International Journal of Rheumatic Diseases 2014; 17: 548–556
ORIGINAL ARTICLE
Consensus statement on the investigation and management of non-radiographic axial spondyloarthritis (nr-axSpA) Philip C. ROBINSON,1,2 Paul BIRD,3 Irwin LIM,4 Nivene SAAD,5,6 Lionel SCHACHNA,7 Andrew L. TAYLOR,8 Samuel L. WHITTLE9 and Matthew A. BROWN1,2 1
University of Queensland Diamantina Institute, 2Department of Rheumatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia, 3St George Clinical School, University of New South Wales, Sydney, New South Wales, 4BJC Health, Sydney, New South Wales, 5Department of Radiology, Princess Alexandra Hospital, 6University of Queensland, Brisbane, Queensland, 7Department of Rheumatology, Austin Health, Melbourne, Victoria, 8Royal Perth Hospital, Perth, Western Australia, and 9Rheumatology Unit, Queen Elizabeth Hospital, Woodville, South Australia, Australia
Abstract Aim: Non-radiographic axial spondyloarthritis (nr-axSpA) is axial inflammatory arthritis where plain radiographic damage is not evident. An unknown proportion of these patients will progress to ankylosing spondylitis (AS). The increasing recognition of nr-axSpA has been greatly assisted by the widespread use of magnetic resonance imaging. The aim of this article was to construct a set of consensus statements based on a literature review to guide investigation and promote best management of nr-axSpA. Methods: A literature review using Medline was conducted covering the major investigation modalities and treatment options available. A group of rheumatologists and a radiologist with expertise in investigation and management of SpA reviewed the literature and formulated a set of consensus statements. The Grade system encompassing the level of evidence and strength of recommendation was used. The opinion of a patient with nr-axSpA and a nurse experienced in the care of SpA patients was also sought and included. Results: The literature review found few studies specifically addressing nr-axSpA, or if these patients were included, their results were often not separately reported. Fourteen consensus statements covering investigation and management of nr-axSpA were formulated. The level of agreement was high and ranged from 8.1 to 9.8. Treatment recommendations vary little with established AS, but this is primarily due to the lack of available evidence on the specific treatment of nr-axSpA. Conclusion: The consensus statements aim to improve the diagnosis and management of nr-axSpA. We aim to raise awareness of this condition by the public and doctors and promote appropriate investigation and management. Key words: ankylosing spondylitis, non-radiographic axial spondyloarthritis, spondyloarthritis, tumor necrosis factor-alpha inhibitors.
INTRODUCTION
Correspondence: Professor Matthew Brown, University of Queensland Diamantina Institute, Translational Research Building, Princess Alexandra Hospital, 37 Kent Street, Woolloogabba, Queensland, Australia. Email: [email protected]
Spondyloarthritis (SpA) is a group of inter-related immune-mediated diseases with the hallmark clinical feature of axial inflammatory arthritis.1 Recent efforts have focused on redefining their classification, with patients manifesting predominant axial features classified as axial spondyloarthritis (axSpA).2 axSpA
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
nr-axSpA consensus statement
encompasses both ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA).3 nr-axSpA was first described as ‘spondylitic disease without radiological evidence of sacroiliitis’.4 Patients with AS meet the modified New York criteria including radiographic sacroiliitis of at least grade 2 bilaterally or grade 3 unilaterally.5 This degree of radiographically evident sacroiliac joint (SIJ) damage takes years to appear.6 Patients with nr-axSpA do not meet this radiographic criterion, but are classified as nr-axSpA either through evidence of acute inflammation on magnetic resonance imaging (MRI) and one SpA feature (for example psoriasis, dactylitis or uveitis) or the presence of human leucocyte antigen (HLA)-B27 and two SpA features.2 The Assessment of Spondyloarthritis International Society (ASAS) axial SpA classification criteria were developed in an attempt to: (i) enable earlier diagnosis, as early treatment may improve outcome;7,8 and (ii) include patients with unclassifiable or undifferentiated SpA who fail to meet other classification or diagnostic criteria but who require treatment.2,9 Although all patients with nr-axSpA do not progress to modified New York-defined AS,10 the disease activity, functional impairment, quality of life effects and health status as measured by Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life questionnaire and the Short Form 36 health survey are similar to patients with AS.11,12 In addition, the number of inflammatory lesions in the spine and SIJs on whole body MRI do not differ between active nr-axSpA and AS.13 Over the last decade, there have been major developments in the investigation, classification and treatment of SpA. To address these developments there have been a number of position or consensus statements on the treatment of spondyloarthritis, but to date they have focused primarily on AS14,15 or concentrated only on tumour necrosis factor inhibitor (TNFi) treatment.16,17 Why is another consensus statement needed? nr-axSpA is a distinct clinical entity because its demographics, genetics and response to treatment are different from AS.10,18 In addition the prognosis and outcome of nraxSpA is more heterogenous so one needs to view it as different from AS, where radiographic damage has already occurred.10 The aim of this study was to construct a set of consensus statements, supported by a literature review that encompasses the optimal investigation and management of nr-axSpA. The target population for this statement is all those involved in referring, treating and reviewing nr-axSpA. The
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relevance of the statement is both Australian and international by virtue of the exhaustive literature search. Recognition and referral of suspected nr-axSpA was not addressed, but has been studied19–21 and reviewed22,23 recently.
METHODS A group of clinician rheumatologists and a radiologist, all experienced in the clinical presentation, imaging and management of nr-axSpA was assembled. A set of questions was developed to define the topics to be addressed by the literature review (see Table S1). These questions were reviewed by the consensus panel and edited to ensure inclusion of the most clinically pertinent topics in investigation and management of nr-axSpA. A literature search was conducted covering Medline (English language-restricted) 1966 to 31 August 2013 using the search terms: ‘spondyloarthritis’ OR ‘axial spondyloarthritis’ OR ‘non-radiographic axial spondyloarthritis’. This was combined with specific search terms as detailed in Table S2. Titles and abstracts of all search results were then reviewed and full text reviewed if there was a possibility that the publication was relevant to the question. Other literature known to the panel or found in parallel searches was also included. ‘Ankylosing spondylitis’ was not used as a search term in the literature review as the major goal was to review studies related specifically to nr-axSpA. The results of the literature review were then discussed and consensus statements developed. Participants agreed on the level of evidence, strength of recommendation and level of individual agreement with each consensus statement. The Grade level of evidence and strength of recommendation system for assigning scores was used.24 These recommendations were then reviewed by a patient representative diagnosed with nr-axSpA and a nurse specialized in the care of patients with SpA. Their comments and feedback are reported herein.
RESULTS The consensus group formulated statements on 11 of 14 questions addressed in the literature review. Three questions are therefore discussed solely in the text of the manuscript. In addition three further consensus statements covering other areas were formulated at the meeting. The consensus statements, levels of evidence, strengths of recommendation and levels of agreement are presented in Table 1.
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Table 1 nr-axSpA investigation and management consensus statements Consensus statements The patient’s views, preferences and goals are central and care should be a partnership between the clinical team and the patient Patient education is a key part of the management of nr-axSpA A comprehensive history and physical examination should be carried out for the assessment of suspected nr-axSpA CRP should be measured when considering the diagnosis of nr-axSpA; high sensitivity CRP does not add value to normal CRP HLA-B27 status should be determined when considering the diagnosis of nr-axSpA Plain pelvic radiographs may be useful to distinguish non-inflammatory and inflammatory causes of back pain; a normal radiograph does not exclude nr-axSpA Sacroiliiac joint MRI should be used in those with clinical suspicion of nr-axSpA. T1 and STIR without gadolinium is the recommended protocol Computed tomography is not recommended for the investigation of suspected nr-axSpA Classification criteria have value in the diagnosis of nr-axSpA, but classification criteria sets should not be used to include or exclude this diagnosis in individual patients Physiotherapy may be useful in the management of nr-axSpA There is no role for DMARDs in the management of axial manifestations in nr-axSpA. Sulphasalazine can be considered for those with peripheral manifestations in nr-axSpA Non-steroidal anti-inflammatories are recommended as first-line pharmacological treatment for the management of nr-axSpA TNF inhibitors are useful in the management of nr-axSpA Glucocorticoids may have a limited role in NSAID-refractory nr-axSpA.
Level of evidence
Grade of recommendation
Level of agreement, mean (SD)
D
1
9.5 (1.1)
D D
1 1
9.4 (1.2) 9.4 (0.7)
C
1
8.8 (1.0)
C
1
9.1 (1.0)
D
2
9.5 (0.8)
B
1
9.8 (0.5)
C
1
9.5 (1.1)
C
1
8.1 (1.0)
D C
2 2
9.1 (0.8) 8.1 (1.9)
B
1
9.1 (1.1)
B D
1 2
9.6 (0.5) 9.0 (0.9)
CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; MRI, magnetic resonance imaging; nr-axSpA, non-radiographic axial spondyloarthritis; NSAID, non-steroidal anti-inflammatory drug; STIR, short T1 inversion recovery.
Consensus statements The patient’s views, preferences and goals are central and care should be a partnership between the clinical team and the patient This recognizes that the care of patients with nr-axSpA is a partnership between healthcare professionals and the patient. There is some evidence that increased involvement of patients in decisions regarding their care improves outcomes, although no evidence is available specifically in nr-axSpA.25 Individual preferences for treatment and an acceptable risk benefit ratio for interventions differ between patients. The patient should therefore be central to the management of their condition. Patient education is a key part of the management of nr-axSpA This recognizes the role of education in empowering patients. Numerous randomized controlled studies, although none in nr-axSpA, have found improvements in
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a variety of outcome measures in both acute and chronic medical conditions with educational interventions.26–29 When patients understand the nature of their medical problems and the significance of investigations, treatments and their prognoses, outcomes are likely to be improved through mechanisms such as alignment of treatment goals,30 increased adherence with therapies, and better attendance at investigations and follow-up appointments. A comprehensive history and physical examination should be carried out for the assessment of suspected nr-axSpA This reflects good medical practice and is supported by evidence that recognitions of the signs and symptoms of nr-axSpA clearly contribute to diagnosis.31,32 C-reactive protein (CRP) should be measured when considering the diagnosis of nr-axSpA; high-sensitivity CRP (hsCRP) does not add value to normal CRP This reflects the evidence that elevated CRP contributes to the diagnosis of a combined group of both nr-
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nr-axSpA consensus statement
axSpA and AS.31 There was no evidence in the literature to support the utility of erythrocyte sedimentation rate (ESR) but this can also be used in practice as a measure of systemic inflammation. Two studies addressed the additional benefit of whether hsCRP offered any significant clinical advantages compared to non-hsCRP measurements. Navarro-Comparos et al. found there was no improvement in classification using hsCRP in the DESIR cohort, although it should be noted the question for the consensus group was related to diagnosis, not classification.33 Poddubbnyy et al. reported that in the GESPIC cohort, there was a correlation between clinical parameters and hsCRP in AS, but not in nr-axSpA.34 Therefore in nr-axSpA the panel felt that there was no greater benefit from the use of hsCRP compared with routine CRP measures. HLA-B27 status should be determined when considering the diagnosis of nr-axSpA This statement reflects evidence that HLA-B27 status has good sensitivity and specificity from studies diagnosing SpA. In the Ability-1 trial 45% of the imagingarm nr-axSpA patients were HLA-B27-positive (i.e., 45% sensitive), although it is required for classification in the ASAS clinical arm and therefore is confounded by circularity.35 In the SPACE cohort of chronic back pain patients with the physician diagnosis as gold standard, HLA-B27 was 78% sensitive and 94% specific for axSpA (both nr-axSpA and AS).32 In the ASAS classification criteria cohort HLA-B27 was 66% sensitive and 73% specific for axSpA (both nr-axSpA and AS), with physician diagnosis as the gold standard. Plain pelvic radiographs may be useful to distinguish non-inflammatory and inflammatory causes of back pain; a normal radiograph does not exclude nr-axSpA Differentiation of nr-axSpA and AS requires X-ray of the SIJs. A plain antero-posterior (AP) radiograph of the pelvis that has gradable change as defined by the modified New York criteria (for example unilateral grade 2) but does not meet the criteria for AS, may increase clinical suspicion of inflammatory disease, but the accuracy, reliability and reproducibility of scoring SIJ changes in plain radiographs is low.36–39 The plain AP radiograph of the pelvis is the recommended view, as oblique pelvic views or angled AP views do not improve diagnostic value compared to the plain AP view and are associated with an increased radiation exposure.40 The AP view also allows assessment of the hip joints that are commonly involved in axSpA. SIJ MRI should be used in those with clinical suspicion of nr-axSpA. T1 and short tau inversion recovery (STIR) without gadolinium is the recommended protocol
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This statement recognizes the increasingly important role of this imaging modality in demonstrating the presence of inflammatory disease in those with chronic back pain. MRI is sensitive for bone marrow edema, a characteristic feature of acute inflammation of the SIJ. Significant research effort has focused on the definitions of positive imaging in the SIJ and the spine. Currently the ASAS definition includes only inflammatory disease in the SIJs,41 but there has been research suggesting the inclusion of structural disease (for example erosions) improves sensitivity.42 In addition, a global assessment of the positive or negative nature of an SIJ scan also improves sensitivity.43 T1 and STIR imaging are the optimal sequences used and gadolinium enhancement is not additive in making the diagnosis of axSpA.41,44,45 There is also research to suggest there is little value in scanning the spine in addition to the SIJs,46 although it should be noted that often an MRI scan is not just used to include/exclude nr-axSpA, but also investigate for the presence of other pathology that could explain chronic back pain. Computed tomography (CT) is not recommended for the investigation of suspected nr-axSpA This statement reflects the poor sensitivity of CT for inflammatory disease and the significant radiation exposure it involves. Although CT has greater sensitivity than plain radiography for chronic structural changes (e.g., sclerosis, erosions), as by definition nr-axSpA does not have significant structural lesions, this property is not advantageous in this setting. Bone marrow edema that is often present in nr-axSpA cannot be detected by CT scan. Classification criteria have value in the diagnosis of nr-axSpA, but classification criteria sets should not be used to include or exclude this diagnosis in individual patients Classification criteria are designed to define a homogenous group of patients for use in research and clinical trial settings, and therefore are not developed specifically for diagnosis. However, in fulfilling the classification criteria for nr-axSpA, a patient’s post-test probability of having a clinician diagnosis of SpA is increased, and not fulfilling the criteria set reduces the post-test probability of SpA. By necessity, classification criteria include many features of the relevant disease, but using the clinician diagnosis as gold standard, no SpA classification criteria set has 100% specificity. Information is lacking for nr-axSpA, but for SpA in general the specificity of different SpA classification criteria ranges from 83% to 88%.47 A hypothetical clinical example of the potential issue is: a 30-year-old patient who has Crohn’s disease and mechanical back pain
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from a herniated disc, who is HLA-B27-positive and has a raised CRP from their bowel disease could be classified as nr-axSpA (based on the ASAS criteria2) when they do not in fact have nr-axSpA. Therefore classification criteria should not be used solely in individual patients to establish or exclude the diagnosis of SpA. Physiotherapy may be useful in the management of nr-axSpA There is a notable absence of published studies on physiotherapy in nr-axSpA. While physiotherapy has been shown to reduce pain and improve function in AS,48 the only trial of physiotherapy that included nr-axSpA found during the literature search was small and did not separately report the results of the nr-axSpA patients.49 There is no role for disease-modifying antirheumatic drugs (DMARDs) in the management of axial manifestations in nr-axSpA. Sulphasalazine can be considered for those with peripheral manifestations in nr-axSpA There is no evidence of DMARD efficacy for axial manifestations of nr-axSpA. In AS, where there is evidence available, the use of sulphasalazine (SSZ) for axial manifestations is not supported.15 The ESTHER trial compared etanercept with SSZ in axSpA (nr-axSpA and AS) and the 64 joint count and enthesitis scores decreased substantially on SSZ, with no difference detected between etanercept and SSZ in these outcome measures; however, there was no placebo arm in this trial.50 Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line pharmacological treatment for the management of nr-axSpA NSAIDs were demonstrated to be effective in the INFAST trial of early axSpA: in the 1000 mg naproxen monotherapy arm 57% achieved ASAS40 and 35% achieved ASAS Partial Remission (the primary outcome) at week 28.7 There was no placebo comparison arm in this trial. Of all the NSAIDs naproxen has the best efficacy data and also the best cardiovascular risk profile.51,52 TNF inhibitors are useful in the management of nr-axSpA There are a number of trials of TNFi for treatment of nr-axSpA, including adalimumab,35 certolizumab,53 etanercept50 and infliximab.7 These demonstrate good efficacy, especially in early disease and in combination with NSAIDs. The INFAST trial7 (comparing infliximab with naproxen with naproxen alone in axSpA) demonstrated ASAS40 response rates of 75% in the infliximab/ naproxen arm at week 28. Treatment responses of nr-axSpA patients with positive SIJ MRI scans are similar to those observed in patients with AS.53,54 The Ability-1 trial included both MRI-positive and -negative nr-axSpA and a post hoc subgroup analysis suggested that those
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patients with a positive SIJ MRI or a CRP above the upper limit of normal (ULN) had higher absolute response rates. All other trials have included only patients with a positive SIJ MRI or CRP above the ULN so the question of whether response to TNFi agents varies according to MRI or CRP status is currently difficult to answer. Ciurea and colleagues reported results from the Swiss Clinical Quality Management cohort and found ASAS40 and ASAS Major Improvement response rates were higher in patients with AS compared to nr-axSpA (odds ration [OR] = 2.2, P = 0.02).11 In those patients with an elevated CRP at baseline (both AS and nr-axSpA) the ASAS40 response was higher in the AS group compared to nr-axSpA (52% and 38%, respectively). Further research is clearly required to determine the best predictors of response in nr-axSpA. Glucocorticoids (GCs) may have a limited role in NSAID-refractory nr-axSpA. There is a lack of evidence for GCs in nr-axSpA. A recent trial of prednisolone in AS demonstrated relatively poor efficacy, which is consistent with clinical experience.55 GCs have substantial medium- and longterm adverse effects, especially on glucose and bone metabolism and therefore their use should be considered carefully in light of the risks, benefits and treatment alternatives. The group did not make statements about the role of bisphosphonates, antibiotics or biological agents other than TNFi agents in the treatment of nr-axSpA. There is no evidence for the efficacy of bisphosphonates in nraxSpA, and some evidence for the use of bisphosphonates in AS,56 but the group had differing clinical experience with these agents. Antibiotics have a role for the treatment of active symptomatic infection that can precipitate reactive arthritis (ReA); the goal for this treatment is elimination of the active symptomatic infection. There is, in addition, some conflicting evidence for the use of chronic antibiotics in the treatment of ReA;57–60 however, this practice is not universally accepted or widespread, potentially reflecting uncertainties around the strength of the evidence, selection of appropriate patients and the risk/benefit balance with the potential adverse effects of long-term antibiotic therapy. A number of alternative biologic agents have been trialed in AS, including rituximab (anti-CD20),61,62 abatacept (CTLA4 Ig),63 tocilizumab (anti-interleukin [IL]-6R),64 sarilumab (anti-IL-6R),65 secukinumab (anti-IL-17)66 and anakinra (IL-1 receptor antagonist)67 but there have been no trials, and limited clinical experience with these agents in nr-axSpA and therefore the group did not make any statement regarding their use.
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nr-axSpA consensus statement
Patient perspective The patient with nr-axSpA agreed with the consensus statements and made the following additional comments: (i) ‘As a patient I want to be treated in the best possible way through solid evidence and what the current research findings are’; (ii) regarding physiotherapy, ‘It is the first tool of pain relief, it is very helpful with the management of this condition. I would like to think all physiotherapists are keeping up to date with new techniques’; and (iii) ‘I would like to see national guidelines for all patients, so that we all receive the same valued care, doesn’t matter where you live’.
Nursing perspective A nurse practitioner with extensive experience in care of SpA patients agreed with the statements and made the following comments: (i) ‘I like the fact that the patient’s views are the first statement as I believe this is of paramount importance and that patient education is also identified as a key issue’; and (ii) ‘For the management of this disease, all patients should have equal access to appropriate investigations and potentially life-changing treatments. Consensus statements from experienced rheumatologists such as these provide evidence for the standards that should be met.’
CONCLUSIONS Improvements in the care of patients with nr-axSpA will come from increased recognition of the condition by the public, primary care physicians and medical specialists as well as the use of effective therapies. A patient passes through the stage of nr-axSpA on their way to AS, although not all patients who have nr-axSpA will eventually develop AS.10 Historically there has been a long delay in recognizing and treating patients with AS,6 and the wider recognition of nr-axSpA is likely to make a significant difference to patient symptom burden due to appropriate treatment, regardless of whether they progress to AS or not. We know that those patients with nr-axSpA have similar levels of disease activity to AS patients, and active nr-axSpA patients have similar levels of inflammation on MRI scan to patients with AS.11–13 The set of consensus statements compiled from both evidence and expert opinion will guide clinicians in the investigation and management of nr-axSpA. In addition the group hopes it will encourage better access to TNFi agents for appropriate patients with nr-axSpA. There are limitations to the evidence base and the consensus statements. In many diseases including
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axSpA, where the etiology and disease mechanisms are incompletely understood, the physician’s opinion is often used as the gold standard to validate diagnostic procedures and tests. However, the result is that assessments of individual diagnostic tests or procedures is then confounded by circularity, because the same tools used to define the gold standard are then tested against the gold standard. This is a limitation of the assessment of diagnostic tests against a gold standard where knowledge of the true disease mechanisms is uncertain. Another limitation is the lack of evidence relating specifically to nr-axSpA, and even when studies include these patients the results of AS and nr-axSpA are not always separately reported.2,32,49 As with early treatment in rheumatoid arthritis, there is the potential for early treatment in SpA to change prognosis. The INFAST 1 and 2 trials of very early axSpA patients showed high response rates from combined NSAID–TNFi treatment and if patients reached partial remission on TNFi almost half remained in partial remission 6 months after discontinuing their TNFi with or without NSAIDs.7,8 This is encouraging early data that early treatment could lead to drug-free remission for a proportion, perhaps the ‘window of opportunity’ may be applicable to SpA as it is to rheumatoid arthritis. Research on TNFi use in AS also suggests that early use may improve radiographic outcome.68 These consensus statements are the product of the currently available evidence, which is somewhat limited. Currently the treatment for nr-axSpA varies little from that of AS, but this relates primarily to the lack of evidence on the specific treatment of nr-axSpA. However, evidence is growing about this important condition, and increased recognition and research focus will enable future iterations of these consensus statements to be progressively improved.
DISCLOSURES PR: consulting, clinical trials, travel support and/or speaking for Abbvie, Janssen and Pfizer. PB: advisory boards for Abbvie, Celgene, Pfizer, Roche, UCB and clinical trials for Abbvie, Celgene, Pfizer, Roche, Eli Lily. IL: consulting, advisory board involvement, travel support and/or speaker honoraria for Abbvie, UCB, Janssen, BMS, Novartis, Roche and Pfizer. ALT: consulting, clinical trials, travel support and/or speaking for Abbvie, Janssen, Roche, UCB and Pfizer. SW: consulting, speaking fees and travel support from Abbvie, Janssen, Pfizer and UCB. MAB: advisory board, speaker’s bureau
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and research funding from Abbvie. Advisory board for Pfizer. LS and NS no disclosures.
CONTRIBUTIONS PR performed the literature review with the assistance of MH (see acknowledgements). PR and MAB constructed the draft consensus statements upon which PR, SW, PB, IL, LS, MAB, NS and AT then reached consensus. All authors contributed to editing and approving the manuscript.
ACKNOWLEDGEMENT AND FUNDING We thank Linda Bradbury, nurse practitioner, and the nr-axSpA patient who contributed their perspectives on the consensus statements. We acknowledge the assistance of Dr Murray Hargrave in the literature review. We acknowledge the provision of an unrestricted grant from Abbvie Australia to the University of Queensland to enable the literature review to be performed, and for convening and provision of facilities for the consensus meeting. Abbvie had no role beyond provision of funding. Specifically, Abbvie did not participate or have any involvement in setting the literature questions, performing the review, drafting the consensus statements, discussing the evidence, agreeing on the consensus statements, the manuscript preparation, or the decision to submit for publication.
REFERENCES 1 Baeten D, Breban M, Lories R, Schett G, Sieper J (2013) Are spondylarthritides related but distinct conditions or a single disease with a heterogeneous phenotype? Arthritis Rheum 65, 12–20. 2 Rudwaleit M, van der Heijde D, Landewe R et al. (2009) The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 68, 777–83. 3 Sieper J, van der Heijde D (2013) Review: Nonradiographic axial spondyloarthritis: new definition of an old disease? Arthritis Rheum 65, 543–51. 4 Khan MA, van der Linden SM, Kushner I, Valkenburg HA, Cats A (1985) Spondylitic disease without radiologic evidence of sacroiliitis in relatives of HLA-B27 positive ankylosing spondylitis patients. Arthritis Rheum 28, 40–3. 5 van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27, 361–8.
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6 Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J (2003) Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis. Rheumatol Int 23, 61–6. 7 Sieper J, Lenaerts J, Wollenhaupt J et al. (2014) Efficacy and safety of infliximab plus naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, Part 1. Ann Rheum Dis 73, 101–7. 8 Sieper J, Lenaerts J, Wollenhaupt J et al. (2014) Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2. Ann Rheum Dis 73, 108–13. 9 Rudwaleit M, Landewe R, van der Heijde D et al. (2009) The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal. Ann Rheum Dis 68, 770–6. 10 Robinson PC, Wordsworth BP, Reveille JD, Brown MA (2013) Axial spondyloarthritis: a new disease entity, not necessarily early ankylosing spondylitis. Ann Rheum Dis 72, 162–4. 11 Ciurea A, Scherer A, Exer P et al. (2013) Tumor necrosis factor alpha inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large observational cohort. Arthritis Rheum 65, 3096–106. 12 Kiltz U, Baraliakos X, Karakostas P et al. (2012) The degree of spinal inflammation is similar in patients with axial spondyloarthritis who report high or low levels of disease activity: a cohort study. Ann Rheum Dis 71, 1207–11. 13 Althoff CE, Sieper J, Song IH et al. (2013) Active inflammation and structural change in early active axial spondyloarthritis as detected by whole-body MRI. Ann Rheum Dis 72, 967–73. 14 Zochling J, van der Heijde D, Burgos-Vargas R et al. (2006) ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 65, 442–52. 15 Braun J, van den Berg R, Baraliakos X et al. (2011) 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 70, 896–904. 16 Braun J, Pham T, Sieper J et al. (2003) International ASAS consensus statement for the use of anti-tumour necrosis factor agents in patients with ankylosing spondylitis. Ann Rheum Dis 62, 817–24. 17 van der Heijde D, Sieper J, Maksymowych WP et al. (2011) 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann Rheum Dis 70, 905–8. 18 Robinson PC, Brown MA (2012) The genetics of ankylosing spondylitis and axial spondyloarthritis. Rheum Dis Clin North Am 38, 539–53.
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19 Sieper J, Srinivasan S, Zamani O et al. (2013) Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study. Ann Rheum Dis 72, 1621–7. 20 Poddubnyy D, Vahldiek J, Spiller I et al. (2011) Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care. J Rheumatol 38, 2452–60. 21 Braun A, Gnann H, Saracbasi E et al. (2013) Optimizing the identification of patients with axial spondyloarthritis in primary care–the case for a two-step strategy combining the most relevant clinical items with HLA B27. Rheumatology (Oxford) 52, 1418–24. 22 Rudwaleit M, Sieper J (2012) Referral strategies for early diagnosis of axial spondyloarthritis. Nat Rev Rheumatol 8, 262–8. 23 Braun J, Sieper J (2012) Classification, diagnosis, and referral of patients with axial spondyloarthritis. Rheum Dis Clin North Am 38, 477–85. 24 Guyatt GH, Oxman AD, Vist GE et al. (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336, 924–6. 25 Say RE, Thomson R (2003) The importance of patient preferences in treatment decisions–challenges for doctors. BMJ 327, 542–5. 26 Stewart MA (1995) Effective physician-patient communication and health outcomes: a review. CMAJ 152, 1423–33. 27 Egbert LD, Battit GE, Welch CE, Bartlett MK (1964) Reduction of postoperative pain by encouragement and instruction of patients. A Study of Doctor-Patient Rapport. N Engl J Med 270, 825–7. 28 Thompson SC, Nanni C, Schwankovsky L (1990) Patientoriented interventions to improve communication in a medical office visit. Health Psychol 9, 390–404. 29 Greenfield S, Kaplan SH, Ware JE Jr, Yano EM, Frank HJ (1988) Patients’ participation in medical care: effects on blood sugar control and quality of life in diabetes. J Gen Intern Med 3, 448–57. 30 Selzer RM, Ellen S, McGartland M (2013) Alignment: a conceptual shift from adherence. Intern Med J 43, 940–2. 31 Molto A, Paternotte S, Comet D et al. (2013) Performances of the ASAS axial spondyloarthritis criteria for diagnostic and classification purposes in patients visiting a rheumatologist because of chronic back pain: The DECLIC study. Arthritis Care Res (Hoboken) 65, 1472–81. 32 van den Berg R, de Hooge M, van Gaalen F, Reijnierse M, Huizinga T, van der Heijde D (2013) Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught Early (SPACE) cohort. Rheumatology (Oxford) 52, 1492–9. 33 Navarro-Compan V, van der Heijde D, Combe B, Cosson C, van Gaalen FA (2013) Value of high-sensitivity C-reactive protein for classification of early axial spondyloarthritis: results from the DESIR cohort. Ann Rheum Dis 72, 785–6.
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34 Poddubnyy DA, Rudwaleit M, Listing J, Braun J, Sieper J (2010) Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Ann Rheum Dis 69, 1338–41. 35 Sieper J, van der Heijde D, Dougados M et al. (2013) Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 72, 815–22. 36 van Tubergen A, Heuft-Dorenbosch L, Schulpen G et al. (2003) Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann Rheum Dis 62, 519–25. 37 Devauchelle-Pensec V, D’Agostino MA, Marion J et al. (2012) Computed tomography scanning facilitates the diagnosis of sacroiliitis in patients with suspected spondylarthritis: results of a prospective multicenter French cohort study. Arthritis Rheum 64, 1412–9. 38 Hollingsworth PN, Cheah PS, Dawkins RL, Owen ET, Calin A, Wood PH (1983) Observer variation in grading sacroiliac radiographs in HLA-B27 positive individuals. J Rheumatol 10, 247–54. 39 Yazici H, Turunc M, Ozdogan H, Yurdakul S, Akinci A, Barnes CG (1987) Observer variation in grading sacroiliac radiographs might be a cause of ‘sacroiliitis’ reported in certain disease states. Ann Rheum Dis 46, 139–45. 40 Maksymowych WP (2012) Controversies in conventional radiography in spondyloarthritis. Best Pract Res Clin Rheumatol 26, 839–52. 41 Rudwaleit M, Jurik AG, Hermann KG et al. (2009) Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis 68, 1520–7. 42 Weber U, Lambert RG, Pedersen SJ, Hodler J, Ostergaard M, Maksymowych WP (2010) Assessment of structural lesions in sacroiliac joints enhances diagnostic utility of magnetic resonance imaging in early spondylarthritis. Arthritis Care Res (Hoboken) 62, 1763–71. 43 Weber U, Lambert RG, Ostergaard M, Hodler J, Pedersen SJ, Maksymowych WP (2010) The diagnostic utility of magnetic resonance imaging in spondylarthritis: an international multicenter evaluation of one hundred eightyseven subjects. Arthritis Rheum 62, 3048–58. 44 de Hooge M, van den Berg R, Navarro-Compan V et al. (2013) Magnetic resonance imaging of the sacroiliac joints in the early detection of spondyloarthritis: no added value of gadolinium compared with short tau inversion recovery sequence. Rheumatology (Oxford) 52, 1220–4. 45 Hermann KG, Landewe RB, Braun J, van der Heijde DM (2005) Magnetic resonance imaging of inflammatory lesions in the spine in ankylosing spondylitis clinical trials: is paramagnetic contrast medium necessary? J Rheumatol 32, 2056–60.
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46 Weber U, Zubler V, Zhao Z et al. (2013) Does spinal MRI add incremental diagnostic value to MRI of the sacroiliac joints alone in non-radiographic axial spondyloarthritis? Ann Rheum Dis 72 (Suppl. 3), 145. 47 Taylor WJ, Robinson PC (2013) Classification criteria: peripheral spondyloarthropathy and psoriatic arthritis. Curr Rheumatol Rep 15, 317. 48 Dagfinrud H, Kvien TK, Hagen KB (2008) Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev, CD002822. 49 Eppeland SG, Diamantopoulos A, Soldal DM, Haugeberg G (2013) Short term in-patient rehabilitation in axial spondyloarthritis - the results of a 2-week program performed in daily clinical practice. BMC Res Notes 6, 185. 50 Song IH, Hermann K, Haibel H et al. (2011) Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial. Ann Rheum Dis 70, 590–6. 51 Coxib and traditional NSAID Trialists’ Collaboration, Bhala N, Emberson J et al. (2013) Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 382, 769–79. 52 Trelle S, Reichenbach S, Wandel S et al. (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342, c7086. 53 Landewe R, Braun J, Deodhar A et al. (2013) Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis 73, 39–47. 54 Song IH, Weiss A, Hermann KG et al. (2013) Similar response rates in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann Rheum Dis 72, 823–5. 55 Haibel H, Fendler C, Listing J, Callhoff J, Braun J, Sieper J (2013) Efficacy of oral prednisolone in active ankylosing spondylitis: results of a double-blind, randomised, placebo-controlled short-term trial. Ann Rheum Dis 73, 243–6. 56 Maksymowych WP, Jhangri GS, Fitzgerald AA et al. (2002) A six-month randomized, controlled, double-blind, doseresponse comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal antiinflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 46, 766–73. 57 Sieper J, Fendler C, Laitko S et al. (1999) No benefit of long-term ciprofloxacin treatment in patients with reactive arthritis and undifferentiated oligoarthritis: a threemonth, multicenter, double-blind, randomized, placebocontrolled study. Arthritis Rheum 42, 1386–96. 58 Carter JD, Espinoza LR, Inman RD et al. (2010) Combination antibiotics as a treatment for chronic Chlamydia-
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induced reactive arthritis a double-blind, placebo-controlled, prospective trial. Arthritis Rheum 62, 1298–307. Lauhio A, Leirisalo-Repo M, Lahdevirta J, Saikku P, Repo H (1991) Double-blind, placebo-controlled study of three-month treatment with lymecycline in reactive arthritis, with special reference to Chlamydia arthritis. Arthritis Rheum 34, 6–14. Carter JD, Valeriano J, Vasey FB (2004) Doxycycline versus doxycycline and rifampin in undifferentiated spondyloarthropathy, with special reference to chlamydiainduced arthritis. A prospective, randomized 9-month comparison. J Rheumatol 31, 1973–80. Song IH, Heldmann F, Rudwaleit M et al. (2013) One-year follow-up of ankylosing spondylitis patients responding to rituximab treatment and re-treated in case of a flare. Ann Rheum Dis 72, 305–6. Song IH, Heldmann F, Rudwaleit M et al. (2010) Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial. Arthritis Rheum 62, 1290–7. Song IH, Heldmann F, Rudwaleit M et al. (2011) Treatment of active ankylosing spondylitis with abatacept: an openlabel, 24-week pilot study. Ann Rheum Dis 70, 1108–10. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M (2013) Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis 73, 95–100. Sieper J, Inman R, Badalamenti S, Radin A, Braun J (2012) Sarilumab for the treatment of ankylosing spondylitis: results of a phase 2, randomized, double-blind, placebocontrolled, international study (ALIGN). Ann Rheum Dis 71 (Suppl. 3), 111. Baeten D, Baraliakos X, Braun J et al. (2013) Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1705–13. Haibel H, Rudwaleit M, Listing J, Sieper J (2005) Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis 64, 296–8. Haroon N, Inman RD, Learch TJ et al. (2013) The Impact of TNF-inhibitors on radiographic progression in Ankylosing Spondylitis. Arthritis Rheum 65, 2645–54.
Supporting Information Additional Supporting Information may be found in the online version of this article:
Table S1. Literature review questions. Table S2. Medline search strategy.
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ORIGINAL ARTICLE
Consensus statement on the investigation and management of non-radiographic axial spondyloarthritis (nr-axSpA) Philip C. ROBINSON,1,2 Paul BIRD,3 Irwin LIM,4 Nivene SAAD,5,6 Lionel SCHACHNA,7 Andrew L. TAYLOR,8 Samuel L. WHITTLE9 and Matthew A. BROWN1,2 1
University of Queensland Diamantina Institute, 2Department of Rheumatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia, 3St George Clinical School, University of New South Wales, Sydney, New South Wales, 4BJC Health, Sydney, New South Wales, 5Department of Radiology, Princess Alexandra Hospital, 6University of Queensland, Brisbane, Queensland, 7Department of Rheumatology, Austin Health, Melbourne, Victoria, 8Royal Perth Hospital, Perth, Western Australia, and 9Rheumatology Unit, Queen Elizabeth Hospital, Woodville, South Australia, Australia
Abstract Aim: Non-radiographic axial spondyloarthritis (nr-axSpA) is axial inflammatory arthritis where plain radiographic damage is not evident. An unknown proportion of these patients will progress to ankylosing spondylitis (AS). The increasing recognition of nr-axSpA has been greatly assisted by the widespread use of magnetic resonance imaging. The aim of this article was to construct a set of consensus statements based on a literature review to guide investigation and promote best management of nr-axSpA. Methods: A literature review using Medline was conducted covering the major investigation modalities and treatment options available. A group of rheumatologists and a radiologist with expertise in investigation and management of SpA reviewed the literature and formulated a set of consensus statements. The Grade system encompassing the level of evidence and strength of recommendation was used. The opinion of a patient with nr-axSpA and a nurse experienced in the care of SpA patients was also sought and included. Results: The literature review found few studies specifically addressing nr-axSpA, or if these patients were included, their results were often not separately reported. Fourteen consensus statements covering investigation and management of nr-axSpA were formulated. The level of agreement was high and ranged from 8.1 to 9.8. Treatment recommendations vary little with established AS, but this is primarily due to the lack of available evidence on the specific treatment of nr-axSpA. Conclusion: The consensus statements aim to improve the diagnosis and management of nr-axSpA. We aim to raise awareness of this condition by the public and doctors and promote appropriate investigation and management. Key words: ankylosing spondylitis, non-radiographic axial spondyloarthritis, spondyloarthritis, tumor necrosis factor-alpha inhibitors.
INTRODUCTION
Correspondence: Professor Matthew Brown, University of Queensland Diamantina Institute, Translational Research Building, Princess Alexandra Hospital, 37 Kent Street, Woolloogabba, Queensland, Australia. Email: [email protected]
Spondyloarthritis (SpA) is a group of inter-related immune-mediated diseases with the hallmark clinical feature of axial inflammatory arthritis.1 Recent efforts have focused on redefining their classification, with patients manifesting predominant axial features classified as axial spondyloarthritis (axSpA).2 axSpA
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
nr-axSpA consensus statement
encompasses both ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA).3 nr-axSpA was first described as ‘spondylitic disease without radiological evidence of sacroiliitis’.4 Patients with AS meet the modified New York criteria including radiographic sacroiliitis of at least grade 2 bilaterally or grade 3 unilaterally.5 This degree of radiographically evident sacroiliac joint (SIJ) damage takes years to appear.6 Patients with nr-axSpA do not meet this radiographic criterion, but are classified as nr-axSpA either through evidence of acute inflammation on magnetic resonance imaging (MRI) and one SpA feature (for example psoriasis, dactylitis or uveitis) or the presence of human leucocyte antigen (HLA)-B27 and two SpA features.2 The Assessment of Spondyloarthritis International Society (ASAS) axial SpA classification criteria were developed in an attempt to: (i) enable earlier diagnosis, as early treatment may improve outcome;7,8 and (ii) include patients with unclassifiable or undifferentiated SpA who fail to meet other classification or diagnostic criteria but who require treatment.2,9 Although all patients with nr-axSpA do not progress to modified New York-defined AS,10 the disease activity, functional impairment, quality of life effects and health status as measured by Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Ankylosing Spondylitis Quality of Life questionnaire and the Short Form 36 health survey are similar to patients with AS.11,12 In addition, the number of inflammatory lesions in the spine and SIJs on whole body MRI do not differ between active nr-axSpA and AS.13 Over the last decade, there have been major developments in the investigation, classification and treatment of SpA. To address these developments there have been a number of position or consensus statements on the treatment of spondyloarthritis, but to date they have focused primarily on AS14,15 or concentrated only on tumour necrosis factor inhibitor (TNFi) treatment.16,17 Why is another consensus statement needed? nr-axSpA is a distinct clinical entity because its demographics, genetics and response to treatment are different from AS.10,18 In addition the prognosis and outcome of nraxSpA is more heterogenous so one needs to view it as different from AS, where radiographic damage has already occurred.10 The aim of this study was to construct a set of consensus statements, supported by a literature review that encompasses the optimal investigation and management of nr-axSpA. The target population for this statement is all those involved in referring, treating and reviewing nr-axSpA. The
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relevance of the statement is both Australian and international by virtue of the exhaustive literature search. Recognition and referral of suspected nr-axSpA was not addressed, but has been studied19–21 and reviewed22,23 recently.
METHODS A group of clinician rheumatologists and a radiologist, all experienced in the clinical presentation, imaging and management of nr-axSpA was assembled. A set of questions was developed to define the topics to be addressed by the literature review (see Table S1). These questions were reviewed by the consensus panel and edited to ensure inclusion of the most clinically pertinent topics in investigation and management of nr-axSpA. A literature search was conducted covering Medline (English language-restricted) 1966 to 31 August 2013 using the search terms: ‘spondyloarthritis’ OR ‘axial spondyloarthritis’ OR ‘non-radiographic axial spondyloarthritis’. This was combined with specific search terms as detailed in Table S2. Titles and abstracts of all search results were then reviewed and full text reviewed if there was a possibility that the publication was relevant to the question. Other literature known to the panel or found in parallel searches was also included. ‘Ankylosing spondylitis’ was not used as a search term in the literature review as the major goal was to review studies related specifically to nr-axSpA. The results of the literature review were then discussed and consensus statements developed. Participants agreed on the level of evidence, strength of recommendation and level of individual agreement with each consensus statement. The Grade level of evidence and strength of recommendation system for assigning scores was used.24 These recommendations were then reviewed by a patient representative diagnosed with nr-axSpA and a nurse specialized in the care of patients with SpA. Their comments and feedback are reported herein.
RESULTS The consensus group formulated statements on 11 of 14 questions addressed in the literature review. Three questions are therefore discussed solely in the text of the manuscript. In addition three further consensus statements covering other areas were formulated at the meeting. The consensus statements, levels of evidence, strengths of recommendation and levels of agreement are presented in Table 1.
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Table 1 nr-axSpA investigation and management consensus statements Consensus statements The patient’s views, preferences and goals are central and care should be a partnership between the clinical team and the patient Patient education is a key part of the management of nr-axSpA A comprehensive history and physical examination should be carried out for the assessment of suspected nr-axSpA CRP should be measured when considering the diagnosis of nr-axSpA; high sensitivity CRP does not add value to normal CRP HLA-B27 status should be determined when considering the diagnosis of nr-axSpA Plain pelvic radiographs may be useful to distinguish non-inflammatory and inflammatory causes of back pain; a normal radiograph does not exclude nr-axSpA Sacroiliiac joint MRI should be used in those with clinical suspicion of nr-axSpA. T1 and STIR without gadolinium is the recommended protocol Computed tomography is not recommended for the investigation of suspected nr-axSpA Classification criteria have value in the diagnosis of nr-axSpA, but classification criteria sets should not be used to include or exclude this diagnosis in individual patients Physiotherapy may be useful in the management of nr-axSpA There is no role for DMARDs in the management of axial manifestations in nr-axSpA. Sulphasalazine can be considered for those with peripheral manifestations in nr-axSpA Non-steroidal anti-inflammatories are recommended as first-line pharmacological treatment for the management of nr-axSpA TNF inhibitors are useful in the management of nr-axSpA Glucocorticoids may have a limited role in NSAID-refractory nr-axSpA.
Level of evidence
Grade of recommendation
Level of agreement, mean (SD)
D
1
9.5 (1.1)
D D
1 1
9.4 (1.2) 9.4 (0.7)
C
1
8.8 (1.0)
C
1
9.1 (1.0)
D
2
9.5 (0.8)
B
1
9.8 (0.5)
C
1
9.5 (1.1)
C
1
8.1 (1.0)
D C
2 2
9.1 (0.8) 8.1 (1.9)
B
1
9.1 (1.1)
B D
1 2
9.6 (0.5) 9.0 (0.9)
CRP, C-reactive protein; DMARDs, disease-modifying anti-rheumatic drugs; MRI, magnetic resonance imaging; nr-axSpA, non-radiographic axial spondyloarthritis; NSAID, non-steroidal anti-inflammatory drug; STIR, short T1 inversion recovery.
Consensus statements The patient’s views, preferences and goals are central and care should be a partnership between the clinical team and the patient This recognizes that the care of patients with nr-axSpA is a partnership between healthcare professionals and the patient. There is some evidence that increased involvement of patients in decisions regarding their care improves outcomes, although no evidence is available specifically in nr-axSpA.25 Individual preferences for treatment and an acceptable risk benefit ratio for interventions differ between patients. The patient should therefore be central to the management of their condition. Patient education is a key part of the management of nr-axSpA This recognizes the role of education in empowering patients. Numerous randomized controlled studies, although none in nr-axSpA, have found improvements in
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a variety of outcome measures in both acute and chronic medical conditions with educational interventions.26–29 When patients understand the nature of their medical problems and the significance of investigations, treatments and their prognoses, outcomes are likely to be improved through mechanisms such as alignment of treatment goals,30 increased adherence with therapies, and better attendance at investigations and follow-up appointments. A comprehensive history and physical examination should be carried out for the assessment of suspected nr-axSpA This reflects good medical practice and is supported by evidence that recognitions of the signs and symptoms of nr-axSpA clearly contribute to diagnosis.31,32 C-reactive protein (CRP) should be measured when considering the diagnosis of nr-axSpA; high-sensitivity CRP (hsCRP) does not add value to normal CRP This reflects the evidence that elevated CRP contributes to the diagnosis of a combined group of both nr-
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axSpA and AS.31 There was no evidence in the literature to support the utility of erythrocyte sedimentation rate (ESR) but this can also be used in practice as a measure of systemic inflammation. Two studies addressed the additional benefit of whether hsCRP offered any significant clinical advantages compared to non-hsCRP measurements. Navarro-Comparos et al. found there was no improvement in classification using hsCRP in the DESIR cohort, although it should be noted the question for the consensus group was related to diagnosis, not classification.33 Poddubbnyy et al. reported that in the GESPIC cohort, there was a correlation between clinical parameters and hsCRP in AS, but not in nr-axSpA.34 Therefore in nr-axSpA the panel felt that there was no greater benefit from the use of hsCRP compared with routine CRP measures. HLA-B27 status should be determined when considering the diagnosis of nr-axSpA This statement reflects evidence that HLA-B27 status has good sensitivity and specificity from studies diagnosing SpA. In the Ability-1 trial 45% of the imagingarm nr-axSpA patients were HLA-B27-positive (i.e., 45% sensitive), although it is required for classification in the ASAS clinical arm and therefore is confounded by circularity.35 In the SPACE cohort of chronic back pain patients with the physician diagnosis as gold standard, HLA-B27 was 78% sensitive and 94% specific for axSpA (both nr-axSpA and AS).32 In the ASAS classification criteria cohort HLA-B27 was 66% sensitive and 73% specific for axSpA (both nr-axSpA and AS), with physician diagnosis as the gold standard. Plain pelvic radiographs may be useful to distinguish non-inflammatory and inflammatory causes of back pain; a normal radiograph does not exclude nr-axSpA Differentiation of nr-axSpA and AS requires X-ray of the SIJs. A plain antero-posterior (AP) radiograph of the pelvis that has gradable change as defined by the modified New York criteria (for example unilateral grade 2) but does not meet the criteria for AS, may increase clinical suspicion of inflammatory disease, but the accuracy, reliability and reproducibility of scoring SIJ changes in plain radiographs is low.36–39 The plain AP radiograph of the pelvis is the recommended view, as oblique pelvic views or angled AP views do not improve diagnostic value compared to the plain AP view and are associated with an increased radiation exposure.40 The AP view also allows assessment of the hip joints that are commonly involved in axSpA. SIJ MRI should be used in those with clinical suspicion of nr-axSpA. T1 and short tau inversion recovery (STIR) without gadolinium is the recommended protocol
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This statement recognizes the increasingly important role of this imaging modality in demonstrating the presence of inflammatory disease in those with chronic back pain. MRI is sensitive for bone marrow edema, a characteristic feature of acute inflammation of the SIJ. Significant research effort has focused on the definitions of positive imaging in the SIJ and the spine. Currently the ASAS definition includes only inflammatory disease in the SIJs,41 but there has been research suggesting the inclusion of structural disease (for example erosions) improves sensitivity.42 In addition, a global assessment of the positive or negative nature of an SIJ scan also improves sensitivity.43 T1 and STIR imaging are the optimal sequences used and gadolinium enhancement is not additive in making the diagnosis of axSpA.41,44,45 There is also research to suggest there is little value in scanning the spine in addition to the SIJs,46 although it should be noted that often an MRI scan is not just used to include/exclude nr-axSpA, but also investigate for the presence of other pathology that could explain chronic back pain. Computed tomography (CT) is not recommended for the investigation of suspected nr-axSpA This statement reflects the poor sensitivity of CT for inflammatory disease and the significant radiation exposure it involves. Although CT has greater sensitivity than plain radiography for chronic structural changes (e.g., sclerosis, erosions), as by definition nr-axSpA does not have significant structural lesions, this property is not advantageous in this setting. Bone marrow edema that is often present in nr-axSpA cannot be detected by CT scan. Classification criteria have value in the diagnosis of nr-axSpA, but classification criteria sets should not be used to include or exclude this diagnosis in individual patients Classification criteria are designed to define a homogenous group of patients for use in research and clinical trial settings, and therefore are not developed specifically for diagnosis. However, in fulfilling the classification criteria for nr-axSpA, a patient’s post-test probability of having a clinician diagnosis of SpA is increased, and not fulfilling the criteria set reduces the post-test probability of SpA. By necessity, classification criteria include many features of the relevant disease, but using the clinician diagnosis as gold standard, no SpA classification criteria set has 100% specificity. Information is lacking for nr-axSpA, but for SpA in general the specificity of different SpA classification criteria ranges from 83% to 88%.47 A hypothetical clinical example of the potential issue is: a 30-year-old patient who has Crohn’s disease and mechanical back pain
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from a herniated disc, who is HLA-B27-positive and has a raised CRP from their bowel disease could be classified as nr-axSpA (based on the ASAS criteria2) when they do not in fact have nr-axSpA. Therefore classification criteria should not be used solely in individual patients to establish or exclude the diagnosis of SpA. Physiotherapy may be useful in the management of nr-axSpA There is a notable absence of published studies on physiotherapy in nr-axSpA. While physiotherapy has been shown to reduce pain and improve function in AS,48 the only trial of physiotherapy that included nr-axSpA found during the literature search was small and did not separately report the results of the nr-axSpA patients.49 There is no role for disease-modifying antirheumatic drugs (DMARDs) in the management of axial manifestations in nr-axSpA. Sulphasalazine can be considered for those with peripheral manifestations in nr-axSpA There is no evidence of DMARD efficacy for axial manifestations of nr-axSpA. In AS, where there is evidence available, the use of sulphasalazine (SSZ) for axial manifestations is not supported.15 The ESTHER trial compared etanercept with SSZ in axSpA (nr-axSpA and AS) and the 64 joint count and enthesitis scores decreased substantially on SSZ, with no difference detected between etanercept and SSZ in these outcome measures; however, there was no placebo arm in this trial.50 Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line pharmacological treatment for the management of nr-axSpA NSAIDs were demonstrated to be effective in the INFAST trial of early axSpA: in the 1000 mg naproxen monotherapy arm 57% achieved ASAS40 and 35% achieved ASAS Partial Remission (the primary outcome) at week 28.7 There was no placebo comparison arm in this trial. Of all the NSAIDs naproxen has the best efficacy data and also the best cardiovascular risk profile.51,52 TNF inhibitors are useful in the management of nr-axSpA There are a number of trials of TNFi for treatment of nr-axSpA, including adalimumab,35 certolizumab,53 etanercept50 and infliximab.7 These demonstrate good efficacy, especially in early disease and in combination with NSAIDs. The INFAST trial7 (comparing infliximab with naproxen with naproxen alone in axSpA) demonstrated ASAS40 response rates of 75% in the infliximab/ naproxen arm at week 28. Treatment responses of nr-axSpA patients with positive SIJ MRI scans are similar to those observed in patients with AS.53,54 The Ability-1 trial included both MRI-positive and -negative nr-axSpA and a post hoc subgroup analysis suggested that those
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patients with a positive SIJ MRI or a CRP above the upper limit of normal (ULN) had higher absolute response rates. All other trials have included only patients with a positive SIJ MRI or CRP above the ULN so the question of whether response to TNFi agents varies according to MRI or CRP status is currently difficult to answer. Ciurea and colleagues reported results from the Swiss Clinical Quality Management cohort and found ASAS40 and ASAS Major Improvement response rates were higher in patients with AS compared to nr-axSpA (odds ration [OR] = 2.2, P = 0.02).11 In those patients with an elevated CRP at baseline (both AS and nr-axSpA) the ASAS40 response was higher in the AS group compared to nr-axSpA (52% and 38%, respectively). Further research is clearly required to determine the best predictors of response in nr-axSpA. Glucocorticoids (GCs) may have a limited role in NSAID-refractory nr-axSpA. There is a lack of evidence for GCs in nr-axSpA. A recent trial of prednisolone in AS demonstrated relatively poor efficacy, which is consistent with clinical experience.55 GCs have substantial medium- and longterm adverse effects, especially on glucose and bone metabolism and therefore their use should be considered carefully in light of the risks, benefits and treatment alternatives. The group did not make statements about the role of bisphosphonates, antibiotics or biological agents other than TNFi agents in the treatment of nr-axSpA. There is no evidence for the efficacy of bisphosphonates in nraxSpA, and some evidence for the use of bisphosphonates in AS,56 but the group had differing clinical experience with these agents. Antibiotics have a role for the treatment of active symptomatic infection that can precipitate reactive arthritis (ReA); the goal for this treatment is elimination of the active symptomatic infection. There is, in addition, some conflicting evidence for the use of chronic antibiotics in the treatment of ReA;57–60 however, this practice is not universally accepted or widespread, potentially reflecting uncertainties around the strength of the evidence, selection of appropriate patients and the risk/benefit balance with the potential adverse effects of long-term antibiotic therapy. A number of alternative biologic agents have been trialed in AS, including rituximab (anti-CD20),61,62 abatacept (CTLA4 Ig),63 tocilizumab (anti-interleukin [IL]-6R),64 sarilumab (anti-IL-6R),65 secukinumab (anti-IL-17)66 and anakinra (IL-1 receptor antagonist)67 but there have been no trials, and limited clinical experience with these agents in nr-axSpA and therefore the group did not make any statement regarding their use.
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nr-axSpA consensus statement
Patient perspective The patient with nr-axSpA agreed with the consensus statements and made the following additional comments: (i) ‘As a patient I want to be treated in the best possible way through solid evidence and what the current research findings are’; (ii) regarding physiotherapy, ‘It is the first tool of pain relief, it is very helpful with the management of this condition. I would like to think all physiotherapists are keeping up to date with new techniques’; and (iii) ‘I would like to see national guidelines for all patients, so that we all receive the same valued care, doesn’t matter where you live’.
Nursing perspective A nurse practitioner with extensive experience in care of SpA patients agreed with the statements and made the following comments: (i) ‘I like the fact that the patient’s views are the first statement as I believe this is of paramount importance and that patient education is also identified as a key issue’; and (ii) ‘For the management of this disease, all patients should have equal access to appropriate investigations and potentially life-changing treatments. Consensus statements from experienced rheumatologists such as these provide evidence for the standards that should be met.’
CONCLUSIONS Improvements in the care of patients with nr-axSpA will come from increased recognition of the condition by the public, primary care physicians and medical specialists as well as the use of effective therapies. A patient passes through the stage of nr-axSpA on their way to AS, although not all patients who have nr-axSpA will eventually develop AS.10 Historically there has been a long delay in recognizing and treating patients with AS,6 and the wider recognition of nr-axSpA is likely to make a significant difference to patient symptom burden due to appropriate treatment, regardless of whether they progress to AS or not. We know that those patients with nr-axSpA have similar levels of disease activity to AS patients, and active nr-axSpA patients have similar levels of inflammation on MRI scan to patients with AS.11–13 The set of consensus statements compiled from both evidence and expert opinion will guide clinicians in the investigation and management of nr-axSpA. In addition the group hopes it will encourage better access to TNFi agents for appropriate patients with nr-axSpA. There are limitations to the evidence base and the consensus statements. In many diseases including
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axSpA, where the etiology and disease mechanisms are incompletely understood, the physician’s opinion is often used as the gold standard to validate diagnostic procedures and tests. However, the result is that assessments of individual diagnostic tests or procedures is then confounded by circularity, because the same tools used to define the gold standard are then tested against the gold standard. This is a limitation of the assessment of diagnostic tests against a gold standard where knowledge of the true disease mechanisms is uncertain. Another limitation is the lack of evidence relating specifically to nr-axSpA, and even when studies include these patients the results of AS and nr-axSpA are not always separately reported.2,32,49 As with early treatment in rheumatoid arthritis, there is the potential for early treatment in SpA to change prognosis. The INFAST 1 and 2 trials of very early axSpA patients showed high response rates from combined NSAID–TNFi treatment and if patients reached partial remission on TNFi almost half remained in partial remission 6 months after discontinuing their TNFi with or without NSAIDs.7,8 This is encouraging early data that early treatment could lead to drug-free remission for a proportion, perhaps the ‘window of opportunity’ may be applicable to SpA as it is to rheumatoid arthritis. Research on TNFi use in AS also suggests that early use may improve radiographic outcome.68 These consensus statements are the product of the currently available evidence, which is somewhat limited. Currently the treatment for nr-axSpA varies little from that of AS, but this relates primarily to the lack of evidence on the specific treatment of nr-axSpA. However, evidence is growing about this important condition, and increased recognition and research focus will enable future iterations of these consensus statements to be progressively improved.
DISCLOSURES PR: consulting, clinical trials, travel support and/or speaking for Abbvie, Janssen and Pfizer. PB: advisory boards for Abbvie, Celgene, Pfizer, Roche, UCB and clinical trials for Abbvie, Celgene, Pfizer, Roche, Eli Lily. IL: consulting, advisory board involvement, travel support and/or speaker honoraria for Abbvie, UCB, Janssen, BMS, Novartis, Roche and Pfizer. ALT: consulting, clinical trials, travel support and/or speaking for Abbvie, Janssen, Roche, UCB and Pfizer. SW: consulting, speaking fees and travel support from Abbvie, Janssen, Pfizer and UCB. MAB: advisory board, speaker’s bureau
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and research funding from Abbvie. Advisory board for Pfizer. LS and NS no disclosures.
CONTRIBUTIONS PR performed the literature review with the assistance of MH (see acknowledgements). PR and MAB constructed the draft consensus statements upon which PR, SW, PB, IL, LS, MAB, NS and AT then reached consensus. All authors contributed to editing and approving the manuscript.
ACKNOWLEDGEMENT AND FUNDING We thank Linda Bradbury, nurse practitioner, and the nr-axSpA patient who contributed their perspectives on the consensus statements. We acknowledge the assistance of Dr Murray Hargrave in the literature review. We acknowledge the provision of an unrestricted grant from Abbvie Australia to the University of Queensland to enable the literature review to be performed, and for convening and provision of facilities for the consensus meeting. Abbvie had no role beyond provision of funding. Specifically, Abbvie did not participate or have any involvement in setting the literature questions, performing the review, drafting the consensus statements, discussing the evidence, agreeing on the consensus statements, the manuscript preparation, or the decision to submit for publication.
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Supporting Information Additional Supporting Information may be found in the online version of this article:
Table S1. Literature review questions. Table S2. Medline search strategy.
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