Abstract
Non-radiographic axial spondyloarthritis (nr-axSpA) is a subgroup of axial spondyloarthritis (axSpA) without fulfilling the modified New York criteria of sacroiliac joint radiographs for ankylosing spondylitis (AS). AS and nr-axSpA share various demographic and clinical features and disease burden, although sex and objective inflammatory findings such as elevated serum C-reactive protein level are slightly different between AS and nr-axSpA. Recently, diagnostic guidance for nr-axSpA in Japan was proposed for epidemiological studies of a population with a low prevalence of HLA-B27 positivity and the use of molecular targeted agents suitable for the unique medical care system in Japan. A biological agent targeting interleukin-17 was approved for nr-axSpA by the Pharmaceutical and Medical Devices Agency (PMDA) in August 2020. Some other biological agents will be also available for Japanese patients with nr-axSpA in the near future.
Introduction
The concept of axial spondyloarthritis (axSpA) and non-radiographic axSpA (nr-axSpA), a subgroup of axSpA, has recently emerged [Citation1]. Currently, the disease names for clinical diagnoses other than ankylosing spondylitis (AS), such as psoriatic arthritis (PsA), reactive arthritis (ReA), and inflammatory bowel disease (IBD)-associated spondyloarthritis (SpA) partly overlap with the classification name of nr-axSpA, and therefore, those diseases are confusing when classified as nr-axSpA. In this article, we review the concept of nr-axSpA and several related issues, and introduce diagnostic guidance for nr-axSpA in Japan.
Clinical features, epidemiology, and pathogenesis of axSpA
AxSpA is a chronic inflammatory disease that predominantly involves the axial joints including the sacroiliac joints and spinal joints [Citation1,Citation2]. Typically, patients in the third decade of life present with chronic low back pain and stiffness that improves on exercise but not by rest. As peripheral manifestations, arthritis, enthesitis, and even dactylitis are observed in 2%–40% of patients with axSpA [Citation3]. Other manifestations include uveitis, psoriasis, and IBDs.
Ax-SpA shows a clear association with HLA-B27 positivity, in which HLA-B27 is positive in 80%–90% of the patients [Citation4]. Therefore, the number of ax-SpA patients is limited in Japan where only 0.3% of the population has HLA-B27, whereas 2%–30% of the populations in other Asian and Western countries test positive for HLA-B27 [Citation5]. Indeed, the prevalence of AS was estimated as <0.01% in Japan [Citation6] and 0.2%–0.3% in most other countries.
The importance of HLA-B27 positivity was confirmed by genome-wide association studies [Citation7,Citation8]. In addition to HLA-B27 and other major histocompatibility complex variants, endoplasmic reticulum aminopeptidase (ERAP), which plays a role in preparing peptides for antigen presentation to immune cells, was revealed to only affect AS risk in HLA-B27-positive individuals [Citation7]. In addition, interleukin (IL)-23 receptor was associated with AS-related genetic predisposition [Citation7,Citation8]. Concordantly, systemic IL-23 expression in vivo was reported to induce highly specific entheseal inflammation by activating entheseal-resident T cells, which led to osteoproliferation [Citation9].
The sequence of axSpA disease progression from active inflammation to new bone formation—osteitis or bone (marrow) edema, fatty lesions, and syndesmophyte formation—is supported by magnetic resonance imaging (MRI) findings in axial joints [Citation10].
The concept of nr-axSpA
AxSpA is usually defined by the classification criteria of the Assessment of SpondyloArthritis international Society (ASAS) [Citation11]. AxSpA is further subclassified into radiographic axSpA (r-axSpA) by meeting the radiographic criteria of the sacroiliac joint in the modified New York criteria for the diagnosis of AS [Citation12,Citation13], and into nr-axSpA by not meeting that criteria. R-axSpA and AS were demonstrated to be interchangeable because 93% of ax-SpA patients meeting the modified New York criteria for AS (n = 3,882) also fulfilled the ASAS r-axSpA criteria, and conversely, 96% of patients meeting the ASAS r-axSpA criteria (n = 3,434) also fulfilled the modified New York criteria for AS [Citation14]. Therefore, the primary concept of nr-axSpA is axSpA other than AS (or without radiographic sacroiliitis defined by the modified New York criteria for AS [Citation12]).
Of note, patients with axSpA include those with PsA, IBD, ReA, and other diseases. For example, a considerable number of PsA patients have axial diseases that fulfill the ASAS axSpA criteria (sometimes called ‘axial PsA’) [Citation15]. Therefore, the use of the term axSpA, especially nr-axSpA, as a disease diagnosis is confusing (nr-axSpA and [axial] PsA, or nr-axSpA with psoriasis, for example), although a diagnosis of axSpA may be a future direction. Furthermore, the ASAS classification criteria for SpA should not be used as diagnostic criteria [Citation16], and therefore, no diagnostic criteria for axSpA are currently available.
Diagnostic guidance for nr-axSpA in Japan
From a therapeutic point of view, several biological agents targeting tumor necrosis factor (TNF) or IL-17 have been already approved for psoriasis/PsA as well as AS which is a designated intractable disease in Japan. Furthermore, international (including Japan) multicenter clinical trials of biological agents in patients with nr-axSpA defined by the ASAS classification criteria have been performed and the results have been submitted to the Pharmaceutical and Medical Devices Agency (PMDA) in Japan. Under these circumstances, diagnostic guidance for nr-axSpA in Japan was developed () [Citation17]. Briefly, patients with other SpA diseases or SpA-related diseases are excluded and patients must fulfill the ASAS classification criteria for axSpA [Citation11] without meeting the criteria for radiographic sacroiliitis [Citation12], they must have inflammatory back pain defined by one of the three proposed criteria [Citation18–20], and must show serum C-reactive protein (CRP) > upper limit of normal not due to diseases other than nr-axSpA and ≥1 additional SpA feature in cases with an absence of positive MRI findings of sacroiliac joints [Citation21], thus having been diagnosed through a clinical arm defined by HLA-B27 positivity.
Table 1. Diagnostic guidance for nr-axSpA in Japan [Citation17].
Clinical features of nr-axSpA in comparison with AS
A diagnostic delay is commonly observed for axSpA. Indeed, a recent systematic literature review showed that the mean duration from the disease onset to diagnosis was 4.2 years for nr-axSpA and 6.1 years for r-axSpA [Citation22]. These data are consistent with the fact that approximately half of patients with axSpA were classified as AS (r-axSpA) at the time of disease diagnosis [Citation23]. Theoretically, all axSpA patients must be free from radiographic sacroiliitis at disease onset and therefore will be classified as nr-axSpA for those fulfilling the ASAS axSpA classification criteria at that time. However, not all patients with nr-axSpA eventually progress to AS (r-axSpA), supporting the notion that nr-axSpA is not simply the early phase of AS [Citation24]. Risk factors for the progression to AS include male sex and elevated level of serum CRP [Citation22]. Otherwise, nr-axSpA and AS share similar demographic and clinical features in terms of HLA-B27 positivity, comorbidity, clinical disease activity, and response to TNF inhibitors (TNFi), indicating these two diseases are on the same disease spectrum with comparable disease burden in patients [Citation22–26]. However, a recent study suggested numerically lower treatment responses and retention rate of TNFi in the nr-axSpA subcohort compared with other SpA subcohorts, possibly because some patients with less certain diagnoses were included [Citation27]. This is why it is important to focus on the differential diagnosis and exclusion of other SpA and related diseases when developing diagnostic guidance for nr-axSpA in Japan.
Undoubtedly, patients with nr-axSpA include those with early phase AS (r-axSpA) because 10%–20% of patients with nr-axSpA progress to AS by 2 years and the proportion of patients with nr-axSpA among those with axSpA showed an inverse correlation with disease duration. However, approximately half of the patients with nr-axSpA did not advance to AS (r-axSpA) over their lifetime, and such patients represent subgroups of a transient disease with spontaneous remission, mild disease, and clinically severe but radiographically mild disease [Citation21,Citation25].
Issues to be addressed in nr-axSpA
‘Non-radiographic’ is defined as the absence of radiographic sacroiliitis [Citation12] according to the modified New York criteria. Therefore, a radiographic change below criteria such as unilateral grade 2 is regarded as ‘non-radiographic’. In addition, the presence of spinal syndesmophytes or even ‘bamboo spine’ is acceptable unless radiographic sacroiliitis is present, which is occasionally observed in patients with PsA, whereas radiographic changes advance ascendingly from sacroiliac joints to the cervical spine in patients with AS [Citation23,Citation28]. This is why our diagnostic guidance for nr-axSpA set intensive exclusion criteria for related diseases and why the modified New York criteria focuses on the radiographic findings of sacroiliac joints. A recent study revealed that combined spine and sacroiliac joint MRI added little incremental value compared with sacroiliac joint MRI alone for diagnosing patients with nr-axSpA [Citation29]. In addition, long-lasting improvements in the radiographic reading of sacroiliac joints are difficult to achieve, at least through self-education using a training set of films or through uniform workshops [Citation30]. Furthermore, the reading of sacroiliac joint MRI is critical to avoid overdiagnosis as nr-axSpA because bone marrow edema adjacent to the joint space is frequently observed in people without axSpA such as post-partum women and athletes [Citation31].
Clinical trials of TNFi in patients with nr-axSpA
Because of the clinical benefit of TNFi in patients with AS, several clinical trials have been initiated for patients with nr-axSpA. In 2009, the clinical and imaging efficacy of infliximab in HLA-B27-positive patients with MRI-determined early sacroiliitis (≤3 years) was reported [Citation32]. ABILITY-1 was the first study to demonstrate the efficacy of adalimumab in patients with nr-axSpA defined by the ASAS classification criteria [Citation11]. Significantly more patients in the adalimumab group achieved ASAS40 at week 12 (the primary endpoint) compared with those in the placebo group (36% vs 15%, p < .001) [Citation33]. The decrease in the SPARCC MRI scores of sacroiliac joints and spine were greater in the adalimumab group than the placebo group (−3.2 vs −0.6, p = .003 and −1.8 vs −0.2, p = .001, respectively). The above efficacy was maintained for 3 years in the open-label ABILITY-1 extension study [Citation34]. However, a greater proportion of patients who received placebo after achieving sustained remission with adalimumab experienced a flare compared with those continuing adalimumab (53% vs 30%, p < .0001) in the ABILITY-3 study [Citation35].
The efficacy of certolizumab pegol (CZP) was examined in the RAPID-axSpA study, in which ASAS20 response rates of CZP 200 mg every 2 weeks (Q2W) and 400 mg every 4 weeks (Q4W) in patients with nr-axSpA were higher than in placebo at week 12 (58.7% and 62.7%, respectively, vs 40.0%, p < .05 for 400 mg Q4W only) and at week 24 (65.2% and 70.6%, respectively, vs 24.0%, p < .001 for both CZP arms) [Citation36]. The open-label extension of RAPID-axSpA demonstrated almost no radiographic progression in mSASSS changes with CZP in patients with nr-axSpA [Citation37].
Etanercept was also evaluated in patients with nr-axSpA in the EMBARK study [Citation38], in which ASAS40 at week 12 was 14.7% and 33.3% in the placebo and etanercept groups, respectively, which increased to 53.3% and 52.0%, respectively, with open-label extension at week 48. Decreases in MRI sacroiliac joint inflammation and CRP correlated with several clinical outcomes at weeks 12 and 48, and these improvements were maintained for 2 years [Citation39].
Golimumab was efficacious in patients with nr-axSpA in the GO-AHEAD study, in which ASAS20 and 40 response rates at week 16 were significantly higher in the golimumab 50 mg Q4W group versus the placebo group (71.1% and 56.7% vs 40.0% and 23.0%, respectively, both p < .0001) [Citation40].
The clinical benefit of TNFi was evident in patients with positive MRI and/or CRP in the ABILITY-1 [Citation33] and EMBARK studies [Citation38], as well as a cohort in southern Sweden [Citation41]. Furthermore, a meta-analysis of TNFi confirmed clinically meaningful improvements in disease activity and functional capacity for AS and nr-axSpA [Citation42].
Clinical trials of non-TNF inhibitor biologics (non-TNFi) in patients with nr-axSpA
In view of the importance of the IL-23/IL-17 axis in the pathogenesis of enthesitis/SpA [Citation9] and the successful results of anti-IL17A monoclonal antibodies in patients with PsA [Citation43], secukinumab [Citation44–46] and ixekizumab [Citation47,Citation48] were examined for patients with AS.
Recently, the COAST-X study provided evidence for the efficacy of ixekizumab in patients with nr-axSpA [Citation49]. ASAS40 at week 16 was greater for ixekizumab Q4W and Q2W compared with placebo (35%, p = .0094; and 40%, p = .0016; vs 19%, respectively), and at week 52 (30%, p = .0045; and 31%, p = .0037; vs 13%, respectively).
Secukinumab also demonstrated efficacy in patients with nr-axSpA [Citation50]. The ASAS40 response in TNFi-naïve patients was significantly higher in the secukinumab 150 mg with loading group (41.5%) compared with placebo (29.2%; p = .0197) at week 16 and significantly higher in the secukinumab 150 mg without loading group (39.8%) compared with placebo at week 52 (19.9%; p = .0021).
Drug approval status and future perspectives
Two primary endpoints at week 16 and at week 52 in recent clinical trials for nr-axSpA [Citation48,Citation49] were raised according to the suggestions from the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA), respectively. The disease burden of nr-axSpA is the priority of the EMA and the uncertainty in the natural course of nr-axSpA including the rate of spontaneous remission is the main concern of the FDA [Citation51]. Thus, EMA approved adalimumab in 2012, CZP in 2013, etanercept in 2014, and golimumab in 2015 for the indication of nr-axSpA, whereas CZP was the first drug to be approved by the FDA for the indication of nr-axSpA with successful results from the C-AXSPAND study at week 52 (major improvement in the Ankylosing Spondylitis Disease Activity Score [ASDAS-MI] was achieved in 47.2% of CZP-receiving patients vs 7.0% in placebo-receiving patients, p < .0001) [Citation52] in March 2019.
Secukinumab was approved for nr-axSpA by the EMA in April 2020, by the FDA in July 2020, and by the PMDA in August 2020. Ixekizumab and brodalumab, monoclonal antibodies against IL-17 receptor A, have been submitted to the agencies for approval for the indication of nr-axSpA. Furthermore, upadacitinib, a selective Janus kinase 1 inhibitor, showed efficacy in patients with active AS [Citation53], which may be promising for nr-axSpA.
Interestingly, the inhibition of IL-23 did not appear to be beneficial for patients with AS [Citation54]. Thus, SpA is not a uniform molecular taxonomy, although AS and nr-axSpA can be a single disease entity ‘axSpA’.
Conclusion
Despite recent progress in our understanding of SpA pathophysiology and its management, the concept, classification, and diagnosis of nr-axSpA have not been fully established. Diagnostic guidance for nr-axSpA in Japan was developed to avoid the discordance between patient characteristics; for example, HLA-B27 positivity and the presence of psoriasis/pustulosis in Japanese patients with nr-axSpA and those in other countries. The development of specific guidance may support the use of molecular targeted agents suitable for the unique medical care system in Japan.
Acknowledgments
The development of the diagnostic guidance for nr-axSpA in Japan is a collaborative work by Research On Rare And Intractable Diseases, Health and Labour Sciences Research Grant: a Large-scale multi-institutional research committee aiming at an epidemiological survey of spondyloarthritis, creation of diagnostic criteria, and development of clinical guidelines. The authors thank ASCA Corporation for editing the manuscript, the fees of which were supported by the above grant.
Conflict of interest
HK has received consulting fees, speaking fees, and/or honoraria from AbbVie G.K., Asahi Kasei Pharma, Astellas Pharma Inc., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eisai Co. Ltd., Eli Lilly Japan K.K., Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., and Sanofi Pharma, and has received research grants from AbbVie G.K., Asahi Kasei Pharma, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma, Novartis Pharma K.K. and Sanofi Pharma.
SK has received speaker’s fees from Mitsubishi Tanabe Pharma Corp., Bristol-Myers Squibb Company, AbbVie GK, Novartis Pharma K.K., Asahi Kasei Corp., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., and Janssen Pharmaceutical K.K., and received consulting fees from Kyowa Kirin Co., Ltd.
NT received research grants and/or speaking fees from AbbVie G.K., Asahi Kasei Pharma, Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Janssen Pharmaceutical K.K., Mitsubishi-Tanabe Pharma, Novartis Pharma K.K., and Takeda Pharmaceutical Co., Ltd.
YK has received consulting fees, speaking fees, and/or honoraria from AbbVie G.K., Asahi Kasei Pharma, Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, Novartis Pharma K.K., and Ono Pharmaceutical Co., Ltd., and has received research grants from AbbVie G.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma, and Ono Pharmaceutical Co., Ltd.
KT has received speaking fees from AbbVie G.K., Eisai Co. Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Mitsubishi-Tanabe Pharma, and Novartis Pharma K.K.
MY has no conflict of interest.
TT has received consultancy and speaker fees from AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Eli Lilly and Company, Janssen, Kyowa Kirin, Mitsubishi-Tanabe, Novartis, and Pfizer.
Additional information
Funding
References
- Rudwaleit M, Landewé R, van der Heijde D, Listing J, Brandt J, Braun J, 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(6):770–6.
- Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73–84.
- van den Berg R, de Hooge M, Rudwaleit M, Sieper J, van Gaalen F, Reijnierse M, et al. ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort from the Assessment of SpondyloArthritis international Society (ASAS)-cohort. Ann Rheum Dis. 2013;72(10):1646–53.
- Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Ann Rheum Dis. 2004;63(5):535–43.
- Khan MA. Epidemiology of HLA-B27 and arthritis. Clin Rheumatol. 1996;15(S1):10–2.
- Hukuda S, Minami M, Saito T, Mitsui H, Matsui N, Komatsubara Y, et al. Spondyloarthropathies in Japan: nationwide questionnaire survey performed by the Japan Ankylosing Spondylitis Society. J Rheumatol. 2001;28(3):554–9.
- Evans DM, Spencer CC, Pointon JJ, Su Z, Harvey D, Kochan G, 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(8):761–7.
- , Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet. 2013;45(7):730–8.
- Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt + CD3 + CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.
- Machado PM, Baraliakos X, van der Heijde D, Braun J, Landewé 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(8):1486–93.
- Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, 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(6):777–83.
- 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 Rheumatol. 1984;27(4):361–8.
- Bennett PH, Wood PHN. Population studies of the rheumatic diseases; proceedings of the third international symposium, New York, June 5th–10th, 1966. International Congress Series. 1966;148:456–7.
- Boel A, Molto A, van der Heijde D, Ciurea A, Dougados M, Gensler LS, et al. Do patients with axial spondyloarthritis with radiographic sacroiliitis fulfil both the modified New York criteria and the ASAS axial spondyloarthritis criteria? Results from eight cohorts. Ann Rheum Dis. 2019;78(11):1545–9.
- Feld J, Chandran V, Haroon N, Inman R, Gladman D. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol. 2018;14(6):363–71.
- Braun J, Baraliakos X, Kiltz U, Heldmann F, Sieper J. Classification and diagnosis of axial spondyloarthritis-what is the clinically relevant difference? J Rheumatol. 2015;42(1):31–8.
- Research on rare and intractable diseases, Health and Labour Sciences Research Grant: the Large-scale multi-institutional research committee aiming at an epidemiological survey of spondyloarthritis, creation of diagnostic criteria, and development of clinical guideline, editors. Medical Practice Guide for Spondyloarthritis 2020 (in Japanese). Tokyo: Shindan To Chiryo Sha, Inc.; 2020.
- Calin A, Porta J, Fries JF, Schurman DJ. Clinical history as a screening test for ankylosing spondylitis. JAMA 1977;237(24):2613–4.
- 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(2):569–78.
- Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68(Suppl 2):ii1–44.
- Lambert RGW, Bakker PA, van der Heijde D, Weber U, Rudwaleit M, Hermann KG, et al. Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. Ann Rheum Dis. 2016;75(11):1958–63.
- López-Medina C, Ramiro S, van der Heijde D, Sieper J, Dougados M, Molto A. Characteristics and burden of disease in patients with radiographic and non-radiographic axial spondyloarthritis: a comparison by systematic literature review and meta-analysis. RMD Open. 2019;5(2):e001108.
- Proft F, Poddubnyy D. Ankylosing spondylitis and axial spondyloarthritis: recent insights and impact of new classification criteria. Ther Adv Musculoskelet Dis. 2018;10(5–6):129–39.
- Ghosh N, Ruderman EM. Nonradiographic axial spondyloarthritis: clinical and therapeutic relevance. Arthritis Res Ther. 2017;19(1):286.
- Sieper J, Hu X, Black CM, Grootscholten K, van den Broek RWM, Kachroo S. Systematic review of clinical, humanistic, and economic outcome comparisons between radiographic and non-radiographic axial spondyloarthritis. Semin Arthritis Rheum. 2017;46(6):746–53.
- Boonen A, Sieper J, van der Heijde D, Dougados M, Bukowski JF, Valluri S, et al. The burden of non-radiographic axial spondyloarthritis. Semin Arthritis Rheum. 2015;44(5):556–62.
- Ørnbjerg LM, Brahe CH, Askling J, Ciurea A, Mann H, Onen F, et al. Treatment response and drug retention rate in 24,195 biologic-naïve patients with axial spondyloarthritis initiating TNFi treatment: routine care data from 12 registries in the EuroSpA collaboration. Ann Rheum Dis. 2019;78(11):1536–44.
- 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(5):791–4.
- Weber U, Zubler V, Zhao Z, Lambert RGW, Chan SM, Pedersen SJ, 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(6):985–92.
- van Tubergen A, Heuft-Dorenbosch L, Schulpen G, Landewé R, Wijers R, van der Heijde D, et al. Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann Rheum Dis. 2003;62(6):519–25.
- Seven S, Østergaard M, Morsel-Carlsen L, Sørensen IJ, Bonde B, Thamsborg G, et al. The utility of magnetic resonance imaging lesion combinations in the sacroiliac joints for diagnosing patients with axial spondyloarthritis. A prospective study of 204 participants including post-partum women, patients with disc herniation, cleaning staff, runners and healthy persons. Rheumatology. 2020;71(12):2034–2046.
- Barkham N, Keen HI, Coates LC, O’Connor P, Hensor E, Fraser AD, et al. Clinical and imaging efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. 2009;60(4):946–54.
- Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, Brown MA, 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(6):815–22.
- van der Heijde D, Sieper J, Maksymowych WP, Lambert RG, Chen S, Hojnik M, et al. Clinical and MRI remission in patients with nonradiographic axial spondyloarthritis who received long-term open-label adalimumab treatment: 3-year results of the ABILITY-1 trial. Arthritis Res Ther. 2018;20(1):61.
- Landewé R, Sieper J, Mease P, Inman RD, Lambert RG, Deodhar A, et al. Efficacy and safety of continuing versus withdrawing adalimumab therapy in maintaining remission in patients with non-radiographic axial spondyloarthritis (ABILITY-3): a multicentrre, randomised, double-blind study. Lancet 2018;392(10142):134–44.
- Landewé R, Braun J, Deodhar A, Dougados M, Maksymowych WP, Mease PJ, et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis. 2014;73(1):39–47.
- van der Heijde D, Baraliakos X, Hermann KGA, Landewé RBM, Machado PM, Maksymowych WP, et al. Limited radiographic progression and sustained reductions in MRI inflammation in patients with axial spondyloarthritis: 4-year imaging outcomes from the RAPID-axSpA phase III randomised trial. Ann Rheum Dis. 2018;77(5):699–705.
- Maksymowych WP, Dougados M, van der Heijde D, Sieper J, Braun J, Citera G, et al. Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthitis: 48-week results from the EMBARK study. Ann Rheum Dis. 2016;75(7):1328–35.
- Dougados M, van der Heijde D, Sieper J, Braun J, Citera G, Lenaerts J, et al. Effects of long-term etanercept treatment on clinical outcomes and objective signs of inflammation in early non-radiographic axial spondyloarthritis: 104-week results from a randomized, placebo-controlled study. Arthritis Care Res. 2017;69(10):1590–8.
- Sieper J, van der Heijde D, Dougados M, Maksymowych WP, Scott BB, Boice JA, 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(10):2702–12.
- Wallman JK, Kapetanovic MC, Petersson IF, Geborek P, Kristensen LE. Comparison of non-radiographic axial spondyloarthritis and ankylosing spondylitis patients-baseline characteristics, treatment adherence, and development of clinical variables during three years of anti-TNF therapy in clinical practice. Arthritis Res Ther. 2015;17:378.
- Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis. 2015;74(6):1241–8.
- Taams LS, Steel KJA, Srenathan U, Burns LA, Kirkham BW. IL-17 in the immunopathogenesis of spondyloarthritis. Nat Rev Rheumatol. 2018;14(8):453–66.
- Baeten D, Baraliakos X, Braun J, Sieper J, Emery P, van der Heijde D, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906):1705–13.
- Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med. 2015;373(26):2534–48.
- Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, et al. Secukinumab efficacy in anti-TNF-naïve and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 study. Ann Rheum Dis. 2017;76(3):571–92.
- van der Heijde D, Wei JCC, Dougados M, Mease P, Deodhar A, Maksymowych WP, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondylitis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet 2018;392(10163):2441–51.
- Dougados M, Wei JCC, Landewé R, Sieper J, Baraliakos X, van den Bosch F, et al. Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020;79(2):176–85.
- Deodhar A, van der Heijde D, Gensler LS, Kim TH, Maksymowych WP, Østergaard M, et al. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53–64.
- Deodhar A, Blanco R, Dokoupilová E, Hall S, Kameda H, Kivitz AJ, et al. Secukinumab improves signs and symptoms of non-radiographic axial spondyloarthritis: primary results of a randomized controlled phase III study. Arthritis Rheumatol 2020 Aug 7. doi:10.1002/art.41477. Online ahead of print.
- Deodhar A, Reveille JD, van den Bosch F, Braun J, Burgos-Vargas R, Caplan L, 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(10):2649–56.
- Deodhar A, Gensler LS, Kay J, Maksymowych WP, Haroon N, Landewé R, et al. A fifty-two-week, randomized, placebo-controlled trial of certolizumab pegol in nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 2019;71(7):1101–11.
- van der Heijde D, Song IH, Pangan AL, Deodhar A, van den Bosch F, Maksymowych WP, et al. Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomized, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019;394(10214):2108–17.
- Siebert S, Millar NL, McInnes IB. Why did IL-23p19 inhibition fail in AS: a tale of tissues, trials or translation? Ann Rheum Dis. 2019;78(8):1015–8.