      • JAK inhibitors modulate a central communication node for cells
      • Commercialized JAK inhibitors are superior to methotrexate in rheumatoid arthritis
      • Safety profile of JAK inhibitors is reassuring, but long-term effects are unknown
      • JAK inhibitors are actually tested in >150 registered clinical trials

      Abstract

      JAK inhibitors are recent treatments. Many publications have appeared in recent years, exposing treatment efficiencies in phases 2 and 3 studies, or their tolerance profile in various rheumatological diseases. We propose here a systematic review of JAK inhibitors, from their mechanism of physiological action up to the estimation of their current risk benefit balance, and their possible future applications.
      In order to better synthesize the data, we organized this review into 10 essential points.
      1- What is the role of JAK/Stat pathway?
      2- How can a single signaling pathway regulate as many different signals?
      3- What are the commercialized JAK inhibitors and their validated indications in humans today?
      4- What is the level of efficiency of JAK inhibitors in inflammatory diseases?
      5- What is the delay of efficiency of JAK inhibitors?
      6- Where is the place of JAK inhibitors in the therapeutic strategy today?
      7- What is the infectious tolerance profile of JAK inhibitors?
      8- What is the non-infectious safety profile of JAK inhibitors?
      9- What is the cost of JAK inhibitors compared to other DMARDs?
      10- What future prospects for JAK inhibitors?

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Taylor P.C.
        Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis.
        Rheumatol Oxf Engl. 2019 Feb 1; 58: i17-i26
        • Harigai M.
        Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis.
        Rheumatol Oxf Engl. 2019 Feb 1; 58: i34-i42
        • Choy E.H.S.
        • Miceli-Richard C.
        • González-Gay M.A.
        • Sinigaglia L.
        • Schlichting D.E.
        • Meszaros G.
        • et al.
        The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib.
        Clin Exp Rheumatol. 2019 Feb; 11
        • Schwartz D.M.
        • Bonelli M.
        • Gadina M.
        • O'Shea J.J.
        Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases.
        Nat Rev Rheumatol. 2016 Jan; 12: 25-36
        • Ivashkiv L.B.
        Jak-STAT signaling pathways in cells of the immune system.
        Rev Immunogenet. 2000; 2: 220-230
        • Ihle J.N.
        • Nosaka T.
        • Thierfelder W.
        • Quelle F.W.
        • Shimoda K.
        Jaks and Stats in cytokine signaling.
        Stem Cells Dayt Ohio. 1997; 15 ([discussion 112]): 105-111
        • Horvath C.M.
        The Jak-STAT pathway stimulated by interferon gamma.
        Sci STKE Signal Transduct Knowl Environ. 2004 Nov 23; 2004: tr8
        • Malemud C.J.
        The role of the JAK/STAT signal pathway in rheumatoid arthritis.
        Ther Adv Musculoskelet Dis. 2018 Jun; 10: 117-127
        • Gillinder K.R.
        • Tuckey H.
        • Bell C.C.
        • Magor G.W.
        • Huang S.
        • Ilsley M.D.
        • et al.
        Direct targets of pSTAT5 signalling in erythropoiesis.
        PloS One. 2017; 12e0180922
        • Miyakis S.
        • Lockshin M.D.
        • Atsumi T.
        • Branch D.W.
        • Brey R.L.
        • Cervera R.
        • et al.
        International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
        J Thromb Haemost. 2006 Feb 1; 4: 295-306
        • Sikorski K.
        • Czerwoniec A.
        • Bujnicki J.M.
        • Wesoly J.
        • Bluyssen H.A.R.
        STAT1 as a novel therapeutical target in pro-atherogenic signal integration of IFNγ, TLR4 and IL-6 in vascular disease.
        Cytokine Growth Factor Rev. 2011 Aug; 22: 211-219
        • Richard A.J.
        • Stephens J.M.
        The role of JAK-STAT signaling in adipose tissue function.
        Biochim Biophys Acta. 2014 Mar; 1842: 431-439
        • Ferrajoli A.
        • Faderl S.
        • Ravandi F.
        • Estrov Z.
        The JAK-STAT pathway: a therapeutic target in hematological malignancies.
        Curr Cancer Drug Targets. 2006 Dec; 6: 671-679
        • Gurzov E.N.
        • Stanley W.J.
        • Pappas E.G.
        • Thomas H.E.
        • Gough D.J.
        The JAK/STAT pathway in obesity and diabetes.
        FEBS J. 2016; 283: 3002-3015
        • Villarino A.V.
        • Kanno Y.
        • O'Shea J.J.
        Mechanisms and consequences of Jak-STAT signaling in the immune system.
        Nat Immunol. 2017; 18: 374-384
        • 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: 521-546
        • Horvath C.M.
        The Jak-STAT pathway stimulated by interferon alpha or interferon beta.
        Sci STKE Signal Transduct Knowl Environ. 2004 Nov 23; 2004: tr10
        • Kuhrt D.
        • Wojchowski D.M.
        Emerging EPO and EPO receptor regulators and signal transducers.
        Blood. 2015 Jun 4; 125: 3536-3541
        • Waters M.J.
        • Brooks A.J.
        JAK2 activation by growth hormone and other cytokines.
        Biochem J. 2015 Feb 15; 466: 1-11
        • Barreiros L.A.
        • Segundo G.R.S.
        • Grumach A.S.
        • Roxo-Júnior P.
        • Torgerson T.R.
        • Ochs H.D.
        • et al.
        A novel homozygous JAK3 mutation leading to T-B+NK- SCID in two Brazilian patients.
        Front Pediatr. 2018; 6: 230
        • O'Sullivan J.M.
        • Harrison C.N.
        JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms.
        Mol Cell Endocrinol. 2017; 15: 71-79
      1. JAKs and STATs in Immunity, Immunodeficiency, and Cancer | NEJM.
        New England Journal of Medicine. 2013 Jan; (Internet): 161-170https://doi.org/10.1056/NEJMra1202117
        • Waldmann T.A.
        • Chen J.
        Disorders of the JAK/STAT Pathway in T Cell Lymphoma Pathogenesis: Implications for Immunotherapy.
        Annu Rev Immunol. 2017; 26: 533-550
        • Kiel M.J.
        • Sahasrabuddhe A.A.
        • Rolland D.C.M.
        • Velusamy T.
        • Chung F.
        • Schaller M.
        • et al.
        Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.
        Nat Commun. 2015; 29: 8470
        • Minegishi Y.
        • Karasuyama H.
        Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency.
        Int Immunol. 2009 Feb; 21: 105-112
        • Greenfield G.
        • McPherson S.
        • Mills K.
        • McMullin M.F.
        The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms.
        J Transl Med. 2018 Dec 17; 16: 360
        • Gras J.
        Baricitinib: JAK inhibition for rheumatoid arthritis.
        Drugs Today Barc Spain. 1998; 52 (2016 Oct): 543-550
        • Norman P.
        Selective JAK inhibitors in development for rheumatoid arthritis.
        Expert Opin Investig Drugs. 2014 Aug; 23: 1067-1077
        • Sands B.E.
        • Sandborn W.J.
        • Feagan B.G.
        • Lichtenstein G.R.
        • Zhang H.
        • Strauss R.
        • et al.
        Peficitinib, an Oral Janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study.
        J Crohns Colitis. 2018 Nov 9; 12: 1158-1169
        • van der Heijde D.
        • Baraliakos X.
        • Gensler L.S.
        • Maksymowych W.P.
        • Tseluyko V.
        • Nadashkevich O.
        • et al.
        Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a randomised, placebo-controlled, phase 2 trial.
        Lancet Lond Engl. 2018; 392: 2378-2387
        • Mesa R.A.
        • Vannucchi A.M.
        • Mead A.
        • Egyed M.
        • Szoke A.
        • Suvorov A.
        • et al.
        Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial.
        Lancet Haematol. 2017 May; 4: e225-e236
        • Fleischmann R.
        • Kremer J.
        • Cush J.
        • Schulze-Koops H.
        • Connell C.A.
        • Bradley J.D.
        • et al.
        Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.
        N Engl J Med. 2012 Aug 9; 367: 495-507
        • Lee E.B.
        • Fleischmann R.
        • Hall S.
        • Wilkinson B.
        • Bradley J.D.
        • Gruben D.
        • et al.
        Tofacitinib versus methotrexate in rheumatoid arthritis.
        N Engl J Med. 2014 Jun 19; 370: 2377-2386
        • Fleischmann R.
        • Mysler E.
        • Hall S.
        • Kivitz A.J.
        • Moots R.J.
        • Luo Z.
        • et al.
        Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial.
        Lancet Lond Engl. 2017; 390: 457-468
        • Smolen J.S.
        • Kremer J.M.
        • Gaich C.L.
        • DeLozier A.M.
        • Schlichting D.E.
        • Xie L.
        • et al.
        Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON).
        Ann Rheum Dis. 2017; 76: 694-700
        • van der Heijde D.
        • Durez P.
        • Schett G.
        • Naredo E.
        • Østergaard M.
        • Meszaros G.
        • et al.
        Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the phase 3 RA-BEGIN study.
        Clin Rheumatol. 2018 Sep; 37: 2381-2390
        • Burmester G.R.
        • Blanco R.
        • Charles-Schoeman C.
        • Wollenhaupt J.
        • Zerbini C.
        • Benda B.
        • et al.
        Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.
        Lancet Lond Engl. 2013 Feb 9; 381: 451-460
        • van Vollenhoven R.F.
        • Fleischmann R.
        • Cohen S.
        • Lee E.B.
        • García Meijide J.A.
        • Wagner S.
        • et al.
        Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.
        N Engl J Med. 2012 Aug 9; 367: 508-519
        • van der Heijde D.
        • Strand V.
        • Tanaka Y.
        • Keystone E.
        • Kremer J.
        • Zerbini C.A.F.
        • et al.
        Tofacitinib in combination with methotrexate in patients with rheumatoid arthritis: clinical efficacy, radiographic and safety outcomes from the 24-month phase 3 ORAL scan study.
        Arthritis Rheumatol Hoboken NJ. 2019 Jan; 22
      2. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. - PubMed - NCBI [Internet].
        (cited 2019 Mar 2. Available from)
        • Strand V.
        • de Vlam K.
        • Covarrubias-Cobos J.A.
        • Mease P.J.
        • Gladman D.D.
        • Chen L.
        • et al.
        Effect of tofacitinib on patient-reported outcomes in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors in the phase III, randomised controlled trial: OPAL beyond.
        RMD Open. 2019; 5e000808
        • Sandborn W.J.
        • Su C.
        • Sands B.E.
        • D'Haens G.R.
        • Vermeire S.
        • Schreiber S.
        • et al.
        Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.
        N Engl J Med. 2017; 376: 1723-1736
        • Ford A.C.
        • Achkar J.-P.
        • Khan K.J.
        • Kane S.V.
        • Talley N.J.
        • Marshall J.K.
        • et al.
        Efficacy of 5-aminosalicylates in ulcerative colitis: systematic review and meta-analysis.
        Am J Gastroenterol. 2011 Apr; 106: 601-616
        • Nagahori M.
        • Kochi S.
        • Hanai H.
        • Yamamoto T.
        • Nakamura S.
        • Omuro S.
        • et al.
        Real life results in using 5-ASA for maintaining mild to moderate UC patients in Japan, a multi-center study.
        OPTIMUM Study BMC Gastroenterol. 2017 Apr 4; 17: 47
        • Singh J.A.
        • Saag K.G.
        • Bridges S.L.
        • Akl E.A.
        • Bannuru R.R.
        • Sullivan M.C.
        • et al.
        2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis.
        Arthritis Care Res. 2016 Jan; 68: 1-25
        • Smolen J.S.
        • Landewé R.
        • Bijlsma J.
        • Burmester G.
        • Chatzidionysiou K.
        • Dougados M.
        • et al.
        EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.
        Ann Rheum Dis. 2017 Jun; 76: 960-977
        • Singh J.A.
        • Guyatt G.
        • Ogdie A.
        • Gladman D.D.
        • Deal C.
        • Deodhar A.
        • et al.
        Special article: 2018 American College of Rheumatology/National Psoriasis Foundation guideline for the treatment of psoriatic arthritis.
        Arthritis Care Res. 2019 Jan; 71: 2-29
        • Gossec L.
        • Smolen J.S.
        • Ramiro S.
        • de Wit M.
        • Cutolo M.
        • Dougados M.
        • et al.
        European league against rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.
        Ann Rheum Dis. 2016 Mar; 75: 499-510
        • Cohen S.B.
        • Tanaka Y.
        • Mariette X.
        • Curtis J.R.
        • Lee E.B.
        • Nash P.
        • et al.
        Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials.
        Ann Rheum Dis. 2017 Jul; 76: 1253-1262
        • Kivitz A.J.
        • Cohen S.
        • Keystone E.
        • van Vollenhoven R.F.
        • Haraoui B.
        • Kaine J.
        • et al.
        A pooled analysis of the safety of tofacitinib as monotherapy or in combination with background conventional synthetic disease-modifying antirheumatic drugs in a phase 3 rheumatoid arthritis population.
        Semin Arthritis Rheum. 2018; 48: 406-415
        • Charles-Schoeman C.
        • Burmester G.
        • Nash P.
        • Zerbini C.A.F.
        • Soma K.
        • Kwok K.
        • et al.
        Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs.
        Ann Rheum Dis. 2016; 75: 1293-1301
        • Smolen J.S.
        • Genovese M.C.
        • Takeuchi T.
        • Hyslop D.L.
        • Macias W.L.
        • Rooney T.
        • et al.
        Safety profile of Baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment.
        J Rheumatol. 2019 Jan; 46: 7-18
        • Harigai M.
        • Takeuchi T.
        • Smolen J.S.
        • Winthrop K.L.
        • Nishikawa A.
        • Rooney T.P.
        • et al.
        Safety profile of baricitinib in Japanese patients with active rheumatoid arthritis with over 1.6 years median time in treatment: an integrated analysis of Phase 2 and 3 trials.
        Mod Rheumatol. 2019 Feb 20; : 1-23
        • Strand V.
        • Ahadieh S.
        • French J.
        • Geier J.
        • Krishnaswami S.
        • Menon S.
        • et al.
        Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials.
        Arthritis Res Ther. 2015 Dec 15; 17: 362
        • Geier J.
        • Saunders K.
        • Reed G.
        AB1057 contextualisation of safety endpoints in the Tofacitinib rheumatoid arthritis (RA) development programme: collaboration with the consortium of rheumatology researchers of North America (CORRONA) registry.
        Ann Rheum Dis. 2014 Jun 1; 73: 1149-1150
        • Greenberg J.D.
        • Reed G.
        • Kremer J.M.
        • Tindall E.
        • Kavanaugh A.
        • Zheng C.
        • et al.
        Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry.
        Ann Rheum Dis. 2010 Feb; 69: 380-386
        • Dhillon S.
        Tofacitinib: a review in rheumatoid arthritis.
        Drugs. 2017 Dec; 77: 1987-2001
        • Al-Salama Z.T.
        • Scott L.J.
        Baricitinib: a review in rheumatoid arthritis.
        Drugs. 2018 May; 78: 761-772
        • Taylor P.C.
        • Weinblatt M.E.
        • Burmester G.R.
        • Rooney T.P.
        • Witt S.
        • Walls C.D.
        • et al.
        Cardiovascular Safety During Treatment with Baricitinib in Rheumatoid Arthritis.
        Arthritis Rheumatol Hoboken NJ. 2019 Jan; 0: 1-14
        • Charles-Schoeman C.
        • Wicker P.
        • Gonzalez-Gay M.A.
        • Boy M.
        • Zuckerman A.
        • Soma K.
        • et al.
        Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor.
        Semin Arthritis Rheum. 2016; 46: 261-271
        • Kiladjian J.-J.
        • Guglielmelli P.
        • Griesshammer M.
        • Saydam G.
        • Masszi T.
        • Durrant S.
        • et al.
        Efficacy and safety of ruxolitinib after and versus interferon use in the RESPONSE studies.
        Ann Hematol. 2018 Apr; 97: 617-627
        • Chikugo M.
        • Sebe M.
        • Tsutsumi R.
        • Iuchi M.
        • KIshi J.
        • Kuroda M.
        • et al.
        Effect of Janus kinase inhibition by tofacitinib on body composition and glucose metabolism.
        J Med Investig JMI. 2018; 65: 166-170
      3. Prescrire Int. 2016 Oct; 25: 229-231
        • Scott I.C.
        • Hider S.L.
        • Scott D.L.
        Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk?.
        Drug Saf. 2018; 41: 645-653
        • Verden A.
        • Dimbil M.
        • Kyle R.
        • Overstreet B.
        • Hoffman K.B.
        Analysis of spontaneous Postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors.
        Drug Saf. 2018 Apr; 41: 357-361
        • Desai R.J.
        • Pawar A.
        • Weinblatt M.E.
        • Kim S.C.
        Comparative risk of venous thromboembolism in rheumatoid arthritis patients receiving Tofacitinib versus those receiving tumor necrosis factor inhibitors: an observational cohort study.
        Arthritis Rheumatol Hoboken NJ. 2018 Dec; 15
        • Claxton L.
        • Jenks M.
        • Taylor M.
        • Wallenstein G.
        • Mendelsohn A.M.
        • Bourret J.A.
        • et al.
        An economic evaluation of Tofacitinib treatment in rheumatoid arthritis: Modeling the cost of treatment strategies in the United States.
        J Manag Care Spec Pharm. 2016 Sep; 22: 1088-1102
        • D'Amico F.
        • Fiorino G.
        • Furfaro F.
        • Allocca M.
        • Danese S.
        Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials.
        Expert Opin Investig Drugs. 2018 Jul; 27: 595-599
        • Genovese M.C.
        • Fleischmann R.
        • Combe B.
        • Hall S.
        • Rubbert-Roth A.
        • Zhang Y.
        • et al.
        Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial.
        Lancet Lond Engl. 2018; 391: 2513-2524
        • Burmester G.R.
        • Kremer J.M.
        • Van den Bosch F.
        • Kivitz A.
        • Bessette L.
        • Li Y.
        • et al.
        Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial.
        Lancet Lond Engl. 2018; 391: 2503-2512
        • Genovese M.C.
        • Yang F.
        • Østergaard 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 Nov; 75: 1979-1983
        • Genovese M.C.
        • Greenwald M.
        • Codding C.
        • Zubrzycka-Sienkiewicz A.
        • Kivitz A.J.
        • Wang A.
        • et al.
        Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying Antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis.
        Arthritis Rheumatol Hoboken NJ. 2017; 69: 932-942
        • Genovese M.
        • Westhovens R.
        • Meuleners L.
        • Van der Aa A.
        • Harrison P.
        • Tasset C.
        • et al.
        Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes.
        Arthritis Res Ther. 2018; 20: 57
        • Dougados M.
        • van der Heijde D.
        • Chen Y.-C.
        • Greenwald M.
        • Drescher E.
        • Liu J.
        • et al.
        Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.
        Ann Rheum Dis. 2017 Jan; 76: 88-95
        • Strand V.
        • Kremer J.M.
        • Gruben D.
        • Krishnaswami S.
        • Zwillich S.H.
        • Wallenstein G.V.
        Tofacitinib in combination with conventional disease-modifying Antirheumatic drugs in patients with active rheumatoid arthritis: patient-reported outcomes from a phase III randomized controlled trial.
        Arthritis Care Res. 2017; 69: 592-598
        • Alten R.
        • Nitschmann S.
        Janus kinase inhibitor baricitinib for rheumatoid arthritis : randomized, double-blind, placebo- and active-controlled, phase 3 study evaluating the efficacy and safety of baricitinib in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate therapy (RA-BEAM).
        Internist. 2017 Dec; 58: 1341-1344