How delayed diagnosis could be increasing disease burden of ankylosing spondylitis in women

Historically, ankylosing spondylitis (AS) has been identified as the ‘disease of men’. But a recent study published in Seminars in Arthritis and Rheumatism journal by Wright et al has highlighted that disease activity and severity is worse in women than in men despite less visible damage on X-ray of sacroiliac joints and spine. Additionally, the lingering perception of AS as a predominantly male disease may bias clinicians away from proper identification of axial spondyloarthritis’ disease features in women.

To increase awareness of gender differences in this little understood autoimmune rheumatological condition, Dr Pravin Patil, consultant rheumatologist, Apex Centre of Rheumatology, Pune discusses the clinical features, disease impact and recent treatment options of AS

Ankylosing Spondylitis (AS) is an inflammatory condition that predominantly affects the spine.  The most feared complication is fusion of the spine. In AS, other joints such as hips  and  internal organs can also be affected.

AS is common in young adults usually in the age group between 25-45 years of age. The symptoms, especially in the early stages, can be very similar to more common back problems. Because of this, many people put up with the pain, sometimes for a longer duration before seeking help. Also, over the counter (OTC) pain killers are available in such a wide range around us, that usually masks symptoms of this condition. Hence unfortunately, AS often remains misdiagnosed as ‘the usual back pain’ for many years due to the delay in correct diagnosis. This is also because most of the mainstream population in our country has very little knowledge of rheumatic diseases.

 As the name suggests, the word ankylosing spondylitis (AS) has two parts.

Ankylosing (Ankylosis): It describes fusion of bones. The spine’s bones (vertebrae) fuse together, resulting in a rigid spine.

Spondylitis: It is a broad term that describes inflammation (swelling and redness) in the joints of spine. Spondylosis is completely different term which means wear and tear in spine.

In the last two decades, there has been a lot of progress in the field of rheumatology. The research work on early stages of AS has led to the introduction of the term ‘Axial Spondyloarthritis’ (AxSpA) as per 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria.

Axial Spondyloarthritis is an umbrella term which includes following both spectrums of spinal arthritis.

Ankylosing spondylitis (AS) – In this category, the patients have inflammatory back pain and there are definitive changes/damage visible on radiographic imaging. This is more commonly seen in men.

 Non-radiographic axSpA (nr-axSpA) – This means patient has symptoms of inflammatory back pain but there is no visible damage on radiograph (X-ray). This type is more common in women.

Emerging evidence suggests that women and men experience axSpA differently. Although the prevalence of AS is approximately two to three fold higher in men than in women, nr-axSpA is slightly more common in women.

Why women tend to have less structural damage

Overall, women tend to have lesser structural damage in the spine. This lower prevalence of definitive damage on X-ray in women than in men is the reason why historically, AS has been identified as the ‘disease of men’.

Initial studies have overestimated the male to female ratio. The lesser number of women been included in these studies could be one of the explanations for this disparity. With the adoption of the wider concept of axSpA to include an earlier stage of the disease (nr-AxSpA), it is now understood that nr-axSpA may be equally prevalent in men and women. X-ray changes of inflammation in sacroiliac joints may take years to develop or may never develop in women and diagnosis of axSpA in women is frequently delayed or never made.

Protein in the body promoting inflammation (pro-inflammatory cytokines) like IL-17A, tumour necrosis factor (TNF) alpha and IL-18 levels are elevated in men compared to women. These differences may influence the progression of spinal damage because IL-17A and TNF accelerate inflammation leading to permanent bone damage.

Gene expression profiles and hormonal differences between men and women with AS could be another explanation for the difference in clinical features of axSpA. For example, female sex hormones- estrogen- has been shown to reduce TNF-α production which in turn affects inflammatory pathways distinctly in women.

Disease burden in women

 Recent study published in Seminars in Arthritis and Rheumatism journal by Wright et al have highlighted that the disease burden is different in women and men. Importantly, disease activity and severity is worse in women than in men despite less visible damage on X-ray of sacroiliac joints and spine.

Symptoms in men tend to be more axial (primarily affects spine, chest, and hip joints), however in women symptoms can be peripheral and more widespread. Women tend to have greater enthesitis (pain where tendons and ligaments meet bone), more dactylitis (swelling of entire digit), peripheral or widespread pains. Extra-articular manifestations like inflammatory bowel disease and psoriasis has been reported to more frequently affect women.

Widespread pains do interfere with a timely and accurate diagnosis of axSpA in women. Studies have also shown that mere presence of widespread pain in women more than doubles the time to diagnosis of SpA. It is a less recognised features of AxSpA in women.

For many years, female patients with AxSpA often get misdiagnosed as fibromyalgia (a stress related disorder casing widespread pains). Additionally, a lingering perception of AS as a predominantly male disease may bias clinicians away from proper identification of axSpA disease features in women.

Even if the radiographic damage is at the same level as men, women tend to have more functional impairment. Quality of life is generally poorer in women than in men with axSpA. This indicates that women are perceiving greater disease burden because they may indeed be experiencing worse disease activity. High prevalence of anxiety and depression in women may also be contributing to the overall burden of disease.

Delay in diagnosis in women

 Women generally experience a longer time to diagnosis of axSpA than men. Slow onset of disease progression and differential diagnoses such as fibromyalgia or mechanical back pain could contribute to delays in diagnosis among women. Central sensitisation—a pain dysregulation resulting in higher perceived pain intensity disproportionate to the stimulus, or pain perceived in areas remote from inflammation —is associated with fibromyalgia and axSpA.

Because of this association, central sensitisation may represent a pain mechanism that both disproportionately affects women and complicates the diagnosis of axSpA in women. Delayed diagnosis potentially leading to high radiographic damage at baseline and obesity are considered poor prognostic factors both in men and women.

Treatment response

 Multiple studies have shown a significantly poorer responses to biologics like TNF inhibitor (TNFi) therapies in women. Since women with axSpA experience more enthesitis than men, incomplete TNFi efficacy towards enthesitis may contribute to these observed sex-dependent differences in treatment response. Novel biological agents like IL17 blocker have shown promising results in controlling many enthesitis dominant diseases.

Recent studies indicate that almost 80 per cent of AS patients treated with an IL-17A inhibitor biologic had no radiographic progression of the spine at four years and exhibited sustained improvement in signs and symptoms.

Way forward

 Many aspects of axSpA differ between men and women. AxSpA is less understood and less accurately diagnosed in women than in men. Hence, awareness of axSpA manifestations and progression in women will improve outcomes. It is important that sex differences in axSpA are understood and considered when diagnosing and treating the spectrum of axSpA, including AS and nr-axSpA.

With recent advances in medical research, IL-17A inhibitors have been shown to revolutionise the management of ankylosing spondylitis. Medical practitioners should also make the patients aware about the these advances in medical fields.

With the help of these newer and safer targeted therapies, the long-term goal of treatment in AS patients should extend beyond pain relief, to preventing disability and ensuring an improved quality of life