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Recognizing axial spondyloarthritis
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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The global aim of the studies described in this thesis was to increase the recognition of axial spondyloarthritis (axial SpA). Recognition by its two definitions: both acknowledgement as well as (early) identification of the disease. In this final chapter we will summarize the main findings of the studies in this thesis and share our vision of research challenges in the field for the coming years.
Figure 1. The spectrum of healthy to full-blown axial SpA, crossing subsequently the ‘at-risk’ phase, a phase characterized with back pain and other SpA features, and early axial SpA. The numbers on the left side represent the chapters in this thesis and their place in the disease spectrum. The disease probability increases with each following disease stage.
Recognizing the disease burden of axial SpA
To recognize and identify the magnitude and nature of disease manifestations in axial SpA is of importance for several reasons. First, treatment can only focus on the whole spectrum of disease manifestations in the patient with axial SpA if these manifestations are truly acknowledged. Second, exploring the heterogeneity between subsets of the disease (for example radiographic versus non-radiographic axial SpA) tells us in part whether axial SpA can be seen as one disease. Part I therefore elaborated on the disease burden of axial SpA. Chapter 2 aimed at describing the burden of peripheral disease (arthritis, enthesitis, dactylitis) in a real-life cohort of SpA patients fulfilling the ASAS criteria for axial or peripheral SpA. Of the SpA patients included, 230 fulfilled the axial and 84 the peripheral SpA criteria. Of the 230 axial SpA patients, 113 (49%) had purely axial disease
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without peripheral disease manifestations and 117 (51%) had combined axial and peripheral disease. The group with combined axial and peripheral disease had the highest disease activity.
These results are of importance, since the treatment of axial disease in patients classified as ‘axial SpA’ by the ASAS criteria might prevail over the treatment of peripheral disease, while we showed that the latter contributes significantly to the disease activity. Clinical research programs on axial SpA should systemically include a careful evaluation of peripheral disease symptoms. Future research will have to show if indeed the current classification of patients with both axial and peripheral disease as axial SpA leads to worse treatment outcomes. In order to solve this issue, patients might be classified according to their prevailing symptom, as several recent studies pragmatically already did (1–5).
AS and non-radiographic axial SpA are phenotypically largely equal
In Chapter 3, we compared the prevalence of peripheral and extra-articular (uveitis, psoriasis, inflammatory bowel disease (IBD)) disease manifestations in the radiographic (ankylosing spondylitis, AS) and non-radiographic phenotype of axial SpA (nr-axial SpA) by performing a systematic literature search to identify publications describing the prevalence of peripheral and extra-articular disease manifestations in patients with AS and nr-axial SpA. We calculated the pooled prevalence and difference in prevalence.
Our study data show that peripheral and extra-articular disease manifestations are, with the exception of uveitis, frequent and equally prevalent in AS and nr-axial SpA. These data further support the concept of nr-axial SpA being one disease continuum irrespective of the presence and extent of radiographic changes (6–8). Importantly, we should emphasize that phenotypic similarities do not logically imply that different forms of axial SpA are indeed identical, although family studies (9–15), studies after the immunopathologic basis of SpA (16–19), and clinical studies do provide evidence that justify handling them as one disease (20).
Recognizing the diagnosis of axial spondyloarthritis
To date, there are no biomarkers that yield sufficient specificity and sensitivity to identify axial SpA with a high level of certainty. The development of robust diagnostic biomarkers might shorten the current significant time to diagnosis of 5 to 11 years (21–24). Part II therefore focused on the identification and validation of promising biomarkers in the axial SpA field, predominantly those biomarkers suggested to serve a role in the diagnostic process.
There is no role for anti-CD74 antibodies in the diagnostic process of early axial SpA
Anti-CD74 IgG antibodies are reported to be elevated in axial SpA patients (25,26) In Chapter 4, we aimed to show the diagnostic value of anti-CD74 antibodies in axial SpA, particularly in early axial SpA. The results of Chapter 4 suggest that anti-CD74 antibodies have limited diagnostic value in patients with early back
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pain. In conclusion, serum anti-CD74 IgG and IgA antibodies are both elevated in patients with AS compared to healthy controls, serum anti-CD74 IgG antibodies are not elevated in patients with early axial SpA compared to patients with chronic back pain (CBP), serum anti-CD74 IgA antibody levels are elevated in patients with early axial SpA compared to patients with CBP, but serum anti-CD74 IgA antibodies lacked diagnostic value in patients with early back pain due to limited numerical differences. And although anti-CD74 antibodies do not seem to have a role in the diagnostic process, they might help to predict radiographic damage or serve as a marker for treatment response. The results of this study are in line with a recent study showing that there is little hope for robust serum biomarkers such as antibodies in the diagnostic process of axSpA (27). However, initiatives as the SPondyloArthritis Caught Early (SPACE) cohort, the GErman SPondyloarthritis Inception Cohort (GESPIC) and the Pre-SpA cohort will hopefully enable us to identify new and promising biomarkers.
SpA-specific sacroiliitis on MRI-SI occurs frequently in healthy individuals
In recent decades, MRI has been increasingly used to visualize inflammation in the sacroiliac (SI) joints since inflammation on MRI facilitates the early identification of patients with axial SpA by preceding structural damage on radiography (28,29). The ASAS criteria reflect this development, since they are the first criteria including sacroiliitis on MRI to aid identification of axial SpA patients in an early stage (30,31). Chapter 5 therefore focused on the specificity of MRI in the detection of SpA-specific sacroiliitis. For this purpose we compared MRI of the sacroiliac joints (MRI-SI) of healthy individuals and those with known mechanical strain acting upon the sacroiliac joints (SI joints). To that purpose, we scored MRI-SI 1) 47 healthy individuals 2) 47 positive controls; axial SpA patients with a previously positive scored MRI-SI 3) 47 negative controls; CBP patients irrespective of MRI-SI outcome, 4) 22 frequent runners and 5) women with postpartum back pain. The results of this study suggest that a substantial proportion of healthy and asymptomatic individuals, runners, and women with postpartum back pain may have positive findings on MRI of the SI joints that are highly suggestive, but not reflective, of axial SpA. Patients with axial SpA have more extensive lesions (reflected by SPARCC scores ≥5 and the presence of deep (extensive) lesions) than healthy, asymptomatic individuals.
The key message of this study is that misclassification of MRIs of the SI joints as positive is a real threat, which may lead to a falsely high number of patients being diagnosed with axial SpA. Evidence of such a mechanism has been reported by previous studies (32,33), showing that nearly 25% of patients with chronic back pain could be classified as having axial SpA when MRI of the SI joints was the leading factor in the diagnostic consideration. Since we and others (34) have demonstrated that MRIs that are highly suggestive of axial SpA may be seen frequently in unaffected individuals, relying too much on a positive MRI finding will result in over-diagnosis, and consequently in over-treatment of these patients
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who may have nonspecific chronic back pain rather than axial SpA. The only means to avoid over-diagnosis of axial SpA is to act based on thorough knowledge of the clinical syndrome of axial SpA and MRI abnormalities. The finding of this and other recent studies with comparable outcome will hopefully influence the role of MRI in the diagnostic process, where there are two options. 1) MRI of the SI joints should only be considered in patients with a high suspicion of axial SpA, and 2) the threshold for ‘positive MRI of the SI joints highly specific for axSpA’ should be redefined. In other words, either the threshold for testing or the threshold for a positive test should be set higher, in order to gain specificity and avoid false-positives.
HLA-C*07 absence is associated with susceptibility to axial SpA
In Chapter 6, we report the novel finding that absence of HLA-C*07 is associated with axial SpA. We showed a lower prevalence of HLA-C*07 in axial SpA when compared to controls in three different settings: an exploratory cohort of AS patients versus healthy controls (HC), a cohort of patients with full-blown AS versus a large cohort of German donors, and an early back pain cohort (the SPACE cohort) where we compared HLA-C*07 in axial SpA patients with chronic back pain (CBP) patients. In the exploratory cohort, 79% of the AS patients were HLA-C*07 negative compared to 35% of the HC (p<0.001). This difference was confirmed in GESPIC with 73% of AS patients being HLA-C*07 negative compared to 50% of the controls (p<0.0001); 59% of the nr-axial SpA patients were HLA-C*07 negative. In the SPACE cohort, 70% of axial SpA patients were HLA-C*07 negative compared to 44% of CBP patients (p<0.0001). The effect of HLA-C*07 is associated with genetic susceptibility to axial SpA additionally to the effect of HLA-B*27. HLA-C*07 status is possibly linked to an axial SpA phenotype with high inflammation and radiographic damage and with a low psoriasis prevalence.
Although other MHC genes than HLA-B*27 are suggested to be involved in axial SpA susceptibility by genome-wide association studies (GWAS) (35–37), this study reports the first robust HLA association with axial SpA since the discovery of the HLA-B*27 association in 1973 (38). The proposed genetic association of HLA-C*07 with axial SpA could be relevant for several reasons. First, HLA-C*07 might serve as a biomarker facilitating an early axial SpA diagnosis. Second, our data suggest that HLA-C*07 is linked to radiographic progression, and beyond diagnosis, HLA-C*07 could therefore help to stratify axial SpA subpopulations and function as a prognostic marker. Third, this finding could potentially be relevant for pathophysiology. And, forth, this finding could lead to defining new treatment targets in specific subpopulations of patients. Future research in other (larger) cohorts of patients and controls will have to confirm the association of HLA-C*07 absence with axial SpA, investigate the effect of linkage disequilibrium and thus independence of this finding from HLA-B*27 and study the role of HLA-C*07 in axial SpA pathogenesis.
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Recognizing the preclinical phases of axial SpA
Studying the preclinical phase of axial SpA is of major importance. Identifying patients even before the onset of symptoms might 1) reveal the pathogenic onset of inflammation and new bone formation, 2) help to identify diagnostic biomarkers and 3) enable us to treat at-risk individuals very early in the course of the disease or even before the onset of symptoms, to prevent structural damage to occur. In
Chapter 7 we report the baseline characteristics of the first 51 seemingly healthy
first-degree relatives of HLA-B*27 positive AS patients, the Pre-SpA cohort. A major conclusion is that at baseline 33% of first-degree relatives have clinical and/ or imaging features that allow a classification of SpA according to the ASAS axial SpA and/or ESSG classification criteria. The Pre-SpA cohort is to our knowledge a unique inception cohort, showing that a major part of seemingly healthy first-degree relatives already has SpA features. Future follow-up will identify first-first-degree relatives developing full-blown disease and possibly define predicting biomarkers in retrospect.
The study described in Chapter 8 explored the fictitious willingness of first-degree relatives of axial SpA patients, who are participating in the Pre-SpA cohort study to use preventive medication. When the axial SpA risk is clearly increased (70%) or when preventive medication has no side effects, the vast majority of first-degree relatives of axial SpA patients seems willing to use preventive medication. This willingness roughly drops by 50% by the possible occurrence of mild side effects. Secondly, the willingness to use preventive medication is influenced by the participants’ own perception of the severity of the disease and the disease risk, regardless of the given hypothetical risk.
In contrast to rheumatoid arthritis (39), in spondyloarthritis no previous studies explored the willingness of individuals at increased risk for axial SpA to start preventive medication, merely because of the difficult diagnostic process. The Pre-SpA cohort enabled us to study the willingness of seemingly healthy first-degree relatives of axial SpA patients to use preventive medication. Which is of importance, since today’s research increasingly focuses on the early detection and treatment, or even prevention of disease and/or structural damage. The data of our study suggest that the willingness of at-risk individuals is substantial, and might even increase if physicians emphasize the severity and risk of axial SpA to at-risk individuals. The importance of these results is supported by data showing that a delayed start of treatment is linked to worse clinical outcome (40,41). In recent years, the general research focus has shifted from suppressing symptoms to preventing structural damage, aided by the shortening of the diagnostic delay (23,24,42) and the ongoing development of biologics targeting the early disease process. And although these results encourage early or even preclinical therapeutic studies, some comments are in place. First, the fictitious willingness of a healthy first-degree relative might differ significantly from the willingness of at-risk individuals to actually start using medication. Second, several scenarios in our study suggested that the preventive medication guaranteed not to cause any side
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effects, while this is a surrealistic scenario. Third, we should emphasize that by treating at-risk individuals we will presumably also treat individuals that otherwise would not have gained axial SpA. To minimize this side effect, initiatives as the Pre-SpA cohort will first have to define precisely those individuals at sufficient increased risk to justify treatment or follow-up.
Concluding remarks and future directions
In the past decade, major progress has been made in the recognition of the disease burden, the recognition of the diagnosis and the recognition of the very early ore even pre-clinical phase of axial SpA.
Concerning the recognition of the disease burden in axial SpA, the focus has shifted from only the radiographic subtype (ankylosing spondylitis, AS) towards axial SpA, including other and early phenotypic expressions of the disease. The broad implementation of the classification criteria by the ASAS reflect that development (43), criteria that indicate the close resemblance of different SpA subtypes.
Increasing evidence exists that the early, non-radiographic form of axial SpA and the radiographic subtype are similar, at least from a phenotypical point of view. Furthermore, peripheral and extra-articular manifestations very frequently occur in axSpA, causing a significant burden of disease. Clinical studies should therefore not only focus on the treatment of axial disease, but also on the effects of treatment on peripheral and extra-articular disease.
Recognizing an axial SpA diagnosis early in the disease course is an aim that is worthy to achieve and challenging at the same time.
Worthy to achieve, since the current diagnostic delay of more than 5 years calls for improvement. Axial SpA has a significant burden of disease, already in its early phase. And although not robustly proven, studies indicate that treating axial SpA early in the disease course modifies the disease course and limits structural damage. Referral strategies for early back pain patients (33,44–46) have proven useful in detecting axial SpA in an early phase, and initiatives as the SPACE (47), GESPIC, PreSpA and DESIR cohort (48) all aim to diagnose axial SpA in an earlier phase and to study the early phase of the disease.
The recognition of early axial SpA challenges today’s clinician, since 1) Robust diagnostic biomarkers solely confirming a diagnosis of axial SpA are lacking. And, to date, investigations of serum biomarkers have not yet resulted in reliable diagnostic tools. Our finding that HLA-C*07 absence is associated with axSpA could aid the diagnostic process. The value of HLA-C*07 in the diagnostic process needs to be confirmed in other, larger cohort studies, thereby able to control for a possible linkage disequilibrium with HLA-B*27. Testing HLA-C*07 prevalence in an early setting as the inception cohort Pre-SpA might help to define individuals at increased risk to develop axial SpA. In the search after specific and sensitive biomarkers, the availability of large and well-documented early and preclinical SpA
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cohorts as the Pre-SpA cohort, the SPACE cohort, GESPIC and the DESIR cohort, are essential. And, referring to Figure 1, the position of a biomarker in the disease process should be considered when testing and evaluating biomarkers. Since the a priori chance of having axial SpA increases lower down the process, the study setting should be well-defined to mimic the real-life setting as close as possible. 2) The diagnostic arsenal has expanded with techniques enabling the early detection of axial SpA, such as MRI of the SI joints. A two-sided development, since on the one hand inflammation shown on MRI of the SI joints precedes structural damage and thus enables an early diagnosis, and on the other hand the current definition of an MRI of the SI joints suggestive for axial SpA lacks specificity. This calls both for redefining the definition of a positive MRI of the SI joints as well as for restraint in using MRI in the diagnostic process. Physicians should ask for diagnostic MRI of the SI joints only in patients in whom there is a moderately high suspicion of axial SpA, and should always consider other, more likely diagnoses. The recognition of the preclinical phase of axial SpA is emerging. Boosted by recent developments in early and preclinical RA research, initiatives as the Pre-SpA cohort might prove a valuable tool to identify, stratify and describe the early and preclinical disease state, both prospectively as well as retrospectively and both clinically as well as translationally. Building on these developments, when individuals at truly increased risk are identified, treating them in a very early phase might delay or even prevent disease onset.
Together with all these developments in the early axial SpA field should come awareness. Awareness, that 1) diagnosing earlier and being more sensitive in making a diagnosis should not imply compromising on specificity. Patients are possibly over-diagnosed and over-treated (49). This potential ‘collateral damage’ should be weighed against the profits of earlier diagnosis and diagnosis of less severe and obvious disease subtypes. Treatment recommendations should be reformed to that purpose, since the current SpA nomenclature and treatment guidelines do not justify the differentiation in disease stage. 2) Although several SpA subtypes are phenotypically similar, to define one disease includes more than only the phenotype. The goal should not be to be as inclusive as possible, since phenotypically identical diseases might differ in pathobiology and thus respond differently to treatment. Homogeneous disease groups are of major importance in therapeutic trials: otherwise treatment effects could be diluted and therapeutic options that are promising could be wrongly discarded. Future research should focus on detailed profiling of axial SpA subgroups based on pathobiology. This might result in subgroups that are driven predominantly TNF driven, predominantly IL-17 driven or driven by both or other cytokines. Additionally, defining subgroups characterized by inflammation and/or by new bone formation would aid targeted treatment strategies. The novel finding of HLA-C*07 might appear useful to define those subgroups.
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Key requisite to recognize axial SpA in all its appearances is to have well-defined, carefully monitored inception cohorts, and to critically appraise and test all biomarkers for their specificity and sensitivity in real-life settings. Attention to the early and preclinical phase of axial SpA will learn us hopefully to better define, diagnose and treat and thereby to diminish the disease burden of axial SpA.
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