nr-axSpA today, AS tomorrow – the day we discovered the spectrum

Ankylosing spondylitis (AS) is now known as one of the partly heterogeneous group of rheumatic diseases known as spondyloarthritis (SpA).1 Recognised decades ago, AS was typically identified using conventional radiographs of the sacroiliac joints where patients exhibited definite structural changes and presented with inflammatory back pain.1-3

Since the application of magnetic resonance imaging (MRI), identification of earlier stages of disease became possible. With MRI and screening of markers, the spectrum of SpA has broadened. To understand the changes in classification and to understand the burden of disease, the limbic spoke with Professor Paul Bird, Rheumatologist, Chair of the International Magnetic Resonance Imaging Research Association and Director of Optimus Clinical Research.

“We’ve known about AS for years, but with improved imaging and better characterisation of markers of disease, we are able to identify earlier and earlier stages of disease well before we see radiographic evidence of disease in patients. A major turning point for understanding earlier phases of disease was the 2009 Assessment of SpondyloArthritis Society (ASAS) classification criteria, which broadened our understanding of the spectrum of disease,” notes Prof. Bird.

As Prof. Bird described, advances in imaging and molecular markers have identified a long pre-radiographic phase that is universal in AS called non-radiographic axial spondyloarthritis (nr-AxSpA).2 It’s an inflammatory axial arthritis that presents without the typical changes observed on x-ray with AS.2

Traditionally patients would experience long delays in the diagnosis of AS, 7 years on average.4 Along with a long wait, patients were limited in their access of AS-specific treatments, suffering with pain and stiffness and ultimately progression to the late radiographic stage of the disease.3,4

“We could see the phases of inflammatory back pain progress, but were unable to formally diagnose until it was too late,” adds Prof. Bird.

SpA may be more common than we think

With the introduction of changing criteria in diagnosing SpA, its true prevalence is speculated to be higher than existing reports.1 In the USA, inflammatory back pain is reported at a prevalence of around 6%, with SpA possibly >1%, but could be as high as 5%.1

Professor Bird agrees that the incidence of SpA should be expected to rise as we get better at diagnosing earlier and earlier stages of disease. “Key to correctly diagnosing people as early as possible is not only the expertise of rheumatologists and radiologists, but awareness of referrers including general practitioners and physiotherapists. As soon as they can identify the clinical signs or a family history of inflammatory back pain, we need to screen these patients carefully.”

Spotting the difference – similarities and differences between nr-axSpA and AS

There is no argument that patients with nr-axSpA suffer as significantly with their disease as those with AS.4,5 Both AS and nr-axSpA are often associated with peripheral articular and extra-articualar disease (except uveitis which is more prevalent in AS). Aside from uveitis, the clinical distinction of the diseases is not very pronounced.4

Recent results from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry confirmed a similar burden of disease, impact on quality of life, pain, fatigue, absenteeism and work productivity loss for patients with AS and nr-axSpA.5 Of course, correct identification of nr-axSpA is critical for patients to access the latest treatments in the hope that the 7-year delay in diagnosis can be reduced.4

While there are improved markers for diagnosis of nr-axSpA, there is only limited capacity to predict which patients will progress or not.2 Regardless of progression, even with nr-axSpA, patients experience a similar disease burden.2 Around half of patients will progress to AS within a decade of symptom onset, with some studies reporting a conversion rate of 12% after 2 years.1,2

Some of the factors that have been associated with a risk of progression to AS include male gender, HLA-B27 carriage, smoking, higher baseline C-reactive protein (CRP), extent of MRI evidence of inflammation and younger age of onset. In general, more women present with nr-axSpA than men.2

Some reviewers hypothesise that AS may have higher levels of inflammation, with higher levels of CRP and inflammation seen on MRI.4 “What we possibly need to consider now is how much more do we need to delve, and whether the distinction between stages of axSpA are clinically relevant, or whether the treatments we have available now are going to meet our needs,” adds Prof. Bird.5

Battle of the biomarkers

The biomarker of most interest from a clinical point of view has been CRP.1,2,4,5 “In general we see CRP at lower levels in nr-axSpA and higher in AS, suggestive of the level of inflammation present at the time. It proves a good predictor of treatment outcome, with patients who have high baseline CRP responding well to non-steroidal anti-inflammatory drugs and tumour necrosis factor inhibitors,” notes Prof. Bird. However, high CRP is also an indicator of risk of progression.4 In the GESPIC early disease patient cohort, CRP stood out as the strongest predictor of disease progression of radiographic sacroiliitis (3.65x).4

But there are other biomarkers on the block. HLA-B27 is another of the markers in the ASAS criteria.2,5 What’s interesting for Prof. Bird regarding HLA-B27 is the role it may play in identifying axSpA in families. “It is more common these days for children of my patients to ask to be screened for axSpA. The challenge is that without symptoms, it’s really a watch and wait scenario. Given the relative infancy of biomarkers like HLA-B27 for screening, it’s not routine practice, and the specificity is unknown. This is an area of much interest and my colleague Matt Brown is keenly exploring,”2 explains Prof. Bird.

In an era of genome-wide screening, it is anticipated that highly sensitive molecular testing and targets for disease modification will evolve.2 Already work on the interleukin (IL)-23 pathway has uncovered additional lines of investigation and application of therapies for axSpA.2 “It certainly is an exciting time for clinicians as we not only further our understanding of the disease process, we unlock potential avenues to help patients earlier so that they no longer have to suffer in silence,” reflects Prof. Bird.

This article was sponsored by Janssen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Janssen.



  1. Baraliakos X, et al. RMD Open 2015;1(Suppl 1):e000053.
  2. Brown M, Bradbury LA. Med J Aust 2017;206(5):192-194e1.
  3. Khmelinskii N, et al. Front Med 2018;5(106):1-4.
  4. Ghosh N, Ruderman EM. Arth Res Ther 2017;19:286.
  5. Mease PJ, et al. Arthritis Care Res (Hoboken) 2018;70(11):1661-1670.

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