Recognizing axial spondyloarthritis

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de Boer, J.J.H.

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2018

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de Boer, J. J. H. (2018). Recognizing axial spondyloarthritis.

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CHAPTER 1

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9 GENERAL INTRODUCTION AND OUTLINE

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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

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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.

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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

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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.

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