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An ankylosing spine in which the vertebrae become fused together.
Ankylosing spondylitis (AS, from Greek ankylos, fused; spondylos, vertebrae; -itis, inflammation), previously known as Bechterew's disease (or syndrome) and Marie-Strümpell disease, is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures. AS is a form of spondyloarthritis, a chronic, inflammatory arthritis where immune mechanisms are thought to have a key role. It mainly affects joints in the spine and the sacroiliac joint in the pelvis, and can cause eventual fusion of the spine.
Ankylosing spondylitis is a member of the group of the spondyloarthropathies with a strong genetic predisposition. Complete fusion results in a complete rigidity of the spine, a condition known as "bamboo spine". There is no cure for AS, although treatments and medications can reduce symptoms and pain.
Signs and symptoms
Symptoms appear gradually, usually around 23 years of age. Initial symptoms are typically chronic pain and stiffness in the middle part of the spine or the entire spine, often with pain referred to one or other buttock or the back of thigh from the sacroiliac joint. Since the initial signs and symptoms are not specific for ankylosing spondylitis, there is a lag-time between onset of disease and diagnosis, which averages between 8.5 years and 11.4 years.
About 40 percent of AS patients experience inflammation in the anterior chamber of the eye (uveitis), causing redness, eye pain, vision loss, floaters and photophobia. This is thought to be due to the association that both AS and uveitis have with the inheritance of the HLA-B27 antigen. Other common symptoms of AS include: generalized fatigue and sometimes nausea. Less commonly, aortitis, aortic valve insufficiency, apical lung fibrosis and ectasia of the sacral nerve root sheaths may occur. Another symptom of the disease is chest pain.
When the condition presents before the age of 18, it is relatively likely to cause pain and swelling of large limb joints, particularly the knee. In prepubescent cases, pain and swelling may also manifest in the ankles and feet, where calcaneal spurs may also develop.
Pain is often severe at rest, but improves with physical activity. However, many experience inflammation and pain to varying degrees regardless of rest and movement.
Ankylosing spondylitis is one of a cluster of conditions known as seronegative spondyloarthropathies, in which rheumatoid factor tests are negative and the characteristic pathological lesion is an inflammation of the enthesis (the insertion of tensile connective tissue into bone).
Ankylosing spondylitis (AS) is a systemic rheumatic disease, meaning it affects the entire body. Approximately 90% of AS patients express the HLA-B27 genotype, meaning there is a strong genetic association. However, only 5% of individuals with the HLA-B27 genotype contract the disease. Tumor necrosis factor-alpha (TNF α) and IL-1 are also implicated in ankylosing spondylitis. Autoantibodies specific for AS have not been identified. Anti-neutrophil cytoplasmic antibodies (ANCAs) are associated with AS, but do not correlate with disease severity. In a study of 40 patients with AS, ANCA was an infrequent finding, being present in only six patients.
The association of AS with HLA-B27 suggests the condition involves CD8 T cells, which interact with HLA-B. This interaction is not proven to involve a self antigen, and at least in the related Reiter's syndrome (reactive arthritis), which follows infections, the antigens involved are likely to be derived from intracellular microorganisms. There is, however, a possibility that CD4 T cells 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 with CD4 (usually only cytotoxic T lymphocytes with CD8 react with HLAB antigen as it is a MHC class 1 antigen).
In 2001, it was suggested that AS arises from a cross-reaction between HLA-B27 and antigens of the Klebsiella bacterial genus. The problem with this idea is that no such cross reactivity with B27 has been found (i.e. although antibody responses to Klebsiella may be increased, there is no antibody response to B27, so there seems to be no cross reactivity). Some authorities argue that the elimination of the prime nutrients of Klebsiella (i.e. starches) would decrease antigenemia and improve the musculoskeletal symptoms. However, as Khan (2002) argues, evidence for a correlation between Klebsiella and AS is circumstantial so far, and the efficacy of low-starch diets has not yet been scientifically evaluated. Studies on low-starch diet and AS could be difficult to fund; new biologics developed by the pharmaceutical industry may demonstrate efficacy, as well as financial benefit to the industry, whereas changing the diet would not. A randomized controlled trial in Turkey demonstrated that 12-week therapy with moxifloxacin (which would kill Klebsiella) resulted in "significant and sustained improvement" in inflammatory symptoms in patients with ankylosing spondylitis.
Toivanen (1999) found no support for the role of Klebsiella in the etiology of primary AS.
There is no direct test to diagnose AS. A clinical examination, magnetic resonance imaging (MRI), and X-ray studies of the spine, which show characteristic spinal changes and sacroiliitis, and a simple genetic marker blood test are the major diagnostic tools. A drawback of X-ray diagnosis is the signs and symptoms of AS have usually been established as long as 8–10 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. Options for earlier diagnosis are tomography and MRI of the sacroiliac joints, but the reliability of these tests is still unclear. The Schober's test is a useful clinical measure of flexion of the lumbar spine performed during examination.
During acute inflammatory periods, AS patients will sometimes show an increase in the blood concentration of C-reactive protein (CRP) and an increase in the erythrocyte sedimentation rate (ESR), 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.
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. HLA-B27, demonstrated in a blood test, can occasionally help with diagnosis, but in itself is not diagnostic of AS in a person with back pain. Over 95% of people that have been diagnosed with AS are HLA-B27 positive, although this ratio varies from population to population (only 50% of African American patients with AS possess HLA-B27, and it is close to 80% among AS patients from Mediterranean countries). In early onset disease HLA-B7/B*2705 heterozygotes exhibited the highest risk for disease.
The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), developed in Bath (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. (See: "Diagnostic Tools", below) It can be easily calculated and accurately assesses a patient's need for additional therapy; a patient 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 a patient's functional impairment due to the disease, as well as improvements following therapy. (See: "Diagnostic Tools", below) The BASFI is not usually used as a diagnostic tool, but rather as a tool to establish a patient's current baseline and subsequent response to therapy.
Medical professionals and experts in AS have speculated that maintaining good posture can reduce the likelihood of a fused or curved spine which occurs in a significant percentage of diagnosed persons.
The major types of medications used to treat ankylosing spondylitis are pain-relievers and drugs aimed at stopping or slowing the progression of the disease. Pain-relieving drugs come in two major classes:
- Anti-inflammatory drugs, which include NSAIDs such as ibuprofen, phenylbutazone, diclofenac, indomethacin, naproxen and COX-2 inhibitors, which reduce inflammation and pain. 2012 research showed that patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs.
- Opioid analgesics, which are addictive and not generally prescribed.
Drugs used to treat the progression of the disease include:
- Disease-modifying antirheumatic drugs (DMARDs) such as cyclosporin, methotrexate, sulfasalazine, and corticosteroids, are used to reduce the immune system response through immunosuppression;
- Tumor necrosis factor-alpha (TNFα) blockers (antagonists), such as the biologics etanercept, infliximab, golimumab and adalimumab, have shown good short-term effectiveness and trials are ongoing to determine their long-term effectiveness and safety. One drawback is the cost.
- Anti-interleukin-6 inhibitors such as Tocilizumab, currently approved for the treatment of rheumatoid arthritis, and rituximab, a monoclonal antibody against CD20, are also undergoing trials.
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 which make anaesthesia more complex. Changes in the upper airway can lead to difficulties in intubating the airway, spinal and epidural anaesthesia may be difficult owing to calcification of ligaments, and a small number of patients have aortic insufficiency. The stiffness of the thoracic ribs results in ventilation being mainly diaphragm-driven, so there may also be a decrease in pulmonary function.
Some of the therapies that have been shown to benefit AS patients include:
- Exercise programs, either at home or supervised, are better than not having an exercise program;
- Group exercises are better than home exercises;
- Extending regular group exercises with few weeks exercising at a spa resort is better than group exercises alone.
Moderate-to-high impact exercises like jogging are generally not recommended or recommended with restrictions due to the jarring of affected vertebrae that can worsen pain and stiffness in some patients.
AS can range from mild to progressively debilitating and from medically controlled to refractory. Some have times of active inflammation followed by times of remission, while others never have times of remission and have acute inflammation and pain.
Unattended cases of AS accompanied by dactylitis or enthesitis, especially when spine inflammation is not yet active, may result in a misdiagnosis of normal rheumatism. In a long-term undiagnosed period, osteopenia or osteoporosis of the AP spine may occur, causing eventual compression fractures and a back "hump". Typical signs of progressed AS are the visible formation of syndesmophytes on X-rays and abnormal bone outgrowths similar to osteophytes affecting the spine. The fusion of the vertebrae paresthesia is a complication due to the inflammation of the tissue surrounding nerves.
Organs commonly affected by AS, other than the axial spine and other joints, are the heart, lungs, eyes, colon, and kidneys. Other complications are aortic regurgitation, Achilles tendinitis, AV node block and amyloidosis. Owing to lung fibrosis, chest X-rays may show apical fibrosis, while pulmonary function testing may reveal a restrictive lung defect. Very rare complications involve neurologic conditions such as the cauda equina syndrome.
Mortality is increased in patients with AS and circulatory disease is the most frequent cause of death; and because increased mortality in ankylosing spondylitis is related to disease activity, factors negatively affecting patient outcome include:
- Male gender
- Plus 3 of the following in the first 2 years of disease:
In 2007, a collaborative effort by an international team of researchers in the United Kingdom, Australia and the United States led to the discovery of two genes that also contribute to the cause of AS: ARTS-1 and IL23R. The findings were published in the November 2007 edition of Nature Genetics, a journal that emphasizes research on the genetic basis for common and complex diseases. Together with HLA-B27, these two genes account for roughly 70 percent of the overall incidence of the disease.
The overall prevalence of AS is 0.25 percent, and it is more common in men; three males are diagnosed with AS for every one female. However, many rheumatologists believe the number of women with AS is underdiagnosed, as most women tend to experience milder symptoms. The majority of AS patients, including 95 percent of white patients, express the HLA-B27 antigen and high levels of immunoglobulin A (IgA) in the blood. The onset of the disease is typically between 15 and 25 years of age.
The HLA-B27 antigen is also expressed by Klebsiella bacteria, which are found in high levels in the feces of AS patients. A theory suggests the presence of the bacteria may be a trigger of the disease, and reducing the amount of starch in the diet (which these bacteria require to grow) may be of benefit to AS patients. A test of this diet resulted in reduced symptoms and inflammation in patients with AS as well as IgA levels in individuals with and without AS. Further research is required to determine if diet changes may have a clinical effect on the course of the disease.
AS has a long history, having been distinguished from rheumatoid arthritis by Galen as early as the second century AD. Skeletal evidence of the disease (ossification of joints and entheses primarily of the axial skeleton, known as "bamboo spine") was found in an archaeological dig that unearthed the skeletal remains of a 5000-year–old Egyptian mummy with evidence of bamboo spine.
The anatomist and surgeon Realdo Colombo described what could have been the disease in 1559, and the first account of pathologic changes to the skeleton possibly associated with AS was published in 1691 by Bernard Connor. In 1818, Benjamin Brodie became the first physician to document a patient believed to have active AS who also had accompanying iritis.
In 1858, David Tucker published a small booklet which clearly described a patient, Leonard Trask, who suffered from severe spinal deformity subsequent to AS. 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.||”|
This account 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.
It was not until the late nineteenth century, however, when the neurophysiologist Vladimir Bekhterev of Russia in 1893, Adolph Strümpell of Germany in 1897, and Pierre Marie of France in 1898 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.
- Ankylosing Spondylitis Quality of Life (ASQoL) Questionnaire
- NIAMS, the National Institute of Arthritis and Musculoskeletal and Skin Diseases
- SAA, Spondylitis Association of America
- AF, Arthritis Foundation
- "Ankylosing Spondylitis: MedlinePlus". U.S. National Library of Medicine. Archived from the original on 27 March 2011. Retrieved 26 April 2011.
- J Sieper, J Braun, M Rudwaleit, A Boonen, and A Zink (2002). "Ankylosing spondylitis: an overview". Annals of the Rheumatic Diseases 61 (3): iii8. doi:10.1136/ard.61.suppl_3.iii8. PMC 1766729. PMID 12381506.
- Jiménez-Balderas FJ, Mintz G. (1993). "Ankylosing spondylitis: clinical course in women and men". J Rheumatol 20 (12): 2069–72. PMID 7516975.
- Toivanen A, Möttönen T. (1998). "Ankylosing spondylitis: current approaches to treatment". BioDrugs 10 (3): 193–200. doi:10.2165/00063030-199810030-00003. PMID 18020595.
- Williams RO, Paleolog E, Feldmann M. (2007). "Cytokine inhibitors in rheumatoid arthritis and other autoimmune diseases". Curr Opin Pharmacol 7 (4): 412–7. doi:10.1016/j.coph.2007.06.001. PMID 17627887.
- Feldtkeller, E.; Khan, M.; Van Der Heijde, D.; Van Der Linden, S.; Braun, J. (2003). "Age at disease onset and diagnosis delay in HLA-B27 negative vs. Positive patients with ankylosing spondylitis". Rheumatology international 23 (2): 61–66. doi:10.1007/s00296-002-0237-4. PMID 12634937.
- "Ankylosing Spondylitis - Exams and Tests". WebMD. Retrieved 19 July 2013.
- Reveille JD (2006). "Major histocompatibility genes and ankylosing spondylitis". Best Practice & Research Clinical Rheumatology 20 (3): 601–609. doi:10.1016/j.berh.2006.03.004. PMID 16777585.
- H Locht, T Skogh, and E Kihlström (1999). "Anti-lactoferrin antibodies and other types of anti-neutrophil cytoplasmic antibodies (ANCA) in reactive arthritis and ankylosing spondylitis". The Journal of Clinical & Experimental Immunology 117 (3): 568–569. doi:10.1046/j.1365-2249.1999.01008.x. PMC 1905360. PMID 10469064.
- Tiwana H, Natt R, Benitez-Brito R, Shah S, Wilson C, Bridger S, Harbord M, Sarner M, Ebringer A (2001). "Correlation between the immune responses to collagens type I, III, IV and V and Klebsiella pneumoniae in patients with Crohn's disease and ankylosing spondylitis". Rheumatology (Oxford) 40 (1): 15–23. doi:10.1093/rheumatology/40.1.15. PMID 11157137.
- Khan MA. (2002). Ankylosing spondylitis: The facts. Oxford University Press. ISBN 0-19-263282-5.
- Ogrendik, M (2007). "Treatment of ankylosing spondylitis with moxifloxacin.". Southern Medical Journal 100 (4): 366–70. PMID 17458395.
- Toivanen P, Hansen D, Mestre F, Lehtonen L, Vaahtovuo J, Vehma M, Möttönen T, Saario R, Luukkainen R, Nissilä M (1 September 1999). "Somatic serogroups, capsular types, and species of fecal Klebsiella in patients with ankylosing spondylitis". J Clin Microbiol 37 (9): 2808–12. PMC 85385. PMID 10449457.
- Thomas E, Silman AJ, Papageorgiou AC, Macfarlane GJ, Croft PR. (1998). "Association between measures of spinal mobility and low back pain. An analysis of new attenders in primary care". Spine 23 (2): 343–7. doi:10.1097/00007632-199802010-00011. PMID 9507623.
- Harjacek M, Margetić T, Kerhin-Brkljacić V, Martinez N, Grubić Z (2008). "HLA-B*27/HLA-B*07 in combination with D6S273-134 allele is associated with increased susceptibility to juvenile spondyloarthropathies". Clin. Exp. Rheumatol. 26 (3): 498–504. PMID 18578977.
- Garrett S, Jenkinson T, Kennedy L, Whitelock H, Gaisford P, Calin A (1994). "A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index". J Rheumatol 21 (12): 2286–91. PMID 7699630.
- Calin A, Garrett S, Whitelock H, Kennedy L, O'Hea J, Mallorie P, Jenkinson T (1994). "A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index". J Rheumatol 21 (12): 2281–5. PMID 7699629.
- "Ankylosing Spondylitis, Treatment Options". Arthritis Foundation (arthritis.org). 2010. Retrieved August 2010
- Kroon F, Landewé R, Dougados M, van der Heijde D (October 2012). "Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis". Ann. Rheum. Dis. 71 (10): 1623–9. doi:10.1136/annrheumdis-2012-201370. PMID 22532639.
- Chen, J; Veras, MM; Liu, C; Lin, J (2013 Feb 28). "Methotrexate for ankylosing spondylitis.". The Cochrane database of systematic reviews 2: CD004524. doi:10.1002/14651858.CD004524.pub4. PMID 23450553.
- Chen, J; Liu, C (2005 Apr 18). "Sulfasalazine for ankylosing spondylitis.". The Cochrane database of systematic reviews (2): CD004800. doi:10.1002/14651858.CD004800.pub2. PMID 15846731.
- Henes, Joerg; Horger, Guenaydin, Kanz, Koetter (February 2010). "Mixed response to tocilizumab for ankylosing spondylitis". Annals of the Rheumatic Diseases 69 (12): 2217–2218. doi:10.1136/ard.2009.126706. PMID 20851032.
- Rodriguez-Escalera, C.; Fernandez-Nebro, A. (2008). "The use of rituximab to treat a patient with ankylosing spondylitis and hepatitis B". Rheumatology 47 (11): 1732–1733. doi:10.1093/rheumatology/ken362. PMID 18786966.
- Dagfinrud, H; Kvien, TK; Hagen, KB (2008 Jan 23). "Physiotherapy interventions for ankylosing spondylitis.". The Cochrane database of systematic reviews (1): CD002822. doi:10.1002/14651858.CD002822.pub3. PMID 18254008.
- Alpert, Joseph S. (2006). The AHA Clinical Cardiac Consult. Lippincott Williams & Wilkins. ISBN 0-7817-6490-4.
- Nicholas U. Ahn, Uri M. Ahn, Elizabeth S. Garrett et al. (2001). "Cauda Equina Syndrome in AS (The CES-AS Syndrome): Meta-analysis of outcomes after medical and surgical treatments". J of Spinal Disorders 14 (5): 427–433. doi:10.1097/00002517-200110000-00009. PMID 11586143.
- Bakland G, Gran JT, Nossent JC (November 2011). "Increased mortality in ankylosing spondylitis is related to disease activity". Ann. Rheum. Dis. 70 (11): 1921–5. doi:10.1136/ard.2011.151191. PMID 21784726.
- Radford EP, Doll R, Smith PG (September 1977). "Mortality among patients with ankylosing spondylitis not given X-ray therapy". N. Engl. J. Med. 297 (11): 572–6. doi:10.1056/NEJM197709152971103. PMID 887115.
- Brionez TF, Reveille JD (July 2008). "The contribution of genes outside the major histocompatibility complex to susceptibility to ankylosing spondylitis". Curr Opin Rheumatol 20 (4): 384–91. doi:10.1097/BOR.0b013e32830460fe. PMID 18525349.
- "Arthritis Research Campaign – Ankylosing Spondylitis Case History". Arthritis Research Campaign. 2009. Retrieved 25 August 2009.
- Goldman, Lee (2011). Goldman's Cecil Medicine (24th ed.). Philadelphia: Elsevier Saunders. p. 607. ISBN 1-4377-2788-3.
- Ebringer A, Wilson C (15 Jan 1996). "The use of a low starch diet in the treatment of patients suffering from ankylosing spondylitis". Clin Rheumatol. 15 Suppl 1: 62–66. PMID 8835506.
- Dieppe P (1988). "Did Galen describe rheumatoid arthritis?". Annals of the Rheumatic Diseases 47 (1): 84–87. doi:10.1136/ard.47.1.84-b. PMC 1003452. PMID 3278697.
- Calin A (April 1985). "Ankylosing spondylitis". Clin Rheum Dis 11 (1): 41–60. PMID 3158467.
- Benoist M (April 1995). "Pierre Marie. Pioneer investigator in ankylosing spondylitis". Spine 20 (7): 849–52. doi:10.1097/00007632-199504000-00022. PMID 7701402.
- BLUMBERG BS (December 1958). "Bernard Connor's description of the pathology of ankylosing spondylitis". Arthritis Rheum. 1 (6): 553–63. doi:10.1002/art.1780010609. PMID 13607268.
- Leden I (1994). "Did Bechterew describe the disease which is named after him? A question raised due to the centennial of his primary report". Scand J Rheumatol 23 (1): 42–5. doi:10.3109/03009749409102134. PMID 8108667.
- "Life and sufferings of Leonard Trask" (PDF). Ankylosing Spondylitis Information Matrix.
- Bechterew W. (1893). "Steifigkeit der Wirbelsaule und ihre Verkrummung als besondere Erkrankungsform". Neurol Centralbl 12: 426–434.
- Strumpell A. (1897). "Bemerkung uber die chronische ankylosirende Entzundung der Wirbelsaule und der Huftgelenke". Dtsch Z Nervenheilkd 11 (3–4): 338–342. doi:10.1007/BF01674127.
- Marie P. (1898). "Sur la spondylose rhizomelique". Rev Med 18: 285–315.
- Ankylosing spondylitis at the Open Directory Project
- NASS – National Anklosying Spondylitis Society
- Ankylosing spondylitis - University of Washington Department of Orthopaedics & Sports Medicine Patient Article
- Bath Ankylosing Spondylitis Disease Activity Index Calculator (BASDAI)
- Bath Ankylosing Spondylitis Functional Index Calculator (BASFI)