UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)
Recognizing axial spondyloarthritis
de Boer, J.J.H.
Publication date
2018
Document Version
Final published version
License
Other
Link to publication
Citation for published version (APA):
de Boer, J. J. H. (2018). Recognizing axial spondyloarthritis.
General rights
It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulations
If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible.
any means without permission of the auhtor. ISBN 978-94-6332-425-0
Cover Johannes Rustenburg, Loes Kema Layout Loes Kema
Printed by GVO drukkers & vormgevers, Ede, NL
The background image at the start of each chapter is a radiograph of a symptomless participant of the Pre-SpA cohort, showing cervical syndesmophytes suggestive of SpA.
Printing of this thesis is financially supported by the Dutch Arthritis Foundation, AMC-UvA, ChipSoft and UCB Pharma.
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. ir. K.I.J. Maex
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Aula der Universiteit
op vrijdag 23 november 2018, te 11:00 uur door Janna Johanna Hendrika de Boer
Prof. dr. D.L.P Baeten AMC-UvA
Prof. dr. R.B.M. Landewé AMC-UvA
Copromotor
Dr. M.G.H. van de Sande AMC-UvA
Overige leden
Prof. dr. J.M. van Laar Universiteit Utrecht
Prof. dr. M. Maas AMC-UvA
Dr. S. Ramiro Universiteit Leiden
Prof. dr. D. van Schaardenburg AMC-UvA
Prof. dr. P.I. Spuls AMC-UvA
Part I Chapter 2 Chapter 3 Part II Chapter 4 Chapter 5 Chapter 6 Part III Chapter 7 Chapter 8 Chapter 9 Appendices 17 19 35 59 61 75 91 107 109 131 141 157 165 167 169 171
Recognizing the disease burden of axial spondyloarthritis
Peripheral disease contributes significantly to the disease burden in axial spondyloarthritis
Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis
Rocognizing the diagnosis of axial spondyloarthritis
Magnetic Resonance Imaging of the Sacroiliac Joints Indicating Sacroiliitis According to the Assessment of SpondyloArthritis international Society Definition in Healthy Individuals, Runners, and Women With Postpartum Back Pain
Anti-CD74 antibodies have no diagnostic value in early axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort
Absence of HLA-C*07 is associated with susceptibility to axial spondyloarthritis
Recognizing the preclinical phases of axial spondyloarthritis
Clinical and imaging signs of spondyloarthritis in first degree relatives of HLA-B27 positive ankylosing
spondylitis patients: the pre-spondyloarthritis (Pre-SpA) cohort
First-degree relatives of axial spondyloarthritis patients of the Pre-SpA cohort would consider using medication in a preventive setting
General discussion and summary Nederlandse samenvatting Curriculum vitae
PhD portfolio List of publications Dankwoord
ONE
Spondyloarthritis (SpA) is a heterogeneous form of inflammatory arthritis affecting the axial skeleton, including the sacroiliac joints and the spine, as well as peripheral joints and extra-articular sites. SpA has a prevalence of 0.5-1.0% (1,2). Traditionally, SpA was classified according to its phenotypic presentation as ankylosing spondylitis (AS), psoriatic arthritis (PsA), inflammatory bowel disease (IBD)-related SpA, reactive arthritis and undifferentiated SpA. Although SpA subtypes present heterogeneously, their common genetic background and strong familial aggregation (3–9), overlapping immunopathology (10–13), and largely similar response to treatment, justify handling them as one disease (14).
In 2009 the Assessment of SpondyloArthritis international Society (ASAS) developed sets of classification criteria reflecting the close resemblance of the different subtypes. Figure 1 shows the classification as axial SpA according to the ASAS criteria. The ASAS criteria distinguish between the axial and peripheral phenotype of SpA (15,16) and they were primarily developed to create homogeneous groups of patients for study purposes. The ASAS criteria classify a patient as axial SpA in the presence of back pain and 1) sacroiliitis on imaging (plain radiograph or magnetic resonance imaging (MRI)) and at least 1 other SpA feature, or 2) when a patient is HLA-B*27 positive and has at least 2 other SpA features. Patients with axial SpA can be classified as radiographic axial SpA, AS: with sacroiliitis on plain radiograph, or as non-radiographic axial SpA: when fulfilling either the clinical arm of the criteria or having SpA-specific sacroiliitis on MRI plus fulfilling one or two other criteria (Figure 1A). A patient classifies as having peripheral SpA in the presence of peripheral arthritis, enthesitis, or dactylitis plus at least one or two other SpA features, depending on the nature of the feature (Figure 1B). A recent meta-analysis showed good performance of the ASAS criteria when compared to a rheumatologists’ diagnosis (17).
Figure 1. A The ASAS criteria for axial SpA. Patients are classified via the clinical arm (HLA-B*27 plus ≥ 2 other SpA features) or via the imaging arm (sacroiliitis on MRI or plain
radiograph) plus ≥ 1 SpA feature. Patients with sacroiliitis on plain radiograph according to the modified New York (mNY) criteria are defined as radiographic axial SpA, patients fulfilling the clinical arm or having sacroiliitis on MRI are defined as non-radiographic axial SpA.
B The ASAS criteria for peripheral SpA. Patients are classified as peripheral SpA in case of peripheral arthritis and/or enthesitis and/or dactylitis, plus at least one or two other SpA features, depending on the nature of the feature.
Diagnostic delay
Classifying axial SpA according to its phenotypic presentation might justify the similarities of the different subtypes, it doesn’t necessarily facilitate an early diagnosis. Back pain, frequently the presenting symptom of axial SpA, and even inflammatory back pain, is very frequent in the general population. Early studies suggested that only 5% of patients presenting with back pain has some form of axial SpA (18). Although enhanced referral techniques (19–21) and the use of MRI to show active SI joint inflammation shortened the time to diagnosis in the recent years, the diagnostic delay is still estimated to be 5 to 11 years (22–25). Shortening this delay is of major importance for two reasons. Firstly, axial SpA has a significant burden of disease, even in its initial phase (26). Secondly, treating axial SpA in an early phase might modify the disease course and limit structural damage (27,28), although there is also evidence suggesting that structural damage Is not influenced by early treatment.
The identification of biomarkers might shorten the current diagnostic delay. In 2001, the National Institutes of Health defined a biomarker as ‘a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention’ (29). Initiatives to study and diagnose axial SpA in an early phase as the SPondyloArthritis Caught Early (SPACE) cohort (30), the early axial SpA cohort DESIR (31) and the early AS and axial SpA cohort GESPIC (32) will hopefully lead to the identification of robust biomarkers, capable to distinguish between axial SpA and resembling diseases. Such biomarkers will most likely be derived from serum, genetic and imaging characteristics.
Serum biomarkers
Despite numerous attempts to show additional value, studies failed to prove the existence of robust serum biomarkers yielding enough sensitivity and specificity to ease diagnosing axial SpA (33). Recent studies provided preliminary evidence that anti-CD74 antibodies are elevated in axial SpA (34,35), results that were by our knowledge not confirmed in a representative diagnostic setting.
Genetic biomarkers
The common origin of SpA phenotypes, particularly of axial SpA, is suggested by its shared genetic background. Axial SpA is considered an oligogenetic disease.
ONE
Genetic risk factors account for 80-90% of the susceptibility to AS (36) with human leukocyte antigen (HLA)-B*27, part of the major histocompatibility complex (MHC), accounting for 25% of the overall contribution to AS heritability (37). HLA-B*27 has been known for more than forty years (38) and is until now the only genetic biomarker with diagnostic value, if used in a well-defined setting. Recently, genome-wide association studies (GWAS) identified new genetic loci, both inside and outside the MHC. Although unable to pinpoint specific genes, a study by Sims et al indicated that MHC genes other than HLA-B*27 are associated with axial SpA (39).
Imaging biomarkers
Traditionally, sacroiliitis on X-ray according to the modified New York (mNY) criteria ascertained a diagnosis of AS. Over the last decades, MRI is increasingly used to support an early diagnosis of axial SpA; a development supported by the fact that MRI detects inflammation of the SI joints before radiographic structural damage appears. Furthermore, recent studies showed that readers’ agreement on the presence of radiographic sacroiliitis is at best moderate (40,41) and training of readers does not improve the assessment (42). Despite the superior relevance of MRI of the SI joints (MRI-SI) when compared to plain radiographs in a context of early axial SpA diagnosis, MRI-SI has its limitations: The specificity of MRI-SI for SpA-specific sacroiliitis is not well known and physicians may rely too much on a positive MRI-finding (43).
AIM AND OUTLINE OF THE THESIS
The global aim of the studies described in this thesis was to increase the recognition of axial SpA. Recognition in its two definitions: both acknowledgement and identification of the disease. In Part I, we focus on the recognition of the disease burden of axial SpA, focusing on extra-articular (uveitis, psoriasis, IBD) and peripheral (arthritis, enthesitis, dactylitis) manifestations. In Part II, we aim to improve early recognition of the diagnosis of axial SpA in individuals with back pain by identifying and validating novel biomarkers. These include imaging (sacroiliitis on MRI), antibodies (anti-CD74) and an MHC class I gene (HLA-C*07). In Part III, we intend to recognize the early disease processes by assessing the preclinical phase of axial SpA in a cohort of seemingly healthy first-degree relatives of HLA-B*27 positive AS patients.
In detail, this thesis is organized as follows:
Part I of the thesis focuses on the disease phenotype of axial SpA. Once an SpA
patient has back pain, the ASAS criteria classify a patient as axial and not as peripheral SpA, regardless of the burden of peripheral disease. In chapter 2 we aimed to assess whether the current classification of SpA as axial or peripheral SpA according to the ASAS criteria justifies the several disease phenotypes by
assessing the disease burden of peripheral disease manifestations in axial SpA. To study if radiographic and non-radiographic axial SpA are phenotypically similar, in chapter 3 we compared the prevalence of peripheral and extra-articular disease manifestations in the radiographic (AS) and non-radiographic phenotype of axial SpA by performing a meta-analysis of cohort studies comparing radiographic and non-radiographic axial SpA.
Part II of the thesis focuses on the identification and validation of promising
biomarkers in the axial SpA field.
MRI-SI is increasingly used to support a diagnosis of axial SpA, although the specificity of MRI of the SI joints is not well known. In chapter 4 we assessed the prevalence of sacroiliitis on MRI of the SI joints in healthy Individuals, runners, and women with postpartum back pain when compared to patients with axial SpA and chronic back pain (CBP) controls.
Anti-CD74 antibodies were proposed as a potential biological marker to diagnose axial SpA. To study their diagnostic value in AS and early axial SpA, in chapter 5 we assessed the prevalence and diagnostic value of anti-CD74 antibodies first in AS patients and healthy controls and second in a ‘real life’ cohort of patients with early, chronic back pain: the SPondyloArthritis Caught Early (SPACE) cohort.
In chapter 6 we tested the prevalence of HLA-C*07, an MHC class I gene, of
which absence might be linked to susceptibility to axial SpA. We tested HLA-C*07 prevalence in three different settings. First in an exploratory cohort of AS patients and healthy individuals. Second in GESPIC: a German cohort of early AS and non-AS patients that we compared with a large cohort of healthy donors. Third we confirmed our findings in an early chronic back pain cohort, the SPACE cohort.
Part III of the thesis focuses on the preclinical recognition of axial SpA and the
desirability of preclinical treatment.
To investigate whether seemingly healthy first-degree relatives of patients with AS have clinical, laboratory, or imaging features of SpA, in chapter 7 we described the baseline data of the Pre-SpA cohort: a cohort of seemingly healthy first-degree relatives of HLA-B*27 positive AS patients, that we prospectively follow over time.
Initiatives as the Pre-SpA cohort might enable to detect the early or pre-clinical phase of SpA. Hereby, early or pre-clinical management of SpA might become feasible, although the desirability for at-risk individuals is yet unknown. In chapter
8 we therefore studied the willingness of first degree relatives of axial SpA patients
of the Pre-SpA cohort to start using preventive medication.
ONE REFERENCES
1. Costantino F, Talpin A, Said-Nahal R, Goldberg M, Henny J, Chiocchia G, et al. Prevalence of spondyloarthritis in reference to HLA-B27 in the French population: Results of the GAZEL cohort. Ann Rheum Dis 2015;74:689–693.
2. 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.
3. Said-Nahal R, Miceli-Richard C,
Berthelot JM, Duché A, Dernis-Labous E, Blévec G Le, et al. The familial form of spondylarthropathy: A clinical study of 115 multiplex
families. Arthritis Rheum
2000;43:1356–1365.
4. Said-Nahal R, Miceli-Richard
C, D’Agostino MA, Dernis-Labous E, Berthelot JM, Duche A, et al. Phenotypic diversity is not determined by independent genetic factors in familial spondylarthropathy. Arthritis Rheum 2001;45:478–484.
5. Rahman P, Inman RD, Gladman DD, Reeve JP, Peddle L, Maksymowych WP. Association of interleukin-23 receptor variants with ankylosing
spondylitis. Arthritis Rheum
2008;58:1020–5.
6. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39:1329– 37.
7. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011;43:246–252.
8. Dernis E, Said-Nahal R, D’Agostino M, Aegerter P, Dougados M, Breban M. Recurrence of spondylarthropathy among first-degree relatives of patients: a systematic cross-sectional study. Ann Rheum Dis 2009;68:502–7.
9. Chandran V, Schentag CT, Brockbank JE, Pellett FJ, Shanmugarajah S, Toloza SMA, et al. Familial aggregation of psoriatic arthritis.
Ann Rheum Dis 2009;68:664–667.
10. Kruithof E, Baeten D, Rycke L
De, Vandooren B, Foell D, Roth J, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis
Res Ther 2005;7:R569-80.
11. Vandooren B, Noordenbos T, Ambarus C, Krausz S, Cantaert T, Yeremenko N, et al. Absence of a classically activated macrophage cytokine signature in peripheral
spondylarthritis, including psoriatic arthritis. Arthritis Rheum
2009;60:966–75.
12. Noordenbos T, Yeremenko N, Gofita I, Sande M van de, Tak PP, Caňete JD, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis.
13. Yeremenko N, Noordenbos T, Cantaert T, Tok M van, Sande M van de, Cañete JD, et al. Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis. Arthritis
Rheum 2013;65:174–85.
14. Dougados M, Baeten D.
Spondyloarthritis. Lancet
2011;377:2127–37.
15. Rudwaleit M, Heijde D van der, Landewé R, Akkoc N, Brandt J, Chou CT, 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.
16. Rudwaleit M, Heijde D van der, Landewe 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;68:777–783.
17. Sepriano AR, Rubio R, Ramiro S, Landewé R, Heijde D Van Der. Performance of the ASAS classification criteria for axial and peripheral spondyloarthritis: A systematic literature review and meta-analysis. Ann Rheum Dis 2017;76:886–890.
18. Underwood M, Dawes P.
Inflammatory back pain in primary care. Br J Rheumatol 1995;34:1074– 7.
19. Poddubnyy D, Vahldiek J, Spiller I, Buss B, Listing J, Rudwaleit M, et al. Evaluation of 2 Screening Strategies for Early Identification of Patients with Axial Spondyloarthritis
in Primary Care. J Rheumatol 2011;38:2452–2460.
20. Sieper J, Rudwaleit M. Early
referral recommendations for ankylosing spondylitis (including pre-radiographic and radiographic forms) in primary care. Ann Rheum
Dis 2005;64:659–663.
21. Brandt HC, Spiller I, Song I-H, Vahldiek JL, Rudwaleit M, Sieper J. Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis. Ann Rheum
Dis 2007;66:1479–84.
22. Chung HY, Machado P, Heijde D van der, D’Agostino MA, Dougados M. HLA-B27 positive patients differ from HLA-B27 negative patients in clinical presentation and imaging: results from the DESIR cohort of patients with recent onset axial spondyloarthritis. Ann Rheum Dis 2011;70:1930–1936.
23. Ozgocmen S, Ardicoglu O, Kamanli A, Kaya A, Durmus B, Yildirim K, et al. Pattern of disease onset, diagnostic delay, and clinical features in juvenile onset and adult onset ankylosing spondylitis. J Rheumatol 2009;36:2830–2833.
24. Salvadorini G, Bandinelli F, Delle Sedie A, Riente L, Candelieri A, Generini S, et al. Ankylosing spondylitis: How diagnostic and therapeutic delay have changed over the last six decades. Clin Exp
Rheumatol 2012;30:561–565.
25. Masson Behar V, Dougados M, Etcheto A, Kreis S, Fabre S, Hudry C, et al. Diagnostic delay in axial spondyloarthritis: A cross-sectional study of 432 patients. Jt Bone Spine 2016.
ONE 26. Boonen A, Sieper J, Heijde D van
der, Dougados M, Bukowski JF, Valluri S, et al. The burden of non-radiographic axial spondyloarthritis.
Semin Arthritis Rheum 2015;44:556–
562.
27. Zhang JR, Liu XJ, Xu WD, Dai SM. Effects of tumor necrosis factor-α inhibitors on new bone formation in ankylosing spondylitis. Jt Bone Spine 2016;83:257–264.
28. Dougados M, Heijde D van der, 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 Nonradiographic Axial Spondyloarthritis: 104-Week Results From a Randomized, Placebo-Controlled Study. Arthritis Care Res 2017;69:1590–1598.
29. Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, et al. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin
Pharmacol Ther 2001;69:89–95.
30. Berg R van den, Hooge M de, Gaalen F van, Reijnierse M, Huizinga T, Heijde D van der. 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;52:1492–9.
31. Blachier M, Canouï-Poitrine F, Dougados M, Lethuaut A, Fautrel B, Ferkal S, et al. Factors associated with radiographic lesions in early axial spondyloarthritis. Results from the DESIR cohort. Rheumatology
(Oxford) 2013;52:1686–93.
32. Baraliakos X, Listing J, Rudwaleit M, Brandt J, Sieper J, Braun J. Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumour necrosis factor alpha antibody infliximab. Ann Rheum Dis 2005;64:1462–1466.
33. Turina MC, Yeremenko N, Gaalen F Van, Oosterhout M Van, Berg IJ, Ramonda R, et al. Serum inflammatory biomarkers fail to identify early axial spondyloarthritis: Results from the SpondyloArthritis Caught Early (SPACE) cohort. RMD
Open 2017;3.
34. 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 2013:1–5.
35. Baerlecken NT, Nothdorft S,
Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, et al. Autoantibodies against CD74 in spondyloarthritis.
Ann Rheum Dis 2014;73:1211–4.
36. Robinson PC, Brown M a. Genetics of ankylosing spondylitis. Mol
Immunol 2014;57:2–11.
37. Reveille JD. Genetics of
spondyloarthritis--beyond the MHC.
Nat Rev Rheumatol 2012;8:296–304.
38. Schlosstein L, Terasaki P, Bluestone R, Pearson C. High association of an HL-A antigen, W27, with ankylosing spondylitis. New English J Med 1973:704–6.
39. Sims A-M, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis. Curr Mol
40. Berg R van den, Lenczner G, Feydy A, Heijde D Van Der, Reijnierse M, Saraux 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;66:2403–2411.
41. Christiansen AA, Hendricks O, Kuettel D, Hørslev-petersen K, Jurik G, Nielsen S, et al. Limited Reliability of Radiographic Assessment of Sacroiliac Joints in Patients with Suspected Early Spondyloarthritis Limited Reliability of Radiographic Assessment of Sacroiliac Joints in Patients with Suspected Early Spondyloarthritis. 2017;44.
42. Tubergen a van, Heuft-Dorenbosch L, Schulpen G, Landewé R, Wijers R, Heijde D van der, et al. Radiographic assessment of sacroiliitis by radiologists and rheumatologists: does training improve quality? Ann
Rheum Dis 2003;62:519–525.
43. Deodhar A. 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–
Peripheral disease contributes significantly to the disease
burden in axial spondyloarthritis
Janneke J. de Winter1, Jacqueline E. Paramarta1, Henriëtte M. de Jong1, Marleen G.
van de Sande1, Dominique L. Baeten1
1Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology
and Rheumatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
ABSTRACT
Objective
Spondyloarthritis (SpA) can encompass axial, peripheral, and extra-articular disease manifestations. Patients are classified as axial or peripheral SpA depending on the presence or absence of back pain, independently of the other disease manifestations. Therefore, we aimed to assess the percentage of axial SpA patients with peripheral disease and how this peripheral disease contributes to the overall disease burden.
Methods
Prevalence and burden of peripheral disease manifestations were assessed in a real-life observational cohort of 314 patients with the clinical diagnosis of SpA and fulfilling the Assessment of SpondyloArthritis international Society (ASAS) criteria.
Results
Of the 314 patients fulfilling the ASAS criteria, 230 fulfilled the axial and 84 the peripheral SpA criteria. Of the 230 axial SpA patients, 49% had purely axial disease without peripheral disease manifestations whereas 51% had combined axial (back pain) and peripheral (arthritis, enthesitis, and/or dactylitis) disease. The latter group had the highest disease activity in comparison with pure axial SpA as well as with peripheral SpA.
Conclusion
Half of the patients classified as axial SpA according to the ASAS criteria have also peripheral disease manifestations such as arthritis, enthesitis, and/or dactylitis. These peripheral disease manifestations contribute significantly to overall disease burden.
Key messages
• SpA patients with back pain are by definition classified as axial SpA, regardless of which disease manifestations, peripheral or axial, predominate.
• Half of the patients classified as axial SpA according to the ASAS criteria also have peripheral disease manifestations such as arthritis, enthesitis and/or dactylitis.
• Patients with combined axial and peripheral SpA have the highest disease activity when compared to purely axial SpA and purely peripheral SpA.
TWO INTRODUCTION
Spondyloarthritis (SpA) is a chronic inflammatory disease with a heterogeneous clinical presentation which can include axial, peripheral, and extra-articular (skin, gut, and eye) disease manifestations. Traditionally, SpA was divided in subtypes based on phenotypic presentation. However, recent insights in the taxonomy of the disease do not justify this phenotypic classification as data from family and genetic studies (1–5), response to treatment (6–9), and immunopathology (10– 13) rather suggest a single disease with overlapping but distinct pathophysiology for axial versus peripheral disease (14). This taxonomy parallels the Assessment of SpondyloArthritis international Society (ASAS) classification criteria distinguishing axial and peripheral SpA (15,16).
One potential issue with the classification into axial versus peripheral SpA is that approximately 30% of the SpA patients have both axial and peripheral involvement (15,17). The ASAS criteria pre-specify that patients with back pain and peripheral disease manifestations (arthritis, enthesitis and/or dactylitis) are classified as axial SpA, independently of which disease manifestations predominates in terms of disease activity and burden. When inappropriately applied by different stakeholders (including not only rheumatologists but also other health care professionals, regulators, and payers), this classification may thus potentially lead to an underestimation of the prevalence and disease burden of peripheral disease in SpA. Therefore, this study aimed to systematically assess the prevalence and burden of peripheral disease in axial and peripheral SpA as defined by the ASAS criteria in a large, real-life observational cohort.
METHODS Patient cohort
Patients presenting on the specialized SpA outpatient clinic of the Department of Clinical Immunology and Rheumatology at the Academic Medical Center/ University of Amsterdam between June 2007 and August 2012 (n=272) and of the University Medical Center Utrecht between January 2011 and August 2012 (n=42) were included in this real-life prospective observational cohort, as approved by the local Medical Ethics Committees. Patients were ≥ 18 years old, had both a clinical diagnosis of SpA according to the expert opinion of the treating rheumatologist and fulfilled the ASAS criteria (15,18). Demographic and disease characteristics, HLA-B27 and X-rays of the sacroiliac joints were collected at the first visit. X-rays were scored locally according to the modified New York (mNY) criteria (19). The patient’s and physician’s global assessment of disease activity, Bath Ankylosing Spondylitis Disease Activity (BASDAI) (20), Ankylosing Spondylitis Disease Activity Score (ASDAS) based on the C-reactive protein (CRP) (21), 66/68 swollen joint count (SJC) and tender joint count (TJC), Schober, chest expansion, CRP, erythrocyte sedimentation rate (ESR), and medication use were measured and
recorded every 3 months. The treating physician recorded the presence (past or present) of psoriasis, uveitis, inflammatory bowel disease (IBD) according to the definition of the ASAS criteria (18). A family history of SpA was defined as at least 1 first or second degree family member with AS, psoriasis, IBD, reactive arthritis or uveitis. Enthesitis and dactylitis were scored clinically by the treating physician. Active inflammatory back pain (IBP) was defined as pain at night at least 1 time a week and/or an average morning stiffness of at least 30 minutes in the past week. Patients were treated according to standard clinical patient care, hence all therapies were allowed. For the current study, we used data of the patients’ first visit to the SpA outpatient clinic.
Statistical analysis
Categorical data are presented as numbers (%), continuous data as mean (SD) or as median (interquartile range, IQR) as appropriate. We used χ2 test for categorical data and Mann-Whitney U or unpaired T test for continuous data. Statistical tests were 2-sided, and p-values less than 0.05 were considered significant.
Figure 1. Flow chart of patients included in the cohort according to the fulfilment of the ASAS criteria
TWO RESULTS
Patient characteristics and disease burden in axial SpA versus peripheral SpA
Of the 314 SpA patients fulfilling the ASAS criteria, 230 patients fulfilled the ASAS axial SpA criteria and 84 patients fulfilled the peripheral SpA criteria (73.2% vs. 26.8%)(Figure 1). The demographic and clinical characteristics of both patient groups are summarized in Table 1. The mean age of the ASAS axial SpA patients was 41 (33-52) compared to 48 (37-56) for the ASAS peripheral SpA patients (p=0.005). Of the 230 ASAS axial SpA patients, 145 were male, compared to 49 of the 84 ASAS peripheral SpA patients (63% vs. 58%, p=0.447). ASAS axial SpA patients had an earlier disease onset (32 (24-41) years) than ASAS peripheral SpA patients (38 (31-48) years, p=0.001). Of the 230 ASAS axial SpA patients, 170 were HLA-B27 positive, compared to 18 of the ASAS peripheral SpA patients (76% vs. 27%, p<0.001). All of the 230 ASAS axial SpA patients had present or past back pain, compared to 18 of the 84 ASAS peripheral SpA patients (only past back pain) (100% vs. 21%, p<0.001), and 161 of the 230 ASAS axSpA patients fulfilled the mNY criteria versus 0 of the 84 ASAS peripheral SpA patients (70% vs. 0%, p<0.0001). Arthritis (p<0.001), enthesitis (p<0.001) and dactylitis (p=0.009) were more frequent in ASAS peripheral SpA patients (Table 1), as were psoriasis (p<0.001) and IBD (p=0.004). In contrast, but in line with the frequency of HLA-B27, uveitis was more prevalent in axial SpA (p<0.001). A positive family history was observed in 86 of the ASAS axial SpA patients and in 23 of the ASAS peripheral SpA patients (37% vs. 27%, p=0.099).
Disease activity measurements specifically addressing axial disease were higher in ASAS axial SpA than in ASAS peripheral SpA patients, respectively, whereas CRP and ESR levels as markers of systemic inflammation were similar between both groups (Table 1). Interestingly, not only composite parameters originally developed for axial disease - such as BASDAI and ASDAS-CRP - but also parameters of global disease activity (patient’s and physician’s global assessment) were significantly higher in axial than peripheral SpA (p<0.001 for all 4 comparisons). This was still the case upon analysis of patients naive to TNF-α blocking therapy (data not shown).
As a reflection of standard clinical care, non-steroidal anti-inflammatory drug (NSAID) usage was higher and corticosteroid and csDMARD usage lower in the ASAS axial SpA group (all p<0.05)(Table 1). The use of TNF-α inhibitors did not differ between patients fulfilling the ASAS axial vs. peripheral SpA criteria.
Patients with purely axial and combined axial and peripheral SpA
The ASAS criteria exclude patients with active axial symptoms from the peripheral SpA group but do not exclude patients with active peripheral symptoms from the axial SpA group. Our results show that peripheral arthritis as well as enthesitis occurred each in more than 30% of the patients with axial SpA (Table 1). Therefore, we additionally differentiated the 230 patients fulfilling the ASAS axial SpA
criteria into purely axial disease (without concomitant arthritis, enthesitis, and/ or dactylitis) (n=112, 48.7%) and combined disease (axial SpA with concomitant arthritis, enthesitis or dactylitis) (n=118, 51.3%) (Figure 1). Table 2 shows the characteristics of patients with purely axial SpA and combined axial and peripheral SpA.
The mean age of the patients with purely axial SpA patients was 39 (32-48) compared to 44 (34-54) for the patients with combined SpA (p=0.064). Seventy of the 112 patients with purely axial SpA were male, compared to 75 of the patients with combined SpA (63% vs. 64%, p=0.868). The patients with purely axial SpA had a mean disease onset at 32 (23-38) years, patients with combined SpA at 34 (24-44) years. Of the 112 patients with purely axial disease, 86 were HLA-B27 positive, compared to 84 of the patients with combined SpA (80% vs. 72%, p=0.163). By definition none of the 112 patients with purely axial SpA had peripheral arthritis, enthesitis or dactylitis, of the patients with combined SpA, 75, 73 and 9 patients had peripheral arthritis, enthesitis or dactylitis, respectively (p=<0.001, p=<0.001 and p=0.003). Of the 112 patients with purely axial SpA, 7 had psoriasis and of the patients with combined SpA 16 had psoriasis (6% vs. 14%, p=0.065). Seven of the 112 patients with purely axial SpA had IBD, compared to 7 of the 118 patients with combined SpA (p=0.920). Of the patients with purely axial SpA, 41 had a positive family history for SpA, compared to 45 of the patients with combined SpA (37% vs. 45%, p=0.811).
The median Patient’s global assessment was 52 (23-68) in patients with purely axial SpA and 61 (45-75) in patients with combined SpA (p=0.0010). The median Physician’s global assessment in patients with purely axial SpA was 44 (16-60) compared to 53 (33-62) in combined SpA (p=0.009). The median BASDAI was 4.4 (2.9-6.0) in patients with purely axial SpA and 5.4 (4.0-6.6) in patients with combined SpA (p=0.001). The median ASDAS-CRP level was 2.6 (1.8-3.5) in the patients with purely axial SpA and 3.0 (2.2-3.7) in patients with combined SpA (p=0.014). There was no significant difference in CRP and ESR levels. The group with combined axial and peripheral disease retained the highest disease activity after exclusion of patients treated with anti-TNF therapy (data not shown). Of the 112 patients with purely axial SpA, 5 used any csDMARD, compared to 27 of the patients with combined disease (5% vs. 23%, p=<0.001).
Peripheral disease in combined axial versus peripheral SpA
To further assess the potential relevance of peripheral disease in the group of ASAS axial SpA, we compared peripheral disease features and treatments between combined SpA and peripheral SpA. Patients with combined SpA had a higher prevalence of enthesitis than patients with peripheral SpA (62% vs. 48%, p=0.044) but a lower prevalence of peripheral arthritis (63% vs. 98%, p<0.001). Dactylitis prevalence was not different between both groups. Prevalence of psoriasis and IBD was higher in patients with peripheral SpA (54% vs. 14%, p<0.001 and 17% vs. 6%, p=0.014, respectively) while uveitis prevalence was higher in patients with
TWO
combined SpA than in peripheral SpA (26% vs. 6.0%, p<0.001). Patients with combined SpA used NSAIDs more frequently than patients with peripheral SpA (74% vs. 56%, p=0.008), and patients with combined SpA used csDMARDs less frequently than patients with peripheral SpA (23% vs. 67%, p<0.001).
Table 1. Clinical characteristics, disease activity and treatment of ASAS axial SpA versus ASAS peripheral SpA
ASAS axial SpA ASAS peripheral SpA P-value (n=230) (n=84)
Age, median (IQR) years 41 (33-52) 48 (37-56) 0.005
Disease duration, median (IQR) years 3.9 (0.9-11.6) 4.2 (1.7-10.2) 0.601
Age at disease onset, median (IQR) years 32 (24-41) 38 (31-48) 0.001
Time to diagnosis, median (IQR) years 1.0 (0.2-4.0) 0.7 (0.1-2.6) 0.172
Male gender, n % 145 (63) 49 (58) 0.447
HLA-B27 positive, % 170 (76) 18 (27) <0.001
Inflammatory back pain (history/presence), % 230 (100) 18 (21) <0.001
mNY criteria, % 161 (70) 0 (0) <0.001
Peripheral arthritis (history/presence), % 75 (33) 82 (98) <0.001
Enthesitis (history/presence), % 73 (32) 40 (48) 0.009
Dactylitis (history/presence), % 9 (4) 10 (12) 0.009
Uveitis (history/presence), % 59 (26) 5 (6) <0.001
Psoriasis (history/presence), % 23 (10) 45 (54) <0.001
IBD (history/presence), % 14 (6) 14 (16.7) 0.004
Positive SpA family history, % 86 (37) 23 (27) 0.099
Patient's global assessment, median (IQR)
0-100 mm 55 (30-72) 38 (17-68) 0.006
Physician's global assessment, median (IQR)
0-100 mm 48 (27-61) 31 (13-44) <0.001
BASDAI, median (IQR) 4.9 (3.5-6.4) 3.0 (1.5-5.4) <0.001
BASDAI ≥4, % 149 (66) 30 (38) <0.001
BASDAI #2 back pain, median (IQR) 6.0 (3.7-7.9) 1.2 (0.1-4.4) <0.001
ASDAS-CRP, median (IQR) 2.8 (2.0-3.5) 2.0 (1.4-3.1) <0.001
ASDAS-CRP ≥2.1, % 137 (75) 32 (46) <0.001
Swollen joint count, median (IQR) 0-66 joints 0.0 (0.0-0.0) 1.0 (0.0-2.0) <0.001
Tender joint count, median (IQR) 0-68 joints 0.0 (0.0-2.0) 1.0 (0.0-5.0) <0.001
Schober, median (IQR) cm 3.5 (2.5-4.5) 4.5 (4.0-5.0) <0.001
CRP, median (IQR) mg/l 3.6 (1.0-11.7) 3.7 (1.8-9.6) 0.479
ESR, median (IQR) mm/h 9.0 (5.0-20.0) 7.5 (3.3-18.0) 0.474
NSAIDs, % 172 (75) 47 (56) 0.001
Corticosteroids, % 4 (2) 5 (6) 0.048
Any csDMARD, % 32 (13.9) 56 (67) <0.001
SpA spondyloarthritis; ASAS Assessment of SpondyloArthritis international Society; IQR interquartile range; mNY modified New York; IBD inflammatory bowel disease; BASDAI Bath Ankylosing Spondylitis Disease Activity Index; ASDAS Ankylosing Spondylitis Disease Activity Score; CRP C-reactive protein; ESR erythrocyte sedimentation rate; NSAIDs non-steroidal anti-inflammatory drugs; csDMARDs conventional synthetic disease-modifying anti-rheumatic drugs; TNF tumor necrosis factor. Significance of the comparisons is determined by Mann-Whitney U tests for continuous variables or chi-square tests for categorical variables.
Data were missing for: diagnostic delay n=153, HLA-B27 n=25, BASDAI n=10, CRP n=57, SJC/TJC n=2, Schober n=11 and ESR n=47 individuals
Table 2. Clinical characteristics, disease activity and treatment of patients with purely axial SpA and combined axial and peripheral SpA
Purely axial SpA Combined SpA P-value (n=112) (n=118)
Age, median (IQR) years 39 (32-48) 44 (34-54) 0.064
Disease duration, median (IQR) years 3.1 (0.4-11.1) 4.6 (1.2-12.6) 0.080
Age at disease onset, median (IQR) years 32 (23-38) 34 (24-44) 0.214
Time to diagnosis, median (IQR) years 1.0 (0.3-4.0) 0.8 (0.1-4.7) 0.257
Male gender, % 70 (63) 75 (64) 0.868
HLA-B27 positive, % 86 (80) 84 (72) 0.163
Inflammatory back pain (history/presence), % 112 (100) 118 (100) NA
Sacroiliitis mNY, % 82 (73) 79 (68) 0.346
Peripheral arthritis (history/presence), % 0 (0) 75 (64) <0.001
Enthesitis (history/presence), % 0 (0) 73 (62) <0.001
Dactylitis (history/presence), % 0 (0) 9 (8) 0.003
Uveitis (history/presence), % 28 (25) 31 (26) 0.825
Psoriasis (history/presence), % 7 (6) 16 (14) 0.065
IBD (history/presence), % 7 (6) 7 (6) 0.920
Positive SpA family history, % 41 (37) 45 (38) 0.811
Patient's global assessment, median (IQR)
0-100 mm 52 (23-68) 61 (45-75) 0.001
Physician's global assessment, median (IQR)
0-100 mm 44 (16-60) 53 (33-62) 0.009
BASDAI, median (IQR) 4.4 (2.9-6.0) 5.4 (4.0-6.6) 0.001
BASDAI ≥4, % 64 (58) 85 (75) 0.007
BASDAI #2 back pain, median (IQR) 6 (3-8) 7 (4-8) 0.272
ASDAS-CRP, median (IQR) 2.6 (1.8-3.5) 3.0 (2.2-3.7) 0.014
ASDAS-CRP ≥2.1, % 59 (67) 78 (82) 0.019
Swollen joint count, median (IQR) 0-66 joints 0.0 (0.0-0.0) 0.0 (0.0-1.0) <0.001
TWO Purely axial SpA Combined SpA P-value (n=112) (n=118)
Tender joint count, median (IQR) 0-68 joints 0.0 (0.0-0.0) 1.0 (0.0-3.5) <0.001
Schober, median (IQR) cm 3.0 (2.0-4.0) 4.0 (3.0-5.0) 0.001
Chest expansion, median (IQR) cm 5.0 (4.0-6.0) 4.0 (3.0-6.0) 0.120
CRP, median (IQR) mg/l 3.3 (1.0-8.5) 4.0 (1.1-14.2) 0.288
ESR, median (IQR) mm/h 8.0 (5.0-15.3) 12.0
(4.5-24.5) 0.078
NSAIDs, % 85 (76) 87 (74) 0.706
Corticosteroids, % 1 (1) 3 (3) 0.339
Any csDMARD, % 5 (5) 27 (23) <.001
Anti-TNF therapy, % 16 (14) 20 (17) 0.578
SpA spondyloarthritis; ASAS Assessment of SpondyloArthritis international Society; IQR interquartile range; IBD inflammatory bowel disease; BASDAI Bath Ankylosing Spondylitis Disease Activity Index; ASDAS Ankylosing Spondylitis Disease Activity Score; CRP C-reactive protein; ESR erythrocyte sedimentation rate; NSAIDs non-steroidal anti-inflammatory drugs; csDMARDs conventional synthetic disease-modifying anti-rheumatic drugs; TNF tumor necrosis factor. Significance of the comparisons is determined by Mann-Whitney U tests for continuous variables or chi-square tests for categorical variables.
Data were missing for: diagnostic delay n=153, HLA-B27 n=25, BASDAI n=10, CRP n=57, SJC/TJC n=2, Schober n=11 and ESR n=47 individuals
DISCUSSION
In this real-life observational cohort of 314 SpA patients we investigated the clinical characteristics and disease burden of axial and peripheral SpA according to the ASAS criteria, leading to the following conclusions: 1) Patients classified as axial SpA according to the ASAS criteria in fact consist of two separate groups of equal size: patients with exclusively axial disease and patients with combined axial and peripheral disease, defined as active IBP plus arthritis, enthesitis and/ or dactylitis, 2) patients with combined axial and peripheral disease consistently showed higher disease activity than patients with purely axial disease, and 3) patients with combined axial and peripheral disease were less often treated with csDMARDs than patients with purely peripheral SpA.
In line with previous reports, axial SpA was more prevalent than peripheral SpA and was associated with specific features such as younger age, higher prevalence of HLA-B27 and uveitis, and lower prevalence of psoriasis and IBD (22). And in line with treatment guidelines (23), a majority of axial SpA was treated with NSAID whereas the use of csDMARDs was higher in peripheral SpA. The overall disease burden, as evaluated by patient’s and physician’s global assessment of disease activity as well as composite indices such as BASDAI and ASDAS, was higher in
axial SpA but did not lead to a higher use of highly effective targeted therapies such as TNF inhibition, suggesting that treatment was not completely tailored to disease activity. For the sake of clarity, it needs to be specified there are no major restrictions to access to TNF inhibition in the Netherlands and that other targeted therapies, such as IL-17 inhibition, were not available at the time of this cross-sectional cohort study.
A striking finding in this axial vs. peripheral SpA analysis was the fact that 21% of the patient with peripheral SpA had a history of back pain. The back pain can be explained by the fact that the criteria for axial SpA require present inflammatory back pain; therefore, a patient with peripheral SpA and a history of or non-inflammatory back pain will still be classified as peripheral SpA and it remains unknown if this back pain is related to SpA or to other, concomitant conditions such as degenerative disc disease. This question could be addressed by MRI imaging of the axial skeleton in these patients, an approach which was not systematically applied in the current study.
The main finding of the study, however, is that half of the patients with axial SpA have also signs of peripheral disease. Further analysis of ‘pure axial SpA’ versus combined axial and peripheral SpA revealed that, albeit both subgroups were very similar in terms of demographics, HLA-B27 positivity, family history, and presence of extra-articular manifestations, the combined SpA had significantly higher disease activity despite increased use of csDMARDs. Moreover, a comparison with peripheral SpA revealed that combined SpA patients used less csDMARDs despite higher disease activity (data not shown). Interestingly, we noted that the higher disease activity in combined SpA did not translate in higher use of TNF inhibition in this patient subset. Whereas cDMARDs are not effective for axial disease (24–26) and may have limited efficacy for peripheral disease (24,26–28), it is well established that TNF inhibition is effective for both axial and peripheral disease (29–38). In the setting of the current study, patients with combined axial and peripheral SpA are eligible for targeted therapies and access to TNF inhibition was not restricted. Collectively, these data therefore indicate that patients with combined axial and peripheral disease form an important subgroup of patients with axial SpA as defined by the ASAS criteria as they represent half of the axial SpA patients and have a higher disease burden. However, they do not appear to be treated ‘to target’ based on disease activity, suggesting that the additional disease burden related to concomitant peripheral disease is underestimated in axial SpA. Whereas the design of this cross-sectional observational cohort study did not allow to formally test the potential benefit of treatment intensification in the subset of SpA patients with combined axial and peripheral disease, different approaches may be considered in follow-up studies to increase recognition and appropriate treatment of peripheral disease in patients classified as axial SpA. For example, several previous studies used the ASAS criteria differently than proposed - that is classifying patients with combined axial and peripheral disease exclusively according to the axial arm of the criteria- in order to better reflect
TWO
the real phenotype of the patients. In the Leiden early arthritis cohort the ASAS peripheral SpA criteria were applied on early arthritis patients with past and/or present IBP (39) while strictly speaking the ASAS axial SpA criteria should always be applied in case of active IBP and not the peripheral SpA criteria. The COSPA (Cochin SpondyloArthritis study) cohort of established SpA used either the ASAS axial or peripheral SpA criteria based on what the predominant manifestation was according to the treating physician (40). A study analyzing the performance of the ASAS criteria in early SpA within the ESPERANZA program applied the axial SpA criteria only in patients with exclusively back pain and the peripheral SpA only on patients with peripheral arthritis, dactylitis or enthesitis in the absence of axial pain (41), which is also not in line with the ASAS classification criteria. Another study assessing the prevalence of SpA in southern Sweden concluded that 57% fulfilled the ASAS classification criteria for peripheral SpA, 91% the ASAS classification criteria for axial SpA, and that 45% of this latter group also fulfilled the ASAS criteria for peripheral SpA (42), while according to the ASAS criteria it is not possible to fulfill both criteria arms. Finally, in our recent proof-of-concept clinical trial with adalimumab in non-AS, non-PsA peripheral SpA according to the ESSG criteria post-hoc application revealed that 38/40 patients would fulfill the ASAS criteria for peripheral SpA if not taking into account that 22/40 patients also had active IBP when actively questioned for axial complaints (34). Therefore, it could theoretically be considered to use the ASAS criteria differently and either classify patient according to the major disease manifestations (rather than use axial SpA as default setting) or to classify them as axial SpA, peripheral SpA, or axial and peripheral SpA.
The key question, however, is if merely changing the criteria would impact recognition and treatment of peripheral disease in clinical practice? It may be more relevant to maintain the current classification but clarify in management and treatment guidelines how this should be applied. Careful evaluation and monitoring of peripheral disease (and similarly: extra-articular manifestations and co-morbidities) remains needed in all SpA patients, even in the axial SpA subset. And treatment decisions should be based not only on axial disease targets and/ or peripheral disease targets, but should include composite indices and/or PRO’s reflecting the global disease burden where appropriate (6,43). An example of such an approach is the Minimal Disease Activity (MDA) in psoriatic arthritis, which includes different domains of the disease (44,45). Interestingly, we previously demonstrated that both BASDAI and ASDAS perform well in peripheral SpA (46). Therefore, it would be relevant to evaluate in a real-life study if systematic use of these tools to monitor disease activity and guide treatment decisions– not only for axial SpA but also for combined axial and peripheral SpA- may favorably impact outcome in not only purely axial SpA but also combined axial and peripheral SpA.
Conclusions
Half of the patients classified as axial SpA according to the ASAS criteria also have peripheral disease manifestations such as arthritis, enthesitis, and/or dactylitis. These patients have higher disease activity than patients with purely axial SpA and patients with peripheral SpA. Further research should 1) assess in a longitudinal study if the additional disease burden related to concomitant peripheral disease negatively impacts the long-term outcome in axial SpA, and 2) evaluate whether adaption of the classification criteria and/or systematic monitoring of disease activity using composite indices may lead to better recognition and treatment of peripheral disease in axial SpA.
Acknowledgements: We would like to thank all physicians working in the SpA
outpatient clinics during the inclusion of the study. Dominique Baeten was supported by a VIDI grant from The Netherlands Organization for Scientific Research (NWO), by a grant from the Dutch Arthritis Foundation (Reumafonds) and by a grant from the European Research Counsil (ERC).
TWO REFERENCES
1. Said-Nahal R, Miceli-Richard C,
Berthelot JM, Duché A, Dernis-Labous E, Blévec G Le, et al. The familial form of spondylarthropathy: A clinical study of 115 multiplex
families. Arthritis Rheum
2000;43:1356–1365.
2. Said-Nahal R, Miceli-Richard
C, D’Agostino MA, Dernis-Labous E, Berthelot JM, Duche A, et al. Phenotypic diversity is not determined by independent genetic factors in familial spondylarthropathy. Arthritis Rheum 2001;45:478–484.
3. Rahman P, Inman RD, Gladman DD, Reeve JP, Peddle L, Maksymowych WP. Association of interleukin-23 receptor variants with ankylosing
spondylitis. Arthritis Rheum
2008;58:1020–5.
4. Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007;39:1329– 37.
5. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011;43:246–252.
6. Smolen JS, Schöls M, Braun J, Dougados M, Gerald OF, Gladman DD, 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.
7. Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet 2009;373:633– 40.
8. Poddubnyy D, Hermann KGA,
Callhoff J, Listing J, Sieper J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: Results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum
Dis 2014;73:817–823.
9. Baeten D, Østergaard M, Wei JC-C, Sieper J, Järvinen P, Tam L-S, et al. Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study. Ann Rheum
Dis 2018:1–8.
10. Kruithof E, Baeten D, Rycke L
De, Vandooren B, Foell D, Roth J, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis
Res Ther 2005;7:R569-80.
11. Vandooren B, Noordenbos T, Ambarus C, Krausz S, Cantaert T, Yeremenko N, et al. Absence of a classically activated macrophage cytokine signature in peripheral
psoriatic arthritis. Arthritis Rheum 2009;60:966–75.
12. Noordenbos T, Yeremenko N, Gofita I, Sande M van de, Tak PP, Caňete JD, et al. Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis.
Arthritis Rheum 2012;64:99–109.
13. Yeremenko N, Noordenbos T, Cantaert T, Tok M van, Sande M van de, Cañete JD, et al. Disease-specific and inflammation-independent stromal alterations in spondylarthritis synovitis. Arthritis
Rheum 2013;65:174–85.
14. Dougados M, Baeten D.
Spondyloarthritis. Lancet
2011;377:2127–37.
15. Rudwaleit M, Heijde D van der, Landewé R, Akkoc N, Brandt J, Chou CT, 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.
16. Rudwaleit M, Heijde D van der, Landewe 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;68:777–783.
17. Winter JJ de, Mens LJ van, Heijde D van der, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther 2016;18:196.
18. Rudwaleit M, Heijde D van der,
Landewe 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;68:777–783.
19. Linden S Van der, Valkenburg H, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheumatol 1984;27:361–8.
20. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P CA. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–2291.
21. MacHado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): Defining cut-off values for disease activity states and improvement scores. Ann
Rheum Dis 2011;70:47–53.
22. Río-Martínez P del, Navarro-Compán V, Díaz-Miguel C, Almodóvar R, Mulero J, Miguel E De. Similarities and differences between patients fulfilling axial and peripheral ASAS criteria for spondyloarthritis: Results from the Esperanza Cohort. Semin
Arthritis Rheum 2016;45:400–403.
23. Heijde D Van Der, Ramiro S,
Landewé R, Baraliakos X, Bosch F Van Den, Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum
Dis 2017;76:978–991.
TWO Alten R, Burmester G, Grasedyck
K, 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;65:1147–53.
25. Haibel H, Brandt HC, Song IH, Brandt A, Listing J, Rudwaleit M, et al. No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: A 16-week open-label trial. Ann Rheum Dis 2007;66:419– 421.
26. Chen J, Mms V, Liu C, Lin J. Methotrexate for ankylosing spondylitis ( Review ). 2013.
27. Chandran V, Schentag CT, Gladman DD. Reappraisal of the effectiveness of methotrexate in psoriatic arthritis: results from a longitudinal observational cohort. J Rheumatol 2008;35:469–471.
28. Ash Z, Gaujoux-Viala C, Gossec L, Hensor EMA, FitzGerald O, Winthrop K, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: Current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis.
Ann Rheum Dis 2012;71:319–326.
29. Kavanaugh A, McInnes IB, Mease PJ, Krueger GG, Gladman DD, Heijde D van der, et al. Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study. Ann Rheum Dis 2013;72:1777–1785.
30. Kavanaugh A, Heijde D van der, McInnes IB, Mease P, Krueger GG, Gladman DD, et al. Golimumab in psoriatic arthritis: one-year clinical efficacy, radiographic, and safety results from a phase III, randomized, placebo-controlled trial. Arthritis
Rheum 2012;64:2504–2517.
31. Mease PJ, Kivitz AJ, Burch FX, Siegel EL, Cohen SB, Ory P, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis
Rheum 2004;50:2264–2272.
32. Song I-H, Weis A, Hermann K-GA, Haibel H, Althoff CE, Poddubnyy D, 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.
33. Mease PJ, Ory P, Sharp JT, Ritchlin CT, Bosch F Van den, Wellborne F, et al. Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT). Ann Rheum Dis 2009;68:702–709.
34. Paramarta JE, Rycke L De, Heijda TF, Ambarus C a, Vos K, Dinant HJ, et al. Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis. Ann Rheum Dis 2013;72:1793–9.
35. Antoni CE, Kavanaugh A, Heijde D van der, Beutler A, Keenan G, Zhou B, et al. Two-year efficacy and safety of infliximab treatment in patients with active psoriatic arthritis: findings of
the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). J
Rheumatol 2008;35:869–876.
36. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, 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;73:101–7.
37. Mease PJ, Fleischmann R, Deodhar AA, Wollenhaupt J, Khraishi M, Kielar D, et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis 2014;73:48–55.
38. 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 including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis 2014;73:39–47.
39. Berg R Van Den, Gaalen F Van, Helm-Van Mil A Van Der, Huizinga T, Heijde D Van Der. Performance of classification criteria for peripheral spondyloarthritis and psoriatic arthritis in the Leiden early arthritis cohort. Ann Rheum Dis 2012;71:1366–1369.
40. Cheung PP, Tymms KE, Wilson BJ, Shadbolt B, Brook AS, Dorai Raj
AK, et al. Infliximab in severe active ankylosing spondylitis with spinal ankylosis. Intern Med J 2008;38:396– 401.
41. Tomero E, Mulero J, Miguel E de, Fernández-Espartero C, Gobbo M, Descalzo M a, 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.
42. Haglund E, Bremander AB,
Petersson IF, Strömbeck B, Bergman S, Jacobsson LTH, et al. Prevalence of spondyloarthritis and its subtypes in southern Sweden. Ann Rheum Dis 2011;70:943–948.
43. Gladman DD. Toward treating to target in psoriatic arthritis. J
Rheumatol 2015;93:14–16.
44. Mens LJJ Van, Sande MGH Van De, Kuijk AWR Van, Baeten D, Coates LC. Ideal target for psoriatic arthritis? Comparison of remission and low disease activity states in a reallife cohort. Ann Rheum Dis 2018;77:251– 257.
45. Coates LC, Helliwell PS. Validation of minimal disease activity criteria for psoriatic arthritis using interventional trial data. Arthritis
Care Res (Hoboken) 2010;62:965–
969.
46. Turina MC, Ramiro S, Baeten DL, Mease P, Paramarta JE, Song IH, et al. A psychometric analysis of outcome measures in peripheral spondyloarthritis. Ann Rheum Dis 2016;75:1302–1307.
Prevalence of peripheral and extra-articular disease in
ankylosing spondylitis versus non-radiographic axial
spondyloarthritis: a meta-analysis
Janneke J. de Winter1, Leonieke J. van Mens1, Désirée van der Heijde2, Robert
Landewé1, Dominique L. Baeten1,3
1Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and
immunology Center, Amsterdam UMC, University of Amsterdam, Amsterdam,
The Netherlands 2Department of Rheumatology, Leiden University Medical Center, Leiden,
The Netherlands 3Department of Experimental Immunology, Academic Medical Center/
University of Amsterdam, Amsterdam, The Netherlands Arthritis Res Ther. 2016 Sep 1;18:196
ABSTRACT
Background
Peripheral disease (arthritis, enthesitis and dactylitis) and extra-articular disease (uveitis, psoriasis and inflammatory bowel disease) is common in ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). So far, however, summary data on the prevalence are lacking. The objective of this meta-analysis was to assess the prevalence of peripheral and extra-articular manifestations in AS and nr-axSpA.
Methods
We performed a systematic literature search to identify publications describing the prevalence of peripheral and extra-articular disease manifestations in patients with AS and nr-axSpA. We assessed the risk of bias and between-study heterogeneity, and extracted data. Pooled prevalence and prevalence differences were calculated.
Results
Eight studies comprising 2236 patients with AS and 1242 with nr-axSpA were included: 7 of the studies were longitudinal cohort studies. There was a male predominance in AS (70.4%; 95%CI 64.4-76.0%) but not in nr-axSpA (46.8%; 95% CI 41.7-51.9), which was independent of the prevalence of human leukocyte antigen (HLA)-B27. The prevalence of HLA-B27 was similar in AS (78.0%; 95% CI 73.9-81.9%) and nr-axSpA (77.4%; 95% CI 68.9-84.9%). The pooled prevalence of arthritis (29.7% (95% CI 22.4-37.4%) versus 27.9% (95% CI 16.0-41.6%)), enthesitis (28.8% (95% CI 2.6-64.8) versus 35.4% (95% CI 6.1-71.2). dactylitis (6.0% (95% CI 4.7-7.5%) versus 6.0% (95% CI 1.9-12.0%)), psoriasis (10.2% (95% CI 7.5-13.2%) versus 10.9% (95% CI 9.1-13.0%)) and IBD (4.1% (95% CI 2.3-6.5%) versus 6.4% (95% CI 3.6-9.7%)) was similar in AS and nr-axSpA. The pooled prevalence of uveitis was higher in AS (23.0% (95% CI 19.2-27.1%)) than in nr-axSpA (15.9% (95% CI 11.8-20.4%)).
Conclusion
Peripheral and extra-articular manifestations are frequently and equally prevalent in AS and nr-axSpA, except for uveitis, which is slightly more prevalent in AS. These data provide evidence for the largely equal nature of disease manifestations in nr-axSpA and AS.
THREE BACKGROUND
Spondyloarthritis (SpA) is a prevalent and potentially disabling form of chronic inflammatory arthritis, affecting 0.5-1.5% of the Western population (1,2). SpA has classically been subdivided into several subtypes, including ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, arthritis/spondylitis associated with inflammatory bowel disease (IBD), and undifferentiated SpA. Classification criteria for SpA have been developed by the Assessment of SpondyloArthritis international Society (ASAS), which classify SpA as axial or peripheral SpA (3–5). The axial SpA disease spectrum classifies patients as having either radiographic axial SpA (AS) whether the modified New York criteria (mNYc) are fulfilled, or as having non-radiographic axial SpA (nr-axSpA) in the absence of definite SI joint changes on plain radiograph.
Whether nr-axSpA is a different form (6,7) of AS, an early form (8–10) of AS or two manifestations in the same disease continuum (11–13) is still subject to debate. There are several reasons to assume that AS and nr-axSpA should be considered as the same disease. First, AS and nr-axSpA have in general similar clinical characteristics, especially when related to disease activity (9–11). Patients with AS and nr-axSpA not only show similar levels of disease activity, they also show a similar clinical disease course in the absence of tumor necrosis factor (TNF) α inhibiting treatment, as shown by recent longitudinal results from the German Spondyloarthritis Inception Cohort (GESPIC) (14). Second, patients with nr-axSpA respond similarly to TNF α inhibiting treatment (15–18). Third, radiographic changes only appear after several years; therefore the requirement of radiographic changes clearly reduces the sensitivity of the mNYc. Not only is sensitivity of the mNYc rather limited; several studies have shown that scoring of radiographs is subject to considerable inter- and intra-reader variability. Scoring by both trained readers and local rheumatologists/radiologists not only yield modest sensitivity and specificity at best, but also show moderate agreement with respect to the recognition of radiographic sacroiliitis (19,20). These limitations challenge the crucial role of radiographic scoring in the process of diagnosing AS. Magnetic resonance imaging (MRI) is increasingly used to visualize inflammation in the SI joints, since active inflammatory lesions are present on MRI before radiographic lesions are detected (13). However, MRI also has limitations in terms of scoring agreement, sensitivity, specificity and costs.
On the other hand, AS is characterized by a male predominance and a higher level of C-reactive protein (CRP) in comparison to nr-axSpA (9–11). Other studies suggest that AS and nr-axSpA differ in their genetics (21), since in some studies human leukocyte antigen (HLA)-B27 carriage is higher in AS than in nr-axSpA (11,15,22), whilst other studies suggest no difference in HLA-B27 carriage between both groups (9,23,24).
Even though spinal inflammation and structural damage are the main features of axial SpA, many patients have concomitant peripheral (arthritis, enthesitis,
