The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis

Abstract The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra-articular disease manifestations of PsA and AS.

[1]  A. Gottlieb,et al.  Group for Research and Assessment of Psoriasis and Psoriatic Arthritis/Outcome Measures in Rheumatology Consensus‐Based Recommendations and Research Agenda for Use of Composite Measures and Treatment Targets in Psoriatic Arthritis , 2018, Arthritis & rheumatology.

[2]  D. Gladman,et al.  Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors , 2017, The New England journal of medicine.

[3]  D. M. van der Heijde,et al.  Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis , 2017, The New England journal of medicine.

[4]  M. Genovese,et al.  Peficitinib, a JAK Inhibitor, in the Treatment of Moderate‐to‐Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate , 2017, Arthritis & rheumatology.

[5]  Yuka Kanno,et al.  Mechanisms and consequences of Jak–STAT signaling in the immune system , 2017, Nature Immunology.

[6]  S. Vermeire,et al.  Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials , 2017, Gut.

[7]  J. Raes,et al.  Brief Report: Dialister as a Microbial Marker of Disease Activity in Spondyloarthritis , 2017, Arthritis & rheumatology.

[8]  L. Catrysse,et al.  A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis , 2016, Annals of the rheumatic diseases.

[9]  D. M. van der Heijde,et al.  Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study , 2016, Annals of the rheumatic diseases.

[10]  W. Sandborn,et al.  Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. , 2017, The New England journal of medicine.

[11]  M. Gooderham,et al.  Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial , 2016, The British journal of dermatology.

[12]  J. Kremer,et al.  A Phase IIb Study of ABT‐494, a Selective JAK‐1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti–Tumor Necrosis Factor Therapy , 2016, Arthritis & rheumatology.

[13]  L. Lanier,et al.  NK cells and type 1 innate lymphoid cells: partners in host defense , 2016, Nature Immunology.

[14]  T. Wiele,et al.  How the microbiota shapes rheumatic diseases , 2016, Nature Reviews Rheumatology.

[15]  K. Papp,et al.  A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate‐to‐severe psoriasis , 2016, The British journal of dermatology.

[16]  A. Gottlieb,et al.  Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis , 2016, Arthritis & rheumatology.

[17]  J. D. Clark,et al.  Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: A randomized phase 2 study. , 2016, The Journal of allergy and clinical immunology.

[18]  T. Korn,et al.  Interleukin‐23–Dependent γ/δ T Cells Produce Interleukin‐17 and Accumulate in the Enthesis, Aortic Valve, and Ciliary Body in Mice , 2016, Arthritis & rheumatology.

[19]  J. Kremer,et al.  Baricitinib in Patients with Refractory Rheumatoid Arthritis. , 2016, The New England journal of medicine.

[20]  Søren Brunak,et al.  Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci , 2016, Nature Genetics.

[21]  J. D. Clark,et al.  The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. , 2016, Clinical and experimental rheumatology.

[22]  J. Telliez,et al.  JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines. , 2016, American journal of physiology. Gastrointestinal and liver physiology.

[23]  I. McInnes,et al.  Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases. , 2016, Annual review of medicine.

[24]  S. Abramson,et al.  Review: Microbiome in Inflammatory Arthritis and Human Rheumatic Diseases , 2016, Arthritis & rheumatology.

[25]  C. Ritchlin,et al.  Bone remodeling in psoriasis and psoriatic arthritis: an update , 2016, Current opinion in rheumatology.

[26]  D. Veale,et al.  Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors , 2015, Annals of the rheumatic diseases.

[27]  Filgotinib, a selective JAK1 inhibitor, induces clinical remission in patients with moderate-to-severe Crohn's disease: interim analysis from the Phase 2 FITZROY study , 2016 .

[28]  Tony J. Kenna,et al.  Intestinal Dysbiosis in Ankylosing Spondylitis , 2016 .

[29]  S. Krebs,et al.  Melanocyte antigen triggers autoimmunity in human psoriasis , 2015, The Journal of experimental medicine.

[30]  Dennis McGonagle,et al.  'MHC-I-opathy'—unified concept for spondyloarthritis and Behçet disease , 2015, Nature Reviews Rheumatology.

[31]  S. Chimenti,et al.  Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial , 2015, The Lancet.

[32]  L. Iversen,et al.  Tofacitinib withdrawal and retreatment in moderate‐to‐severe chronic plaque psoriasis: a randomized controlled trial , 2015, The British journal of dermatology.

[33]  P. Diderichsen,et al.  Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection , 2015, Clinical Pharmacokinetics.

[34]  Mhairi Marshall,et al.  Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis , 2014, Arthritis & rheumatology.

[35]  G. Yancopoulos,et al.  Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN) , 2014, Annals of the rheumatic diseases.

[36]  Dirk Elewaut,et al.  The role of the gut and microbes in the pathogenesis of spondyloarthritis. , 2014, Best practice & research. Clinical rheumatology.

[37]  J. Telliez,et al.  OP0147 Lack of Differentiation of Janus Kinase Inhibitors in Rheumatoid Arthritis Based on Janus Kinase Pharmacology and Clinically Meaningful Concentrations , 2014 .

[38]  E. Lee,et al.  Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies , 2014, The Journal of Rheumatology.

[39]  D. Veale,et al.  Is there a need for new agents with novel mechanisms of action in psoriatic arthritis? , 2014, Annals of the rheumatic diseases.

[40]  B. Kirkham,et al.  Interleukin-17+CD8+ T Cells Are Enriched in the Joints of Patients With Psoriatic Arthritis and Correlate With Disease Activity and Joint Damage Progression , 2014, Arthritis & rheumatology.

[41]  G. S. Walker,et al.  The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans , 2014, Drug Metabolism and Disposition.

[42]  R. Colbert,et al.  Review: The Interleukin‐23/Interleukin‐17 Axis in Spondyloarthritis Pathogenesis: Th17 and Beyond , 2014, Arthritis & rheumatology.

[43]  Massimo Gadina,et al.  Jakpot! New small molecules in autoimmune and inflammatory diseases , 2014, Experimental dermatology.

[44]  K. Takeda,et al.  Combination of Tumor Necrosis Factor α and Interleukin‐6 Induces Mouse Osteoclast‐like Cells With Bone Resorption Activity Both In Vitro and In Vivo , 2014, Arthritis & rheumatology.

[45]  George Kollias,et al.  Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells , 2013, Annals of the rheumatic diseases.

[46]  Phoebe Lin,et al.  The future of uveitis treatment. , 2014, Ophthalmology.

[47]  D. Sexton.  Tofacitinib versus methotrexate in rheumatoid arthritis. , 2014, The New England journal of medicine.

[48]  John D Isaacs,et al.  Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis , 2013, Annals of Internal Medicine.

[49]  K. Papp,et al.  A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis , 2013, The British journal of dermatology.

[50]  J. O’Shea,et al.  Janus kinase inhibitors in autoimmune diseases , 2013, Annals of the rheumatic diseases.

[51]  B. Wyman,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. , 2013, Arthritis and rheumatism.

[52]  Tamas Koncz,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 , 2013, The Lancet.

[53]  G. Schett,et al.  Are spondylarthritides related but distinct conditions or a single disease with a heterogeneous phenotype? , 2013, Arthritis and rheumatism.

[54]  I. E. van der Horst-Bruinsma,et al.  Management and evaluation of extra-articular manifestations in spondyloarthritis , 2012, Therapeutic advances in musculoskeletal disease.

[55]  J. Kremer,et al.  Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. , 2012, The New England journal of medicine.

[56]  E. Lee,et al.  Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. , 2012, The New England journal of medicine.

[57]  Min Zhang,et al.  Tofacitinib (CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial. , 2012, Ophthalmology.

[58]  M. Brown,et al.  β-glucan triggers spondylarthritis and Crohn's disease-like ileitis in SKG mice. , 2012, Arthritis and rheumatism.

[59]  T. Mcclanahan,et al.  IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells , 2012, Nature Medicine.

[60]  R. Lories,et al.  Insights into the pathophysiology of ankylosing spondylitis: contributions from animal models. , 2012, Joint, bone, spine : revue du rhumatisme.

[61]  D. Marks.  Defective innate immunity in inflammatory bowel disease: a Crohn's disease exclusivity? , 2011, Current opinion in gastroenterology.

[62]  John J. O’Shea,et al.  Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550) , 2011, The Journal of Immunology.

[63]  L. Messerini,et al.  Evidence for the prevention of enthesitis in HLA-B27/hβ2m transgenic rats treated with a monoclonal antibody against TNF-α , 2009, Journal of cellular and molecular medicine.

[64]  D. Morris,et al.  Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis , 2010, Journal of Inflammation.

[65]  Y. Mikami,et al.  Bone morphogenetic protein 2 and dexamethasone synergistically increase alkaline phosphatase levels through JAK/STAT signaling in C3H10T1/2 cells , 2009, Journal of cellular physiology.

[66]  Frank O. Nestle,et al.  Mechanisms of Disease: Psoriasis. , 2009 .

[67]  J. O’Shea,et al.  Janus kinases in immune cell signaling , 2009, Immunological reviews.

[68]  A. Gottlieb,et al.  Treatment recommendations for psoriatic arthritis , 2008, Annals of the rheumatic diseases.

[69]  M. Benjamin,et al.  Histopathologic changes at "synovio-entheseal complexes" suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis. , 2007, Arthritis and rheumatism.

[70]  R. de Waal Malefyt,et al.  IL‐12 and IL‐23: master regulators of innate and adaptive immunity , 2004, Immunological reviews.

[71]  G. Kollias,et al.  Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. , 1999, Immunity.

[72]  R. Hammer,et al.  Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β 2m: An animal model of HLA-B27-associated human disorders , 1990, Cell.