Axial spondyloarthritis

Seminar

Axial spondyloarthritis Joachim Sieper, Denis Poddubnyy

The term axial spondyloarthritis covers both patients with non-radiographic and radiographic axial spondyloarthritis, which is also termed ankylosing spondylitis. The disease usually starts in the third decade of life with a male to female ratio of two to one for radiographic axial spondyloarthritis and of one to one for non-radiographic axial spondyloarthritis. More than 90% heritabilty has been estimated, the highest genetic association being with HLA-B27. The pathogenic role of HLA-B27 is still not clear although various hypotheses are available. On the basis of evidence from trials the cytokines tumour necrosis factor (TNF)-α and interleukin-17 appear to have a relevant role in pathogenesis. The mechanisms of interaction between inflammation and new bone formation is still not completely understood but clarification will be important for the prevention of long-term structural damage of the bone. The development of new criteria for classification and for screening of patients with axial spondyloarthritis have been crucial for the early indentification and treatment of such patients, with MRI being the most important existing imaging method. Non-steroidal anti-inflammatory drugs and TNF blockers are effective therapies. Blockade of interleukin-17 is a new and relevant treatment option.

Introduction Axial spondyloarthritis is a chronic inflammatory disease that mainly affects the axial skeleton. It is a type of spondyloarthritis, which also includes psoriatic arthritis, arthritis associated with inflammatory bowel disease, and reactive arthritis. The term axial spondyloarthritis covers both patients who have already developed structural damage in the sacroiliac joints or spine visible on radiographs (radiographic axial spondyloarthritis, also termed ankylosing spondylitis) and patients without such structural damage, labelled as non-radiographic axial spondyloarthritis. Non-radiographic axial spondyloarthritis can be seen as an earlier or milder part of axial spondyloarthritis and patients might or might not develop structural boney damage in the axial skeleton. The Assesment in Spondylo-Arthriits international Society (ASAS) has published new classificaiton criteria for axial spondyloarthritis.1 The development of the new criteria was necessary because the older modified New York criteria for anklyosing spondylitis2 did not allow identification of axial spondyloarthritis patients early in the course of the disease in the absence of radiographic changes in the sacroiliac joints, which can take years to manifest. Other criteria such as the European Spondyloarthropathy Study Group (ESSG)3 and the Amor criteria4 had not yet included MRI assessment. The term axial spondyloarthritis should be used preferentially for diagnosis and classification, unless medical reasons are present to differentiate between ankylosing spondylitis or non-radiographic axial spondyloarthritis.5,6

Clinical presentation Patients present with chronic back pain and stiffness predominantly of the pelvis and the lower back, but any part of the spine can be involved. Typical is inflammatory back pain, which is clinically defined. Patients complain of morning stiffness mostly of the lower back with improvement on exercise but not by rest. They can also be awakened by back pain in the night, typically in the www.thelancet.com Vol 390 July 1, 2017

second part of the night. Different sets of criteria have been developed for the classification of inflammatory back pain, which are largely overlapping.7–9 However, the sensitivity and specificity of any of these criteria for the diagnosis of axial spondyloarthritis is not higher than about 80%, meaning that not every axial spondyloarthritis patient has this kind of back pain and that this symptom is also present in a substantial proportion of patients with chronic back pain of other causes. Inflammation and, as a consequence of inflammation, structural damage can occur in the axial skeleton, which can result in restriction of spinal mobility. This restriction can be quantified by applying established methods (such as the modified Schober test for measurement of lumbar flexion).10,11 Arthritis and enthesitis are the most common peripheral manifestations (found in 30–50% of axial spondyloarthritis at presentation or in the past), which can occur at any time in the course of the disease. These manifestations are predominantly found in the lower limbs, frequently in an asymmetrical fashion. The joints are generally swollen and painful. Inflammation at the insertion of tendons, ligaments, or capsule into bone is called enthesitis. A typical location is at the insertion of the Achilles tendon or the plantar fascia at the calcaneus, but inflammation is possible at any enthesial site. A rather rare peripheral manifestation in axial is

Lancet 2017; 390: 73–84 Published Online January 19, 2017 http://dx.doi.org/10.1016/ S0140-6736(16)31591-4 Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité Universitätsmedizin Berlin, Berlin, Germany (Prof J Sieper MD, Prof D Poddubnyy MD) Correspondence to: Prof Joachim Sieper, Department of Gastroenterology. Infectious Diseases and Rheumatology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany [email protected]

Search strategy and selection criteria We searched for original English language articles and reviews in MEDLINE (via PubMed) published between Jan 1, 2000, and April 30, 2016, using the following search terms: “ankylosing spondylitis” or “spondyloarthritis” in combination with the terms “diagnosis”, “pathogenesis”, “imaging”, “management”, “treatment”. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We also searched the reference lists of articles identified by the search strategy and selected those we judged relevant.

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See Online for appendix

dactylitis, which is a swelling of a finger or toe as the consequence of tendovaginitis. Disease activity is generally quantified by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)12 or the Ankylosing Spondylitis Disease Activity Score (ASDAS)13—both are composite scores. ASDAS contains an acute phase reactant, usually C-reactive protein (CRP), in addition to a patient’s reported outcome indices. Uveitis is the most frequent extra-articular manifestation and presents typically as uveitis anterior, is limited in duration, acute in onset, unilaterally, and frequently alternating from one eye to the other. Psoriasis and inflammatory bowel disease are less frequent extra-articular findings (appendix).14–16

Epidemiology The disease usually starts in the third decade of life, and about 5 years earlier in HLA-B27 positive patients than in HLA-B27-negative patients.15,17 Slightly more patients with ankylosing spondylitis are male than female (approximate male to female ratio is 2–3:1); whereas the sex distribution among patients with non-radiographic axial spondyloarthritis is equal.15,18 Accurate prevalence figures are difficult to obtain for axial spondyloarthritis because studies rely on a selection of patients or population-based surveys that generally do not include imaging investigations and HLA-B27 testing. More data are available for the prevalence of ankylosing spondylitis than are for axial spondyloarthritis as a whole. The prevalence of ankylosing spondylitis mirrors the prevalence of HLA-B27 in a given population. In populations of European descent HLA-B27 is present in about 8% and ankylosing spondylitis in about 0·5%.19 In those with a lower HLA-B27 prevalence, for example

Genetic background HLA-B27 ERAP-positive Interleukin-23 receptor Other identified and unidentified genes

+

Disturbed gut barrier (Crohn’s)

Or

Disturbed skin barrier (psoriasis)

Or

Infection

Exposure to microbes

Mediated by mechanical stress

Sacroiliitis/spondylitis/enthesitis (inflammation)

Facultative Repair: fibrous tissue invaded subchronal area New bone formation: activation of osteoblasts

Figure 1: Pathogenesis of axial spondyloarthritis Inflammation might or might not (facultative) lead to repair and new bone formation. Molecular and cellular aspects are not presented. ERAP=endoplasmic reticulum aminopeptidase.

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in African-Americans, ankylosing spondylitis occurs less frequently.20 The pooled prevalence for all types of spondyloarthritis (including peripheral forms) ranges from 0·20% in South-East Asia to 1·61% in Northern Arctic communities.19 The reported prevalence of axial spondyloarthritis is between 0·32% and 1·4% in different surveys.21–23

Pathogenesis Most studies of pathogenesis, especially those of genetics, have focused in the past on ankylosing spondylitis, which constitutes a more homogeneous group than do all patients with axial spondyloarthritis (figure 1). On the basis of studies of twins with ankylosing spondylitis greater than 90% heritabilty has been estimated.24 Genome-wide association studies (GWAS) have detected several genes associated with ankylosing spondylitis. In one large such study,25 20·44% of the genetic predispositon was attributable to major histocompatibility complex (MHC) variants (mainly HLA-B27, but also HLA-B40, HLA-B51, HLA-B7, HLA-A2, and HLA-DPB1), and 7·38% to non-MHC variants. The remaining 72% of genetic predisposition remains to be identified. In addition to HLA-B27, two further genetic loci have been associated with ankylosing spondylitis and might be of functional relevance: endoplasmic reticulum amino­ petidase (ERAP),26 which encodes an aminopeptidase expressed in the endoplasmic reticulum and is involved in preparing peptides for MHC class 1 presentation to immune effector cells, and the interleukin-23 receptor,26 which activates T-helper cells secreting the cytokine interleukin-17 but also other proinflammatory cells. The ERAP1-association—but not the ERAP2-association—is confined to HLA-B27-positive cases, indicating that peptides presented by HLA-B27 might be of relevance.27 Axial spondyloarthritis is clincially associated with inflammatory bowel disease, psoriasis, or reactive arthritis in about 15–20% of cases.14,15 However, any of these diseases can be clinically silent;28,29 therefore, this association might be much higher. Thus, barrier damage of dermal (psoriasis) and mucosal (inflammatory bowel disease) surfaces and the subsequent exposure of the immune system to microorganisms seems to be of relevance for the pathogenesis. Considerable overlap between ankylosing spondylitis susceptibility loci and inflammatory bowel disease loci has been found.26 An altered microbiota has been identified in patients with inflammatory bowel disease30 and intestinal microbiota could also play an important part in spondyloarthritis.31,32 Anti-CD74 antibodies (directed against the class 2-associated invariantchain peptide, CLIP), might play a part in the diagnosis of axial spondyloarthritis and might be implicated in its pathogenesis by binding to CD74 on the surface of immune competent cells.33,34 However, these findings need confirmation in larger studies. On the basis of therapeutic successes, two pathways in the inflammatory responses, probably located rather at www.thelancet.com Vol 390 July 1, 2017

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the end of the immune response hierarchy, have attracted a lot of interest over past years—ie, the tumour necrosis factor (TNF)-α-axis and the the interleukin-23/ interleukin-17-axis. T-helper-17 cells release the cytokine interleukin-17 on stimulation with interleukin-23. However, interleukin-17 is not only released by T cells but is also expressed by cells of the innate immune system such as mast cells and granulocytes in affected tissue of patients with ankylosing spondylitis35 and psoriatic arthritis, and by mucosal-associated invariant cells in such patients.36 Human mast cells do not produce interleukin-17 themselves but actively capture exogenous interleukin-17 through receptor-mediated endocytosis, which can then subsequently be released on stimulation.37 How the TNFα and interleukin-17-pathways are connected and whether or not there is a hierachical order between the two is not clear.38 Interleukin-17 also inhibits bone formation, an effect that might be blocked pharmacologically by inhibiting interleukin17A,39 although the exact effect of interleukin-17 on new bone formation still needs to be clarified. Systemic overexpression of interleukin-23 in an animal model induced an enthesitis, which resembles the one seen in spondyloarthritis, supporting the idea that interleukin-23 might play a pathogenic part for enthesitis.40 In the context of axial spondyloarthritis it was of special interest that these cells ([ROR-γt]+CD3+CD4– CD8– T-cells) secrete interleukin-17 to activate osteoclasts but could also release interleukin-22 upon stimulation with interleukin-23, which can induce osteoproliferation. Interleukin-23 is expressed in the subchondral bone marrow in a higher amount in the spine from patients with ankylosing spondylitis than in subchondral bone marrow in the spine from osteoarthritis patients.41 The characteristic inflammation of spondyloarthritis occurs at the interface between cartilage and bone in the sacroiliac joints, the spine, and the entheses. Mechanical stress might be important for the initiation (and possibly the maintainance) of inflammation42 and might explain why the disease process most affects the weight bearing parts of the skeleton. In addition to inflammation, axial spondyloarthritis is also characterised by new bone formation in the sacroiliac joints and spine. New bone formation seems to be the consequence of previous bone damage42 and might be part of a repair process aiming for stabilisation.43 Investigation of facet joints obtained from patients with ankylosing spondylitis showed that cartilaginous fusion and ankylosis of facet joints in such patients is promoted by cartilage degeneration and not mediated by chondrocyte hypertrophy.44 At the molecular level, osteoproliferation in axial spondyloarthritis seems to be directed by bone morphogenetic proteins, Wingless pathway proteins, hedgehog proteins, and fibroblast growth factors and their respective signalling cascades.43,45 Osteoproliferation is inhibited43 by molecules such as sclerostin, dickkopf 1, and noggin, and low levels of sclerostin46 and dickkopf 147 www.thelancet.com Vol 390 July 1, 2017

in the serum of patients with ankylosing spondylitis were associated with more syndesmophyte formation in the spine. Furthermore, higher levels of noggin-IgG, or sclerostin-IgG, or both, immune complexes have been identified in the serum of patients with ankylosing spondylitis, which might contribute to the increase in new bone formation in such patients.48 Several biomarkers positively associated with the development of structural damage in the spine have also been identified: C-reactive protein (CRP),49 matrix-metalloproteinase-3,50 vascular endothelial growth factor,51 calprotectin,52 and visfatin.53 These biomarkers might help to identify patients at high risk for radiographic spinal progression; however, only CRP is currently recommended for use in clinical practice. MRI studies have been used to get a better idea about the sequence of events from inflammation to new bone formation in the axial skeleton. These studies have suggested that active inflammatory lesions (bone marrow oedema visible on MRI) later evolve into repair lesions (visible as fatty lesions on MRI) from which stimuli for new bone formation are released.54,55 A recent immunohistological study56 from facet joints from patients with ankylosing spondylitis, showed that a fibroblast-rich granulation tissue erodes the subchondral bone plate but also has bone-forming capacities. This granulation tissue was only partly associated with adipocytes and fat vacuoles and might therefore evade detection by MRI T1-weighted sequence.55,57

Classification criteria for axial spondyloarthritis In 2009, the ASAS criteria for axial spondyloarthritis1 (figure 2) and in 2011 for peripheral spondyloarthritis,58 were published, which differentiate between patients with predominantly axial and patients with predominantly peripheral manifestations and that include MRI findings In patients with ≥3 months back pain and age at onset <45 years Sacroiliitis on imaging* plus ≥1 feature of spondyloarthritis

Spondyloarthritis features: • Inflammatory back pain • Arthritis • Enthesitis (heel) • Uveitis

or

HLA-B27 plus ≥2 other features of spondyloarthritis

• Dactylitis • Psoriasis • Crohn’s/colitis • Good response to NSAIDs

• Family history for SpA • HLA-B27 • Elevated CRP

Figure 2: The ASAS classification criteria for axial spondyloarthritis Adapted from Rudwaleit and colleagues.1 Overall sensitivity of the criteria is 82·9%, overall specificity is 84·4%. Imaging arm alone: sensitivity, 66·2%; specificity, 97·3%. Clinical arm alone: sensitivity, 56·6%; specificity, 83·3%. ASAS=Assessment of SpondyloArthritis International Society. CRP=C-reactive protein. NSAIDs=non-steroidal anti-inflammatory drugs. SpA=spondyloarthritis. *Sacroiliitis on imaging refers to definite radiographic sacroiliitis according to the modified New York criteria or sacroiliitis on MRI according to the ASAS consensus definition.

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and HLA-B27 testing. However, because axial and peripheral spondyloarthritis can overlap and exist together, criteria were also developed for patients presenting with both axial and peripheral spondyloarthritis.58 Because the disease usually starts in the sacroiliac joints, chronic or active inflammatory bony changes of the spine are not part of the classification criteria but involvement of the spine without sacroiliac joints can occur in a small percentage of patients and could be used for diagnosis. The so-called clinical arm, for which the presence of a positive HLA-B27 test is mandatory, was added to the classification criteria to increase sensitivity, resulting in an acceptable senstivitiy of 82·9% and specificity of 84·4%. Discussion is ongoing about whether these classification criteria need modification, mostly for the improvement of specificity.5,6,59–61 When patients from the original study1 were followed up over 3–5 years and seen again by the local rheumatologist the positive predictive value that patients who fulfilled the criteria initially would still be diagnosed as axial spondyloarthritis by the rheumatologist was 93·3%.62 Futhermore, when the ASAS classification criteria were tested in other cohorts with the rheumatologist’s diagnosis as the gold standard, an acceptable sensitivity and specificity was comparable with the initial study, resulting in a sensitivity of between 68% and 87% and a specificity of between 62% and 95%.63–66

Diagnosis of axial spondyloarthritis Classification criteria are often wrongly used for diagnostic purposes because separate diagnostic criteria are generally not available. Because of the lack of gold standards in rheumatology, including axial spondyloarthritis, several clinical indices (presence of chronic back pain started at an age ≤45 years, inflammatory back pain, peripheral and extraarticular manifestations, response of symptoms to non-steroidal anti-inflammatory drugs [NSAIDs], family history of A

B

spondyloarthritis and related disorders), and several laboratory indices (HLA-B27 and acute phase reactants testing, and imaging findings) have to be combined for classification and diagnosis of axial spondyloarthritis with only a moderate overlap between the two. The same clinical, laboratory, and imaging indices are used for classification and diagnosis but clear differences exist in their application.67,68 Classification criteria are developed to get a clear yes or no answer, to create a rather homogeneous group of patients, usually for inclusion into a clinical trial or cohort. For diagnosis, negative findings are also taken into account (appendix) and other reasons why typical indices of spondyloarthritis are positive have to be considered for differential diagnosis.69

Imaging Imaging is crucial for the correct (and early) diagnosis as well as differential diagnosis of axial spondyloarthritis. Because the disease affects sacroiliac joints (as opposed to the spine) in most patients, imaging of sacroiliac joints has a pivotal role for diagnosis (and to a further extent in classification) of axial spondyloarthritis.10 Conventional radiography of the sacroiliac joints (figure 3, appendix) is recommended as the first imaging method to diagnose sacroiliitis as part of axial spondyloarthritis.2,69,70 Even in patients with short disease duration (up to 3 years), a definite radiographic sacroiliitis could be seen in 30–50%, which would make further diagnostic procedures unnecessary.71 Generally, this number depends predominantly on the duration of disease at time of first diagnosis and has been reported to vary between 22% and 77%.60 Nonetheless, radiography of sacroiliac joints has limitations in patients with early axial spondyloarthritis, because structural changes generally take months to years to take place.72 Furthermore, the interpretation of radiographs of the sacroiliac joints is often challenging. Indeed, a considerable inter-reader variation has repeatedly been reported, even among experienced readers.73,74 C

T1

Figure 3: Radiograph of the sacroiliac joints MRI of sacroiliac joints in a STIR and T1-weighted sequences of a 25-year-old patient with inflammatory back pain for about 1·5 years, positive HLA-B27, and slightly raised C-reactive protein levels (7·2 mg/L). (A) Conventional pelvic radiograph shows some subchondral sclerosis on the right side, otherwise the joint is difficult to assess; the latter is also true for the entire left sacroiliac joints, where an overlap with intestinal gas could be seen. No definite judgment on the presence or absence of radiographic sacroiliitis could be made. (B) MRI in the STIR sequence shows two areas of bone marrow oedema (green arrows); the lesion in the right sacroiliac joint is large and localised subchondrally and is therefore compatible with spondyloarthritis. The lesion on the left side is localised not directly subchondrally and might represent the rest of a larger lesion or enthesitis. (C) MRI in the T1-weighted sequence shows large areas of fat metaplasia of bone marrow—so-called fatty lesions (white arrows) localised subchondrally, sharply boarded, and homogeneous; further, subchondral sclerosis (pink arrows) and cortical bone defects (erosions, blue arrow) are evident. Final diagnosis: axial spondyloarthritis. STIR=short TI-weighted inversion recovery.

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Normal or ambiguous radiographic results of sacroiliac joints examination in the context of a possible diagnosis of spondyloarthritis (figure 3, appendix) require MRI investigation of the sacroiliac joints as the next step.70 The following MRI sequences are useful for diagnosis and differential diagnosis of axial spondyloarthritis (figure 3, appendix): a T2-weighted sequence with fat suppression (such as a short tau inversion recovery [STIR] sequence) for detection of active inflammatory changes (bone marrow oedema) (figure 3, appendix); a T1-weighted sequence for detection of post-inflammatory changes, such as erosions, sclerosis, ankyloses, and fatty lesions (figure 3, appendix). A gradient echo sequence (appendix),75 which allows better detection of erosions than a T1-weighted sequence because of improved contrast between bone and cartilage, can be helpful but is not yet used in routine care. The application of a contrast agent is only rarely needed and does not usually provide more information in addition to the T2-weighted sequence with fat suppression. The ASAS group recently updated76 the definition of an active sacroiliitis on MRI for classification of axial spondyloarthritis. According to this definition, clear presence of bone marrow oedema on MRI in subchondral bone is mandatory (figure 3). Importantly, the appearance of bone marrow oedema has to be highly suggestive of spondyloarthritis, taking into account the size of the lesions, its subchondral location and the exclusion of other—mostly mechanical reasons—that could explain a positive finding. The presence of post-inflammatory structural changes, especially erosions, but also subchondral sclerosis, fatty lesions, changes of the joint space should also be taken into account.70,76,77 CT of sacroiliac joints is regarded as a gold standard of structural damage detection (especially erosions), but conventional radiography and MRI of sacroiliac joints usually allow a comprehensive assessment of structural damage. However, CT of these joints (including a so-called low-dose CT, which is associated with a low radiation exposure) might be considered in cases of inconclusive results.70 The most common differential diagnoses for axial spondyloarthritis are degenerative or mechanical problems (degenerative disc disease, spondylosis, congenital vertebral anomalies, diffuse skeletal hyperostosis, osteitis condensans [appendix], and osteoarthritis of sacroiliac joints); other differential diagnoses such as fractures, infectious sacroiliitis, and bone metastasis or primary bone tumours are less frequent. Imaging of the spine (radiography or MRI, appendix) is not usually required78 for early diagnosis because active inflammatory changes and structural damage generally arise in the sacroiliac joints first, but might also be considered as a part of differential diagnosis. On the basis of a literature review and expert consensus, ASAS defined a positive (for active inflammation) spinal MRI in axial spondyloarthritis as the presence of www.thelancet.com Vol 390 July 1, 2017

anterior or posterior spondylitis in at least three sites;79 however, the presence of five or more inflammatory lesions might discriminate even better from control groups.80 The diagnostic value of other imaging methods such as skeletal scintigraphy,81 ultrasonography of the sacroiliac joints, and positron emission tomography is low or undetermined in axial spondyloarthritis and, therefore, these methods are not recommended for diagnosis.70

Screening in patients with chronic back pain A major delay of several years remains between the start of chronic back pain and a final diagnosis in patients with axial spondyloarthritis. In addition to relying on the presence of radiographic changes that can take several years to develop, another reason is the difficulty of diagnosing patients with axial spondyloarthritis in the large number of chronic back pain patients in primary care. Studies have tested different screening methods using the presence of chronic (≥3 months) back pain starting at up to 45 years as an entry criterion in primary care. Generally one or a combination of possible screening idicators have been applied. In nearly all these studies a final diagnosis of axial spondyloarthritis was possible in 25–45%82–86 of patients referred from primary care to the rheumatologist. The percentage of patients with non-radiographic axial spondyloarthritis among those diagnosed with axial spondyloarthritis after referral was between 20% and 80%.60,84 ASAS subsequently developed international recom­ mendations for the early referral of patients with a suspicion of axial spondyloarthritis (appendix).87 These recommendations include the entry criteria together with any additional spondyloarthritis indices, which allows a more flexible approach and a selection of one or several of these measures88 dependent on the regional conditions.

Management The existing international management recom­ mendations (ASAS/EULAR89 and ACR/SAA/ 90 SPARTAN ) are similar (figure 4). The approval of the interleukin-17 inhibitor secukinumab for treatment of ankylosing spondylitis has already been integrated into the ASAS/EULAR recommendations.89 Treat-to-target recommendations for spondyloarthritis, including axial spondyloarthritis, psoriatic arthritis, and peripheral spondyloarthritis in general, were formulated in 2014 by an international task force.91 The main treatment target was defined as remission, with low disease activity regarded as a secondary target. For both radiographic and non-radiographic forms axial spondyloarthritis, remission was defined by a low BASDAI score plus normal CRP values or by a low ASDAS,13 which includes the results of measurements of CRP or erythrocyte sedimentation rate. 77

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Predominant manifestation First-line therapy

Axial manifestations: Back pain and stiffness

Peripheral manifestations: arthritis, enthesitis, dactylitis NSAIDs

Non-pharmacological treatment: education, exercise, physical therapy, rehabilitation, patient associations, self help groups Local steroids DMARDs sulfasalazine, methotrexate Second-line therapy Additional therapy and therapy in special clinical situations

TNF α blocker or IL-17 blocker Analgesics Surgery

Figure 4: Recommendations for the treatment of axial spondyloarthritis Based on ASAS/EULAR89 and ACR/AAS/SPARTAN,90 including the current approval status for the interleukin-17 blocker secukinumab. Secukinumab—an interleukin-17-antagonist—is currently approved only for ankylosing spondylitis. NSAIDs=non-steroidal anti-inflammatory drugs. DMARDs=disease modifying antirheumatic drugs. TNF=tumour necrosis factor.

Non-steroidal anti-inflammatory agents Non-steroidal anti-inflammatory agents (NSAIDs) are highly effective in reducing back pain and stiffness in patients with axial spondyloarthritis and are therefore recommended as first-line treatment for these patients. There is no clear difference in the effectiveness of NSAIDs,92 and they are similarly effective in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Patients generaly respond in the first 2 weeks of NSAID therapy but in responders the response rate increases further during the first 24 weeks.93 NSAIDs should be used according to the patient’s symptoms. Dose reduction or discontinuation should be tried if the patient is in remission. NSAIDs seem to be more effective if patients with axial spondyloarthritis are treated early in the course of their disease, achieving a clinicial remission rate of 35% in patients with early disease (<3 years of disease duration)93 in comparison with about 12–15% in patients with longstanding disease.94,95 The safety of long-term NSAIDs therapy has been a concern. Longterm data for ankylosing spondylitis are limited and these data are mostly available for osteoarthritis and rheumatoid arthritis.92 Two reviews96,97 of randomised controlled trials did not show increased side effects of NSAIDs therapy in ankylosing spondylitis compared with placebo during 12 weeks. Infrequent NSAID use was even associated with increased mortality in a Norwegian cohort of patients with long-term ankylosing spondylitis,98 and in a population-based retrospective study99 of administrative health data from Canada NSAID use was also associated with reduced cardiovascular risk in this population. NSAID treatment is associated with a decrease in inflammation and increased mobility in patients with axial spondyloarthritis, factors that might reduce cardiovascular morbidity. Nonetheless, patients should be informed about the potential risks of long-term treatment, including 78

cardiovascular, gastrointestinal, and renal risks.92 A meta-analysis100 of randomised trials in patients with any disease who were treated with NSAIDs for at least 4 weeks, the relative risks of major adverse cardiovascular events were 1·37 for celecoxib and 1·41 for diclofenac, indicating no difference between cycloo­xygenase (COX)-2 selective and non-selective NSAIDs—with the exception of naproxen, which was not associated with an increase.

Conventional disease modifying antirheumatic drugs and glucocorticoids Conventional disease modifying antirheumatic drugs (DMARDs; as opposed to biological DMARDs—TNF and interleukin-17 antagonists in axial spondyloarthritis), such as methotrexate, sulfasalazine, or leflunomide, are generally not effective in the treatment of axial manifestations of spondyloarthritis, but these agents might have a limited role for the treatment of peripheral manifestations when it coexists with axial disease.88,90 Discussion is ongoing over whether a combination of a conventional DMARD with a biological drug might prevent the development of anti-drug antibodies (ADAs) directed against the biological drug and thus increases the drug survival rate in these patients. However, such an advantage for a combination of a DMARD (mostly methotrexate) with a TNF blocker was shown in some investigations101,102 of patients with axial spondyloarthritis but not in others.103–105 Therefore, such a combination is not recommended, which is also in line with current treatment recommendations.89,90 Long-term systemic glucocorticoid therapy is not recommended because high doses of prednisolone of about 50 mg per day106 or higher are needed to achieve a measurable effect on disease acitvity.

TNF inhibitors Five TNF inhibitors are available with approval for ankylosing spondylitis in the EC, USA, and most other parts of the world: infliximab,107 etanercept,108 adalimumab,109 golimumab,110 and certolizumab (table).111 Treatment with any of these TNF blockers leads to a good or very good improvement in all articular manifestations, CRP levels, and MRI-detectable inflammation in the sacroiliac joints or spine in active patients with ankylosing spondylitis in whom conventional treatment with NSAIDs failed. Etanercept is not effective for active inflammatory bowel disease, by contrast with monoclonal antibodies, and evidence favouring monoclonal antibodies rather than etanercept is better for uveitis than for psoriasis.89,90 TNF blockers, with the exception of infliximab, have also been approved for the other clinical subset of axial spondyloarthritis, non-radiographic spondyloarthritis, in the European Union (EU) and elsewhere on the basis of the results of phase 3 trials111,115–117 (table), but not yet in the USA. The European label is restricted to patients with objective signs of inflammation, such as positive CRP or active MRI-inflammation in the sacroiliac joint or spine www.thelancet.com Vol 390 July 1, 2017

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Dosing regimen

Assessment timepoint (week)

Drug response (ASAS40), % (n/N)

Placebo response (ASAS40), % (n/N)

Difference, %

Ankylosing spondylitis Adalimumab109

40 mg, every other week, subcutaneous

12

40 (83/208)

13 (14/107)

27

Certolizumab pegol111

200 mg, every other week, subcutaneous

12

40 (26/65)

19 (11/57)

21

Certolizumab pegol111

400 mg, every 4 weeks, subcutaneous

12

50 (28/56)

19 (11/57)

31

Etanercept112

25 mg, twice weekly, subcutaneous

12

45 (58/128)

16 (21/129)

29

Golimumab110

50 mg, every 4 weeks, subcutaneous

14

45 (62/138)

15 (12/78)

30

Infliximab113

5 mg/kg, weeks 0, 2, and 6, and every 6 weeks thereafter, intravenous

24

47 (93/201)

12 (9/78)

35

Secukinumab114

150 mg, subcutaneous, every 4 weeks, after initial intravenous loading dose of 10 mg/kg at baseline, week 4 and 8

16

42 (52/125)

13 (16/122)

29

Secukinumab114

150 mg, subcutaneous, every 4 weeks, after initial loading with 150 mg, subcutaneous, weekly through week 4

16

36 (26/72)

11 (8/74)

25

Non-radiographic axial spondyloarthritis (all included patients)* Adalimumab115

40 mg, every other week, subcutaneous

12

36 (33/91)

15 (14/94)

21

Certolizumab pegol111

200 mg, every other week, subcutaneous

12

48 (22/46)

16 (8/50)

32

Certolizumab pegol111

400 mg, every 4 weeks, subcutaneous

12

47 (24/51)

16 (8/50)

31

Etanercept116

50 mg, weekly, subcutaneous

12

33 (35/105)

15 (16/108)

18

Golimumab117

50 mg, every 4 weeks, subcutaneous

16

57 (55/97)

23 (23/100)

34

Non-radiographic axial spondyloarthritis (with raised CRP, or active sacroiliitis on MRI, or both)* Adalimumab115

40 mg, every other week, subcutaneous

12

41 (28/69)

14 (10/73)

27

Certolizumab pegol111

200 mg, every other week, subcutaneous

12

48 (22/46)

16 (8/50)

32

Certolizumab pegol111

400 mg, every 4 weeks, subcutaneous

12

47 (24/51)

16 (8/50)

31

Etanercept116,118†

50 mg, weekly, subcutaneous

12

35 (33/94)

17 (16/93)

18

Golimumab117

50 mg, every 4 weeks, subcutaneous

16

60 (47/78)

23 (18/80)

37

No data are available for infliximab and secukinumab for non-radiographic axial spondyloarthritis. These are not head-to-head trials and, therefore, comparison of results is limited. Only the certolizumab trial was stratified for radiographic and non-radiographic axial spondyloarthritis, whereas the other trials for TNF blockers in radiographic and non-radiographic axial spondyloarthritis were undertaken separately and at different timepoints. n=number of patients responding. N=number of patients in this group. TNF=tumour necrosis factor. CRP=C-reactive protein. *Target population according to the approval status for anti-TNF drugs in non-radiographic axial spondyloarthritis in the European Union and some other countries: patients with non-radiographic axial spondyloarthritis with raised CRP, or active sacroiliitis on MRI, or both. †Approximate response rates calculated on the basis of the information obtained from the cited sources.

Table: ASAS40 response to biologicals in phase 3 clinical trials in patients with axial spondyloarthritis

(figure 5). Presence of positive CRP or MRI inflammation is not mandatory for the treatment of ankylosing spondylitis, although those patients do also respond better than patients negative for these indices.119 If the treatment results between ankylosing spondylitis and non-radiographic spondyloarthritis are compared for those patients who are treated according to the label in the EU, the results are similar (table).120 For patients with axial spondyloarthritis, raised CRP, short symptom duration (or young age), and active MRI inflammation seem to be the best predictors for a good response to TNF blockers.120 Discontinuation of TNF blocker in patients with axial spondyloarthritis who had had a good response generally resulted in a relapse in 75–90% of cases,121–123 without any major differences if NSAID therapy was continued or not,124 but a reduction of the TNF-blocker dose in good responders was tolerated by 52–86% of patients.125,126 However, these results are based on small numbers of patients and this question should be further examined in larger trials. www.thelancet.com Vol 390 July 1, 2017

Other biological disease modifying antirheumatic drugs Anakinra, an interleukin-1 receptor antagonist, and abatacept, a T-cell modulator, were tested in small prospective open-label trials89,90 in patients with ankylosing spondylitis and did not have a better effect than an expected (historical) placebo response. A similar prospective open-label study127,128 with rituximab, a monoclonal antibody directed against CD20 on B cells, produced inconclusive results. Tocilizumab129 and sarilumab,130 both monoclonal antibodies directed against the interleukin-6 receptor, were tested in two placebo-controlled double-blind studies in anti-TNFnaive patients with active ankylosing spondylitis, with no efficacy compared with placebo. By contrast, treatments targeting the interleukin-23– interleukin-17 axis seem to be very promising in patients with axial spondyloarthritis. Until now, all completed studies of these treatments have been done in patients with ankylosing spondylitis, but studies including those with non-radiographic axial spondyloarthritis are ongoing. In two phase 3 trials, the anti-interleukin-17 79

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Diagnosis*

Failure of the previous treatment High disease activity

Ankylosing spondylitis

At least 2 NSAIDs given for 4 weeks in total BASDAI ≥4 or ASDAS ≥2·1†

Non-radiographic axial spondyloarthritis

At least 2 NSAIDs given for 4 weeks in total BASDAI ≥4 or ASDAS ≥2·1† and Objective signs of inflammatory activity:

or

CRP+

Active sacroiliitis

Figure 5: Current approval status for TNF-blocker treatment of axial spondyloarthritis patients in the European Union No current approval for non-radographic axial spondyloarthritis in the USA; approval also in many other parts of the world, but note that in some non-European Union countries the presence of objective signs of inflammation is not mandatory. TNF=tumour necrosis factor. NSAIDs=non-steroidal anti-inflammatory drugs. ASDAS=Ankylosing Spondylitis Disease Activity Score. CRP=C-reactive protein. BASDAI=Bath Ankylosing Spondylitis Disease Activity Index. *Based on a combination of clinical, laboratory, and imaging parameters. †According to the ASAS/EULAR recommendations.89

inhibitor secukinumab was effective in patients with ankylosing spondylitis,114 and—on the basis of the results of these trials—have now been approved for ankylosing spondylitis in the EU, USA, and other parts of the world (table). The positive treatment response was maintained throughout 52 weeks of treatment in both studies. A dose of 300 mg secukinumab, which is more effective than 150 mg for the treatment of psoriasis, has not yet been investigated for ankylosing spondylitis. Although no head-to-head trials have been done so far, the demonstrated effectiveness of secukinumab seems to be close to the response rates seen in TNF-blocker trials undertaken in a similar patient group. Secukinumab was also effective in a subgroup of patients in whom TNF-blocker therapy failed or was discontinued for other reasons.131 Nevertheless, the place of interleukin-17 inhibitors in the treatment of axial spondyloarthritis remains to be determined as larger clinical experience grows. The efficacy of secukinumab treatment in patients who failed to respond to a first TNF blocker needs to be compared with the effectiveness of treatment with a second TNF blocker. Additionally, whether interleukin-17 blockade might reduce the progression of new bone formation, as was speculated on the basis of the results of one uncontrolled ankylosing spondylitis trial,132 is unknown. One prospective open-label trial133 of ustekinumab (a monoclonal antibody against the p40 subunit of 80

interleukin-12 and interleukin-23) has been undertaken in patients with ankylosing spondylitis showing good efficacy. This efficacy is being assessed further in ongoing placebo-controlled trials in ankylosing spondylitis and non-radiographic axial spondyloarthritis. The oral Janus kinase inhibitor tofacitinib has been tested in one phase 2 double-blind placebo-controlled dose-ranging study134 in patients with ankylosing spondylitis, providing a positive signal for a good clinical and MRI response that needs confirmation in a larger trial. Apremilast, an oral PDE4 inhibitor, was tested in a small proof of concept trial135 in active patients with ankylosing spondylitis for 12 weeks either with apremilast or placebo showing a moderate reduction of the disease activity but a larger placebo-controlled phase 2 trial136 in patients with ankylosing spondylitis did not show a response superior to placebo treatment.

Treatment options for inhibition of radiographic progression Possible treatments to stop radiographic progression involve early suppression of inflammation and targeting of molecules stimulating bone formation. TNF-blocker treatment does not have an effect on radiographic progression over 2 or 4 years of treatment in patients with established longstanding ankylosing spondylitis.137,138 But evidence shows that early treatment139 and treatment for more than 4 years140 might affect radiographic progression by suppression of inflammation and the avoidance of subchondral granulation tissue.54 Direct targeting of new bone formation might be associated with too many side-effects affecting the general bone metabolism. Biomarkers that predict new bone formation are needed to identify patients who would benefit from such treatments. An inhibitory effect of contiuous NSAID therapy for 2 years was reported in patients with ankylosing spondylitis in one randomised prospective trial.141 This effect was backed by additional data from a retrospective analysis,142 and from a prospective observational spondyloarthritis cohort.143 A direct inhibitory effect of NSAIDs on osteoblasts, mediated by prostaglandin inhibition, was postulated as a possible mechanism to explain these results. However, these findings could not be confirmed by another randomised prospective trial.144 In the trial by Sieper and colleagues,144 most patients were treated with diclofenac, whereas in the trial by Wanders and colleagues,141 most were given celecoxib. Thus it is unclear whether the inhibitory effect was COX-2-specific (or even celecoxib-specific effect) in the trial by Wanders and colleagues141 or whether NSAIDs are just not effective for the inhibiton of new bone formation. Until additonal data become available, NSAID treatment is only recommended for the treatment of signs and symptoms but not to inhibit syndesmophyte growth.89,90 www.thelancet.com Vol 390 July 1, 2017

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Controversies and outstanding research questions More of the genes involved in the pathogenesis of axial spondyloarthritis need to be identified, the functional mechanisms of the known genetic associations should be determined, and understanding of the interaction between genetic predispositon and environment, such as exposure to microbes, needs to be improved. Discussion will continue as to whether and how classification and diagnosis, with a focus on early identification, can be improved—and the role of MRI in this process should be further specified. The proven effectiveness of interleukin-17 inhbition for the treatment of axial spondyloarthritis raises the question of whether the same or different patients respond to TNF-blockade and interleukin-17 inhibiton and about the potential of a combination of these two treatments. Finally, which treatment can stop radiographic progression remains to be shown and how best to identify patients who will benefit most from such an intervention. References 1 Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009; 68: 777–83. 2 van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984; 27: 361–68. 3 Dougados M, van der Linden S, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991; 34: 1218–27. 4 Amor B, Dougados M, Mijiyawa M. Criteria of the classification of spondylarthropathies. Rev Rhum Mal Osteoartic 1990; 57: 85–89. 5 Deodhar A, Strand V, Kay J, Braun J. The term ‘non-radiographic axial spondyloarthritis’ is much more important to classify than to diagnose patients with axial spondyloarthritis. Ann Rheum Dis 2016; 75: 791–94. 6 Deodhar A, Reveille JD, van den Bosch F, et al. The concept of axial spondyloarthritis: joint statement of the spondyloarthritis research and treatment network and the Assessment of SpondyloArthritis international Society in response to the US Food and Drug Administration‘s comments and concerns. Arthritis Rheumat 2014; 66: 2649–56. 7 Calin A, Porta J, Fries JF, Schurman DJ. Clinical history as a screening test for ankylosing spondylitis. JAMA 1977; 237: 2613–14. 8 Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum 2006; 54: 569–78. 9 Sieper J, van der Heijde D, Landewe R, et al. New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS). Ann Rheum Dis 2009; 68: 784–88. 10 Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009; 68 (suppl 2): ii1–44. 11 Ramiro S, van Tubergen A, Stolwijk C, van der Heijde D, Royston P, Landewe R. Reference intervals of spinal mobility measures in normal individuals: the MOBILITY study. Ann Rheum Dis 2015; 74: 1218–24. 12 Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994; 21: 2286–91. 13 Machado P, Landewe R, Lie E, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 2010; 70: 47–53.

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14 Vander Cruyssen B, Ribbens C, Boonen A, et al. The epidemiology of ankylosing spondylitis and the commencement of anti-TNF therapy in daily rheumatology practice. Ann Rheum Dis 2007; 66: 1072–77. 15 Rudwaleit M, Haibel H, Baraliakos X, et al. The early disease stage in axial spondylarthritis: Results from the german spondyloarthritis inception cohort. Arthritis Rheum 2009; 60: 717–27. 16 Dougados M, Etcheto A, Molto A, et al. Clinical presentation of patients suffering from recent onset chronic inflammatory back pain suggestive of spondyloarthritis: The DESIR cohort. Joint Bone Spine 2015; 82: 345–51. 17 Jaakkola E, Herzberg I, Laiho K, et al. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006; 65: 775–80. 18 van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev Rheumatol 2015; 11: 110–18. 19 Stolwijk C, van Onna M, Boonen A, van Tubergen A. The global prevalence of spondyloarthritis: A systematic review and meta-regression analysis. Arthritis Care Res (Hoboken) 2016; 68: 1320–31. 20 Khan MA, Kushner I, Braun WE. Letter: Low incidence of HLA-B27 in American Blacks with spondyloarthropathies. Lancet 1976; 1: 483. 21 Reveille JD, Witter JP, Weisman MH. Prevalence of axial spondylarthritis in the United States: estimates from a cross-sectional survey. Arthritis Care Res (Hoboken) 2012; 64: 905–10. 22 Bakland G, Alsing R, Singh K, Nossent JC. Assessment of SpondyloArthritis International Society criteria for axial spondyloarthritis in chronic back pain patients with a high prevalence of HLA-B27. Arthritis Care Res (Hoboken) 2013; 65: 448–53. 23 Costantino F, Talpin A, Said-Nahal R, et al. Prevalence of spondyloarthritis in reference to HLA-B27 in the French population: results of the GAZEL cohort. Ann Rheum Dis 2015; 74: 689–93. 24 Brown MA, Kennedy LG, MacGregor AJ, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40: 1823–28. 25 Ellinghaus D, Jostins L, Spain SL, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet 2016; 48: 510–18. 26 International Genetics of Ankylosing Spondylitis C, Cortes A, Hadler J, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013; 45: 730–38. 27 Evans DM, Spencer CC, Pointon JJ, et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 2011; 43: 761–67. 28 Carter JD, Gerard HC, Espinoza LR, et al. Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis. Arthritis Rheum 2009; 60: 1311–16. 29 Van Praet L, Jans L, Carron P, et al. Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort. Ann Rheum Dis 2014; 73: 1186–89. 30 Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel diseases. Inflamm Bowel Dis 2012; 18: 968–84. 31 Asquith M, Elewaut D, Lin P, Rosenbaum JT. The role of the gut and microbes in the pathogenesis of spondyloarthritis. Best Pract Res Clin Rheumatol 2014; 28: 687–702. 32 Costello ME, Ciccia F, Willner D, et al. Intestinal dysbiosis in ankylosing spondylitis. Arthritis Rheumatol 2014; published online Nov 21. DOI:10.1002/art.38967. 33 Baraliakos X, Baerlecken N, Witte T, Heldmann F, Braun J. High prevalence of anti-CD74 antibodies specific for the HLA class II-associated invariant chain peptide (CLIP) in patients with axial spondyloarthritis. Ann Rheum Dis 2014; 73: 1079–82. 34 Baerlecken NT, Nothdorft S, Stummvoll GH, et al. Autoantibodies against CD74 in spondyloarthritis. Ann Rheum Dis 2014; 73: 1211–14. 35 Appel H, Maier R, Wu P, et al. Analysis of IL-17(+) cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther 2011; 13: R95.

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36 Gracey E, Qaiyum Z, Almaghlouth I, et al. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Ann Rheum Dis 2016; published online May 10. DOI:10.1136/annrheumdis-2015-208902. 37 Noordenbos T, Blijdorp I, Chen S, et al. Human mast cells capture, store, and release bioactive, exogenous IL-17A. J Leukoc Biol 2016; 100: 453–62. 38 Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 2012; 11: 763–76. 39 Uluckan O, Jimenez M, Karbach S, et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med 2016; 8: 330ra37. 40 Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8entheseal resident T cells. Nat Med 2012; 18: 1069–76. 41 Appel H, Maier R, Bleil J, et al. In situ analysis of interleukin-23and interleukin-12-positive cells in the spine of patients with ankylosing spondylitis. Arthritis Rheum 2013; 65: 1522–29. 42 Jacques P, Lambrecht S, Verheugen E, et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 2014; 73: 437–45. 43 Lories R. The balance of tissue repair and remodeling in chronic arthritis. Nat Rev Rheumatol 2011; 7: 700–07. 44 Bleil J, Maier R, Hempfing A, et al. Histomorphologic and histomorphometric characteristics of zygapophyseal joint remodeling in ankylosing spondylitis. Arthritis Rheumatol 2014; 66: 1745–54. 45 Ruiz-Heiland G, Horn A, Zerr P, et al. Blockade of the hedgehog pathway inhibits osteophyte formation in arthritis. Ann Rheum Dis 2012; 71: 400–07. 46 Appel H, Ruiz-Heiland G, Listing J, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 2009; 60: 3257–62. 47 Heiland GR, Appel H, Poddubnyy D, et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 2012; 71: 572–74. 48 Tsui FW, Tsui HW, Las Heras F, Pritzker KP, Inman RD. Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis. Ann Rheum Dis 2014; 73: 1873–79. 49 Poddubnyy D, Haibel H, Listing J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum 2012; 64: 1388–98. 50 Maksymowych WP, Landewe R, Conner-Spady B, et al. Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis. Arthritis Rheum 2007; 56: 1846–53. 51 Poddubnyy D, Conrad K, Haibel H, et al. Elevated serum level of the vascular endothelial growth factor predicts radiographic spinal progression in patients with axial spondyloarthritis. Ann Rheum Dis 2014; 73: 2137–43. 52 Turina MC, Sieper J, Yeremenko N, et al. Calprotectin serum level is an independent marker for radiographic spinal progression in axial spondyloarthritis. Ann Rheum Dis 2014; 73: 1746–48. 53 Syrbe U, Callhoff J, Conrad K, et al. Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression. Arthritis Rheumat 2015; 67: 678–85. 54 Maksymowych WP, Morency N, Conner-Spady B, Lambert RG. Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2013; 72: 23–28. 55 Baraliakos X, Heldmann F, Callhoff J, et al. Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. Ann Rheum Dis 2014; 73: 1819–25. 56 Bleil J, Maier R, Hempfing A, Sieper J, Appel H, Syrbe U. Granulation tissue eroding the subchondral bone also promotes new bone formation in ankylosing spondylitis. Arthritis Rheumat 2016; 68: 2456–65.

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57 Machado PM, Baraliakos X, van der Heijde D, Braun J, Landewe R. MRI vertebral corner inflammation followed by fat deposition is the strongest contributor to the development of new bone at the same vertebral corner: a multilevel longitudinal analysis in patients with ankylosing spondylitis. Ann Rheum Dis 2016; 75: 1486–93. 58 Rudwaleit M, van der Heijde D, Landewe R, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011; 70: 25–31. 59 Robinson PC, Wordsworth BP, Reveille JD, Brown MA. Axial spondyloarthritis: a new disease entity, not necessarily early ankylosing spondylitis. Ann Rheum Dis 2013; 72: 162–64. 60 Sieper J, van der Heijde D. Review: nonradiographic axial spondyloarthritis: new definition of an old disease? Arthritis Rheum 2013; 65: 543–51. 61 van der Linden S, Akkoc N, Brown MA, Robinson PC, Khan MA. The ASAS Criteria for Axial Spondyloarthritis: Strengths, Weaknesses, and Proposals for a Way Forward. Curr Rheumatol Rep 2015; 17: 62. 62 Sepriano A, Landewe R, van der Heijde D, et al. Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis. Ann Rheum Dis 2016; 75: 1034–42. 63 van den Berg R, de Hooge M, van Gaalen F, Reijnierse M, Huizinga T, van der Heijde D. 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) 2013; 52: 1492–99. 64 Molto A, Paternotte S, Comet D, et al. Performances of the Assessment of SpondyloArthritis International Society axial spondyloarthritis criteria for diagnostic and classification purposes in patients visiting a rheumatologist because of chronic back pain: results from a multicenter, cross-sectional study. Arthritis Care Res (Hoboken) 2013; 65: 1472–81. 65 Tomero E, Mulero J, de Miguel E, et al. Performance of the Assessment of Spondyloarthritis International Society criteria for the classification of spondyloarthritis in early spondyloarthritis clinics participating in the ESPERANZA programme. Rheumatology (Oxford) 2014; 53: 353–60. 66 Strand V, Rao SA, Shillington AC, Cifaldi MA, McGuire M, Ruderman EM. Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res (Hoboken) 2013; 65: 1299–306. 67 Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? Arthritis Rheum 2005; 52: 1000–08. 68 Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria? Arthritis Care Res (Hoboken) 2015; 67: 891–97. 69 van den Berg R, de Hooge M, Rudwaleit M, et al. ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort and from the Assessment of SpondyloArthritis international Society (ASAS)-cohort. Ann Rheum Dis 2013; 72: 1646–53. 70 Mandl P, Navarro-Compan V, Terslev L, et al. EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice. Ann Rheum Dis 2015; 74: 1327–39. 71 Poddubnyy D, Brandt H, Vahldiek J, et al. The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic. Ann Rheum Dis 2012; 71: 1998–2001. 72 Poddubnyy D, Rudwaleit M, Haibel H, et al. Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis 2011; 70: 1369–74. 73 van Tubergen A, Heuft-Dorenbosch L, Schulpen G, et al. Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann Rheum Dis 2003; 62: 519–25. 74 van den Berg R, Lenczner G, Feydy A, et al. Agreement between clinical practice and trained central reading in reading of sacroiliac joints on plain pelvic radiographs. Results from the DESIR cohort. Arthritis Rheumatol 2014; 66: 2403–11.

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75 Krohn M, Braum LS, Sieper J, et al. Erosions and fatty lesions of sacroiliac joints in patients with axial spondyloarthritis: evaluation of different MRI techniques and two scoring methods. J Rheumatol 2014; 41: 473–80. 76 Lambert RG, Bakker PA, van der Heijde D, et al. Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann Rheum Dis 2016; 75: 1958–63. 77 Weber U, Ostergaard M, Lambert RG, et al. Candidate lesion-based criteria for defining a positive sacroiliac joint MRI in two cohorts of patients with axial spondyloarthritis. Ann Rheum Dis 2015; 74: 1976–82. 78 Weber U, Zubler V, Zhao Z, et al. Does spinal MRI add incremental diagnostic value to MRI of the sacroiliac joints alone in patients with non-radiographic axial spondyloarthritis? Ann Rheum Dis 2015; 74: 985–92. 79 Hermann KG, Baraliakos X, van der Heijde DM, et al. Descriptions of spinal MRI lesions and definition of a positive MRI of the spine in axial spondyloarthritis: a consensual approach by the ASAS/ OMERACT MRI study group. Ann Rheum Dis 2012; 71: 1278–88. 80 Weber U, Zhao Z, Rufibach K, et al. Diagnostic utility of candidate definitions for demonstrating axial spondyloarthritis on magnetic resonance imaging of the spine. Arthritis Rheumatol 2015; 67: 924–33. 81 Song IH, Carrasco-Fernandez J, Rudwaleit M, Sieper J. The diagnostic value of scintigraphy in assessing sacroiliitis in ankylosing spondylitis: a systematic literature research. Ann Rheum Dis 2008; 67: 1535–40. 82 Poddubnyy D, Vahldiek J, Spiller I, et al. Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care. J Rheumatol 2011; 38: 2452–60. 83 Sieper J, Srinivasan S, Zamani O, et al. Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study. Ann Rheum Dis 2013; 72: 1621–27. 84 Rudwaleit M, Sieper J. Referral strategies for early diagnosis of axial spondyloarthritis. Nat Rev Rheumatol 2012; 8: 262–68. 85 van Hoeven L, Vergouwe Y, de Buck PD, Luime JJ, Hazes JM, Weel AE. External validation of a referral rule for axial spondyloarthritis in primary care patients with chronic low back pain. PLoS One 2015; 10: e0131963. 86 Deodhar A, Mittal M, Reilly P, et al. Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay. Clin Rheumatol 2016; 35: 1769–76. 87 Poddubnyy D, van Tubergen A, Landewe R, Sieper J, van der Heijde D, for the Assessment of Spondylo Arthritis international group. Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis. Ann Rheum Dis 2015; 74: 1483–87. 88 Poddubnyy D, van Tubergen A, Landewe R, Sieper J, van der Heijde D. Defining an optimal referral strategy for patients with a suspicion of axial spondyloarthritis: what is really important? Response to: ‘Evaluating the ASAS recommendations for early referral of axial spondyloarthritis in patients with chronic low back pain; is one parameter present sufficient for primary care practice?’ by van Hoeven et al. Ann Rheum Dis 2015; 74: e69. 89 Van Heijde D, Ramiro S, Landewé R, et al. 2016 update of the ASAS/EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017; published online Jan 13. DOI:10.1136/annrheumdis-2016-210770. 90 Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Care Res (Hoboken) 2016; 68: 151–66. 91 Smolen JS, Braun J, Dougados M, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 2014; 73: 6–16. 92 Song IH, Poddubnyy DA, Rudwaleit M, Sieper J. Benefits and risks of ankylosing spondylitis treatment with nonsteroidal antiinflammatory drugs. Arthritis Rheum 2008; 58: 929–38. 93 Sieper J, Lenaerts J, Wollenhaupt J, et al. 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 2014; 73: 101–07.

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94 Sieper J, Klopsch T, Richter M, et al. Comparison of two different dosages of celecoxib with diclofenac for the treatment of active ankylosing spondylitis: results of a 12-week randomised, double-blind, controlled study. Ann Rheum Dis 2008; 67: 323–29. 95 van der Heijde D, Baraf HS, Ramos-Remus C, et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study. Arthritis Rheum 2005; 52: 1205–15. 96 Kroon FP, van der Burg LR, Ramiro S, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis). Cochrane Database Syst Rev 2015; 7: CD010952. 97 Wang R, Dasgupta A, Ward MM. Comparative efficacy of non-steroidal anti-inflammatory drugs in ankylosing spondylitis: a Bayesian network meta-analysis of clinical trials. Ann Rheum Dis 2016; 75: 1152–60. 98 Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis 2011; 70: 1921–25. 99 Haroon NN, Paterson JM, Li P, Inman RD, Haroon N. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med 2015; 163: 409–16. 100 Coxib and traditional NSAID Trialists’ Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382: 769–79. 101 Lie E, Kristensen LE, Forsblad-d‘Elia H, et al. The effect of comedication with conventional synthetic disease modifying antirheumatic drugs on TNF inhibitor drug survival in patients with ankylosing spondylitis and undifferentiated spondyloarthritis: results from a nationwide prospective study. Ann Rheum Dis 2015; 74: 970–78. 102 Nissen MJ, Ciurea A, Bernhard J, et al. The effect of comedication with a csDMARD on drug retention and clinical effectiveness of anti-TNF therapy in patients with axial spondyloarthritis. Arthritis Rheumat 2016; 68: 2140–50. 103 Breban M, Ravaud P, Claudepierre P, et al. Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment. Arthritis Rheum 2008; 58: 88–97. 104 Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. Arthritis Rheum 2008; 59: 234–40. 105 Sepriano A, Ramiro S, van der Heijde D, et al. Effect of comedication with conventional synthetic DMARDs on TNF inhibitors-retention in patients with spondyloarthritis: A prospective cohort. Arthritis Rheumat 2016; 68: 2671–79. 106 Haibel H, Heldmann F, Braun J, Listing J, Kupper H, Sieper J. Long-term efficacy of adalimumab after drug withdrawal and retreatment in patients with active non-radiographically evident axial spondyloarthritis who experience a flare. Arthritis Rheum 2013; 65: 2211–13. 107 Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–93. 108 Davis JC Jr, Van Der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 3230–36. 109 van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006; 54: 2136–46. 110 Inman RD, Davis JC Jr, Heijde D, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008; 58: 3402–12. 111 Landewe R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis 2014; 73: 39–47.

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