2022 – A year in axSpA research! Part three

Hello Everyone!

Today’s blog continues with fortnightly research updates for 2022.

The article summaries below cover topics on: 1) people’s experience of living with axial spondyloarthritis (axSpA) and fatigue, 2) the effect of lifestyle modification on inflammation and disease burden in ankylosing spondylitis, and 3) treatment failure definition in axSpA.

Qualitative interview study exploring the patient experience of living with axial spondyloarthritis and fatigue: difficult, demanding and draining

February 2022. Pearson and colleagues. https://bmjopen.bmj.com/content/12/2/e053958

In a previous blog, we touched on the symptom of fatigue and how it can be an important symptom for people with axial spondyloarthritis (axSpA). Research suggests that healthcare professionals rarely discuss fatigue in axSpA, and more effective communication is needed between people experiencing fatigue and clinicians due to their different perspectives.

Fatigue is not a well-researched symptom but in the studies that have explored this, it is described as “a complex condition that includes physical and mental fatigue, is different from normal tiredness, is unpredictable, can be affected by the weather or overexertion, and leads to a reduction in social engagement”. Fatigue has been rated as one of the top 3 symptoms that people with axSpA want to see addressed, with as many as 66% of people with axSpA reporting fatigue; of these people, up to 75% report severe fatigue. The aim of this study was therefore to explore fatigue in the daily lives of people with axSpA.

Seventeen people with a diagnosis of axSpA from the UK took part in interviews to discuss their experience of fatigue. The average time since being diagnosed was 14 years, and according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), 7 out of the 17 (41%) participants had high disease activity. Some of the questions included in the interviews were:

· How would you describe your fatigue?
· What do you think causes your fatigue?
· What effect does fatigue have on your daily life?
· How do you deal with your fatigue?
· Is your fatigue discussed during your visits with healthcare professionals?
· What are the things that you would like a healthcare professional to ask you about when discussing fatigue?

The results of the interviews found that fatigue is a symptom that affected all aspects of people’s lives, was unresponsive to rest or sleep, was unpredictable, uncontrollable, and derailed plans. People talked about the difference between normal tiredness (due to lack of sleep) and fatigue, which had no pattern and no known cause. Pain could also worsen fatigue, and well-managed pain could relieve feelings of fatigue for some. People described having to make practical, personal, psychological, social and environmental changes to maximise their engagement in daily life as a result of fatigue.

The major finding from this study was the importance of ‘achieving balance’ in relation to the impact of fatigue. This reflects what people felt they must do to self-manage their condition, cope with their fatigue and its effects, and maintain their energy. Energy was referred to in a lot of detail in this study, and was described as “a short-term, daily resource that can be drawn on and replenished to sustain physical or mental activity”. In order to manage the level of energy and fatigue, people were having to identify, develop and appraise different approaches to ease or self-manage their symptoms. This new way of living life took years of ‘expertise’ to develop effective strategies tailored to their needs, incorporating trial-and-error approaches along the way. This highlights the burden of axSpA and fatigue on mental well-being.

Due to its ‘invisibility’, fatigue could also affect people’s mood, relationships, and degree of engagement. Low mood could in turn affect levels of exercise taken, which is crucial in axSpA as it can help to lower disease activity, and support better functional, pain and fatigue outcomes. However, as we have seen before, emotional and psychological well-being are not part of routine clinical assessment for axSpA. The National Axial Spondyloarthritis Society (NASS), who funded this study into fatigue and axSpA, has responded to this need by providing mental health support services on their website to help with emotional well-being.

In summary, this study identified the importance of: (1) the concept of energy as a component related to fatigue experience, but also distinct from it; (2) the development of expertise to enable self-management; and, (3) perseverance due to the unpredictability of symptoms.

Understanding the experience of fatigue could help people with axSpA and clinicians to work together to tailor treatments and facilitate the development of expertise, which could be key in ‘achieving balance’.

If you would like to access NASS’ help on mental well-being and fatigue, please see the following resources on their website:

https://nass.co.uk/about-as/ what-is-as/your-wellbeing/

Do you suffer from fatigue due to axSpA? Would you like to share your story? If so, feel free to email me on: ns2271@bath.ac.uk

Lifestyle modification and inflammation in people with axial spondyloarthropathy—A scoping review

February 2022. Roberts and colleagues. https://onlinelibrary.wiley.com/doi/10.1002/msc.1625

People with ankylosing spondylitis (AS- the radiographic form of axial spondyloarthritis) suffer a higher risk of cardiovascular disease. Cardiovascular disease is a general term for conditions affecting the heart or blood vessels. Some modifiable risk factors (risk factors that can be modified through lifestyle changes to reduce your risk of disease) are estimated to account for more than 50% of all cardiovascular disease deaths including smoking, hypertension (high blood pressure), diabetes, and obesity. Inflammation is a key contributor to these cardiovascular risk factors.

The evidence on the effect of lifestyle modification on measures of inflammation, disease burden, and disease activity in people with AS is limited. Therefore, the aim of this study was to collate all evidence on the interaction between environmental factors and inflammation in people with AS, to help direct future research. The data found was grouped broadly under six lifestyle modifications, and evidence was provided for each of these lifestyle modifications.

1. Physical activity and sedentary behaviour

· High levels of sedentary behaviour are associated with chronic inflammation. Research investigating the effect of breaking up sedentary time on disease activity is needed, as this has not been studied.
· Exercise is effective for improving Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath AS Metrology Index (BASMI), pain, mobility, and quality of life in people with AS, even though there were no major changes in inflammation.
· Future work should include levels of inflammation being measured such as cytokines (substances in the body that can cause inflammation including interleukin).

2. Diet

· A reduction in mammalian meat (beef, pork, lamb, or venison) and an increase in consumption of vegetables and fish has been recommended as a core set of dietary recommendations for AS.
· The relationship between diet and AS is inconclusive due to the varied types of studies conducted.
· Future studies should assess if change in symptoms is related to inflammation, body weight, or gut responses to the diet.

3. Body weight
· Obesity and being overweight cause a pro-inflammatory environment in the body. Obesity is approximately 7% more common in people with AS than the general population.
· In AS, obesity is associated with higher BASDAI, greater inflammation, spinal stiffness, worse physical function, and worse quality of life.
· No studies have investigated the longitudinal effect of body weight or weight loss on inflammation in people with AS.

4. Smoking

· The proportion of people smoking with AS is higher (24-29%) than in the general population (15%), although they are already at greater risk of cardiovascular disease.
· Smoking can be difficult to measure due to the changing status of smokers. The effect of smoking is also dependent on various other factors such as manual occupations, lower socioeconomic status, higher stress and BMI, and other lifestyle factors.
· In people with AS, smoking can raise peripheral blood leucocyte counts (involved in inflammation) by ∼20–25%.
· Evidence in people with AS suggests that current and former smokers (classed as ‘ever smokers’), have higher BASDAI and BASFI, worse spinal pain, and higher C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) (markers of inflammation) compared to those who have never smoked.
· No studies on smoking cessation and AS measured inflammation levels, which is necessary in smoking cessation studies to improve the understanding of what contributes to improved disease status upon smoking cessation in AS.

5. Alcohol
· Less is known about the relationship between alcohol consumption and inflammation, than smoking and inflammation.
· It is important to assess this relationship as evidence in healthy populations suggests low alcohol intake reduces inflammation and cardiovascular disease risk.
· No studies have incorporated levels of inflammation when assessing the effect of alcohol consumption on health outcomes in people with AS.

6. Psychosocial factors (combined influence of psychological factors and the surrounding social environment)

· Acute stress can result in higher levels of inflammation in the general population. More research is therefore needed into the link between psychosocial factors and AS, as anxiety and depression are more common in people with AS than the general population.
· This will help to better understand what makes people with AS at greater risk of inflammation and cardiovascular disease.
· Depression and feelings of helplessness have been found to be associated with heightened perceptions of disease activity in AS. However, it is uncertain whether heightened depression causes a heightened perception of disease activity, or vice versa.

This study concluded that more research is needed on the effect of lifestyle modification on comorbidities (other conditions diagnosed along with AS), such as cardiovascular disease. Studies that currently measure inflammation use the CRP and ESR measurements, but better indicators of inflammation are required.

Have you had a change in disease activity due to lifestyle modifications? Would you like to share your experience? If so, feel free to email me on ns2271@bath.ac.uk

Treatment Failure in Axial Spondyloarthritis: Insights for a Standardized Definition

February 2022. Juanola and colleagues. https://pubmed.ncbi.nlm.nih.gov/35201604/

The first pharmacological treatment provided to people with active axial spondyloarthritis (axSpA) are non-steroidal anti-inflammatory drugs (NSAIDs). However, not all people achieve adequate disease control with NSAIDs alone, or can tolerate high and/or prolonged doses. Other drugs that are subsequently offered include biologic disease modifying anti-rheumatic drugs (bDMARDs), such as tumour necrosis factor alpha inhibitors (TNFi, e.g. adalimumab), and interleukin inhibitors (IL-17A e.g. secukinumab and ixekizumab). Janus kinase inhibitors (JAKi) are the most recent type of drug to be approved for ankylosing spondylitis (AS). Response rates to bDMARDs are low with about 40% experiencing treatment failure. Clinicians must carefully consider the reason for discontinuing the first bDMARD and decide the next step. This study reviewed literature on this topic and aimed to provide a definition of treatment failure, and discussed approaches on how to address treatment failure.

Treatment failure can be recognised by the clinician using objective measures (e.g. the presence of active disease on clinician examination, raised C-Reactive Protein [CRP] levels, inflammation detected by magnetic resonance imaging [MRI]) or by using patient-reported outcomes (e.g. pain, fatigue). Ensuring that the treatment was taken as intended (treatment compliance), is also an important factor for treatment failure, and this needs to be verified before the treatment is discontinued. Adverse reactions can also happen, so although the treatment is working, the undesirable effects may be too great for the individual to tolerate.

Primary treatment failure is when there is no response to treatment within 6 months of starting treatment, or results are not as expected. Secondary failure is when there is a response to treatment within 6 months, but it is lost thereafter, or results are not as expected over time. The Assessment of Spondyloarthritis International Society (ASAS) developed a tool to assess the health of people with axSpA (as well as AS and peripheral SpA), to test real-life functioning both in clinical trials and daily practice. This tool is the ASAS Health Index (ASAS-HI), first developed in 2015.

Interest in "tight-control” and “treat-to-target” has grown in recent years, supported by international reports and guidelines for rheumatoid arthritis. This strategy involves close monitoring of disease activity and tweaking of treatment until the desired treatment outcome/goal is reached. Observational evidence has suggested that a treat-to-target approach may be beneficial in axSpA, however further investigations are still needed. The first study to evaluate tight control and treat-to-target in a clinical trial for axSpA has recently been completed. Using a tight control approach (visits every 4 weeks and prespecified strategy based on treatment intensification until achieving target) showed a favourable effect in terms of improvement of ASAS-HI, compared to usual care (visits every 12 weeks and treatment at the rheumatologist's discretion). However, this result was not statistically significant and therefore we cannot be confident that the observed results were not due to chance.

Drug switching is required and recommended when there is treatment failure or intolerance. According to the ASAS/European League Against Rheumatism (EULAR) recommendations, in people with a primary failure on the first TNFi, it is better to switch to another class of drugs, (i.e., an anti-IL-17). However, this should only be done after reconsidering if the diagnosis and the reason for the start of the first TNFi were correct. More research is needed to better understand how to optimise the drug treatment and switching process.

Based on their review of the literature, the authors recommend a definition of treatment failure that considers: 1) Ankylosing Spondylitis Disease Activity Score (ASDAS)-CRP, 2) presence/absence of extra-articular manifestations (such as inflammatory bowel disease, uveitis, and psoriasis), and 3) disease impact on general health (measured by ASAS-HI). However, importantly, this definition of treatment failure needs to be tailored to each person’s condition. Other factors also need to be considered such as comorbidities which could deteriorate the person’s function and well-being, and other causes of chronic pain unrelated to the axSpA, such as fractures and degenerative conditions.

Dose escalation could be another option for clinicians to consider. A recent clinical trial has been completed exploring the effects of dose escalation with Secukinumab from 150mg to 300mg, after people did not achieve inactive disease during the first 16 weeks of treatment. Results are due on March 11, 2022 and could be used for a future blog post!

Summary & Sign Off!

I hope you have enjoyed reading these summaries of research, and found the information useful.

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!

Best Wishes,

The Project Nightingale Team