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Abstract

Development of the Assessment in Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (SpA) was one of the major breakthroughs in the field over the past decade. Despite some concerns related to the specificity of the criteria, they stimulated research into the early stage of the disease. This resulted in major advances in the understanding of the course of the disease, revealing predictors of progression, improvement in early diagnosis and treatment in axial SpA. In this review, we summarize the recent developments resulting from the introduction of the ASAS classification criteria for axial SpA and the implications for research and clinical practice.

Keywords

Axial spondyloarthritis ankylosing spondylitis ASAS classification criteria diagnosis

Introduction

A group of chronic inflammatory diseases is subsumed under the generic term ‘spondyloarthritis’ (SpA) (Figure 1). They share common clinical, genetic and pathophysiological features,^1–3 such as involvement of the axial skeleton (sacroiliac joints and spine), characteristic peripheral manifestations (dactylitis, enthesitis and asymmetric mono- or oligoarthritis predominantly affecting the lower extremities) and particular extra-articular manifestations, such as anterior uveitis, psoriasis and inflammatory bowel disease,^1,2 as well as association with the major histocompatibility complex class I human leucocyte antigen-B27 (HLA-B27).^1,4,5

Figure 1.

The spectrum of spondyloarthritis (SpA) and overlap (cross-sectional and longitudinal) between different SpA forms.

Depending on the leading manifestation, two major SpA groups are defined: axial SpA with predominant involvement of the sacroiliac joints and/or spine, and peripheral SpA with predominant peripheral manifestations such as arthritis, enthesitis and dactylitis (Figure 1). In this review, we will focus on recent developments resulting from the introduction of the Assessment in Spondyloarthritis International Society (ASAS) classification criteria for axial SpA,^6,7 and the implications for understanding, diagnosing and treating the disease.

Current classification criteria

In the early years of this century, the concept of axial SpA as one disease with two subsets has arisen: with radiographic changes in the sacroiliac joints (ankylosing spondylitis [AS] or radiographic axial SpA) and without (nonradiographic axial SpA [nr-axSpA]).^8–11 With the introduction of new and effective treatment options, such as tumour necrosis factor (TNF) blockers,^12–16 it has become crucial to identify the disease as early as possible to give patients these opportunities in the early course of the disease. As the commonly used classification criteria, the modified New York (mNY) criteria for AS,¹⁷ were not able to capture individuals with early disease (i.e. without structural damage in the sacroiliac joints on X-rays) and evidence of the ability of magnetic resonance imaging (MRI) to detect active inflammation of the spine and sacroiliac joints early in the disease course emerged,^11,18–21 the new ASAS classification criteria were developed and published in 2009.^6,7 They enabled classification of patients as having axial SpA even before relevant structural damage in the sacroiliac joints occurred. According to the new ASAS classification criteria,⁶ at an early disease stage this is possible either by using the ‘imaging’ arm with signs of active sacroiliitis in MRI with at least one other SpA feature or by using the ‘clinical’ arm, where the presence of HLA-B27 is mandatory with an additional two or more SpA features (Figure 2). Furthermore, classification is also possible at a later stage when already advanced chronic changes of the sacroiliac joints can be seen in the conventional radiograph according to the mNY ¹⁷ and at least one other SpA feature is present. These criteria showed a sensitivity of 82.9% and a specificity of 84.4%, clearly outperforming the original European Spondyloarthropathy Study Group²² and Amor criteria.²³ Focusing on the so-called ‘imaging arm’ alone, the ASAS classification criteria showed a sensitivity of 66.2% and a specificity of 97.5%. Moreover, when these criteria were applied to other cohorts and tested against the rheumatologist’s diagnosis as the gold standard, acceptable results for sensitivity and specificity were shown. These were comparable to the initial results with a sensitivity between 68% and 87% and a specificity between 62% and 95%.^24–27 At follow up of the initial cohort⁶ after 3–5 years by the treating rheumatologist, the positive predictive value that patients who initially fulfilled the criteria would still be diagnosed with axial SpA was excellent with 93.3%.²⁸ These classification criteria have been accompanied by a new definition of inflammatory back pain,²⁹ a new definition of active sacroiliitis on MRI³⁰ and new classification criteria for peripheral SpA and SpA in general.²

Figure 2.

Assessment in Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (SpA).⁶

Controversial appraisal of the ASAS classification criteria of axial SpA

The development of the new axial SpA classification criteria⁶ was a significant step towards a better understanding, definition and unification of the disease concept. Undoubtedly, these classification criteria draw attention to an early stage of the disease and stimulated interventional trials that resulted in approval of effective drugs for patients who had had no approved therapeutic options in the past. However, the concept of axial SpA as one disease and the terminology used, especially when it comes to the term ‘nonradiographic axial SpA’, is still a matter of debate.^3,31–33

First, it has to be pointed out that the assessment of conventional X-rays of the sacroiliac joints is challenging³⁴ and high relevant inter- and intra-observer variations have been reported.^35–38 The inter-observer variability was even more pronounced when the grading from local readers and trained central readers was compared,^39,40 but was also evident between central readers.^41,42 The highest variability was observed in the evaluation of grades 1 and 2.³⁴ This may be clinically important, as the difference in the grading of one sacroiliac joint between grade 1 and grade 2 can change the diagnosis from nr-axSpA to AS and vice versa, with potentially prognostic and therapeutic implications. Surprisingly, the reproducibility of assessing radiographic sacroiliitis could not be substantially improved by training.³⁴ Interestingly, in a follow up of the previously described ASAS cohort, which was used to develop the ASAS classification criteria, a net progression from nr-axSpA at the baseline visit to AS of 5% was seen after a mean follow up of 4.4 years (range: 1.9–6.8).⁴³ However, cross-tabulation revealed that more than every second patient (36 out of 62), who was assessed mNY positive at baseline was classified as mNY negative at the radiological follow up, while 54 out of 295 mNY negatives at baseline ‘progressed’ to the radiological form at follow up.⁴³ The explanation of Sepriano and colleagues is that the subtle radiographic changes cannot reliably be discriminated from measurement errors.⁴³

Second, the term nr-axSpA indicates that no radiographic changes are seen on the conventional radiograph, but this does not always have to be the case. There can be minor but obvious radiographic changes in the sacroiliac joints (e.g. sclerosis and few small erosions of the right sacroiliac joint = grade 2 and suspicious changes in the left sacroiliac joint = grade 1), which are just not enough to fulfil the radiological part of the mNY criteria and therefore would still be labelled as mNY negative and thereby classified as nr-axSpA, although unambiguous changes are present. On the other hand, it can be the case – even though rare – that in the absence of radiographic sacroiliitis there are clear radiographic changes of the spine attributable to AS (e.g. syndesmophytes or complete ankylosis). In this case, the classification term would be still nr-axSpA.

The third point is related to the use of classification criteria as an aid in the diagnostic process. The sensitivity and specificity of the ASAS classification criteria for axial SpA were estimated to be 82.9% and 84.4%, respectively.⁶ This was different for separate analysis of the ‘imaging’ arm (sensitivity of 66.2% and specificity of 97.3%)⁶ and the ‘clinical’ arm (sensitivity of 56.6 % and specificity of 83.3%).⁴⁴ Thus, the multi-arm construct of the ASAS criteria increases the sensitivity of the criteria, at the price of a decrease in specificity (as compared with the imaging arm). In the absence of diagnostic criteria for axial SpA, the ASAS classification criteria may be used by physicians in the clinical routine to diagnose axial SpA in their patients. Hence, it has to be stressed, that just ‘ticking boxes on a checklist’ of the ASAS classification criteria for making a diagnosis means an inappropriate use of these criteria,⁴⁵ which, like all classification criteria, should be applied to patients with an established diagnosis only. Classification criteria, in contrast to the diagnostic approach, give a ‘yes’ or ‘no’ answer with a certain sensitivity and specificity (instead of disease probability with a diagnostic approach), do not consider negative results of diagnostic tests and do not take other explanations of symptoms/differential diagnoses into account. As a result, a young patient with unspecified back pain, who is HLA-B27 positive, could be misdiagnosed with axial SpA because of other subjective items like a ‘good response to nonsteroidal anti-inflammatory drugs (NSAIDs)’ or heel pain suggesting enthesitis, for instance. The same is, however, also true for the imaging arm of the criteria, which requires the presence of bone marrow oedema on the MRI scan of the sacroiliac joints in combination with one additional SpA parameter.

Finally, in the first years after publication of the ASAS classification criteria, the specificity of the ‘clinical’ arm was the main target of criticism.^31,32 In the last years, the focus changed to the ‘imaging’ arm and the specificity of ‘positive’ MRI,^46–50 that led to an update of the ASAS definition of active sacroiliitis on MRI,⁵¹ stressing the importance of the contextual interpretation of bone marrow oedema as ‘highly suggestive of SpA’ if used for classification. Despite the limitations related to specificity, MRI still remains the most important imaging method, especially for the early diagnosis of axial SpA.

In order to address these concerns, to test the performance of the ASAS classification criteria in a large prospective cohort of patients including those recruited in North America, and finally to modify the classification criteria (if needed) in order to increase the specificity, ASAS and the SpA Research and Treatment Network (SPARTAN) have recently announced the CLASSIC (Classification of Axial SpondyloarthritiS Inception Cohort) study that is going to start recruitment in 2018.⁵²

Similarities and differences between nr-axSpA and AS

nr-axSpA and AS share common epidemiological, genetic and clinical characteristics^{4,16,27,53–56} that support the concept of axial SpA as one disease with two stages.^1,53 The prevalence of nr-axSpA is comparable with the prevalence of AS, each with 0.3–0.6% in the population.^4,27 The ratio of nr-axSpA to AS in patients first diagnosed with axial SpA is close to 1:1.^57–60 Cohort studies suggest similar characteristics for age, prevalence of HLA-B27, occurrence of peripheral manifestations and extra-articular symptoms as well as disease activity parameters (based on patient-reported outcomes) and burden of the diseases.^9,55,56 However, AS is characterized by a significantly higher prevalence of men and higher C-reactive protein (CRP) levels in comparison with nr-axSpA.^9,55,56 This might be explained by the fact that female patients and patients with lower activity of inflammation (low CRP, less inflammation on MRI) are less likely develop radiographic changes, and therefore might sustain at the nonradiographic stage.⁵³ This implies the existence of a certain subgroup of patients with axial SpA with a rather mild, nonprogressive disease course.^1,53 Approximately 12% of the patients with nr-axSpA progress to AS over a period of 2 years, with elevated CRP levels and active sacroiliitis on MRI being the strongest predictors for this progression^41,42. Concerning the response to anti-TNF-alpha treatment, there seems to be no significant difference between the two groups when the level of active inflammation at baseline is comparable.^16,54,56,61

Treatment of axial SpA

Axial SpA is at present a ‘hot topic’ in the field of rheumatology and new therapeutic options are in the pipeline and will be available in the near future. The exact role of new therapies in the treatment algorithm in axial SpA still has to be defined.

NSAIDs and TNF blockers are well-known effective treatment options in patients with axial SpA. With secukinumab, a monoclonal antibody against interleukin-17A (IL-17A), a new compound has been available since 2015 as an important treatment option for patients with ankylosing spondylitis, while phase III studies for nr-axSpA are still ongoing.

In the last years, the major treatment target in SpA was defined as clinical remission/inactivity of musculoskeletal (arthritis, dactylitis, enthesitis, axial disease) and extra-articular manifestations.⁶² The current versions of the leading international management recommendations for axial SpA (ASAS and the European League Against Rheumatism recommendations from 2017⁶³) and treatment recommendations (from the American College of Rheumatology/Spondylitis Association of America /SPARTAN from 2016⁶⁴) are similar (Figure 3).

Figure 3.

Treatment algorithm for axial spondyloarthritis (SpA) based on the Assessment in Spondyloarthritis International Society/European League Against Rheumatism⁶⁵ and American College of Rheumatology/Spondylitis Association of America/SpA Research and Treatment Network⁶⁴ recommendations.

According to these recommendations, first-line therapies for patients with symptomatic axial SpA are NSAIDs, including selective cyclooxygenase-2 (COX-2) antagonists, together with exercise/physiotherapy and education of the patients.⁶⁵ Therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) such as sulphasalazine may have some beneficial effect in patients with peripheral joint involvement, but are not effective in the majority of patients with axial involvement.^66–68 If these patients have a poor response to NSAIDs, contraindications or intolerance for NSAIDs, the only effective treatment currently available is therapy with biological DMARDs (bDMARDs): TNF-alpha inhibitors⁶⁵ or with secukinumab, the recently introduced monoclonal antibody against IL-17A.⁶⁵

Currently there are five TNF inhibitors (infliximab,¹² etanercept,¹⁴ adalimumab,¹³ golimumab¹⁵ and certolizumab pegol¹⁶) and one monoclonal antibody against IL-17A (secukinumab⁶⁹) approved for the treatment of patients with AS in the EU, the USA and most other parts of the world. In the EU, four TNF inhibitors (etanercept,⁷⁰ adalimumab,⁷¹ golimumab⁷² and certolizumab pegol¹⁶) also have approval for the treatment of nr-axSpA after failure of the standard treatments, whereas the label is restricted to such patients with objective signs of active inflammation: elevated CRP or active sacroiliitis on MRI (Figure 4).

Figure 4.

(a) Approval status and year of approval for biological disease-modifying antirheumatic drugs (bDMARDs) by the European Medicines Agency for axial spondyloarthritis (SpA) in the EU and a number of other countries. (b) Approval status and year of approval for bDMARDs by the US Food and Drug Administration for SpA in the USA.

The European Medicines Agency (EMA) further demanded a therapy-withdrawal trial design to investigate whether patients with nr-axSpA can achieve a disease state of ‘drug-free remission’ after a treatment cycle like an ‘induction therapy’. These trials are still ongoing.

Contrary to the EMA decision, the US Food and Drug Administration rejected the approval for TNF inhibitors for nr-axSpA, due to questions about the specificity of the ASAS criteria and the natural history of the disease entity, hinting that a significant proportion of these patients may show spontaneous remission and therefore might not require the costly and potentially harmful anti-TNF therapy.⁷³

There is some evidence that NSAIDs, in particular celecoxib, might possess not only a symptomatic efficacy but also disease-modifying properties in AS, retarding the progression of structural damage (syndesmophytes and ankylosis) in the spine if taken continuously.⁷⁴ However, for diclofenac, a nonselective COX inhibitor, such an effect was not proven in a recently published trial.⁷⁵ The data on the effect of TNF inhibitors on radiographic spinal progression in ankylosing spondylitis, despite their high anti-inflammatory efficacy, remains controversial. While some studies could not show a retardation of radiographic spinal progression in AS over a period of 2 years^76–78 or 4⁷⁹ years, three observational studies suggested that it may take more than 4 years to detect such an effect^80–82 and that early (within the first 5 years or 10 years of the disease) initiation of anti-TNF therapy might play a key role.^81,82 Also, achievement of sustained remission with TNF inhibitors was associated with retardation of radiographic spinal progression within a 2-year time frame as shown in a recent analysis of an observational cohort study.⁸³ However, no prospective controlled trials have been conducted so far to confirm these observations.

Concept of axial SpA in the context of other inflammatory diseases

In many other systemic inflammatory-rheumatic diseases, patients classified as one generic diagnosis might present with relevant prognostic variations among subgroups. This is obviously the case for rheumatoid arthritis, with or without anti-citrullinated protein antibodies, where no one would separate this heterogeneous patient cohort and limit the existing effective treatment options, for example, for patients without radiographic erosions. It is generally true that capturing inflammatory disease (such as rheumatoid arthritis, psoriatic arthritis, Crohn’s disease, etc.) at an early stage implies a broader spectrum of possible outcomes including both milder forms with no or only slow progression of structural damage and more severe forms with a rather more rapid progression of structural damage.

A higher heterogeneity of the nr-axSpA subgroup compared with AS is also acknowledged in the wording of the current approval of TNF inhibitors for nr-axSpA in the EU: in addition to the lack of response to NSAIDs, objective signs of inflammation (elevated CRP and/or positive MRI) are required to start the treatment. So far, only one phase III trial with a bDMARD (a TNF inhibitor certolizumab pegol) has been performed in patients with axial SpA (both nonradiographic and radiographic) fulfilling the ASAS classification criteria. In this study, all patients were required to have objective signs of inflammation (positive CRP or active sacroiliitis on MRI). As a result, the response rates in both subgroups (nr-axSpA and AS) were very similar supporting again the concept of axial SpA as one entity.¹⁶ We expect that the number of clinical trials including the entire population of axial SpA will increase in future.

Conclusion

Development of the ASAS classification criteria for axial SpA has been one of the major breakthroughs in the field over the past decade. Despite some concerns related to the specificity of the criteria and some uncertainties around new nomenclature, the criteria stimulated research related to the early stage of the disease. This resulted in major advances in understanding the course of the disease, revealing predictors of progression, and improvement in the early diagnosis and treatment of axial SpA.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflict of interests in preparing this article.

ORCID iD

Denis Poddubnyy

References

Sieper

Poddubnyy

Axial spondyloarthritis. Lancet 2017; 390: 73–84.

Rudwaleit

van der Heijde

Landewe

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.

Raychaudhuri

Deodhar

The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun 2014; 48–49: 128–133.

Reveille

Weisman

MH.

The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci 2013; 345: 431–436.

Reveille

Ball

Khan

MA.

HLA-B27 and genetic predisposing factors in spondyloarthropathies. Curr Opin Rheumatol 2001; 13: 265–272.

Rudwaleit

van der Heijde

Landewe

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: 777–783.

Rudwaleit

Landewe

van der Heijde

et al . 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 2009; 68: 770–776.

Rudwaleit

Khan

Sieper

The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria?

Arthritis Rheum 2005; 52: 1000–1008.

Rudwaleit

Haibel

Baraliakos

et al . The early disease stage in axial spondylarthritis: results from the German spondyloarthritis inception cohort. Arthritis Rheum 2009; 60: 717–727.

10.

Rudwaleit

Sieper

. [Early diagnosis of spondyloarthritis with special attention to the axial forms.] Z Rheumatol 2005; 64: 524–530.

11.

Rudwaleit

van der Heijde

Khan

et al . How to diagnose axial spondyloarthritis early. Ann Rheum Dis 2004; 63: 535–543.

12.

Braun

Brandt

Listing

et al . Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–1193.

13.

van der Heijde

Kivitz

Schiff

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: 2136–2146.

14.

Davis

Jr van der Heijde

Braun

et al . Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003; 48: 3230–3236.

15.

Inman

Davis

Jr Heijde

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: 3402–3412.

16.

Landewe

Braun

Deodhar

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.

17.

Mau

Zeidler

Mau

et al . Clinical features and prognosis of patients with possible ankylosing spondylitis. Results of a 10-year followup. J Rheumatol 1988; 15: 1109–1114.

18.

Braun

Bollow

Eggens

et al . Use of dynamic magnetic resonance imaging with fast imaging in the detection of early and advanced sacroiliitis in spondylarthropathy patients. Arthritis Rheum 1994; 37: 1039–1045.

19.

Bollow

Hermann

Biedermann

et al . Very early spondyloarthritis: where the inflammation in the sacroiliac joints starts. Ann Rheum Dis 2005; 64: 1644–1646.

20.

Oostveen

Prevo

den Boer

et al . Early detection of sacroiliitis on magnetic resonance imaging and subsequent development of sacroiliitis on plain radiography. A prospective, longitudinal study. J Rheumatol 1999; 26: 1953–1958.

21.

Bennett

McGonagle

O’Connor

et al . Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years. Arthritis Rheum 2008; 58: 3413–3418.

22.

Dougados

van der Linden

Juhlin

et al . The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991; 34: 1218–1227.

23.

Amor

Dougados

Mijiyawa

. [Criteria of the classification of spondylarthropathies.] Rev Rhum Mal Osteoartic 1990; 57: 85–89.

24.

van den Berg

de Hooge

van Gaalen

et al . 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: 1492–1499.

25.

Molto

Paternotte

Comet

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: 1472–1481.

26.

Tomero

Mulero

de Miguel

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: 353–360.

27.

Strand

Rao

Shillington

et al . 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: 1299–1306.

28.

Sepriano

Landewe

van der Heijde

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: 1034–1042.

29.

Sieper

van der Heijde

Landewe

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: 784–788.

30.

Rudwaleit

Jurik

Hermann

et al . 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 2009; 68: 1520–1527.

31.

Akkoc

Khan

MA.

ASAS classification criteria for axial spondyloarthritis: time to modify. Clin Rheumatol 2016; 35: 1415–1423.

32.

van der Linden

Akkoc

Brown

et al . The ASAS criteria for axial spondyloarthritis: strengths, weaknesses, and proposals for a way forward. Curr Rheumatol Rep 2015; 17: 62.

33.

Deodhar

Strand

Kay

et al . The term ‘non-radiographic axial spondyloarthritis’ is much more important to classify than to diagnose patients with axial spondyloarthritis. Ann Rheum Dis 2016; 75: 791–794.

34.

van Tubergen

Heuft-Dorenbosch

Schulpen

et al . Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann Rheum Dis 2003; 62: 519–525.

35.

Yazici

Turunc

Ozdogan

et al . Observer variation in grading sacroiliac radiographs might be a cause of ‘sacroiliitis’ reported in certain disease states. Ann Rheum Dis 1987; 46: 139–145.

36.

Hollingsworth

Cheah

Dawkins

et al . Observer variation in grading sacroiliac radiographs in HLA-B27 positive individuals. J Rheumatol 1983; 10: 247–254.

37.

Braun

Sieper

Bollow

Imaging of sacroiliitis. Clin Rheumatol 2000; 19: 51–57.

38.

Christiansen

Hendricks

Kuettel

et al . Limited reliability of radiographic assessment of sacroiliac joints in patients with suspected early spondyloarthritis. J Rheumatol 2017; 44: 70–77.

39.

van den Berg

Lenczner

Feydy

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: 2403–2411.

40.

van den Berg

Lenczner

Thevenin

et al . Classification of axial SpA based on positive imaging (radiographs and/or MRI of the sacroiliac joints) by local rheumatologists or radiologists versus central trained readers in the DESIR cohort. Ann Rheum Dis 2015; 74: 2016–2021.

41.

Poddubnyy

Rudwaleit

Haibel

et al . Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis 2011; 70: 1369–1374.

42.

Dougados

Sepriano

Molto

et al . Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort. Ann Rheum Dis 2017; 76: 1823–1828.

43.

Sepriano

Rudwaleit

Sieper

et al . Five-year follow-up of radiographic sacroiliitis: progression as well as improvement? Ann Rheum Dis 2016; 75: 1262–1263.

44.

Sieper

van der Heijde

Review: nonradiographic axial spondyloarthritis: new definition of an old disease?

Arthritis Rheum 2013; 65: 543–551.

45.

Aggarwal

Ringold

Khanna

et al . Distinctions between diagnostic and classification criteria? Arthritis Care Res (Hoboken) 2015; 67: 891–897.

46.

Weber

Jurik

Lambert

et al . Imaging in spondyloarthritis: controversies in recognition of early disease. Curr Rheumatol Rep 2016; 18: 58.

47.

Weber

Maksymowych

WP.

Sensitivity and specificity of magnetic resonance imaging for axial spondyloarthritis. Am J Med Sci 2011; 341: 272–277.

48.

Weber

Maksymowych

WP.

Advances and challenges in spondyloarthritis imaging for diagnosis and assessment of disease. Curr Rheumatol Rep 2013; 15: 345.

49.

Deodhar

Sacroiliac joint magnetic resonance imaging in the diagnosis of axial spondyloarthritis: “a tiny bit of White on two consecutive slices” may be objective, but not specific. Arthritis Rheumatol 2016; 68: 775–778.

50.

Weber

Lambert

Ostergaard

et al . The diagnostic utility of magnetic resonance imaging in spondylarthritis: an international multicenter evaluation of one hundred eighty-seven subjects. Arthritis Rheum 2010; 62: 3048–3058.

51.

Lambert

Bakker

van der Heijde

et al . Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann Rheum Dis 2016; 75: 1958–1963.

52.

Investigators S. http://www.spartangroup.org/projects/classic-classification-axial-spondyloarthritis-inception-cohort/ (accessed 5 May 2018).

53.

Poddubnyy

Sieper

Similarities and differences between nonradiographic and radiographic axial spondyloarthritis: a clinical, epidemiological and therapeutic assessment. Curr Opin Rheumatol 2014; 26: 377–383.

54.

Song

Weiss

Hermann

et al . 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 2013; 72: 823–825.

55.

Kiltz

Baraliakos

Karakostas

et al . Do patients with non-radiographic axial spondylarthritis differ from patients with ankylosing spondylitis? Arthritis Care Res (Hoboken) 2012; 64: 1415–1422.

56.

Ciurea

Scherer

Exer

et al . Tumor necrosis factor alpha inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large observational cohort. Arthritis Rheum 2013; 65: 3096–3106.

57.

Poddubnyy

Vahldiek

Spiller

et al . Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care. J Rheumatol 2011; 38: 2452–2460.

58.

Poddubnyy

Brandt

Vahldiek

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.

59.

Brandt

Spiller

Song

et al . Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis. Ann Rheum Dis 2007; 66: 1479–1484.

60.

Sieper

Srinivasan

Zamani

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: 1621–1627.

61.

van der Heijde

Dougados

Landewe

et al . Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA. Rheumatology (Oxford) 2017; 56: 1498–1509.

62.

Smolen

Schols

Braun

et al . Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis 2018; 77: 3–17.

63.

van der Heijde

Ramiro

Landewe

et al . 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017; 76: 978–991.

64.

Ward

Deodhar

Akl

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 Rheumatol 2016; 68: 282–298.

65.

van der Heijde

Ramiro

Landewe

et al . 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017; 76: 978–991.

66.

Braun

Zochling

Baraliakos

et al . Efficacy of sulfasalazine in patients with inflammatory back pain due to undifferentiated spondyloarthritis and early ankylosing spondylitis: a multicentre randomised controlled trial. Ann Rheum Dis 2006; 65: 1147–1153.

67.

Haibel

Rudwaleit

Braun

et al . Six months open label trial of leflunomide in active ankylosing spondylitis. Ann Rheum Dis 2005; 64: 124–126.

68.

Haibel

Brandt

Song

et al . No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial. Ann Rheum Dis 2007; 66: 419–421.

69.

Baeten

Sieper

Braun

et al . Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 2015; 373: 2534–2548.

70.

Maksymowych

Dougados

van der Heijde

et al . Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis: 48-week results from the EMBARK study. Ann Rheum Dis 2016; 75: 1328–1335.

71.

Sieper

van der Heijde

Dougados

et al . Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013; 72: 815–822.

72.

Sieper

van der Heijde

Dougados

et al . A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2015; 67: 2702–2712.

73.

Deodhar

Reveille

van den Bosch

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 Rheumatol 2014; 66: 2649–2656.

74.

Wanders

Heijde

Landewe

et al . Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 2005; 52: 1756–1765.

75.

Sieper

Listing

Poddubnyy

et al . Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis 2016; 75: 1438–1443.

76.

van der Heijde

Landewe

Einstein

et al . Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum 2008; 58: 1324–1331.

77.

van der Heijde

Landewe

Baraliakos

et al . Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008; 58: 3063–3070.

78.

van der Heijde

Salonen

Weissman

et al . Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 2009; 11: R127.

79.

Braun

Baraliakos

Hermann

et al . The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial. Ann Rheum Dis 2014; 73: 1107–1113.

80.

Baraliakos

Haibel

Listing

et al . Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis 2014; 73: 710–715.

81.

Haroon

Inman

Learch

et al . The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum 2013; 65: 2645–2654.

82.

Maksymowych

Zheng

Wichuk

et al . The effect of TNF inhibition on radiographic progression in ankylosing spondylitis: an observational cohort study of 374 patients [abstract]. Arthritis Rheumatol 2015; 67: 1275–1276.

83.

Molnar

Scherer

Baraliakos

et al . TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum Dis 2018; 77: 63–69.

Ankylosing spondylitis and axial spondyloarthritis: recent insights and impact of new classification criteria

Abstract

Keywords

Introduction

Current classification criteria

Controversial appraisal of the ASAS classification criteria of axial SpA

Similarities and differences between nr-axSpA and AS

Treatment of axial SpA

Concept of axial SpA in the context of other inflammatory diseases

Conclusion

Footnotes

Funding

Conflict of interest statement

ORCID iD

References