The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. Item Type Article Authors Veale, Douglas J;McGonagle, Dennis;McInnes, Iain B;Krueger, James G;Ritchlin, Christopher T;Elewaut, Dirk;Kanik, Keith S;Hendrikx, Thijs;Berstein, Gabriel;Hodge, Jennifer;Telliez, Jean- Baptiste DOI 10.1093/rheumatology/key070 Journal Rheumatology (Oxford, England) Download date 23/09/2021 23:23:38 Link to Item http://hdl.handle.net/10147/627108 Find this and similar works at - http://www.lenus.ie/hse Rheumatology 2019;58:197205 RHEUMATOLOGY doi:10.1093/rheumatology/key070 Advance Access publication 3 April 2018 Review The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis 1,2 3,4 5 6 Douglas J. Veale , Dennis McGonagle , Iain B. McInnes , James G. Krueger , Downloaded from https://academic.oup.com/rheumatology/article-abstract/58/2/197/4959184 by 81234751 user on 30 January 2020 Christopher T. Ritchlin7, Dirk Elewaut8, Keith S. Kanik9, Thijs Hendrikx10, Gabriel Berstein11, Jennifer Hodge12 and Jean-Baptiste Telliez11 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 mech- anisms 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 upada- citinib 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, sup- REVIEW ported 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. Key words: spondyloarthropathies (including psoriatic arthritis), DMARDs, cytokines and inflammatory medi- ators, bone, gastrointestinal, ligaments and tendons, skin, synovium Rheumatology key messages . Janus kinases mediate cytokine signaling for many immune cell responses underlying the pathogenesis of spondyloarthritis. Janus kinase inhibition offers the potential for improvements in articular and extra-articular spondyloarthritis disease manifestations. Tofacitinib and other Janus kinase inhibitors may provide clinically meaningful benefits for patients with spondyloarthritis. Introduction options than RA, and sometimes exhibits heterogeneous therapeutic responses between skeletal, eye and gut SpA encompass PsA and AS, and a wider spectrum of involvement. Given the complexity of SpA and the need inflammatory diseases. In addition to skeletal involvement for new therapeutic options, this review considers the encompassing peripheral arthritis, axial disease, isolated entire disease spectrum with respect to Janus kinase enthesitis and dactylitis, PsA and AS are associated with a (JAK) inhibition and was undertaken after a meeting by a range of extra-articular manifestations, including uveitis, group of experts active in SpA research. psoriasis and IBD [1]. SpA currently has fewer therapeutic Unmet treatment need in SpA 1The Centre for Arthritis and Rheumatic Diseases, St Vincent’s 2 3 University Hospital and University College, Dublin, Ireland, Leeds Treatment recommendations recognize that appropriate Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, 4NIHR Leeds Musculoskeletal Biomedical Research Unit, choice of therapy for SpA depends upon multiple factors Chapel Allerton Hospital, Leeds, 5Institute of Infection, Immunity and and should be optimized based on the presenting Inflammation, University of Glasgow, Glasgow, UK, 6Laboratory of Investigative Dermatology, The Rockefeller University, New York, 7Allergy, Immunology & Rheumatology Division, University of Rochester Submitted 2 October 2017; revised version accepted Medical Center, Rochester, NY, USA, 8Unit for Molecular Immunology 20 February 2018 and Inflammation, VIB Inflammation Research Center, Ghent University Correspondence to: Dennis McGonagle, Leeds Institute of Rheumatic and Department of Rheumatology, Ghent University Hospital, Ghent, and Musculoskeletal Medicine, Second floor, Chapel Allerton Hospital, Belgium, 9Pfizer Inc, Groton, CT, 10Pfizer Inc, Collegeville, PA, Chapeltown Road, Leeds, LS7 4SA, UK. 11Pfizer Inc, Cambridge, MA and 12Pfizer Inc, New York, NY, USA E-mail: [email protected] ! The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Douglas J. Veale et al. symptoms, involvement of other diseases and comorbid- infiltration of macrophages and activated T cells into ities, disease activity and prior therapies. TNF inhibitors articular locations leads to the production of effector (TNFi) feature in recent treatment recommendations for cytokines, including IL-1b, IL-2, IL-10, IFNg and TNFa, PsA in all key domains, including peripheral arthritis, and further recruitment and proliferation of immune cells axial disease, enthesitis, dactylitis, plaque psoriasis and associated with tissue destruction [14]. However, in PsA nail psoriasis [2]. Similarly, TNFi are approved in AS and and AS, there is strong experimental evidence that have demonstrated efficacy in improving axial and periph- disease localization and the initial inflammation occurs at eral arthritis as well as other articular and entheseal dis- entheses and other sites of high mechanical stress, ease manifestations. While TNFi demonstrate efficacy including the sacroiliac (SI) joints [15]. across key disease domains, a significant proportion of The IL-23/IL-17 axis is strongly implicated in the patho- Downloaded from https://academic.oup.com/rheumatology/article-abstract/58/2/197/4959184 by 81234751 user on 30 January 2020 patients have inadequate or poor response and others genesis of PsA and AS [14] and in the psoriatic skin pheno- may not tolerate these therapies [3]. Consequently, treat- type [16]. IL-23 contributes to differentiation of innate and ments with alternative mechanisms of action (MoA) may adaptive cognate T cell-expressing lymphocytes which, in be welcomed for patients with SpA. turn, secrete IL-17 A, IL-22 and TNFa [14]. These effector As our understanding of SpA pathogenesis has cytokines are linked to keratinocyte production associated increased, the importance of innate immunity and cytokine with skin manifestations of psoriatic disease and to signaling pathways rather than classical adaptive immunity erosions and new bone formation, although the exact has fully emerged. This is evidenced through the emergence mechanisms underlying the altered phenotypes in the of novel agents that target IL-12/23, IL-17 A and IL-23 [4], skin and joint are not well understood [14]. which have been developed and have often shown better There is increased interest in the potential role that the efficacy in PsA compared with in RA [5]. human intestinal microbiome plays in the pathogenesis of diseases such as PsA and AS [1719]. When the normal JAK inhibitors homeostasis that exists between the gut microbiota and immune cells in the gut lining is disrupted, the ensuing JAK inhibitors are an emerging class of therapies that dysbiosis may contribute to systemic inflammation. have demonstrated efficacy for the treatment of inflamma- Similar to the pathogenesis of IBD, in SpA the inflamma- tory diseases, in which they have broad effects on cyto- tory response is likely typified by IL-23mediated activa- kine production [6]. There are several excellent recent tion of innate and adaptive intestinal lymphocytes, papers on the JAK pathway itself, which will not be dis- providing further support for therapeutic strategies target- cussed further [7, 8]. In this paper, we review and interpret ing the IL-22 and IL-23/IL-17 axis [20]. the available basic and clinical evidence to provide con- text and rationale for the use of JAK inhibitors for the JAKSTAT signaling treatment of PsA and AS. We discuss why it is that, at the population level, neither TNF nor IL-17 directly signal A large number of cytokines, including many of those via JAK pathways, and relate this to the efficacy of JAK implicated in the pathogenesis of SpA, signal through inhibition in experimental SpA and emergent clinical data. JAK pathways (Fig. 2). The JAK family of intracellular pro- tein tyrosine kinases consists of JAK1, JAK2, JAK3 and Immunopathogenesis of SpA tyrosine kinase 2 (TYK2) [21]. In conjunction with Signal Transducer and Activator of Transcription (STAT) intracel- The aetiology of SpA is complex, with interacting environ- lular transcription factors, JAKs mediate signaling for a mental and genetic factors combining to elicit a chronic range of extracellular cytokines and growth factors and inflammatory response involving the innate and adap- ultimately influence a variety of cellular functions [21]. tive immune systems (Fig. 1). At the