2020 – A year in axSpA research! Part five

Hello Everyone!

I hope you are all well and enjoying the revival of the Project Nightingale blogs! The last blog post was to inform you about NASS (National Axial Spondyloarthritis Society) Facebook live sessions and the My AS, My Life website. I hope you enjoyed reading the information. If you missed it, please have a look as there are some exciting and informative Facebook sessions scheduled through to December.

The current blog returns to the 2020 publication updates that we are providing you with. Currently, we are on October-December 2020, so we’re slowly getting there! I have found 3 articles which are very interesting.

Axial spondyloarthritis 10 years on: still looking for the lost tribe

October 2020. Barnett and colleagues. https://doi.org/10.1093/rheumatology/keaa472

The first of these articles is co-authored by our very own Rosie Barnett and Dr Raj Sengupta. The information provided in this article overlaps with the Act on Axial SpA: A Gold Standard Time to Diagnosis campaign in a previous blog post, which looked at ways of improving the current 8.5 years to diagnosis for axial spondyloarthritis (axSpA - which includes ankylosing spondylitis). The article outlines key factors contributing to delayed diagnosis in axSpA, and recommendations that should be implemented in order to reduce this delay.

This article provided information on axSpA having a very common symptom of chronic low back pain (CLBP), which can be reported in about 20% of the population aged 20–59 years worldwide. But of those that have CLBP, only 5-24% have axSpA. Therefore, if someone doesn’t present with classical symptoms, the diagnosis of axSpA can be missed. There is also low awareness of the differences between mechanical back pain and inflammatory back pain amongst GPs and other non-rheumatology healthcare providers. Another important note is that absence of inflammatory back pain doesn’t mean a diagnosis of axSpA is excluded- so you can see the complexities involved in diagnosing! It is therefore vital to raise awareness and knowledge of axSpA symptoms among the public and healthcare professionals, to ensure early referral to rheumatology and faster diagnosis.

Treatment strategies in axial spondyloarthritis: what, when and how?

October 2020. Fragoulis and Siebert. https://pubmed.ncbi.nlm.nih.gov/33053192/

Although there are some treatment options for axSpA, there are still unanswered questions regarding how best to use existing and upcoming treatments, in order to achieve the best outcomes for people with axSpA. Treatment for axSpA doesn’t necessarily mean taking medicine; it also includes non-pharmacological treatment such as exercise therapies, education, lifestyle and behavioural changes, and self-management. This non-pharmacological treatment should be a mainstay in axSpA care – particularly structured exercise programmes as delivered by a specialist physiotherapist. At the time of this article being published, the current licensed drug treatments, or pharmacological treatment, for axSpA included non-steroidal anti-inflammatory drugs (NSAIDs) and biologic disease-modifying anti-rheumatic drugs (bDMARDs). The combination of pharmacological and non-pharmacological treatment is the best way to treat axSpA – I’m sure many of you will agree with this!

The authors mention that regular exercise and stretching is recommended for the management of axSpA. Indeed, NASS (the national patient organisation for axSpA) suggest that “Exercise is the single most important thing you can do to help yourself”. A review of evidence in this area showed there are likely to be long-term benefits of exercise/stretching on aspects of the disease, including for those diagnosed with other conditions (co-morbidities), as well as on general physical and mental health. The National Institute for Health and Care Excellence (NICE) recommend that people with axSpA should be referred to a specialist physiotherapist to start structured exercise programmes to meet individuals’ changing needs – where benefits can include reducing the impact of the disease, improving or maintaining mobility, function and quality of life, enabling self-management, and reducing pain and fatigue. Indeed, in one of our recent studies in Bath, we showed that there were long-term improvements in spinal mobility, function and disease activity scores following intensive education, physiotherapy and rehabilitation in the Bath residential rehabilitation programme. The data on spinal mobility, function and disease activity went all the way back to the 1990s- with an average duration between first and last visit in the clinic at 13.5 years! That is really impressive! This evidence strongly supports the integral role of education, physical activity and rehabilitation in the management of axSpA.

NSAIDs are the first type of drug treatment which are given to people with axSpA as this type of drug manages symptoms very well, and appears to show reductions in inflammation on MRI scans. NICE recommends that NSAIDs are given at the lowest effective dose to begin with, changing to another NSAID if at the maximum tolerated dose for 2–4 weeks does not provide adequate pain relief. bDMARDs, or biologic cytokine inhibitors, are the most effective currently available treatments across the axSpA spectrum - recommended as options for treating those who do not respond well to, or who cannot tolerate, NSAIDs.

Some predictors of response to treatment with bDMARDs in axSpA have been identified, in other words factors to identify those people that may be most likely to react well to the treatment. These include HLA-B27 positivity, younger age, shorter time having been diagnosed (disease duration), male gender, elevated C-Reactive Protein (CRP) and inflammatory MRI features. Obesity and smoking are associated with not responding well. These predictors for ‘good’ response are useful, as there may be a higher likelihood of these people truly having active axSpA, as opposed to other causes of back pain, as discussed in the article above.

The authors state that it is currently unclear what the combined effect is of bDMARDs and NSAIDs on clinical outcomes and slowing radiographic disease progression (as shown on X-rays) in axSpA. Factors that predict radiographic progression may be helpful in identifying those people that would benefit from more intense and earlier treatment, however, these are currently unknown. Some studies have suggested that these may include higher disease activity, including CRP, HLA-B27 positivity, the presence of baseline syndesmophytes (bony growth originating inside a ligament), male gender, physically demanding jobs, smoking and socioeconomic status. The authors also raise an interesting point about whether those with shorter disease or symptom duration result in a better response to treatment. Again, currently there is no evidence that providing bMARDS earlier leads to better radiographic outcomes in axSpA (i.e. control of the inflammation and changes on x-ray).

This article raises some interesting questions and areas for further research, which could make the disease easier to manage both for people who are diagnosed and those helping to manage the condition. Even since the publication of this article, there have been advances in the treatment of axSpA – with a new type of drug known as a JAK inhibitor, recently being approved for use in radiographic axSpA (ankylosing spondylitis – where changes to the spine or sacroiliac joints are visible on x-ray). You can read about it in one of our prior blog posts: https://www.projectnightingale.org/blogs/upadacitinib-ema-approval/

There is a lot of positive movement in axSpA, so hopefully one day all of the ‘predictors’ will be identified and these discussions will be a thing of the past! 😊

Sex and gender differences in axial spondyloarthritis: myths and truths

October 2020. Rusman and colleagues. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566372/

This article looks at myths in axSpA on sex and gender differences, and aims to provide some facts after exploring each myth. Four myths are explored: 1) men and women with axSpA are physiologically the same, 2) axSpA is a predominately male disease, 3) men with axSpA have a worse disease outcome compared with women, and 4) no sex differences are present in efficacy and drug survival of biologics in axSpA. The article highlights the difference between sex and gender, emphasising the use of ‘sex’ differences which are the biological processes that differ between men and women, rather than gender which refers to a person’s self-perception as a man or woman, and the behaviour they show during their life or the disease (coping style and disease perception).

Myth 1: Men and women with axSpA are physiologically the same

It has been reported that women with axSpA are more likely to be HLA-B27 negative compared to males who are reported to be more likely HLA-B27 positive. This is important to note because HLA-B27 positive is associated with a greater chance for a positive x-ray of the sacroiliac joints (that means finding any changes under x-ray). People who are HLA-B27 positive are reported to react better to treatment and manage biologic drugs better. Women have been reported to have higher pain scores from patient questionnaires in rheumatic diseases, which could be explained as women have a greater number of pain receptors, and experience hormonal changes which cause fluctuating pain sensations. Body composition, especially fat disposition, can affect how the body reacts to a disease like axSpA. For example, women have more subcutaneous fat (under the skin) whereas men have visceral fat (inside the abdomen, packed between the organs- stomach, liver, intestines, kidneys). Higher disease activity scores have been reported in women with higher percentage of body fat or fat mass index, and interestingly men have been found to have higher disease activity scores when they had low body fat or fat mass index.

Truth: The myth that men and women with axSpA are physiologically the same is not true. The above findings show that there are sex differences in gene expression and body composition. In addition, women with axSpA have different pain mechanisms and hormonal influences that might contribute to higher disease activity scores compared with men.

Myth 2: axSpA is a predominately male disease

As axSpA is associated with being HLA-B27 positive, which is more likely in males, axSpA was previously thought to be a ‘male’ disease. This was because historically, x-rays were an important part of diagnosing axSpA/ankylosing spondylitis, and as touched upon above, the radiographic changes detectable via x-ray are more common in males. The use of magnetic resonance imaging (MRI) to detect more subtle changes in inflammation has only been recently introduced. Therefore, cases of non-radiographic axSpA (nr-axSpA) with changes not detectable via x-ray would have previously been missed.

In 1949, initial studies showed a male:female ratio of 10:1. However, in 1993, this ratio was reported to have decreased to about 3:1. In nr-axSpA, there are no reported differences in sex. As we have seen in previous blogs, the delay in diagnosing axSpA is approximately 8 years in the UK, but the age of onset is reported to be the same in men and women. However, it has been reported that this delay is longer for women than men. A study of 23,889 patients (in which 32.3% were women) showed women waited about 8 years for a diagnosis compared to men who waited 6.5 years. There are multiple reasons why the length to diagnosis is longer for women than men but these can include: 1) different pain symptoms, such as more widespread pain in women which can double the delay; 2) some women may get misdiagnosed with fibromyalgia as some of the symptoms overlap; 3) the perception that axSpA is a male disease could lead to a bias within healthcare system that results in delays; and, 4) women with axSpA can experience acute anterior uveitis (AAU), which is pain and redness in the eyes, and sensitivity to light (photophobia) that develops rapidly.

Women are more often diagnosed with axSpA after their first attack of AAU, whereas men are diagnosed many years before developing AAU. This highlights the importance of screening women for AAU if they report having back pain, as this could reduce their diagnosis time. Some MRI changes of the pelvis are important for the diagnosis in women as they can show bone marrow oedema (excessive water signals in the marrow space), however, this method also has pitfalls as more fluid in the sacroiliitis joint can occur in women following pregnancy- even one year after childbirth.

Truth: AxSpA is not a male disease, and this perception has caused many women to wait a long time for a diagnosis. The occurrence of AAU may help women get a quicker diagnosis, however, identifying bone marrow oedema could lead to overdiagnosis.

Myth 3: Men with axSpA have a worse disease outcome compared with women

As we have discussed already, there is reported to be an association of male sex with more radiological changes in axSpA, meaning changes can be detected on x-ray. Men are also said to have higher scores on measures such as Bath Ankylosing Spondylitis Radiology Index (BASRI) spine and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), compared with women. Severe radiographic deformities can occur in both men and women, but it has been suggested that women may have slower radiological progression- which means that the changes visible on x-ray appear slower than for men. This can explain why more women have a diagnosis of nr-axSpA and a longer delay in diagnosis.

Extra-articular manifestations are occurrences of bodily symptoms alongside axSpA. These can include AAU, as seen above, enthesitis, inflammatory bowel disease (IBD), psoriasis and peripheral arthritis. Studies have suggested that these extra-articular manifestations are higher in women than in men. A co-occurring condition (or comorbidity) such as osteoporosis, which causes bones to weaken and break over time due to low bone mass, is sometimes described as a “woman’s disease” (maybe a myth?) due to the high number of women with the condition, and the number of fractures in post-menopausal women. In axSpA, even young males can have osteoporosis and low bone mass density.

When measuring quality of life, many different measures can be used such as the Ankylosing Spondylitis Quality of Life questionnaire, the Assessment of SpondyloArthritis international Society (ASAS) Health Index, and the Bath Ankylosing Spondylitis Patient Global Score (BAS-G). These are all disease-specific, so they are tailored to the disease and capture more relevant symptoms and outcomes. In these disease-specific measures, worse quality of life scores were observed for women. In other quality of life measures which are not disease specific, such as the EuroQoL and the 36-item Short Form Health Survey, no large sex differences were revealed.

Truth: Overall, men with axSpA show a higher rate of radiological progression compared with women. Women with axSpA in general have higher disease activity scores and more extra-articular manifestations compared with men. Osteoporosis is mainly seen in post-menopausal women, but it is unexpectedly high in young males with axSpA.

Myth 4: No sex differences are present in efficacy and drug survival of biologics in axSpA

Most clinical studies are not designed to assess sex differences. One study has looked at the results of several randomised controlled trials on one biologic drug (etanercept), and analysed them to look for sex differences. This study revealed that women had a lower treatment response at 12 weeks according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score compared with males. Women also had a lower Ankylosing Spondylitis Disease Activity Score with C-Reactive Protein level (ASDAS-CRP) response compared with men at 12 weeks. Women spend less time receiving biologic drugs compared with men due to treatment failure. Several predictors have been found for a good treatment response and drug survival, namely HLA-B27 positive, not having received tumour necrosis factor inhibitors (TNFi) previously, short disease duration, and absence of enthesitis. Sadly, women are the opposite of all of these predictors! In addition to this, having a greater fat mass is associated with a lower TNFi treatment response.

Truth: Substantial evidence has been found indicating women have lower levels of biologic drugs working and higher treatment failure for TNFis.

The authors conclude that it is of great importance to be aware of the sex differences in axSpA for diagnosis as well as treatment.


If you want to help eliminate myths in axSpA, why not become a member of the NASS axSpA community of over 4000 supportive members! As a member, you can contribute to #ditchthemyth. People diagnosed with axSpA are taking part in the myth busting challenge on Facebook, and giving their personal experience.

There is also a Myth Busting Quiz on the NASS website, where you can test your own knowledge of axSpA!

Summary & Sign-Off!

I hope you enjoyed reading these summaries of the three different articles on axSpA.

There was quite a lot of information on treatment for axSpA, so if you want to read more on this please see the resources on the NASS website, as well as other related resources to the information in this blog:

Biologic therapy: https://nass.co.uk/resource/nass-guide-to-biologic-therapy/

Uveitis: https://nass.co.uk/resource/nass-guide-to-uveitis/

Living well with axSpa, including information on exercise and medication: https://nass.co.uk/resource/nass-guidebook/

If you have been affected by any of the information in these summaries, please reach out to help and support available here.

If you want to share your experience of any issues related to this blog, please contact me on: ns2271@bath.ac.uk. I would love to hear from you!

We also currently have a survey running, where we are gathering views and opinions on monitoring axSpA symptoms via a smartphone app. If you would like to have your say, you can access the survey here: https://bathreg.onlinesurveys.ac.uk/to-track-or-not-to-track-in-axialspondyloarthritis. It will be closing at 7.30am on 15th November!

Have a good rest of the week all!

Best Wishes,

The Project Nightingale Team