Ankylosing Spondylitis Causes and Risk Factors

While the exact cause of ankylosing spondylitis is unknown, the development of the condition is primarily related to genetic predisposition for immune system dysregulation.

Genetic Causes of Ankylosing Spondylitis

There is a clear link between ankylosing spondylitis and the human leukocyte antigen (HLA) B27 gene.^,

Inheritance of the HLA-B27 gene from one or both parents or a family history of ankylosing spondylitis increases the likelihood of developing the condition.

It is estimated that 90% of people with the condition are carriers of HLA-B27. However, only some people who have the gene develop the disease.

The role of the HLA-B27 gene in ankylosing spondylitis

HLA genes are responsible for helping the immune system differentiate between foreign antigens (such as bacteria and viruses) and the body's cells, flagging the foreign antigens for destruction.

In cases of ankylosing spondylitis, evidence indicates that when HLA-B27 binds to a foreign antigen, it creates a new structure resembling the body’s cells (particularly in the joints), causing the immune system to mistakenly attack normal cells.

3 Newly Discovered Causes of Ankylosing Spondylitis

Research suggests that certain environmental factors trigger inflammatory immune responses that initiate or worsen ankylosing spondylitis in genetically predisposed individuals. These factors are discussed below.

1. Gut microbiome and ankylosing spondylitis

The bacteria and other organisms that live in the gastrointestinal tract – also called the gut microbiome – regulate digestion and immunity and play a significant role in developing ankylosing spondylitis.

• An overgrowth of harmful bacteria in the gut causes inflammation and damage to the lining of the gastrointestinal tract.^,,
• The bacteria then leak out through the damaged lining and enter the bloodstream, initiating an immune response.^,,

The imbalance of the microbiome in the gut is thought to be caused by genetic susceptibility and/or a history of infection.^,,

Additionally, one study has proposed that lack of breastfeeding fails to impart protective gut mechanisms, contributing to an imbalance of the microbiome, which potentially increases susceptibility to developing ankylosing spondylitis.

See Foods for a Healthier Gut and Less Arthritis Pain

2. Vitamin D deficiency and ankylosing spondylitis

Research shows an association between higher vitamin D levels and a lower risk of developing ankylosing spondylitis.^,

In individuals already diagnosed with ankylosing spondylitis, adequate vitamin D contributes to reduced disease activity.^,

See Dietary Supplements for Treating Arthritis

3. Mechanical stress and ankylosing spondylitis

There is some evidence that repeated mechanical stress on the spine, such as from physically demanding jobs, potentially triggers an immune response that leads to the development of ankylosing spondylitis.^,

However, additional research is needed to understand the connection between physical injury and the onset of a chronic inflammatory response.

Risk Factors for Ankylosing Spondylitis

While inheritance of the HLA-B27 gene appears to be the strongest predictor of ankylosing spondylitis, additional risk factors have been associated with developing the condition in individuals with or without genetic susceptibility.

The role of additional genetic variations in ankylosing spondylitis

Several genetic variations have been implicated in the development and susceptibility of ankylosing spondylitis, including^,:

• Additional HLA genes, such as HLA-B7, HLA-B16, HLA-B35, HLA-B38, HLA-B39, and HLA-B50
• Endoplasmic reticulum aminopeptidase (ERAP) 1 and ERAP2, which are enzymes responsible for allowing HLAs to recognize foreign versus normal cells
• Interleukin 23 receptor (IL23R), which is a protein involved in promoting inflammation through activation of immune cells

Ankylosing spondylitis also frequently occurs when there is a family history of inflammatory bowel disease and psoriasis, as these conditions are thought to share genetic risk factors.

Gender and ankylosing spondylitis

The occurrence of ankylosing spondylitis is approximately three times higher in men compared to women. However, this difference is possibly related to a longer time-to-diagnosis in women due to more widespread (nonspecific) pain.

Smoking cigarettes and ankylosing spondylitis

It is well-established that smoking causes an inflammatory response, and current smoking status (not necessarily a history of smoking) is considered a risk factor for developing ankylosing spondylitis. Smoking is also considered a contributing factor to increased disease activity in those already diagnosed with the condition.

When Ankylosing Spondylitis Pain Increases

The most common cause of ankylosing spondylitis flare-ups is a change in treatment regimen, especially tapering or discontinuing a biologic medication (eg, Humira or Remicade).

Relapses may also be triggered by alterations in immune function, such as repeated mechanical stress or acute infections.^,

Not everyone experiences a flare-up in these circumstances, and adhering to medication regimens, reducing stress levels, and maintaining a healthy lifestyle reduces the risk of a flare-up.

Diagnosing Ankylosing Spondylitis

Diagnosis of ankylosing spondylitis is primarily a process of ruling out other musculoskeletal and inflammatory conditions due to the relatively non-specific nature of symptoms.

Diagnostic factors associated with ankylosing spondylitis typically include:

• Chronic low back pain for at least 3 months
• Inflammatory back pain that develops gradually, improves with activity, and worsens at night or with periods of rest 
• Age of onset before 45 years old
• Evidence of grade 2 or grade 3 sacroiliitis (inflammation of the SI joint) on an x-ray 

Sacroiliitis typically confirms a diagnosis of ankylosing spondylitis, but for individuals without SI joint involvement seen on imaging, additional tests are recommended.

Read more about Sacroiliitis on Spine-health.com

Diagnosis of ankylosing spondylitis without radiographic evidence of sacroiliitis 

In patients without radiographic evidence of sacroiliitis, the diagnosing criteria includes:

• Enthesitis (inflammation of the enthesis - the site where tendons, ligaments, and joint capsules attach to bone)
• Dactylitis (inflammation of the fingers and toes that causes sausage digits)
• Uveitis (inflammation of the uveal tract in the eyes)
• Positive family history of spondyloarthropathies
• Inflammatory bowel disease (inflammation of the gastrointestinal tract)
• Alternating buttock pain
• Psoriasis (an inflammatory condition affecting the skin)
• Asymmetric arthritis
• Elevated inflammatory markers
• Pain reduction when treated with non-steroidal anti-inflammatory drugs (NSAIDs)

The presence of at least 4 of these findings is potentially indicative of ankylosing spondylitis. 

Clinical Tests for Ankylosing Spondylitis

A physical exam is generally the first clinical test performed in the diagnosis of ankylosing spondylitis and includes an assessment of^,:

• Posture and abnormalities in the curvature of the spine
• Range of motion and flexibility of the spine
• Evidence of inflammation in the spine, joints, eyes, and skin, such as swelling and tenderness

A thorough review of the patient’s medical history, which includes medical conditions, medications, and family history, is also conducted to rule out other potential diagnoses.

Imaging Tests for Ankylosing Spondylitis

X-rays are the primary medical imaging modality in diagnosing ankylosing spondylitis, but magnetic resonance imaging (MRI) and ultrasound are also used to detect more subtle inflammatory changes.^,

The common imaging abnormalities seen in ankylosing spondylitis include sacroiliitis, enthesitis, and ankylosis.^,

During the early stages (first few years) of ankylosing spondylitis, spinal and SI joint changes are not always noticeable but become more apparent on imaging tests within a decade of onset.³

Blood Tests Performed When Diagnosing Ankylosing Spondylitis

There is no single laboratory test used to diagnose ankylosing spondylitis, but standard blood tests that assess inflammation include:

• C-reactive protein (CRP)
• Erythrocyte sedimentation rate (ESR)

Elevated CRP or ESR levels are present in about 50% of active ankylosing spondylitis cases, but normal levels do not necessarily rule out the condition.

Additional blood tests (eg, complete blood count and rheumatoid factor) are also useful in ruling out other conditions with similar symptoms and signs, such as spinal or bone tumors, infection, rheumatoid arthritis, or systemic lupus erythematosus (lupus).

Genetic Tests for Diagnosing Ankylosing Spondylitis

A positive test for the HLA-B27 gene is not diagnostic on its own, but it helps confirm ankylosing spondylitis in the presence of active signs and symptoms.^,