Axial Spondyloarthritis

Ankylosing Spondylitis and Non-Radiographic AxSpA

Ankylosing Spondylitis (AS) is the leading chronic progressive inflammatory rheumatic disease that involves the sacroiliac joints (SIJs) and the spinal column but is often difficult to recognize in early stage. One of the main reasons for long delay in its diagnosis is the need for X-ray evidence of sacroiliitis (defined as bilateral grade 2 or unilateral grade 3 or 4) according to the modified New York (mNY) criteria for AS. To optimize the diagnostic accuracy at a very early stage, it is crucial to use a comprehensive approach and to have a deep understanding of the disease and its wider clinical spectrum. It is possible to recognize the disease even when X-rays of SIJs are normal by obtaining a complete history and paying close attention to all the elements of this systemic disease. This was clearly demonstrated more than 36 years ago when this clinical entity was first reported and named as “spondylitic disease without radiographic evidence of sacroiliitis.”

Rudwaleit and colleagues proposed the term “axial spondyloarthritis” (axSpA) to encompass patients in the “pre-radiographic” as well as the radiographic stages of AS. It was presumed that the occurrence of radiographic sacroiliitis is mainly a function of time, with some influence of severity factors. But this early stage of axSpA was subsequently defined as non-radiographic axial spondyloarthritis (nr-axSpA) rather than a pre-radiographic stage of AS because a proportion of these patients may never develop structural damage in their SIJs, just as not every patient with radiographic evidence of sacroiliitis progresses to spinal ankylosis (Figure 1-3 and Figure 5-1). Therefore, nr-axSpA is not simply an early stage in the spectrum of axSpA that evolves into AS over time, although they share many epidemiologic, genetic and clinical characteristics.

In a study of a population-based inception cohort of patients with nr-axSpA, progression to AS occurred in only a minority (26%) of these patients over as long as 15 years of follow-up. This suggests that the classification criteria for nr-axSpA identifies many patients in whom the condition is unlikely to progress to AS, or that nr-axSpA represents a prolonged prodromal state that takes longer to evolve to AS and thus requires longer follow-up. A more frequent and more rapid progression has been reported among subjects in the imaging arm than among those in the clinical arm of the Assessment of Spondyloarthritis International Society (ASAS) criteria.

Patients with nr-axSpA have been reported to have a relatively higher prevalence of females and lower level of C-reactive protein (CRP) compared with AS, although this may be a result of a subgroup of patients with a rather mild or nonprogressive disease (Table 5-1 and Table 5-2). Table 5-1 shows comparison of patient characteristics and efficacy data from randomized placebo controlled trials of tumor necrosis factor inhibitors (TNFis) conducted in patients with AS and nr-axSpA. A recent systematic analysis covering 60 studies found large similarities between AS and nr-axSpA regarding to patient characteristics including HLA-B27 frequency, burden of disease, treatment modalities and treatment effect. However, male gender and elevated CRP was noted more frequently in patients with AS than in those with nr-axSpA, as has been pointed out also by several other publications. This meta-analysis reported also higher prevalence of uveitis and peripheral involvement in AS vs nr-axSpA.

Comparison of HLA-B27 prevalence between patients with AS and nr-axSpA needs careful interpretation, as HLA-B27 positivity which is a mandatory criterion for the clinical arm for nr-axSpA may result in its artificial overrepresentation in nr-axSpA. HLA-B27 frequency observed among the patients participating the pivotal randomized placebo controlled trials of TNFis (72%-82%) were similar to those noted in AS trials (79%-87%), however it was markedly lower if the imaging arm is considered only (54%-73.5%) (Table 5-2). Moreover, patients with nr-axSpA, relative to those with AS, have a much lower average genetic risk score, using only genome-wide significant AS loci. This indicates that, nr-axSpA may be a genetically distinct disease from AS, or that nr-axSpA has a greater clinical and etiopathogenic heterogeneity than AS.

There is a general support for the concept of axSpA as an entity, but nr-axSpA seems to be more heterogeneous than AS because of the presence of some patients with a self-limiting, self-remitting or a rather mild nonprogressive or slow disease course. There had been in the past a greater degree of underdiagnosis and delayed recognition of AS among women because the disease was wrongly considered to be much more common in men. For example, only 10% of the patients diagnosed around 1960 in Germany were females, but this percentage has increased in the subsequent decades to reach 46% among those diagnosed since 1990. Classic AS with radiographic changes of sacroiliitis has now been considered to be only two to three times more common in males than females. It is expected that this gender gap may decrease further with better understanding and recognition of the clinical spectrum of this condition in females.

The disease seems to progress to radiographic sacroiliitis relatively more slowly in women than in men. That may be one of the reasons why women outnumber men among patients with nr-axSpA (Table 5-2). With the introduction of the Amor and the European Spondyloarthropathy Study Group (ESSG) classification criteria, and, more recently, the ASAS classification criteria for axSpA, along with the more widespread use of magnetic resonance imaging (MRI) for detecting spinal inflammation early, the demographics of this clinical entity has shifted remarkably. The need for an early disease detection has become increasingly important because much more effective therapies with biologics are now becoming available that are even more effective if used in early stages of the disease. Therefore, the general tendency is to perceive nr-axSpA and AS to be early and late phases of axSpA spectrum, respectively.

Women with nr-axSpA had lower average polygenic risk scores (PRS) and HLA-B27 prevalence than men with nr-axSpA or patients with AS. Interestingly, the PRS was unable to distinguish male patients with nr-axSpA from both related and unrelated healthy controls, but it had no discriminatory ability for female patients with nr-axSpA when compared to either related or unrelated controls. Whether this implies a need for reclassification of nr-axSpA or simply an expansion of the axSpA spectrum remains to be elucidated.

The differences between the two subgroups of patients with regard to CRP levels, gender and HLA-B27 status has been explained by a milder disease progression in patients who do not have these prognostic factors. However, it should be underlined that male gender in patients with nr-axSpA in the GESPIC cohort was associated with a significantly lower, rather than higher, probability of progression to radiographic sacroiliitis. Moreover, no clear association was found between HLA-B27 and radiographic progression of sacroiliitis in the same patient cohort. CRP was identified as the only strong predictor of progression of sacroiliitis in patients with nr-axSpA in this study.

Poddubnyy and Sieper contend that the two groups respond similarly well to therapy with TNF inhibitors (TNFis) if the level of inflammation at baseline is also similar. This view is supported also by some others. Thus, the bulk of current evidence suggests that patients with nr-axSpA show good clinical response to TNFis only in the presence of objective signs of inflammation.

In the nr-axSpA trials of adalimumab and etanercept, Assessment of Spondyloarthritis International Society criteria for 40% improvement (ASAS40) response rates at week 12 with TNF were not different from placebo in patients with normal CRP at baseline. In the GO-AHEAD trial of golimumab in nr-axSpA, Assessment of Spondyloarthritis International Society criteria for 20% improvement (ASAS20) response rate at Week 16, was almost the same with golimumab and with placebo in the group of patients with negative MRI and normal CRP at baseline. In the Swiss Clinical Quality Management (SCQM) Cohort of patients with axSpA and who were treated with TNFis, the ASAS40 response rate was significantly lower among those with nr-axSpA and this difference was smaller when the subgroups of patients with elevated baseline CRP levels were compared.

Routine care data from DANBIO registry and from two smaller studies have reported similar TNFi response rates and drug survival in patients with nr-axSpA and AS, while real life data from 12 registries in the EuroSpA collaboration suggested numerically lower treatment responses and retention rate of TNFi in the nr-axSpA sub-cohort compared with other spondyloarthritis (SpA) sub-cohorts. They did admit the possibility of inclusion of patients with less certain diagnoses for the observed difference. Lastly, a very recent study showed no efficacy of etanercept therapy in patients suspected of nr‐axSpA, who had high disease activity but lacked positive MRI and/or elevated CRP. On the other hand, in the AS trial of etanercept ASAS20 response rate at week 24 was significantly higher than placebo in the group of patients with normal CRP. Similar results were observed in the AS trial of golimumab.

The information given above justify the regulatory licensing requirements both in the US and Europe for using TNFis (certolizumab, the only FDA approved TNFi) and IL-17is in patients with axSpA which require the presence of objective signs of inflammation demonstrated by MRI and/or elevated CRP for patients with nr-axSpA but not for patients with AS. It should be also noted that registration trials of certolizumab, ixekizumab and secukinumab of nr-axSpA all included patients only if they showed objective signs of inflammation (elevated CRP or positive MRI).

As explained in a recent editorial by Khan and van der Linden, use of the term axSpA should be preferred over AS in clinical practice, in part because the word “ankylosing” has a negative prognostic connotation for patients as that degree of structural damage may take a long time to develop or may not occur at all. Boel and coworkers have suggested that the term “axSpA with radiographic sacroiliitis” (r-axSpA) could be used interchangeably with the term AS. But it needs to be stated that, strictly speaking, AS and nr-axSpA are not identical. For example, 7% of their patients with AS could not fulfill the definition for radiographic axSpA (r-axSpA), and conversely 4% of the patients with r-axSpA did not fulfill the mNY criteria for AS. The reason is that while the radiographic criteria are the same, the two terms differ with regard to some of the additional clinical or laboratory criteria that have to be fulfilled. The mNY criteria require that the patient’s chronic back pain has to have inflammatory features, but

it is not a requirement for defining r-axSpA. In conclusion, the term AS, as defined by the mNY criteria should remain for research studies as such patients form a more homogenous group, whereas the use of the term axSpA should be preferred over AS in clinical practice.

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