Ankylosing Spondylitis

History 

Ankylosing spondylitis (AS) is a chronic systemic inflammatory disorder affecting the axial skeleton, peripheral joints, entheses, eyes, skin, and intestines and is characterized by inflammatory back pain, radiographic sacroiliitis, excess spinal bone formation, and a high prevalence of human leukocyte antigen (HLA)-B27.1,2 Clinical manifestations of ankylosing spondylitis include back pain, progressive spinal rigidity, and inflammation of the hips, shoulders, peripheral joints, and fingers or toes.3

The first historical description of ankylosing spondylitis appeared in 1559 in Realdo Colombo’s De Re Anatomica. Ankylosing spondylitis as a disease entity was established by Wladimir von Bechterew in Russia, Adolph Strümpell in Germany, and Pierre Marie in France.3

Radiology for diagnostic and treatment purposes was first applied to ankylosing spondylitis in the 1920s. In the 1930s, physicians were able to use radiology to describe the early and late disease manifestations of ankylosing spondylitis; their descriptions are still used today to diagnose and stage the disease.3 The discovery of the human leukocyte antigen (HLA) in the 1940s confirmed that there was a genetic predisposition to ankylosing spondylitis. Susceptibility to the disease was strongly linked to HLA-B27.3,4 

Radiographic, epidemiological, and clinical reports in the mid-1900s established relationships between ankylosing spondylitis and other forms of arthritis, resulting in the concept of spondyloarthritis (SpA).3

Introduced to represent a group of interrelated diseases that shared clinical and genetic characteristics,4 SpA was originally organized into several subtypes, including AS, psoriatic arthritis (PsA), reactive arthritis, enteropathic arthritis, and undifferentiated SpA.5

According to the Assessment of SpondyloArthritis international Society (ASAS), SpA is classified as either axial SpA (axSpA) or peripheral SpA. Patients who fall under the axSpA disease spectrum and are in the absence of definite sacroiliac joint changes on plain radiograph are considered to have either AS or non-radiographic axial SpA (nr-axSpA).5 Spondylitis and sacroiliitis are the main features of axial SpA, while peripheral arthritis, enthesitis, and dactylitis are the main features of peripheral SpA.6 

Limitations of the 1984 modified New York criteria led to the development of the Amor criteria and European Spondyloarthropathy Study Group criteria. These classifications could be applied to patients with early‐stage and mild SpA.6  

It was later discovered that magnetic resonance imaging (MRI) could detect sacroiliitis years before abnormalities were visible on radiographs, which led to the ASAS to develop new criteria sets for axSpA in 2009 and for peripheral SpA in 2011 to better identify patients early and differentiate axial from peripheral disease.6 

Epidemiology

The global prevalence of SpA is estimated to be approximately 1%.6 Data from the 2009-2010 US National Health and Nutrition Examination Survey (NHANES) indicates that the prevalence of AS is between 0.52% to 0.55%.7 The prevalence of AS is estimated to be 23.8 per 100,000 individuals in Europe, 16.7 per 100,000 individuals in Asia, 31.9 per 100,000 individuals in North America, 10.2 per 100,000 individuals in Latin American, and 7.4 per 100,000 individuals in Africa.8

Approximately 6.1% of the US population is estimated to have the HLA-B27 allele. HLA-B27 is seen in 7.5% of non-Hispanic White individuals and 3.5% of all other races and ethnicities in the United States.7 

The age of onset for AS ranges from the late teens to 40 years. Onset after 50 years of age is unusual and may be the result of a delayed diagnosis.1 Men have a 2 to 3 times greater chance of being affected by ankylosing spondylitis than women and AS tends to be more severe in men. The most commonly affected areas are the spine and pelvis, with some involvement of the chest wall, hips, shoulders, and feet. In women, there tends to be less severe involvement of the spine, with symptoms more commonly occurring in the knees, wrists, ankles, hips, and pelvis.3

As many as one-third of patients diagnosed with ankylosing spondylitis will experience peripheral disease and extra-articular disease. In patients with AS, the pooled prevalence of arthritis is 29.7%, enthesitis is 28.8%, uveitis is 23%, psoriasis is 10.2%, dactylitis is 6%, and inflammatory bowel disease (IBD) is 4.1%.5

Etiology and Risk Factors

Genetic factors predispose an individual to ankylosing spondylitis while environmental factors may trigger the disease. Genetic susceptibility results have shown a 63% recurrent risk factor in monozygotic twins vs 23% recurrent risk factor in dizygotic twins, emphasizing the strong genetic nature of the disease.9 

One of the largest genetic risk factors for ankylosing spondylitis is the major histocompatibility complex (MHC) class I allele HLA-B27. Studies show that HLA-B27 is present in 90% to 95% of all individuals who are diagnosed with ankylosing spondylitis.4,9 AS can occur in the absence of HLA-B27, and 1% to 10% of people with HLA-B27 allele will develop ankylosing spondylitis. However, this number may increase to 15% to 20% in the case of a first-degree relative with ankylosing spondylitis. There are other genetic factors contributing to AS along with HLA-B27.3,9

Over 100 subtypes of HLA-B27 have been identified. HLA-B2705 has been noted to be more prevalent among White individuals, HLA-B2704 in Chinese individuals, and HLA-B2702 in Mediterranean individuals. Other subtypes, including HLA-B2706 and HLA-B2709, do not appear to be associated with an increased risk for ankylosing spondylitis.9

Further, studies show the significance of tumor necrosis factor (TNF)-α in disease pathogenesis. The recent success of TNF inhibitors confirms that TNF and genes related to its expression play an important role in disease development and progression. Additionally, studies recognize the vital role of the interleukin (IL)-23/IL-17 axis in disease development and progression. Therefore, blocking these pathways appears to have a significant effect on disease modulation.1,9,10

Researchers are also exploring the role of other factors in disease development. There is a high association between AS and IBD, suggesting that the microbiome and sex hormones play a role. Certain microbial infections may also trigger ankylosing spondylitis development and vitamin D deficiency may play a role in the disease activity. However, the relationship between vitamin D deficiency and ankylosing spondylitis activity remains unclear.9,10

Ankylosing Spondylitis Prognosis

Ankylosing spondylitis is a progressive ailment that can be managed with pharmacotherapy. The prognosis for patients with ankylosing spondylitis is variable and partly determined by the presence of certain extraspinal manifestations, age at diagnosis, and treatment.7

Disease progression leading to permanent damage and loss of function is the most rapid during the first 10 years. However, diagnosis and treatment are often delayed an average of 5 to 7 years. One-third of patients with ankylosing spondylitis are severely compromised by the time of diagnosis and at least one-third of patients with ankylosing spondylitis have a reduced life expectancy.11

Major predictors of poor outcomes in ankylosing spondylitis include hip arthritis, erythrocyte sedimentation rate greater than 30 mm/hr, poor efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs), limitation of lumbar spine, sausage-like fingers or toes, oligoarthritis, and onset at age 16 or younger.

Other predictors of poor disease outcomes include early hip involvement, limited spinal mobility, laboratory evidence of ongoing disease activity, peripheral arthritis, and dactylitis.11 Hip arthritis was closely associated with a 23-fold increase in the risk for severe disease.3 When assessing for long-term outcomes, the presence of permanent pain, ongoing disease activity, limitations of spinal mobility, loss of function, osteoporosis, and other disease manifestations (hips, peripheral joints, entheses, uvea, heart) should be documented.11

Overall, ankylosing spondylitis is associated with a poor quality of life. A Norwegian study found that after an average of 16 years with ankylosing spondylitis, only 51.5% of patients with AS were still employed full-time. Common quality of life concerns mentioned by patients are stiffness, pain, fatigue, and poor sleep. Patients with ankylosing spondylitis have upwards of 50% increased risk of mortality independent from radiation therapy. Patients with renal amyloidosis and ankylosing spondylitis will undergo permanent dialysis and may experience premature death.11

Patients who are older at onset, men, and current smokers or patients who present with HLA-B*4100, DRB1*0804, DQA1*0401, DQB1*0603, and DPB1*0202 immunogenetic markers have a higher likelihood of severe radiographic damage after 20 years of living with ankylosing spondylitis.12

Ankylosing Spondylitis Symptoms & Diagnosis

The most common initial symptom of AS is dull pain with insidious onset, typically felt deeply in the buttocks and/or in the lower lumbar regions, accompanied by morning stiffness that lasts for a few hours but improves with activity and returns with inactivity. Over the course of several months, the pain becomes more persistent and bilateral, and tends to worsen at night. Approximately 5% of patients presenting with chronic inflammatory back pain will have AS or another SpA subset.3

Other symptoms of ankylosing spondylitis can range widely from mild stiffness to total fusion of the spine with a combination of severe bilateral hip involvement, peripheral arthritis, and/or extra-articular manifestations. The primary finding during physical exam is loss of spinal mobility with restrictions of flexion, extension of the lumbar spine, and expansion of the chest. Pain and stiffness in the sacroiliac joints may be elicited with direct pressure or movement, and inflammation may be detected in peripheral joints. In untreated severe disease, other symptoms like postural changes are evident with exaggeration of the thoracic kyphosis, atrophy of the buttock, and stooping forward of the neck.3 

In an Icelandic study, 58.7% of patients reported an insidious onset of ankylosing spondylitis symptoms. Pain and stiffness were reported as presenting symptoms in 92.8% of both male and female patients (91.7% vs 94.9%, respectively) and lower back pain was the most common pain location (84.9% vs 77.0%, respectively) followed by buttock pain (53.4% vs 52.7%, respectively). Hip and knee joints are the most frequent arthritis conditions reported by patients, along with musculoskeletal and skin diseases, followed by the ankle and shoulder joints.13

For adults under age 45 with back pain lasting more than 3 months, the ASAS criteria states that a diagnosis of axial spondyloarthritis is confirmed if sacroiliitis is present on imaging in addition to at least 1 SpA feature or if HLA-B27 is present in addition to at least 2 other SpA features.14 Additional SpA features include:

  • Inflammatory back pain
  • Arthritis
  • Enthesitis in the heel
  • Uveitis
  • Dactylitis
  • Psoriasis
  • Musculoskeletal and skin diseases
  • Crohn’s disease or ulcerative colitis
  • Good response to NSAIDs
  • Family history of SpA
  • Presence of HLA-B27
  • Elevated C-reactive protein (CRP)

Diagnostic Workup

Laboratory Testing

Currently, no laboratory test is diagnostic of the condition, which is one of the challenges with early diagnosis. Testing for the HLA-B27 is only recommended in certain clinical situations. Both CRP and raised erythrocyte sedimentation rate (ESR) are good indicators of the inflammatory processes but they are only elevated in approximately 50% to 70% of cases. Measuring ESR or CRP has limited value in confirming the diagnosis, though an increase in ESR and CRP may have prognostic value as it indicates a degree of inflammation and disease activity.3

Some individuals may present with mild normochromic normocytic anemia. In individuals with severe disease, alkaline phSome individuals may present with mild normochromic normocytic anemia. In individuals with severe disease, alkaline phosphatase levels may be raised. Elevated immunoglobulin A (IgA) levels are common.3 Patients with AS are usually negative for rheumatoid factor, antinuclear antibodies, and citrullinated peptide unless affected by other illnesses concurrently.4 In patients with restrictive chest wall motion, airflow measurements and ventilatory function remain normal while vital capacity is decreased.3

Imaging Studies

MRI and computed tomography (CT) are more sensitive than radiography in the early identification of inflammation of joints, osteitis, cartilage changes, and edema in sacroiliitis. They can be utilized if radiographs are negative in a patient with clinical signs of ankylosing spondylitis. X-ray can also be used to detect sacroiliitis.  Diagnosis of ankylosing spondylitis in the early stages is only possible by combining imaging with the clinical findings.3,4 

Radiology findings can confirm the diagnosis, but absence of findings should not exclude diagnosis. Early visible changes in the sacroiliac joints seen on radiograph include blurring of cortical margins of subchondral bone, erosions, and sclerosis.3

Generally, visible radiographic changes due to ankylosing spondylitis occur later, and thus they have prognostic value and may help monitor disease progress.

Differential Diagnosis

Although low back pain is one of the primary symptoms of ankylosing spondylitis, most back pain is unrelated to ankylosing spondylitis. Data from the 2009-2010 NHANES shows that almost 20% of adults have experienced low back pain; however, only one-third of those have inflammatory back pain.7

Certain diseases and conditions can appear similar to ankylosing spondylitis, including: 

  • Mechanical lower back pain. Mechanical low back pain can appear at any age. Unlike ankylosing spondylitis, pain improves with rest and worsens with movement. Mechanical lower back pain often results from acute injury and is more common in middle-aged individuals. In addition, the peripheral arthritis or extraskeletal manifestations seen in AS are not evident.15
  • Lumbar spinal stenosis. This narrowing of the spinal canal exerts pressure on the spinal cord, resulting in symptoms that include chronic back pain and morning stiffness. However, the condition usually presents in individuals who are older.16 It is not associated with peripheral arthritis or extraskeletal features.
  • Rheumatoid arthritis. The presence of HLA-B27 predisposes individuals to ankylosing spondylitis while HLA-DR4 predisposes individuals to rheumatoid arthritis. Patients with rheumatoid arthritis will test positive for rheumatoid factor and will have cyclic citrullinated peptide antibodies.17
  • Diffuse idiopathic skeletal hyperostosis. This degenerative disorder is characterized by formation of new bone at the anterolateral spine and peripheral enthuses. It is associated with older age, men, and metabolic factors such as obesity, hypertension, and type 2 diabetes. Individuals are often asymptomatic, but complain of stiffness and/or back pain. Diagnostic criteria include presence of flowing calcification, ossification of the spine, relative preservation of intervertebral disc height in relation to age, and absence of apophyseal joint ankylosis and sacroiliac joint changes.18

Guideline Recommendations

In the 2019 updated guidelines for the treatment of ankylosing spondylitis by the American College of Rheumatology, Spondylitis Association of American, and Spondyloarthritis Research and Treatment Network, the following recommendations were created2:

For Adults With Active Ankylosing Spondylitis

  • Use of NSAIDs is recommended over no use of NSAIDs, and continuous use of NSAIDs is recommended over on-demand use of NSAIDs. There is no preferred NSAID.
  • If AS is active despite treatment with NSAIDs:
    • Treatment with sulfasalazine, methotrexate, or tofacitinib is recommended. Sulfasalazine or methotrexate should be considered in patients with prominent peripheral arthritis or when tumor necrosis factor inhibitors (TNFi) are unavailable. 
    • Treatment with TNFi is recommended over tofacitinib and over no TNFi. There is no preferred TNFi.
    • Treatment with secukinumab or ixekizumab is recommended over no treatment with these agents. Treatment with TNFi should precede use of secukinumab or ixekizumab.
    • Treatment with either secukinumab or ixekizumab is recommended over tofacitinib.
    • If there is a contraindication to TNFi, secukinumab or ixekizumab is recommended over sulfasalazine, methotrexate, or tofacitinib.
  • If ankylosing spondylitis is active despite treatment with the first TNFi:
    • Treatment with secukinumab or ixekizumab is recommended as an alternative TNFi in patients who are primary nonresponders to TNFi.
    • Treatment with an alternative TNFi is recommended over treatment with a non-TNFi agent in patients who are secondary nonresponders to TNFi.
    • Do not switch to a biosimilar of the first TNFi.
    • Do not add sulfasalazine or methotrexate to the treatment regimen in favor of a new biologic.
  • If isolate active sacroiliitis, stable axial disease, or active enthesitis is present despite treatment with NSAIDs, use of locally administered parenteral glucocorticoids is recommended over no use of local glucocorticoids. Avoid peritendon injections of Achilles, patellar, and quadriceps tendons.
  • Physical therapy is recommended over no physical therapy and active physical therapy interventions through supervised exercise is recommended over passive therapy interventions (eg, massage, ultrasound, heat). Land-based physical therapy interventions are recommended over aquatic therapy interventions.
  • Systemic glucocorticoids are not recommended for treatment.

For Adults With Stable Ankylosing Spondylitis

  • On-demand use of NSAIDs is recommended over continuous use of NSAIDs.
  • In adults receiving both TNFi and NSAIDs or a conventional synthetic antirheumatic drug, continuation of TNFi alone is recommended over continuation with both therapies.
  • In adults receiving treatment with a biologic, it is not recommended to discontinue the biologic or taper the biologic dose.
  • In adults receiving treatment with an originator TNFi, continuing treatment with the original TNFi is recommended over switching to its biosimilar.
  • Physical therapy is recommended over no physical therapy.

For Adults With Active or Stable Ankylosing Spondylitis

  • Cotreatment with low-dose methotrexate is not recommended for patients receiving treatment with TNFi.
  • Fall evaluation, counseling, unsupervised back exercises, and participation in formal group or individual self-management education is recommended.
  • In adults with spinal fusion or advanced spinal osteoporosis, treatment with spinal manipulation is recommended.
  • In adults with advanced hip arthritis, a total hip arthroplasty is strongly recommended over no surgery.
  • In adults with severe kyphosis, elective spinal osteotomy is not recommended.

For Adults With Active or Stable Ankylosing Spondylitis

  • In adults with acute iritis, treatment by an ophthalmologist is recommended to decrease the severity, duration, or complication of episodes.
  • In adults with recurrent iritis: 
    • Prescriptions of topical glucocorticoids are recommended for at-home use in the event of eye symptoms to decrease severity or duration of iritis episodes.
    • Treatment with TNFi monoclonal antibodies are recommended over treatment with other biologics.
  • In adults with IBD:
    • No particular NSAID is preferred to decrease the risk of worsening IBD symptoms.
    • Treatment with TNFi monoclonal antibodies is recommended over treatment with other biologics.

Disease Activity Assessment, Imaging, and Screening

  • Regular-interval use and monitoring of a validated ankylosing spondylitis disease activity measure and CRP concentrations or ESR is recommended.
  • Screening for osteopenia and osteoporosis is recommended. In patients with syndesmophytes or spinal fusion, screening is recommended with dual x-ray absorptiometry (DXA) scan of the spine and the hips.
  • Screening for cardiac conduction defects and valvular heart disease with echocardiograms is not recommended.
  • In adults with ankylosing spondylitis of unclear activity while on a biologic, it is recommended to obtain a spinal or pelvis MRI to assess activity.
  • In adults with stable ankylosing spondylitis, it is not recommended to obtain a spinal or pelvis MRI to confirm inactivity.
  • In adults with active or stable ankylosing spondylitis on any treatment, it is not recommended to repeat spine radiographs at a scheduled interval. 

Ankylosing Spondylitis Management

Nonpharmacologic

Rehabilitation, particularly physiotherapy and exercise, patient education, active involvement, and motivation are integral to disease management and affect overall treatment outcomes to manage pain and stiffness and improving mobility and physical function.19

Physical therapy, specifically land-based physical therapy and supervised exercise is recommended for people with ankylosing spondylitis to reduce pain and relieve pain.2

Pharmacologic 

Nonsteroidal Anti-Inflammatory Drugs

In most cases, treatment begins with NSAIDs, including ibuprofen, indomethacin, diclofenac, naproxen, piroxicam, Aside from rare cases, treatment begins with NSAIDs, including ibuprofen, indomethacin, diclofenac, naproxen, piroxicam, celecoxib, ketoprofen, and oxaprozin.20 Continuous treatment with NSAIDs is recommended in patients with active ankylosing spondylitis, while on-demand use is recommended in patients with stable AS. There is no preferred NSAID.2

Patients should be initiated on low-dose NSAIDs and be titrated up to the maximum tolerated dose. Generally, an appropriate trial consists of at least 2 types of NSAIDs administered at the maximum dose at least 2 weeks apart.9 Good responses to NSAIDs include reduction in inflammatory back pain and improvement in function.

Tumor Necrosis Factor Inhibitors

In patients with high disease activity despite NSAID therapy, use of a TNFi (adalimumab, infliximab, etanercept, golimumab, certolizumab, or their biosimilars) is highly recommended. There is no preferred TNFi for adults who develop ankylosing spondylitis. However, for patients with IBD or recurrent iritis, TNFi monoclonal antibodies such as infliximab, adalimumab, certolizumab, and golimumab are recommended over treatment with other biologics.

Use of TNFis are contraindicated in patients with an active infection, active tuberculosis, advanced heart failure, cancer, lupus, and multiple sclerosis. Abrupt discontinuation of TNFi after achieving remission or low disease activity results in relapses in 60% to 74% of patients.2,9 

Alternative Therapies for Ankylosing Spondylitis

If TNFi are unavailable, treatment with disease modifying antirheumatic drugs (DMARDs) such as sulfasalazine or methotrexate can be given to a patient with stable AS. Tofacitinib, a Janus kinase (JAK) inhibitor, can also be considered. 

Secukinumab and ixekizumab are IL-17A inhibitors, a new class of drugs for ankylosing spondylitis treatment. For patients who have a contraindication to TNFi, IL-17A inhibitors are preferred over JAK inhibitors and DMARDs. IL-17A inhibitors are also second-line options for patients with primary nonresponse to TNFi. Several double-blind, placebo-controlled, phase 3 clinical trials reported significant improvement in disease activity for patients with ankylosing spondylitis after use of secukinumab and ixekizumab over the course of the studies.21

The use of opioids and other painkillers are controversial but can be used in settings where inflammation caused by AS is not well controlled or when pain stems from noninflammatory sources, such as neuropathic, mechanical, or psychogenic.

A longitudinal cohort analysis found that opioid use was not independently associated with elevated ESR or CRP analysis or with worsening radiographic severity. Patients with AS taking opioids are more likely to be taking muscle relaxants, anxiolytics, antidepressants, and hypnotics. Use with caution and monitor for drug-drug interactions.22 

Systemic glucocorticoids are not recommended, although local injections of glucocorticoids into peripheral joints, sacroiliac joints, or entheses have shown to provide symptom relief.2,9

Spinal deformity is not rare in AS, and about one-third of patients have thoracolumbar kyphosis. Corrective osteotomy and stabilization are recommended under certain conditions to treat ankylosing spondylitis, such as for those with severe kyphosis or advanced hip arthritis if the benefits outweigh the risk of the surgical procedure.9

Laboratory Testing for Monitoring Ankylosing Spondylitis Side Effects

Both CRP and ESR are unreliable methods to monitor disease activity. Regular MRI or radiographic imaging along with functional tests may help monitor the success of drug therapy.

When using drugs that cause immunosuppression or immunomodulation, such as TNFi, IL-17A inhibitors, JAK inhibitors, and DMARDs, patients should be monitored for tuberculosis, HIV, hepatitis B, and various other conditions often associated with a compromised immune system.23 The continued use of NSAIDs or DMARDs increases risk for gastrointestinal, cardiovascular, renal, and hematological toxicity. Drug-drug interactions for TNFi and other biologics have not been heavily studied. Although they do not appear to have any severe drug-drug interactions, they have some influence CYP450 activity.9

Ankylosing Spondylitis Comorbidities

In addition to extra-articular manifestations of ankylosing spondylitis, patients with AS are at higher risk of developing asthma, cardiovascular disease, depression, hypertension, osteoporosis, sleep apnea, and spinal fracture.1

Ankylosing Spondylitis Complications

One of the most common complications of ankylosing spondylitis is spinal deformity, with thoracolumbar kyphosis occurring in 30% of patients. In patients with progressive kyphotic deformity, chin-on-chest deformity, kyphosis-related muscular neck pain, and sagittal imbalance-induced thoraco lumbar axial pain, surgical procedures have been shown to be effective.24

Other sequelae of ankylosing spondylitis include early osteoporosis and cauda equina syndrome (CES). Spinal stenosis, degenerative disc disease, acute and chronic fractures, kyphosis, osteoporosis, and CES can cause noninflammatory lesions.24 

CES is a rare and debilitating neurologic complication of long-standing ankylosing spondylitis that impacts the pelvis and lower limbs. It can take years to develop and may be treated with surgery to mitigate or improve sensory and motor deficits as well as urinary and rectal function. Symptoms of CES include low back pain, weakness, sensory loss, and urinary and bowel dysfunction.25 

In severe cases of advanced hip arthritis and severe hip pain, hip arthroplasty or replacement may be the best treatment option.

AS has a significant impact on the patient’s quality of life. Coping with stiffness, severe pain, fatigue, sleep problems, and the side effects of drugs is cited as a common challenge.3 

Spondylitis Association of America & Patient Education

Reliable sources of patient education for ankylosing spondylitis include the following associations:

References

1. Walsh JA, Song X, Kim G, Park Y. Evaluation of the comorbidity burden in patients with ankylosing spondylitis using a large US administrative claims data set. Clin Rheumatol. 2018;37(7):1869-1878. doi:10.1007/s10067-018-4086-2

2. Ward 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 non-radiographic axial spondyloarthritis. Arthritis Care Res (Hoboken). 2019;71(10):1285-1299. doi:10.1002/acr.24025

3. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002;61(suppl 3):iii8-iii18. doi:10.1136/ard.61.suppl_3.iii8

4. Raychaudhuri SP, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun. 2014;48-49:128-133. doi:10.1016/j.jaut.2014.01.015

5. de Winter JJ, van Mens LJ, van der Heijde D, Landewé R, Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18(1):196. doi:10.1186/s13075-016-1093-z

6. van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev Rheumatol. 2015;11(2):110-118. doi:10.1038/nrrheum.2014.181

7. Reveille JD, Weisman MH. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States. Am J Med Sci. 2013;345(6):431-436. doi:10.1097/MAJ.0b013e318294457f

8. Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014;53(4):650-657. doi:10.1093/rheumatology/ket387

9. Zhu W, He X, Cheng K, et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res. 2019;7:22. doi:10.1038/s41413-019-0057-8

10. Jethwa H, Bowness P. The interleukin (IL)-23/IL-17 axis in ankylosing spondylitis: new advances and potentials for treatment. Clin Exp Immunol. 2016;183(1):30-36. doi:10.1111/cei.12670

11. Braun J, Pincus T. Mortality, course of disease and prognosis of patients with ankylosing spondylitis. Clinical Exp Rheumatol. 2002;20(suppl 28):S16-S22.

12. Ward MM, Hendrey MR, Malley JD, et al. Clinical and immunogenetic prognostic factors for radiographic severity in ankylosing spondylitis. Arthritis Rheumatol. 2009;61(7):859-866. doi:10.1002/art.24585

13. Geirsson AJ, Eyjolfsdottir H, Bjornsdottir G, Kristjansson K, Guðbjörnsson B. Prevalence and clinical characteristics of ankylosing spondylitis in Iceland—a nationwide study. Clin Exp Rheumatol. 2010;28(3):333-340.

14. Sieper J, Rudwaleit M, Baraliakos X, et al. The Assessment of SpondyloArthritis International Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68(Suppl 2):ii1-ii44. doi:10.1136/ard.2008.104018

15. Grinnell-Merrick LL, Lydon EJ, Mixon AM, Saalfeld W. Evaluating inflammatory versus mechanical back pain in individuals with psoriatic arthritis: a review of the literature. Rheumatol Ther. 2020;7(4):667-684. doi:10.1007/s40744-020-00234-3

16. Kalichman L, Cole R, Kim DH, et al. Spinal stenosis prevalence and association with symptoms: the Framingham Study. Spine J. 2009;9(7):545-50. doi:10.1016/j.spinee.2009.03.005

17. Barczyńska TA, Węgierska M, Żuchowski P, et al. Coexistence of rheumatoid arthritis and ankylosing spondylitis. Reumatologia. 2015;53(5):270-285. doi:10.5114/reum.2015.55832

18. Kuperus JS, Waalwijk JF, Regan EA, et al. Simultaneous occurrence of ankylosing spondylitis and diffuse idiopathic skeletal hyperostosis: a systematic review. Rheumatology. 2018;57(12):2120-2128. doi:10.1093/rheumatology/key211

19. Sharan D, Rajkumar JS. Physiotherapy for ankylosing spondylitis: systematic review and a proposed rehabilitation protocol. Current Rheumatol Rev. 2017;13(2):121-125. doi:10.2174/1573397112666161025112750

20. Kroon FPB, van der Burg LRA, Ramiro S, et al. Non‐steroidal anti‐inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non‐radiographic axial spondyloarthritis). Cochrane Database Syst Rev. 2015;(7):CF010952. doi:10.1002/14651858.CD010952.pub2

21. Garcia-Montoya L, Gul H, Emery P. Recent advances in ankylosing spondylitis: understanding the disease and management. F1000Res. 2018;7:F1000 Faculty Rev-1512. doi:10.12688/f1000research.14956.1

22. Dau JD, Lee MJ, Ward MM, et al. Opioid analgesic use in patients with ankylosing spondylitis: an analysis of the prospective study of outcomes in an ankylosing spondylitis cohort. Rheumatol Ther. 2021;8(3):1371-1382. doi:10.1007/s40744-021-00344-6

23. Nordgaard-Lassen I, Dahlerup JF, Belard E, et al; Danish Society for Gastroenterology. Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J. 2012;59(7):C4480.

24. Mundwiler ML, Siddique K, Dym JM, Perri B, Johnson PJ, Weisman MH. Complications of the spine in ankylosing spondylitis with a focus on deformity correction. Neurosurg Focus. 2008;24(1):E6. doi:10.3171/FOC/2008/24/1/E6

25. Tang C, Moser FG, Reveille J, Bruckel J, Weisman MH. Cauda equina syndrome in ankylosing spondylitis: challenges in diagnosis, management, and pathogenesis. J Rheumatol. 2019;46(12):1582-1588. doi:10.3899/jrheum.181259