Exciting times for axial spondyloarthropathy

Thursday, 27 Apr 2017

These are “exciting times” for patients with axial spondyloarthropathies (axSpA), according to Professor Matthew Brown from the Queensland University of Technology.

“The evidence is increasingly strong that we can benefit people’s long-term health and function by treating early with effective medications,” he told the limbic.

“Even with existing treatments, we can allow people to lead much more normal lives compared to 20 years ago. Over the next decade, new treatments are likely to become available which have the potential for inducing remission or even preventing disease.”

A continuing challenge, though, is earlier recognition of the illness, with patients often experiencing symptoms for many years before they are correctly diagnosed and effectively treated.

Associate Professor Peter Nash, from the Department of Medicine at the University of Queensland and Director of the Rheumatology Research Unit on the Sunshine Coast, says the use of MRI for accurate diagnosis and the advent of biologic therapies has substantially changed practice in the last decade.

“Patients used to disappear into the woodwork once they had been diagnosed, because we didn’t have anything but NSAIDs to offer. This has changed completely,” he says.

Additionally, there is increasing recognition of the significance of non-radiographic axSpA (nr-axSpA), the condition which in a small proportion of patients progresses slowly over time to radiographically-defined ankylosing spondylitis (AS).

A 2014 consensus statement from Australian rheumatologists, led by Dr Philip Robinson from Brisbane Rheumatology and the University of Queensland, stressed that improvements in the care of patients with nr-axSpA will come from increased recognition of the condition by the public, primary care physicians and medical specialists, as well as the use of effective therapies.1

“Historically there has been a long delay in recognising and treating patients with AS, and the wider recognition of nr-axSpA is likely to make a significant difference to patient symptom burden due to appropriate treatment, regardless of whether they progress to AS or not,” they said.

“We know that those patients with nr-axSpA have similar levels of disease activity to AS patients, and active nr-axSpA patients have similar levels of inflammation on MRI scan to patients with AS.”

Evolving disease concepts

The classical definition of AS is still based on the modified New York criteria dating back to 1984, requiring radiographic changes in the sacroiliac joint. They are highly specific for AS but not sensitive, especially in early disease.2

In 2009 the Assessment of Spondyloarthritis International Society (ASAS) proposed diagnostic criteria for nr-axSpA.3 They require a history of at least 3 months of back pain first occurring at age of 45 years or younger, accompanied by either sacroiliitis on imaging and one or more features of SpA, or positive HLA-B27 status plus two or more features of SpA.

SpA features include inflammatory back pain, arthritis, dactylitis, enthesitis, uveitis, psoriasis, inflammatory bowel disease, a good response to NSAIDs, a family history of SpA, positive HLA-B27 and elevated CRP.

Dr Robinson and Professor Brown discussed whether nr-axSpA is a distinct disease compared to AS in a paper published in 2013 in the Annals of the Rheumatic Diseases.2

“There is compelling evidence that axSpA and AS are different though overlapping entities associated with different prognoses, demographics, genetics and responses to treatment,” they wrote.

“The axSpA concept therefore likely captures those who will progress to AS, but also a significant proportion of individuals with other diseases of varying relatedness to AS.”

They said that although this new concept was welcome because it would encourage recognition of early disease and effective treatment, more information was needed on predicting the disease course in individual patients.

nr-axSpA has a similar burden to AS

Professor Brown and rheumatology nurse Linda Bradbury, in a recent ‘Perspective’ in the Medical Journal of Australia, said possible predictors of progression from non-radiographic disease to AS included male sex, HLA-B27 carriage, smoking, higher CRP levels, more extensive inflammation on MRI, and younger age of onset.4

“Whether or not such patients ultimately develop AS, they suffer significantly with their disease, with a similar disease burden to established AS, and therefore need treatment,” they wrote.

A review of the burden of nr-axSpA concluded that radiographic progression is detected in about 10% of patients over 2 years, consistent with a consensus that about half progress over 10 years.5

Although some patients have less inflammation (lower CRP and less spinal inflammation on MRI) and less impairment of spinal mobility, the conditions lead to similar measures of disease activity, functional impairment and reduced quality of life.

A study of individual patients attending rheumatology outpatient clinics came to a similar conclusion.6 “The disease burden in nr-axSpA is substantial and similar to that of AS, with both groups of patients experiencing inadequate disease control,” the researchers said.

“These findings suggest the need for early detection of nr-axSpA and initiation of available treatment options to slow disease progression and improve patient well-being.”

Genetics a key to understanding the cause

Professor Brown told the limbic he was attracted to researching the genetics of AS in the mid-1980s, when the only treatment option was NSAIDs.

“It was clearly a disease that ran strongly in families and was thought to be caused by a single gene, HLA-B27,” he says.

“But it was clear from looking at the data that it must have been more complicated. It has been a rewarding area, and more than 100 other relevant genes have now been identified.”

While the genetic influences are very clear, the exact mechanisms for development of disease remain elusive.

In mechanical terms, the characteristic pattern of inflammation in spondyloarthritis occurs where bone meets cartilage in the sacroiliac joints, the spine, and the entheses.7

Mechanical stress is likely to be important for initiating, and perhaps maintaining, inflammation, bone damage and new bone formation as repair processes aiming to stabilise the spine.

Professor Brown and his colleagues recently provided a comprehensive update on the genetics of AS in Nature Reviews Rheumatology.8 They noted that the association with HLA‑B27 was first described more than 40 years ago, but there was no consensus on how it led to disease and no treatments had been developed to target the antigen or related disease pathways.

HLA-B27 was thought to be solely responsible for AS for more than 30 years. However, it became clear that more than 90% of population variance in the disease could be attributed to genetic factors, but only a minority of the variance was explained by HLA-B27 alone.

The new era of genome-wide association studies in large numbers of individuals, in which Professor Brown’s group has been central, showed a key association with variants of IL23R, the gene encoding the interleukin-23 receptor. This led to the exploration of biologic therapy targeting the IL-23/IL-17 pathway in AS.

Associations between variants of ERAP1, coding endoplasmic reticulum aminopeptidase 1, and AS also emerged from Professor Brown’s work, and are a potential target for therapy in the future. The gene, linked with psoriasis, juvenile idiopathic arthritis and Behçet’s disease as well as AS, is involved in the processing of peptides for presentation to HLA Class 1 molecules.

“AS provides an excellent example of how hypothesis-free research can lead to major advances in understanding pathogenesis and to the development of innovative therapeutic strategies,” Professor Brown and his colleagues said.

Large-scale genetic studies of AS were conducted first by the Wellcome Trust Case Control Consortium, and now by the Australo-Anglo American Spondyloarthritis Consortium and the International Genetics of AS Consortium.

The targets of the research include the shared genetic susceptibilities between AS and common comorbidities such as gut inflammation. Between 5% and 10% of AS patients develop clinically-diagnosed inflammatory bowel disease and another 70% have subclinical gut inflammation.

Triggering of excessive IL‑23 production in the gut of patients with AS is likely to be involved, and there is a new focus on the role of the gut microbiome in modulating inflammatory responses in this very complex environment. The gut is estimated to house up to 100 trillion bacteria, outnumbering the body’s own cells 10 to 1.9

“Unlike reactive arthritis, which can be triggered by gastrointestinal infection with Salmonella, Shigella, Yersinia or Campylobacter spe­cies, AS does not seem to have an obvious infectious trigger,” Professor Brown and his colleagues wrote.8 “Instead, subtle alterations in the gut microbial community might have an important role in AS pathogenesis.”

Genetic research in AS has pro­gressed very rapidly, increased the understand­ing of disease causation, and led to a substan­tial lift in research activity in spondyloarthropathies and the development of new therapies, they concluded.

“Future studies better defining the genetic landscape of AS risk have great potential to reveal important information regarding the pathogenesis of the disease, and lead us to the ultimate goal of disease prevention and cure.”

Treatment recommendations

A multidisciplinary approach is ideal for the treatment of AS, integrating the input of physiotherapists and nurses with special expertise in rheumatology.4 Key elements of care include the monitoring of disease activity, managing the impact on disease on activities of daily living, maintaining psychosocial health, delivering drug therapy and minimising its side effects. Educating patients is essential to improve their coping strategies and increase their capacity for self-care.

A number of treatment guidelines for nr-axSpA and AS are available, including those of ASAS/EULAR10 and the American College of Rheumatology.11

Consensus statements from Australian rheumatologists on nr-axSpA1 address patients’ preferences and goals, measurement of CRP and determination of HLA-B27 status. They also recommended the use of sacroiliac MRI but not CT, avoiding reliance on classification criteria to include or exclude the diagnosis in individual patients, and support the use of physiotherapy.

Consistent with international guidelines, they state that NSAIDs are the first-line treatment, there is no role for conventional DMARDs in the management of axial manifestations (although sulfasalazine can be considered for peripheral manifestations), and there is a limited role for corticosteroids in NSAID-refractory disease. They state that the benefits of TNF inhibitors are clearly established, and should be considered in NSAID-refractory disease.

However, the ASAS/EULAR 2016 update of its 2009 guidelines add that analgesics have a “rather modest” role in nr-axSpA and AS.10 They recommend TNF inhibitors (TNFi) as first-line treatments and IL-17 inhibitors (IL-17i) as alternative second-line treatments for patients with high disease activity despite the use (or intolerance/ contraindication) of at least two NSAIDs. “In addition, they should either have an elevated CRP and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis,” they state.

Current practice is to start with a TNFi as first-line treatment. Switching to alternative TNFi or an IL-17i in case TNFi fails, they state.

Tapering, but not stopping, a biological DMARD, can be considered in patients in sustained remission.

In patients with active nr-axSpA despite treatment with NSAIDs, the ACR conditionally recommends treatment with a TNF inhibitor.11

In Australia, the TNF inhibitors adalimumab, certolizumab pegol, etanercept, golimumab and infliximab and have been approved for the treatment of AS refractory to NSAID therapy. Blockade of the IL-17 pathway with secukinumab is a new option for biological treatment.

Two biologics Simponi® (golimumab) and Enbrel® (etanercept) have now been approved for the treatment of nr-axSpA, although neither has been listed or subsidised by the Pharmaceutical Benefits Scheme.

However, a key question is whether early treatment of AS or nr-axSpA improves the long-term outcome for patients, in addition to reducing disease activity and relieving symptoms. In their recent MJA perspective, Professor Matthew Brown and Linda Bradbury said there is now strong evidence supporting reduced progression of ankylosis in AS with TNF inhibitor therapy.4

“While short term studies (up to 2 years of treatment) failed to show an effect of TNFi treatment on progression of X-ray changes, longer studies (4 years of treatment) have shown significant benefits, roughly halving X-ray progression,” they said. “This benefit is greater the earlier TNFi treatment is initiated.

“Whether TNFi retards progression of nr-axSpA to AS is not yet clear, although there is suggestive evidence that successful suppression of inflammation can lead to treatment-free disease remissions.”

The major challenge, though, is to accurately identify patients with nr-axSpA who have a poor prognosis, and most to gain from effective therapy.

“Personally, when we have limited resources I think we should be giving more weight to people who are going to progress,” Professor Brown told the limbic. “Bony ankylosis leading to inflexibility is a worse outcome than not developing ankylosis. However, patients who do not progress who truly have inflammatory, but perhaps self-limiting, arthritis still deserve treatment.”

Pathways to care

Professor Peter Nash says the pathway to diagnosis and effective treatment remains slow and inefficient for many young patients with axial spondyloarthropathy.

“One difficulty is that back pain is extremely common. GPs and specialists need to be alert to the symptoms that often accompany SpA, and think of the diagnosis earlier,” he told the limbic.

 “As rheumatologists we see two groups of patients: those with peripheral problems such as one swollen knee or three or four affected joints on one foot, where no one has considered that it might be part of SpA. They are often sent to orthopaedic surgeons and end up having unnecessary investigations and treatment before SpA is considered.

“The other group is patients with back pain where GPs find they are HLA-B27-positive, but are unsure what to do next. The fact is, if you are HLA-B27-positive, you have only a 1 in 20 chance of having an inflammatory spondyloarthropathy, so the presence of inflammatory and not mechanical back pain and MRI with STIR spinal images becomes important in resolving the diagnosis.”

Review by a rheumatologist can help integrate the pattern of symptoms and results from investigations. “We are experienced in looking outside the presenting complaint and identifying related pathology,” he says.

“It can bring a halt to repeated assessments and investigations, and get patients onto effective treatment,” he says. “This is important, because many of the peripheral characteristics like severe enthesitis, tendonitis or dactylitis do not respond to any treatment other than TNF inhibitors, IL-17 inhibitors and IL-12/23 inhibitors.”

Good relationships with other specialists are also essential – for example, with ophthalmologists who are asked to assess a patient presenting with uveitis, or a gastroenterologist seeing a patient with inflammatory bowel disease, when these are components of an axial spondyloarthropathy.

Professor Nash’s hope for the future is that Australian indications, disease activity measures and reimbursement for available therapies will become more aligned with international treatment guidelines.

“But we are lucky to have access to the available therapies, and so many options for these difficult diseases,” he says.

Professor Matthew Brown agrees that delayed diagnosis remains a problem. “Numerous surveys have identified long delays, typically of five to ten years, in diagnosing AS, and it has not improved over time,” he told the limbic.

“Because low back pain is so common and usually not inflammatory, GPs often do not think of the diagnosis. Axial spondyloarthropathy should always be considered in patients with three or more months of back pain, first occurring younger than 45 years, which is otherwise unexplained.”


  1. Robinson PC et al. Consensus statement on the investigation and management of non-radiographic axial spondyloarthritis (nr-axSpA). Int J Rheum Dis 2014; 17: 548-56.
  2. Robinson PC et al. Axial spondyloarthritis: a new disease entity, not necessarily early ankylosing spondylitis. Ann Rheum Dis 2013; 72: 162-4.
  3. Rudwaleit M 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; 68:777–83.
  4. Brown M, Bradbury LA. New approaches in ankylosing spondylitis. Med J Aust 2017; 206: 192-4.
  5. Boonen A et al. The burden of non-radiographic axial spondyloarthritis. Semin Arthritis Rheum 2015; 44: 556-62.
  6. Burgos-Varga R et al. The prevalence and clinical characteristics of nonradiographic axial spondyloarthritis among patients with inflammatory back pain in rheumatology practices: a multinational, multicenter study. Arthritis Res Ther 2016; 18: 132.
  7. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet 2017 Jan 19. pii: S0140-6736(16)31591-4.
  8. Brown MA et al. Genetics of ankylosing spondylitis – insights into pathogenesis. Nat Rev Rheumatol 2016; 12: 81-91.
  9. Costello ME et al. Microbes, the gut and ankylosing spondylitis. Arthritis Res Ther 2013; 15: 214.
  10. van der Heijde D et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 2017 Jan 13. pii: annrheumdis-2016-210770.
  11. Ward MM et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2016; 68: 282-98.
  12. Sieper J et al. A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2015; 67: 2702-12.

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