Disclosures: Liew reports no relevant financial relationships.
March 26, 2021
4 min read

Education on sex disparities can improve AS, axSpA detection

Disclosures: Liew reports no relevant financial relationships.
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Researchers found significantly lower treatment rates for women with ankylosing spondyloarthritis in multiple studies analyzing clinical trials in axial spondylarthritis, resulting in poor outcomes and response to therapies once started.

Jean Liew, MD, professor of rheumatology at Boston University School of Medicine, spoke with Healio about the impact of delayed diagnoses of ankylosing spondyloarthritis (AS) and axial spondylarthritis (axSpA) in women.

Healio: What are some sex disparities in AS?

Jean Liew, MD

Liew: Two main disparities that come readily to mind are the longer delay to diagnosis in women compared with men, and the lower treatment responses rates with biologic therapies.

In axSpA overall, there remains a delay to diagnosis of up to a decade (or more), and many studies conducted over the years showed that this hasn’t appreciably changed. A 2017 meta-analysis of these studies showed that the delay to diagnosis was longer in women (mean, ~9 years) than in men (mean, ~7 years).

Regarding lower treatment response rates for women: This was seen in a pooled analysis of clinical trials studying etanercept for AS. This has also been shown in large observational studies.

Healio: Why would female patients receive a higher diagnostic delay compared with male patients?

Liew: Partly, we continue to suffer from the older teaching that AS is a disease of young men, particularly young white men. This does not mean that women do not get AS. In non-radiographic axSpA, there is a more equal sex distribution. But the traditional teaching has led to cognitive shortcuts and biases among clinicians, who may not think of AS as being high on the differential when a woman presents with inflammatory back pain or other features of AS.

Healio: What are obstacles to female patients receiving a diagnosis in AS?

Liew: Other obstacles to diagnosis are related to presentation. Studies have indicated that presentation may differ between women and men. There are multiple studies from well-characterized prospective cohorts showing that men have more radiographic structural damage in the sacroiliac joints and in the spine than women. These changes that are apparently on X-rays make the diagnosis easier to pick up.

Healio: Describe barriers to diagnosis in women and how can this be addressed.

Liew: First, the main barrier is that AS/axSpA remains poorly understood in the medical community in general, and even among rheumatologists. So, first and foremost, we need better education about axSpA overall.

Healio: How can clinicians sooner diagnose women who underreport symptoms or disease developments?

Liew: One recommendation for clinicians would be having a higher index of suspicion for AS and considering ordering that imaging of the SI joints. And if the clinical features support a diagnosis of AS but the X-ray doesn’t show structural changes in the SI joints, to get that MRI to evaluate for non-radiographic axSpA (nr-axSpA). However, while this kind of recommendation may be easy to make, it can also potentially result in over-diagnosis and over-use of these diagnostic measures. So, it comes back to better education about when to suspect AS, and how to diagnose it.

When discussing the pathway to diagnosis for AS/axSpA, one important starting point to consider are other subspecialty clinics. Anterior uveitis, skin psoriasis and inflammatory bowel disease are extra-musculoskeletal manifestations that can be seen in axSpA. There are conflicting reports of whether there are clear sex differences in the prevalence of these manifestations (which may be limited by diagnostic bias as well as selection bias). But in patients who have uveitis, psoriasis or IBD, we need to ask them about possible joint symptoms and make those referrals to rheumatology for further evaluation.

Healio: What are the results of delayed diagnosis for female patients?

Liew: The main result is a delay in effective treatment, which results in poorer outcomes, and poorer response to therapies once started. Why might this happen? The longer you go without appropriate anti-inflammatory treatment, the more that this inflammation has time to damage the joints, as well as cause stress systemically on the rest of the body. This can increase the burden of cardiovascular disease and risk. The longer you go without appropriate therapy may also contribute to pain sensitization in some, potentially leading to issues with chronic, widespread pain even after therapy is started.

Healio: How does disease progression present differently in male vs. female patients, and how can this be better addressed?

Liew: Observational studies have demonstrated that men have more radiographic progression and are more likely to have inflammatory changes on MRI. But does this necessarily mean that the disease phenotype is more severe in men? Not necessarily.

The same studies have also shown that women have a greater burden of disease activity and report health-related worse quality of life. One older study, looking at a cohort of AS patients with long-standing (20 years or more) symptoms found that male sex was associated with radiographic severity but female sex with worse physical function. The results from these studies come with caution about causal interpretation. There’s an issue with selection bias when we consider who is in these cohorts. And if you study associations within a select group of people, for example those with long-standing AS, you could find associations in the cohort that don’t truly exist if you were to consider all-comers with axSpA. Plus, there are methodologic considerations with these observational studies such as, were they able to measure all important confounders appropriately and adjust for them in their models?

Healio: In what ways do BASDAI scores influence diagnoses for different sexes?

Liew: We don’t use BASDAI for diagnosis, but we do use it for monitoring disease activity and treatment response. BASDAI, more so than the other clinical disease activity measure, ASDAS, is on average higher in women than in men with axSpA. It’s important to note that these are disease activity measures that are largely based on subjective measures — though ASDAS also has a laboratory component, the CRP or ESR).

Healio: In what ways could clinical trials or studies overcome sex disparities?

Liew: Most clinical trials have not been powered to look at sex differences in treatment response. This is a major limitation. While clinical trials are a better type of study (vs. observational studies) to look for causal relations, clinical trials still depend on their design.