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.¹Hanson A, Brown MA. Genetics and the Causes of Ankylosing Spondylitis. Rheum Dis Clin North Am. 2017;43(3):401-414. doi:10.1016/j.rdc.2017.04.006

Genetic Causes of Ankylosing Spondylitis

There is a clear link between ankylosing spondylitis and the human leukocyte antigen (HLA) B27 gene.²Parameswaran P, Lucke M. HLA-B27 Syndromes. [Updated 2023 Mar 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551523/^,3Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

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.⁴van der Linden SM, Khan MA, Li Z, et al. Recurrence of axial spondyloarthritis among first-degree relatives in a prospective 35-year-follow-up family study. RMD Open. 2022;8(2):e002208. doi:10.1136/rmdopen-2022-002208

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.⁵Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology. 2013;53(4):650-657. doi:10.1093/rheumatology/ket387

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.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/

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.²Parameswaran P, Lucke M. HLA-B27 Syndromes. [Updated 2023 Mar 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551523/

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.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7

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.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/

• An overgrowth of harmful bacteria in the gut causes inflammation and damage to the lining of the gastrointestinal tract.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7^,8Dai Q, Xia X, He C, et al. Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis. Pharmacogenet Genomics. 2022;32(7):247-256. doi:10.1097/FPC.0000000000000468^,9Jethwa H, Abraham S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology (Oxford). 2017;56(9):1452-1460. doi:10.1093/rheumatology/kew374
• The bacteria then leak out through the damaged lining and enter the bloodstream, initiating an immune response.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7^,8Dai Q, Xia X, He C, et al. Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis. Pharmacogenet Genomics. 2022;32(7):247-256. doi:10.1097/FPC.0000000000000468^,9Jethwa H, Abraham S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology (Oxford). 2017;56(9):1452-1460. doi:10.1093/rheumatology/kew374

The imbalance of the microbiome in the gut is thought to be caused by genetic susceptibility and/or a history of infection.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7^,8Dai Q, Xia X, He C, et al. Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis. Pharmacogenet Genomics. 2022;32(7):247-256. doi:10.1097/FPC.0000000000000468^,9Jethwa H, Abraham S. The evidence for microbiome manipulation in inflammatory arthritis. Rheumatology (Oxford). 2017;56(9):1452-1460. doi:10.1093/rheumatology/kew374

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.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/

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.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/^,10Chen M, Li W, Li L, Chai Y, Yang Y, Pu X. Ankylosing spondylitis disease activity and serum vitamin D levels: A systematic review and meta-analysis. Medicine (Baltimore). 2022;101(46):e31764. doi:10.1097/MD.0000000000031764

In individuals already diagnosed with ankylosing spondylitis, adequate vitamin D contributes to reduced disease activity.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/^,7Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7

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.⁶Nordquist H, Jamil RT. Biochemistry, HLA Antigens. [Updated 2023 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546662/^,11Xiong Y, Cai M, Xu Y, et al. Joint together: The etiology and pathogenesis of ankylosing spondylitis. Front Immunol. 2022;13:996103. Published 2022 Oct 17. doi:10.3389/fimmu.2022.996103

However, additional research is needed to understand the connection between physical injury and the onset of a chronic inflammatory response.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7

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.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7

The role of additional genetic variations in ankylosing spondylitis

Several genetic variations have been implicated in the development and susceptibility of ankylosing spondylitis, including¹Hanson A, Brown MA. Genetics and the Causes of Ankylosing Spondylitis. Rheum Dis Clin North Am. 2017;43(3):401-414. doi:10.1016/j.rdc.2017.04.006^,12Zhu W, He X, Cheng K, et al. Ankylosing spondylitis: etiology, pathogenesis, and Treatments. Bone Research. 2019;7(1):1-16. doi:10.1038/s41413-019-0057-8:

• 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.¹Hanson A, Brown MA. Genetics and the Causes of Ankylosing Spondylitis. Rheum Dis Clin North Am. 2017;43(3):401-414. doi:10.1016/j.rdc.2017.04.006

Gender and ankylosing spondylitis

The occurrence of ankylosing spondylitis is approximately three times higher in men compared to women.⁵Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology. 2013;53(4):650-657. doi:10.1093/rheumatology/ket387 However, this difference is possibly related to a longer time-to-diagnosis in women due to more widespread (nonspecific) pain.¹³Rusman T, van Bentum RE, van der Horst-Bruinsma IE. Sex and gender differences in axial spondyloarthritis: myths and truths. Rheumatology (Oxford). 2020;59(Suppl4):iv38-iv46. doi:10.1093/rheumatology/keaa543

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.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7

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).¹⁴Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-1613. doi:10.1002/art.41042

Relapses may also be triggered by alterations in immune function, such as repeated mechanical stress or acute infections.⁷Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079-3093. doi:10.1007/s10067-021-05679-7^,15Cooksey R, Brophy S, Dennis M, et al. Severe flare as a predictor of poor outcome in ankylosing spondylitis: a cohort study using questionnaire and routine data linkage. Rheumatology. 2015;54(9):1563-1572. doi:10.1093/rheumatology/kev015

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.¹⁶Spondyloarthritis in over 16s: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2017 Jun. (NICE Guideline, No. 65.) Available from: https://www.ncbi.nlm.nih.gov/books/NBK553609/

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.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

Diagnostic factors associated with ankylosing spondylitis typically include¹⁷van den Berg R, de Hooge M, Rudwaleit M, et al. ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort and from the Assessment of SpondyloArthritis international Society (ASAS)-cohort. Ann Rheum Dis. 2013;72(10):1646-1653. doi:10.1136/annrheumdis-2012-201884:

• 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.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

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 includes¹⁵Cooksey R, Brophy S, Dennis M, et al. Severe flare as a predictor of poor outcome in ankylosing spondylitis: a cohort study using questionnaire and routine data linkage. Rheumatology. 2015;54(9):1563-1572. doi:10.1093/rheumatology/kev015:

• 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 of¹⁵Cooksey R, Brophy S, Dennis M, et al. Severe flare as a predictor of poor outcome in ankylosing spondylitis: a cohort study using questionnaire and routine data linkage. Rheumatology. 2015;54(9):1563-1572. doi:10.1093/rheumatology/kev015^,18Deodhar A, Reveille JD, van den Bosch F, et al. The concept of axial spondyloarthritis: joint statement of the spondyloarthritis research and treatment network and the Assessment of SpondyloArthritis international Society in response to the US Food and Drug Administration's comments and concerns. Arthritis Rheumatol. 2014;66(10):2649-2656. doi:10.1002/art.38776:

• 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.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

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.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/^,12Zhu W, He X, Cheng K, et al. Ankylosing spondylitis: etiology, pathogenesis, and Treatments. Bone Research. 2019;7(1):1-16. doi:10.1038/s41413-019-0057-8

The common imaging abnormalities seen in ankylosing spondylitis include sacroiliitis, enthesitis, and ankylosis.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/^,12Zhu W, He X, Cheng K, et al. Ankylosing spondylitis: etiology, pathogenesis, and Treatments. Bone Research. 2019;7(1):1-16. doi:10.1038/s41413-019-0057-8

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 include³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/:

• 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.³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

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).³Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/

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.²Parameswaran P, Lucke M. HLA-B27 Syndromes. [Updated 2023 Mar 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551523/^,5Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology. 2013;53(4):650-657. doi:10.1093/rheumatology/ket387