Ankylosing spondylitis (AS) is a type ofarthritis from the disease spectrum ofaxial spondyloarthritis.[5] The term comes from theGreekankylos meaning crooked, curved or rounded,spondylos meaning vertebra, and-itis meaning inflammation.[2] It is characterized by long-terminflammation of thejoints of thespine, typically where the spine joins the pelvis.[2] Lower back pain is a hallmark, but eye andgastrointestinal problems and arthritis of other joints may also occur.[2] Joint mobility in the affected areas often worsens over time, though the progression of symptoms varies significantly.[2][6]
There is currently no cure for AS. Treatments may include medication, physical therapy, and surgery. Medication therapy focuses on relieving the pain and other symptoms of AS, as well as stopping diseaseprogression by counteracting long-term inflammatory processes. Commonly used medications includeNSAIDs,TNF inhibitors,IL-17 antagonists, andDMARDs.Glucocorticoid injections are often used for acute and localized flare-ups.[10]
About 0.1% to 0.8% of the population are affected, with onset typically occurring in young adults.[2][4] While men and women are equally affected with AS, women are more likely to experience inflammation rather than fusion.[11]
The signs and symptoms of ankylosing spondylitis often appear gradually, with peak onset between 20 and 30 years of age.[12] Initial symptoms are usually achronic dull pain in the lower back orgluteal region combined with stiffness of the lower back.[13] Individuals often experience pain and stiffness that awakens them in the early morning hours.[12]
As the disease progresses, loss of spinal mobility and chest expansion, with a limitation of anteriorflexion, lateral flexion, and extension of the lumbar spine are seen. Systemic features are common with weight loss, fever, or fatigue often present.[12] Pain is often severe at rest but may improve with physical activity. Inflammation and pain may recur to varying degrees regardless of rest and movement.
AS can occur in any part of the spine or the entire spine, often with pain localized to either buttock or the back of the thigh from thesacroiliac joint. Arthritis in the hips and shoulders may also occur. When the condition presents before the age of 18, AS is more likely to cause pain and swelling of large lower limb joints, such as the knees.[14] In prepubescent cases, pain and swelling may also manifest in the ankles and feet whereheel pain andenthesopathy commonly develop.[14] Less common occurrences includeectasia of the sacral nerve root sheaths.[15]
Single nucleotide polymorphism (SNP) A/G variant rs10440635[19] is close to thePTGER4 gene on human chromosome 5 has been associated with an increased number of cases of AS in a population recruited from the United Kingdom, Australia, and Canada. ThePTGER4 gene codes for theprostaglandin EP4 receptor, one of four receptors forprostaglandin E2. Activation of EP4 promotes bone remodeling and deposition (seeprostaglandin EP4 receptor § Bone) and EP4 is highly expressed at vertebral column sites involved in AS. These findings suggest that excessive EP4 activation contributes to pathological bone remodeling and deposition in AS and that the A/G variant rs10440635a ofPTGER4 predisposes individuals to this disease, possibly by influencing EP4's production or expression pattern.[20][21]
The association of AS with HLA-B27 suggests the condition involvesCD8 T cells, which interact withHLA-B.[22] This interaction is not proven to involve a self-antigen, and at least in the relatedreactive arthritis, which follows infections, the antigens involved are likely to be derived from intracellular microorganisms.[7] There is, however, a possibility thatCD4+ T lymphocytes are involved in an aberrant way, since HLA-B27 appears to have a number of unusual properties, including possibly an ability to interact with T cell receptors in association withCD4 (usuallyCD8+ cytotoxic T cell with HLAB antigen as it is aMHC class 1 antigen).
"Bamboo spine" develops when the outer fibers of thefibrous ring (anulus fibrosus disci intervertebralis) of theintervertebral discs ossify, which results in the formation of marginalsyndesmophytes between adjoining vertebrae.
34-year-old male with AS. Inflammatory lesions of the anterior chest wall are shown (curved arrows). Inflammatory changes are seen in the lower thoracic spine and L1 (arrows).
Ankylosing spondylitis is a member of the more broadly defined diseaseaxial spondyloarthritis.[23][24] Axial spondyloarthritis can be divided into two categories: radiographic axial spondyloarthritis (which is a synonym for ankylosing spondylitis) and non-radiographic axial spondyloarthritis (which include less severe forms and early stages of ankylosing spondylitis).[23]
While AS can be diagnosed through the description of radiological changes in thesacroiliac joints andspine, there are currently no direct tests (blood or imaging) to unambiguously diagnose early forms of ankylosing spondylitis (non-radiographic axial spondyloarthritis). Diagnosis of non-radiologic axial spondyloarthritis is therefore more difficult and is based on the presence of several typical disease features.[23][25]
These diagnostic criteria include:
Inflammatory back pain: Chronic, inflammatory back pain is defined when at least four out of five of the following parameters are present: (1) Age of onset below 40 years old, (2) insidious onset, (3) improvement with exercise, (4) no improvement with rest, and (5) pain at night (with improvement upon getting up). Pain often subsides as the day progresses with movement being of importance to alleviate the joint stiffness.
Past history of inflammation in the joints, heels, or tendon-bone attachments
Family history for axial spondyloarthritis or other associated rheumatic/autoimmune conditions
The earliest changes demonstrable by plain X-ray shows erosions and sclerosis in sacroiliac joints. Progression of the erosions leads to widening of the joint space and bony sclerosis. X-ray spine can reveal squaring of vertebrae with bony spur formation calledsyndesmophyte. This causes the "bamboo spine" appearance. A drawback of X-ray diagnosis is the signs and symptoms of AS have usually been established as long as 7–10 years prior to X-ray-evident changes occurring on a plain film X-ray, which means a delay of as long as 10 years before adequate therapies can be introduced.[26]
Options for earlier diagnosis aretomography and MRI of the sacroiliac joints, but the reliability of these tests is still unclear.
Lateral X-ray of the mid back in ankylosing spondylitis
Lateral X-ray of the neck in ankylosing spondylitis
Cervical spine showing ankylosis (fusion)
X-ray showing "bamboo spine" in a person with ankylosing spondylitis
CT scan showing bamboo spine in ankylosing spondylitis
T1-weighted MRI with fat suppression after administration ofgadolinium contrast showing sacroiliitis in a person with ankylosing spondylitis
During acute inflammatory periods, people with AS may show an increase in the blood concentration ofCRP and an increase in theESR, but there are many with AS whose CRP and ESR rates do not increase, so normal CRP and ESR results do not always correspond with the amount of inflammation that is actually present. In other words, some people with AS have normal levels of CRP and ESR, despite experiencing a significant amount of inflammation in their bodies.[27]
Variations of the HLA-B gene increase the risk of developing ankylosing spondylitis, although it is not a diagnostic test. Those with the HLA-B27 variant are at a higher risk than the general population of developing the disorder, yet most individuals with the genetic marker do not develop AS. Thus, HLA-B27, demonstrated in ablood test, can help with diagnosis, but in itself is not diagnostic of AS in a person with back pain.
Over 85% of people that have been diagnosed with AS are HLA-B27 positive, although this ratio varies from population to population: about 50% of African Americans with AS possess HLA-B27 in contrast to the figure of 80% among those with AS who are of Mediterranean descent.[28] In Turkey, a study of 115 patients found 70% positivity for the HLA-B27 allele.[8]
The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), developed inBath (UK), is an index designed to detect the inflammatory burden of active disease. The BASDAI can help to establish a diagnosis of AS in the presence of other factors such as HLA-B27 positivity, persistent buttock pain which resolves with exercise, and X-ray or MRI-evident involvement of the sacroiliac joints.[29] It can be easily calculated and accurately assesses the need for additional therapy; a person with AS with a score of four out of a possible 10 points while on adequate NSAID therapy is usually considered a good candidate for biologic therapy.
The Bath Ankylosing Spondylitis Functional Index (BASFI) is a functional index which can accurately assess functional impairment due to the disease, as well as improvements following therapy.[30] The BASFI is not usually used as a diagnostic tool, but rather as a tool to establish a current baseline and subsequent response to therapy.
Juvenile ankylosing spondylitis (JAS) is a rare form of the disease which differs from the more common adult form.[14]Enthesophathy and arthritis of large joints of the lower extremities is more common than the characteristic early-morning back pain seen in adult AS.[14] Ankylosing tarsitis of theankle is a common feature, as is the more classical findings of seronegativeANA andRF as well as presence of the HLA-B27 allele.[14] Primary engagement of the appendicular joints may explain delayed diagnosis; however, other common symptoms of AS such asuveitis, diarrhea, pulmonary disease and heart valve disease may lead suspicion away from otherjuvenile spondyloarthropathies.[14]
Medications for AS may be broadly considered either "disease-modifying" or "non-disease-modifying". Disease-modifying medications for ankylosing spondylitis aim to slow disease progression and include drugs like tumor necrosis factor (TNF) inhibitors. Non-disease-modifying medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), primarily address symptoms like pain and inflammation but do not alter the course of the disease.[33]
Unless otherwise contraindicated, all people with AS are recommended to takenon-steroidal anti-inflammatory drugs (NSAIDs). The dose, frequency, and specific drug may depend on the individual and the symptoms they experience. NSAIDs, such as ibuprofen and naproxen, are used to alleviate pain, reduce inflammation, and improve joint stiffness associated with AS. These medications work by inhibiting the activity ofcyclooxygenase (COX) enzymes, which are involved in the production of inflammatoryprostaglandins. By reducing the levels of prostaglandins, NSAIDs help mitigate theinflammatory response and relieve symptoms in individuals with ankylosing spondylitis.[10][34]
Tumor necrosis factor inhibitors (TNFi) are a class of biologic drugs used in the treatment of ankylosing spondylitis. TNFi drugs, such asetanercept,infliximab,adalimumab,certolizumab, andgolimumab, target the inflammatory cytokinetumor necrosis factor-alpha (TNF-alpha). TNF-alpha plays a key role in the inflammatory process in ankylosing spondylitis. By blocking TNF-alpha, TNFi drugs help reduce inflammation, pain, and stiffness associated with AS, and may also slow down the progression of spinal damage.[10][35]
Non-TNFi "biologic" drugs used in the treatment of ankylosing spondylitis include drugs that target different pathways involved in the inflammatory process. Two of the most important drugs in this class targetIL-17, an important part of the inflammatory system:secukinumab andixekizumab. They are often considered in cases where TNFi drugs are not effective or cause too many side effects. Additionally, they may sometimes be used as anadjunct to a TNFi when symptoms persist, but improve, while the patient is on the TNFi. The choice of a specific non-TNFi biologic depends on various factors, including the patient's medical history, preferences, and the recommendations of the healthcare provider.[10]
Ustekinumab has frequently been used as asecond-line therapy for AS, but it has recently been scrutinized for a lack of efficacy, and is no longer recommended.[36][10]
Biosimilar drugs are biological products that are highly similar to an already approved biologic drug, with few or no clinically meaningful differences in terms of safety, purity, and potency. These drugs are developed to be equivalent to the reference biologic, often at a lower cost, providing alternative treatment options. In the context of ankylosing spondylitis, biosimilars are typically used as alternatives to the original biologic drugs. Biosimilars for ankylosing spondylitis may include versions of tumor necrosis factor inhibitors or other biologics commonly used in the treatment of the condition. When possible, physicians are recommended to use the original drugs over the biosimilar versions. Even biosimilars with perfect replication of the quality, composition, and other properties of the original drug are susceptible tonocebo effects.[10][37]
Conventional synthetic antirheumatic drugs (csARDs) are a class of disease-modifying medications. Unlike biologics or targeted synthetic drugs, which act on specific pathways in the immune system, csARDs have a broader effect on the immune system and are often considered traditional or conventional treatments. The most common drugs in this class aremethotrexate andsulfasalazine. These medications are only used when others fail, or when certain specific conditions are met, and are often discontinued if a patient's symptoms become manageable with just a TNFi or other medication. ConventionalDMARDs such asleflunomide are also considered to be part of this class.[10]
Concerns exist about a possible lack ofefficacy of some drugs in this class.[38]
Glucocorticoids, such asprednisone ormethylprednisolone, are sometimes used in the treatment of ankylosing spondylitis to manage acute flares and provide short-term relief from inflammation and symptoms. They are powerful anti-inflammatory medications that can help reduce pain, swelling, and stiffness associated with AS. However, glucocorticoids are generally not recommended for long-term use. They are more commonly used as localizedinjections when someone with AS has a temporary pain flare in a particular joint or area.[10]
In severe cases of AS, surgery can be an option in the form of joint replacements, particularly in the knees and hips. Surgical correction is also possible for those with severe flexion deformities (severe downward curvature) of the spine, particularly in the neck, although this procedure is considered very risky. In addition, AS can have some manifestations that make anesthesia more complex. Changes in the upper airway can lead to difficulties in intubating the airway, spinal and epidural anesthesia may be difficult owing to calcification of ligaments, and a small number of people haveaortic insufficiency. The stiffness of the thoracic ribs results in ventilation being mainly diaphragm-driven, so there may also be a decrease in pulmonary function.
Though physical therapy remedies have been scarcely documented, some therapeutic exercises are used to help manage lower back, neck, knee, and shoulder pain. There is moderate quality evidence that therapeutic exercise programs help reduce pain and improve function.[39] Therapeutic exercises include:[40][41]
Research by Alan Ebringer at King's College in London, beginning in the 1980s, implicates overgrowth of the bacteriumKlebsiella pneumoniae in the symptoms of ankylosing spondylitis. The body produces antibodies that attackKlebsiella pneumoniae. Enzymes made by the bacterium resemble human proteins, including three types of collagen (I, III, IV) and the HLA-B27 complex of glycoproteins. The antibodies therefore attack these human proteins, producing the symptoms of ankylosing spondylitis. Ebringer and others recommend low-starch or no-starch diets.[44]
Fracture of the T5 and C7 vertebra due to trauma in a person with ankylosing spondylitis as seen on a CT scan
Prognosis is related to disease severity.[12] AS can range from mild to progressively debilitating and from medically controlled to refractory. Some cases may have times of active inflammation followed by times of remission resulting in minimal disability while others never have times of remission and have acute inflammation and pain, leading to significant disability.[12] As the disease progresses, it can cause the vertebrae and the lumbosacral joint to ossify, resulting in the fusion of the spine.[45] This places the spine in a vulnerable state because it becomes one bone, which causes it to lose its range of motion as well as putting it at risk for spinal fractures. This not only limits mobility but reduces the affected person's quality of life. Complete fusion of the spine can lead to a reduced range of motion and increased pain, as well as total joint destruction which could necessitate a joint replacement.[46]
Osteoporosis is common in ankylosing spondylitis, both from chronic systemic inflammation and decreased mobility resulting from AS. Over a long-term period,osteopenia or osteoporosis of the AP spine may occur, causing eventual compression fractures and a back "hump".[47] Hyperkyphosis from ankylosing spondylitis can also lead to impairment in mobility and balance, as well as impaired peripheral vision, which increases the risk of falls which can cause fracture of already-fragile vertebrae.[47] Typical signs of progressed AS are the visible formation ofsyndesmophytes on X-rays and abnormal bone outgrowths similar toosteophytes affecting the spine. In compression fractures of the vertebrae,paresthesia is a complication due to the inflammation of the tissue surrounding nerves.
Mortality is increased in people with AS and circulatory disease is the most frequent cause of death.[50] People with AS have an increased risk of 60% for cerebrovascular mortality, and an overall increased risk of 50% for vascular mortality.[51] About one third of those with ankylosing spondylitis have severe disease, which reduces life expectancy.[52]
As increased mortality in ankylosing spondylitis is related to disease severity, factors negatively affecting outcomes include:[50][53]
The hunched position that often results from complete spinal fusion can have an effect on a person'sgait. Increased spinalkyphosis will lead to a forward and downward shift incenter of mass (COM). This shift in COM has been shown to be compensated by increased knee flexion and ankledorsiflexion. The gait of someone with ankylosing spondylitis often has a cautious pattern because they have decreased ability to absorb shock, and they cannot see the horizon.[55]
Between 0.1% and 0.8% of people are affected.[4] The disease is most common in Northern European countries, and per observations in the UK, is least frequently seen in people of Afro-Caribbean descent.[12] Although the ratio of male to female disease is reportedly 3:1,[12] manyrheumatologists believe the number of women with AS is underdiagnosed, as most women tend to experience milder cases of the disease. The majority of people with AS, including 95 per cent of people of European descent with the disease, express theHLA-B27 antigen[56] and high levels ofimmunoglobulin A (IgA) in the blood.[57] In 2007, a team of researchers discovered two genes that may contribute to the cause of AS:ARTS-1 andIL23R.[58] Together with HLA-B27, these two genes account for roughly 70 percent of the overall number of cases of the disease.
Drawing from 1857 ofLeonard Trask who had a severe case of AS
Ankylosing spondylitis was distinguished fromrheumatoid arthritis byGalen as early as the 2nd century AD.[59] Skeletal evidence of the disease (ossification of joints and entheses primarily of the axial skeleton, known as "bamboo spine") was thought to be found in the skeletal remains of a 5000-year-old Egyptian mummy with evidence of bamboo spine.[60][61] However, a subsequent report found that this was not the case.[62]
The anatomist and surgeonRealdo Colombo described what could have been the disease in 1559,[63] and the first account of pathologic changes to a skeleton possibly associated with AS was published in 1691 byBernard Connor.[64] In 1818,Benjamin Brodie became the first physician to document a person believed to have active AS who also had accompanyingiritis.[65]
In 1858, David Tucker published a small booklet which clearly described the case ofLeonard Trask, who had severe spinal deformity subsequent to AS.[66] In 1833, Trask fell from a horse, exacerbating the condition and resulting in severe deformity. Tucker reported:
It was not until he [Trask] had exercised for some time that he could perform any labor ... [H]is neck and back have continued to curve drawing his head downward on his breast.
The account of Trask became the first documented case of AS in the United States, owing to its indisputable description of inflammatory disease characteristics of AS and the hallmark of deforming injury in AS.
In the late nineteenth century, theneurophysiologistVladimir Bekhterev of Russia in 1893,[67]Adolf Strümpell of Germany in 1897,[68] andPierre Marie of France in 1898[69] were the first to give adequate descriptions which permitted an accurate diagnosis of AS prior to severe spinal deformity. For this reason, AS is also known as Bekhterev disease, Bechterew's disease or Marie–Strümpell disease.
The word is fromGreekankylos meaning crooked, curved or rounded,spondylos meaning vertebra, and-itis meaning inflammation.[2]
^Cantini F, Nannini C, Cassarà E, Kaloudi O, Niccoli L (November 2015). "Uveitis in Spondyloarthritis: An Overview".The Journal of Rheumatology. Supplement.93:27–9.doi:10.3899/jrheum.150630.PMID26523051.S2CID24715271.
^Rautenstrauch J, Gause A, Csernok E, Holle J, Gross WL (August 2001). "[Presentation of the Lubeck/Bad Bramstedt Competence Center]".Zeitschrift für Rheumatologie.60 (4):255–62.doi:10.1007/s003930170050.PMID11584722.S2CID43006040.
^Deodhar A, Reveille JD, van den Bosch F, Braun J, Burgos-Vargas R, Caplan L, et al. (October 2014). "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 & Rheumatology.66 (10):2649–56.doi:10.1002/art.38776.PMID25154344.S2CID38228595.
^abPoddubnyy D, van Tubergen A, Landewé R, Sieper J, van der Heijde D (August 2015). "Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis".Annals of the Rheumatic Diseases.74 (8):1483–7.doi:10.1136/annrheumdis-2014-207151.PMID25990288.S2CID42585224.
^Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A (December 1994). "A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index".The Journal of Rheumatology.21 (12):2286–91.PMID7699630.
^Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, Jenkinson T (December 1994). "A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index".The Journal of Rheumatology.21 (12):2281–5.PMID7699629.
^Thomas E, Silman AJ, Papageorgiou AC, Macfarlane GJ, Croft PR (February 1998). "Association between measures of spinal mobility and low back pain. An analysis of new attenders in primary care".Spine.23 (3):343–7.doi:10.1097/00007632-199802010-00011.PMID9507623.S2CID41982757.
^Akkoc, Nurullah; van der Linden, Sjef; Khan, Muhammad Asim (June 2006). "Ankylosing spondylitis and symptom-modifying vs disease-modifying therapy".Best Practice & Research. Clinical Rheumatology.20 (3):539–557.doi:10.1016/j.berh.2006.03.003.ISSN1521-6942.PMID16777581.
^Tracey, Daniel; Klareskog, Lars; Sasso, Eric H.; Salfeld, Jochen G.; Tak, Paul P. (February 2008). "Tumor necrosis factor antagonist mechanisms of action: a comprehensive review".Pharmacology & Therapeutics.117 (2):244–279.doi:10.1016/j.pharmthera.2007.10.001.ISSN0163-7258.PMID18155297.
^"Philadelphia Panel evidence-based clinical practice guidelines on selected rehabilitation interventions: overview and methodology".Physical Therapy.81 (10):1629–40. October 2001.PMID11589641.
^Zhao Q, Dong C, Liu Z, Li M, Wang J, Yin Y, Wang R (August 2020). "The effectiveness of aquatic physical therapy intervention on disease activity and function of ankylosing spondylitis patients: a meta-analysis".Psychology, Health & Medicine.25 (7):832–843.doi:10.1080/13548506.2019.1659984.PMID31475583.S2CID201714910.
^Romanowski MW, Straburzyńska-Lupa A (19 March 2020). "Is the whole-body cryotherapy a beneficial supplement to exercise therapy for patients with ankylosing spondylitis?".Journal of Back and Musculoskeletal Rehabilitation.33 (2):185–192.doi:10.3233/BMR-170978.PMID31594196.S2CID203984335.
^abAlpert JS (2006).The AHA Clinical Cardiac Consult. Lippincott Williams & Wilkins.ISBN978-0-7817-6490-2.
^Ahn NU, Ahn UM, Nallamshetty L, Springer BD, Buchowski JM, Funches L, et al. (October 2001). "Cauda equina syndrome in ankylosing spondylitis (the CES-AS syndrome): meta-analysis of outcomes after medical and surgical treatments".Journal of Spinal Disorders.14 (5):427–33.doi:10.1097/00002517-200110000-00009.PMID11586143.
^abBakland G, Gran JT, Nossent JC (November 2011). "Increased mortality in ankylosing spondylitis is related to disease activity".Annals of the Rheumatic Diseases.70 (11):1921–5.doi:10.1136/ard.2011.151191.PMID21784726.S2CID39397817.
^Radford EP, Doll R, Smith PG (September 1977). "Mortality among patients with ankylosing spondylitis not given X-ray therapy".The New England Journal of Medicine.297 (11):572–6.doi:10.1056/NEJM197709152971103.PMID887115.
^Brionez TF, Reveille JD (July 2008). "The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis".Current Opinion in Rheumatology.20 (4):384–91.doi:10.1097/BOR.0b013e32830460fe.PMID18525349.S2CID205485848.
^Saleem SN, Hawass Z (December 2014). "Ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis in royal Egyptian mummies of 18th −20th Dynasties? CT and archaeology studies".Arthritis & Rheumatology.66 (12):3311–6.doi:10.1002/art.38864.PMID25329920.S2CID42296180.
^Leden I (1994). "Did Bechterew describe the disease which is named after him? A question raised due to the centennial of his primary report".Scandinavian Journal of Rheumatology.23 (1):42–5.doi:10.3109/03009749409102134.PMID8108667.
_anagoria.JPG)
