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Emerging Immunomodulatory Therapies and New Treatment Paradigms for Axial Spondyloarthritis

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Emerging Immunomodulatory Therapies and New Treatment Paradigms for Axial Spondyloarthritis Current Rheumatology Reports (2019) 21: 35 https://doi.org/10.1007/s11926-019-0830-0 SPONDYLOARTHRITIS (M KHAN, SECTION EDITOR) Emerging Immunomodulatory Therapies and New Treatment Paradigms for Axial Spondyloarthritis Philip Mease1 Published online: 6 June 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review The purpose of this review is to educate the reader about the evolving classification of axial spondyloarthritis (AxSpA) and describe recent treatment data from clinical trials of medications with mechanisms of action other than TNF inhibition. The review will also address emerging treatment strategies for AxSpA. Recent Findings New and more sensitive classification schema for AxSpA find that the prevalence of the disease is more than twice that of the historic definition of ankylosing spondylitis (AS), when patients without radiographically observable damage to the sacroiliac joints are included. TNF inhibitors have shown efficacy in the full spectrum of disease. IL-17 inhibitors, e.g., secukinumab and ixekizumab and janus kinase (JAK) inhibitors, have shown good efficacy and relatively good safety in radiographically defined AxSpA and are being tested in non-radiographic (nr) AxSpA. Several immunomodulatory medicines approved for psoriasis, psoriatic arthritis, and rheumatoid arthritis have not shown efficacy in AxSpA, highlighting the impor- tance of conducting good-quality, placebo-controlled trials in this condition. Treatment strategies such as “treat to target” and tapering therapy are being studied. Summary There remains a large unmet need to identify and adequately treat the full spectrum of AxSpA. The use of TNF inhibitors has improved our ability to achieve remission or low disease activity in AxSpA. Newer medicines with different mechanisms of action, e.g., IL-17 or JAK inhibition, are also showing similar ability. Continued research, including identification of new targets of treatment, is critical. Keywords Axial spondyloarthritis . Ankylosing spondylitis . Non-radiographic axial spondyloarthritis . Biologic therapy . TNF inhibitor . IL-17 inhibitor Introduction therapies beyond TNF inhibitors (TNFi), thanks to the syner- gism of emerging findings in immunology, increasing numbers The development and approval of TNF inhibitor medications in of investigators coming into the field, encouraged by the ability ankylosing spondylitis (AS) which has occurred over the past to more effectively treat the disease and increased availability two decades revolutionized the management of AS, for which of governmental and biopharmaceutical funding, and an overall there had been scant prior effective therapy. For the first time, increase in interest in diagnosing and treating the remission or low disease activity could be achieved, allowing spondyloarthritis (SpA) disease spectrum by rheumatologists many patients to return to reasonably normal activity and qual- and other specialists. This article will touch on recent data on ity of life. During that time, there has also been a significant TNFi but focus on therapies with different mechanisms of ac- increase in research and education about disease pathophysiol- tion than TNFi that have emerged during the last decade, some ogy, diagnosis, assessment, and the development of new of which are now approved for use in clinical practice. This article is part of the Topical Collection on Spondyloarthritis Classification * Philip Mease [email protected] A starting point in the discussion is to establish disease termi- 1 Rheumatology Research, Swedish Medical Center/Providence-St. nology. Until 2009, the disease known by rheumatologists, Joseph Health, University of Washington School of Medicine, 601 regulatory agencies, and payors has been “ankylosing spon- Broadway Suite 600, Seattle, WA 98122, USA dylitis.” This condition was classified by the modified New 35 Page 2 of 7 Curr Rheumatol Rep (2019) 21: 35 York (mNY) criteria in 1984 [1]. A requisite component of is critical to educate not only rheumatologists but also non- these classification criteria is the identification of characteris- rheumatologists such as primary care clinicians, physiatrists, tic changes of sacroiliac radiographs of sufficient severity, orthopedists, and physical therapists about this evolved under- such as peri-articular sclerosis, joint space narrowing or ero- standing of classification so as to improve case finding at an sions, in addition to clinical features of limitation of back earlier stage of disease when effective treatment may yield mobility and chronicity. By these criteria, it has been significant disease modification and result in shorter duration established that approximately 0.5% of the US population, of disabling symptoms and signs. in a ratio of 2:1 male to female gender, can be classified with In this article, the term “SpA” will refer to the overarching AS [2••]. The great majority of these patients will be positive disease in humans as well as translational studies in animals, for the HLA-B27 gene marker, although the strength of this “AxSpA” will refer to the overall set of both radiographically association varies among different ethnic and racial groups. as well as non-radiographically defined disease, “AS” will be As our understanding of the disease has evolved, including considered synonymous with “radiographic axial increased use of advanced imaging of the spine and sacroiliac spondyloarthritis” (r-AxSpA) and “non-radiographic axial joints with magnetic resonance imaging (MRI) technology spondyloarthritis” or nr-AxSpA will refer to all AxSpA pa- and increased diagnostic sensitivity about earlier diagnosis tients without clearcut radiographic sacroiliac changes. The and effective treatment before fixed spinal structural damage majority of the studies referred to will have been comprised has occurred, the classification schema have also evolved. of patients fulfilling mNY AS criteria. Current drug develop- Several criteria have been proposed, including the European ment programs all include studies of both AS/r-AxSpA and Spondylarthropathy Study Group (ESSG) [3] and Amor [4] nr-AxSpA patient populations. The pathway for regulatory criteria, which allowed for a broader disease definition. The approval for both of these patient groups is now well- most recent classification criteria were developed by the established in Europe and other parts of the world. In the Assessment of SpondyloArthritis International Society USA, the FDA has previously only recognized an indication (ASAS) for predominantly axial SPA (AxSpA), published in for AS, given concerns about potential misclassification of 2009 [5, 6•, 7•] and subsequently accompanied by criteria for other forms of SpA, but has now established a path for regu- predominantly peripheral SpA. A patient with AxSpA may latory approval for a nr-AxSpA indication so that newer ther- fulfill this criteria set by fulfilling the “stem,” i.e., having back apies are anticipated to gain approval in this indication in the pain more than 3 months and onset before 45 years of age, and US in the near future, depending on the outcome of studies. then by fulfilling one of two “arms,” the “imaging” arm or the “HLA-B27/clinical arm”. The former is fulfilled if the patient either demonstrates characteristic radiographic sacroiliac Assessment changes as defined by the original mNY criteria or character- istic sacroiliac MRI changes consistent with inflammation TNF Inhibitors—New Developments along with at least one item from a list of typical SpA fea- tures1. The latter aspect is considered “non-radiographic” Recognizing the pivotal role of the cytokine, TNF, in the path- since MRI is not a radiographic technology. The “clinical” ophysiology of autoimmune and other inflammatory diseases, arm is fulfilled if the patient is positive for the HLA-B27 gene inhibitors of this cytokine were studied in rheumatoid arthritis and also at least two items from the list of SpA features. The (RA) and subsequently psoriatic arthritis (PsA), AS, inflam- two arms taken together yield a specificity of 84.4% and sen- matory bowel disease (IBD), psoriasis and other indications. sitivity of 82.9%. By including the MRI and HLA-B27 ele- Five TNF inhibitors (TNFi), etanercept, infliximab, ments, the new criteria allow for earlier case finding before adalimumab, golimumab, and certolizumab pegol, have been structural damage has occurred, required as part of the mNY approved for AS globally. The most recent approval was for criteria. Eventually, many patients will display characteristic the intravenous form of golimumab, complementing the sub- sacroiliac radiographic changes but not all, so the non- cutaneous form of this agent. All but infliximab have also radiographic “stage” of the disease should not be considered been approved for the treatment of nr-AxSpA in Europe and an automatic precursor to a more structurally damaged state. other parts of the world, but not in the USA. A trial of By the newer criteria, studies suggest that at least 1% of the certolizumab in nr-AxSpA, abiding by FDA regulatory guid- US population may be classified as being afflicted with ance requiring 12 months of placebo control, has been com- AxSpA, with nearly half being “non-radiographic” in presen- pleted; a decision on approval by the FDA in this indication is tation, and the gender ratio of AxSpA is 1:1 male to female. It pending. In this trial, ASAS 40 response was achieved by 48% vs. 11% in the certolizumab 200 mg q 2 weeks arm vs. place- bo
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