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Axial Spondyloarthritis: New Advances in Diagnosis and Management

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Axial Spondyloarthritis: New Advances in Diagnosis and Management STATE OF THE ART REVIEW Axial spondyloarthritis: new advances in diagnosis BMJ: first published as 10.1136/bmj.m4447 on 4 January 2021. Downloaded from and management Christopher Ritchlin,1 Iannis E Adamopoulos2 ABSTRACT Axial spondyloarthritis (axSpA) is an inflammatory disease of the axial skeleton 1Allergy, Immunology & Rheumatology Division, associated with significant pain and disability. Previously, the diagnosis of University of Rochester Medical ankylosing spondylitis required advanced changes on plain radiographs of the Center, Rochester, New York, USA 2Rheumatology, Allergy & Clinical sacroiliac joints. Classification criteria released in 2009, however, identified a Immunology Division, University of California, Davis, Shriners subset of patients, under the age of 45, with back pain for more than three months Hospital, Sacramento, California, in the absence of radiographic sacroiliitis who were classified as axSpA based on USA Correspondence to: C Ritchlin a positive magnetic resonance imaging or HLAB27 positivity and specific clinical christopher_ritchlin@urmc. rochester.edu features. This subgroup was labeled non-radiographic (nr)-axSpA. These patients, Cite this as: BMJ 2021;372:m4447 compared with those identified by the older New York criteria, contained a larger http://dx.doi.org/10.1136/bmj.m4447 percentage of women and demonstrated less structural damage. However, their Series explanation: State of the Art Reviews are commissioned clinical manifestations and response to biologics were similar to radiographic axSpA. on the basis of their relevance to academics and specialists The discovery of the interleukin (IL) IL-23/IL-17 pathway revealed key molecules in the US and internationally. involved in the pathophysiology of axSpA. This discovery propelled the generation For this reason they are written predominantly by US authors. of antibodies directed toward IL-17A, which are highly effective and demonstrate treatment responses in axSpA that are similar to those observed with anti-TNF agents. The finding that agents that block IL-23 were not effective in axSpA came as http://www.bmj.com/ a surprise and the potential underlying mechanisms underlying this lack of response are discussed. New agents with dual inhibition of the IL-17A and F isoforms and some oral small molecule agents that target the Jak-STAT pathway, have also shown efficacy in axSpA. on 24 September 2021 by guest. Protected copyright. Introduction ankylosing spondylitis was 11 years in Europe3 and Low back pain, the fifth most common symptom 13.5 years in the US.4 Other estimates, however, leading to physician visits in the United States, report earlier referral following initial symptoms but affects approximately 80% of individuals over their delay intervals vary from country to country. Analysis lifespan.1 Fortunately, most of these episodes are of a large US commercial administrative database short lived, due to mechanical causes and respond showed a delay of 11 months from the development to medications, physiotherapy, and time. However, of back pain to rheumatology referral5 and a study chronic back pain (duration lasting >three months) based on questionnaires to rheumatologists from 56 occurs in approximately 20% of the US population countries found that a referral delay of >three years based on the National Health and Nutrition was more common in Western Europe and other Examination (NHANES) survey conducted in 2009- countries of the world when compared with Canada 10: applying additional criteria such as individuals and the US.6 under the age of 40, back pain characterized by While the challenges of timely diagnosis and insidious onset, morning stiffness, and improvement treatment remain formidable obstacles, it became with exercise but not rest and pain that is worse at apparent that the diagnosis of ankylosing spondylitis, night is present in 5% to 6% of normal subjects.2 which required advanced changes on radiographs Some of these patients will have spondyloarthritis, of the sacroiliac joints (SIJ), was not capturing a a condition for which an array of therapies is now population of patients with inflammatory back available. Regrettably, delay in the diagnosis of pain and clinical features of spondyloarthritis. This spondyloarthritis remains a major barrier that realization catalyzed a revision of the classification varies widely in different countries but overall time criteria under the heading axial spondyloarthritis to referral has decreased. Previous studies reported (axSpA), to be discussed in detail below, and the delay from symptom onset to the diagnosis of unveiled an expanded subgroup of patients the bmj | BMJ 2021;372:m4447 | doi: 10.1136/bmj.m4447 1 STATE OF THE ART REVIEW pain criteria for the diagnosis of SpA, many clinicians BMJ: first published as 10.1136/bmj.m4447 on 4 January 2021. Downloaded from Sources and selection criteria assume that most patients who meet these criteria We searched PubMed English language manuscripts from January 1 2000 to December will have features of SpA at some time point, if not 2019. We searched on key words or combinations of key words, including “axial evident on initial presentation.2 15 16 This assumption spondyloarthritis”, “spondyloarthropathy”, “ankylosing spondylitis”, “IL-17”, “IL-23”, “monoclonal antibodies”, “inhibitors”, “non-radiographic”, “radiographic”, “treatment is not supported by the evidence. The low prevalence recommendations and pathway”. We also reviewed references within the retrieved of SpA in a population based back pain cohort was manuscripts to identify additional relevant literature, some of which was published before documented in a retrospective longitudinal study 2000. We prioritized phase II and phase III trials but we also included well designed studies of patients with new onset inflammatory back pain derived from observational cohorts. We also focused on quality basic science manuscripts followed over a 12 year period and only 30% of these that contributed to the understanding of key mechanisms underlying cytokine interactions in patients were ultimately diagnosed with axSpA.17 the IL-23/IL-17 pathway. This study, however, had some limitations that included a small sample size and the concern that many primary care doctors did not inquire about without radiographic findings who have chronic inflammatory back pain over time, and, ultimately, back pain and improve with treatment. Moreover, only a fraction of these patients were evaluated by the increased number of patients at risk under the a rheumatologist.18 Nevertheless, characteristic fea- diagnostic heading of axSpA was accompanied by tures of inflammatory back pain or chronic low back an expansion of effective treatment options for these pain in an individual ≤45 years is an important clue patients. Genome-wide pooling studies have shown that should raise suspicion and generate the retrieval a significant association of the rare allele of the IL- of additional information regarding other SpA 23 receptor R381Q single nucleotide polymorphism, features with subsequent testing for HLAB27 and C which conferred protection against psoriatic arthritis, reactive protein, coupled in the appropriate setting ankylosing spondylitis, and Crohn’s disease, empha- with imaging (particularly magnetic resonance sizing the importance of IL-23 in many autoimmune imaging (MRI) of the SIJ). 7-10 diseases. This review will discuss key elements of Classification criteria for ankylosing spondylitis axSpA related to diagnosis, the unveiling of a pivotal published in 1984 were based on the presence of pathogenetic pathway centered on the cytokines radiographic changes in the SIJ consistent with IL-23 and IL-17, and current and future treatment the prevailing opinion that the disease originated options. in this location.19 It became apparent over time, however, that most younger patients with chronic Epidemiology back pain and inflammatory features did not meet http://www.bmj.com/ Incidence estimates per 100 000 patient years these radiographic criteria and they were labeled derived from a systematic review of population “undifferentiated SpA.”20 This diagnosis lacked studies in ankylosing spondylitis varied from 0.4 clarity and generated confusion among clinicians 11 (Iceland) to 15.0 (Canada). Non-radiographic regarding the relevance, natural history, and axSpA incidence rates are not published. The global therapeutic approach for this relatively large patient prevalence of ankylosing spondylitis ranges from 9 subgroup. In recognition of this problem and to to 30 per 10 000 in the general population but again address other deficiencies regarding the diagnosis on 24 September 2021 by guest. Protected copyright. wide variance is observed in studies from different and classification of ankylosing spondylitis, and 12 countries. In the only US population based study, based on clinical observations that the disease based on NHANES data, the overall age adjusted is present for years before the observation of prevalence of definite and probable SpA was 0.9% to radiographic damage to skeletal structures, the 1.4% (95% confidence interval 0.7 to 1.1) depending Assessment of SpondyloArthritis International 13 on the criteria used. Ankylosing spondylitis Society (ASAS) published a set of new classification prevalence rates per 100 000 persons also showed criteria that included both a genetic and an imaging considerable variation (16 studies: 6.5 in Japan to arm (fig 1).21 In addition to radiographic findings, 11 540.0 in Turkey).
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