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Ankylosing spondylitis (AS) is a chronic inflammatory disease of the spine and sacroiliac joints. It may be associated with a number of extra-articular structures, such as the eye, gastrointestinal (GI) tract, skin, lungs, kidneys, and heart. AS usually begins in the second or third decade with a male-to-female prevalence between 2:1 to 3:1. AS is the prototype of the spondyloarthritis. The two major types of spondyloarthritides are AS (axial spondyloarthritis with sacroilitis on the plain X-ray), and non-radiographic spondyloarthritis (no sacrolilitis on plain X-ray). The term axial spondyloarthritis is becoming more commonly used for AS.
Patients with AS have morning stiffness and low back pain, or pain in the buttocks. The etiology remains unclear, but appears to be immune-mediated, and associated with a strong inheritable component: human leukocyte antigen (HLA) B27.
Enthesitis, inflammation at tendinous and ligamentous attachments, is one of the central features of AS, and results in many of the presenting symptoms of pain.
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AS is diagnosed based upon the recognition pattern of clinical, laboratory, and imaging findings characteristic of AS. The likelihood of diagnosis varies depending upon the specific findings that are present. There is no specific test, single historical feature, or imaging finding which is sufficient to diagnose or rule out the disease.
The Modified New York Criteria for AS proposed in 1984 are the following:
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Low back pain for at least 3 months’ duration that is improved by exercise, and not relieved by rest.
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Limitation of the lumbar spine motion in the sagittal, and frontal planes.
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Chest expansion that is decreased relative to normal values for age and sex.
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Radiographic unilateral sacroiliitis grade 3-4.
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Radiographic bilateral sacroiliitis grade 2-4.
The diagnosis of AS is definite if 4 or 5 is present, and any of the criteria 1-3.
The New York criteria are most useful for established disease in the later stages because of its heavy reliance on the demonstration of sacroiliitis radiographically. The utility of these criteria is decreased in patients with early disease that may not have clear radiographic findings.
It is important to establish diagnosis of early AS before the development of irreversible deformity. In 2009, new criteria for axial spondyloarthritis was proposed by the Assessment of Spondyloarthritis International Society (ASAS). These criteria are applicable to individuals with back pain of 3 months or more with age of onset <45years or less.
ASAS criteria also includes spondyloarthritis features, HLA B-27, and CRP/ESR.
Features of SpA (spondyloarthritis)
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Inflammatory back pain
3 months or more
Insidious onset
Not relieved with rest
Improvement with exercise
Pain at night
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Heel pain due to Achilles tendinitis or plantar fasciitis (enthesitis)
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Dactylitis (sausage digit; painful digit inflammation)
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Uveitis
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Family history of AS
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Alternate buttock pain
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Psoriasis
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Asymmetric arthritis
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Positive response to NSAID
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High ESR or CRP
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IBD (crohns disease or ulcerative colitis)
Sacroilitis on imaging PLUS One, or more SpA features
Active inflammation of SI joint on MRI suggestive of SpA, or HLA B -27 Plus 2, or more SpA features, and/or definite sacroilitis, according to modified New York Criteria, the spinal features of AS almost never appear before the age of 16. Less than 5% of patients have symptoms that begin after age 40, although AS is frequently diagnosed after the age of 40 because initial symptoms are mild or ignored. The average age of onset is 26 years and most symptoms tend to present during the third decade.
The typical patient with AS presents with dull pain in the lower lumbar region or gluteal region. They may complain about morning stiffness of the lower back that lasts for a few hours and improves with activity. The onset is usually insidious. The pain tends to persist for more than 3 months, and is notably worsened by rest and improved by exercise. Nocturnal exacerbations of the pain will often force the patient to rise, and move around.
Bony tenderness, likely due to enthesitis, is common at sites such as costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, and heels. Additional findings include synovitis of hips, knees, ankles, and metatarsalphalangeal (MTP) joints. Upper limb joints, except for the shoulder, are almost never involved.
Arthritis in the hips and shoulders occurs in up to 30% of patients with AS. Arthritis of the peripheral joints other than hips and shoulders, usually asymmetric, occurs in 30% of patients. Neck pain and stiffness are usually late manifestations. Peripheral arthritis is transient in 50% of case and permanent in 25% cases. Anterior uveitis develops in approximately 33% of patients with AS, and may occur prior to the onset of spondylitis. Once AS is diagnosed, it is unusual for the uveitis to coincide with flares of arthritis.
There is a distinct relationship between bowel inflammation and sacroiliitis. Although up to 25% of patients with Crohn’s or ulcerative colitis (UC) have sacroiliitis, nearly 60% of patients with AS have subclinical findings of inflammatory changes in the small or large bowel. About 10% of patients with AS have overt Crohn’s or UC.
A few percent of patients with AS develop cardiac conduction abnormalities or aortitis. The risk of these developments increases with age and disease duration, but can manifest as complete heart block, and aortic insufficiency with congestive heart failure.
Pulmonary findings in patients with AS include upper lobe fibrosis and extrapulmonary restrictive lung disease from increased rigidity of the chest wall. The fibrosis is seen only in longstanding disease and is found in only 1% of patients with AS. The extrapulmonary restrictive lung disease is usually compensated for by increased diaphragmatic excursion, and rarely leads to severe pulmonary symptoms, but may exacerbate other forms of pulmonary disease.
Neurologic disease is usually due to cord or nerve root lesions from spinal fracture. Up to 25% of patients with AS may have psoriatic lesions.
The prevalence of AS is highly variable. It is estimated to be approximately 1% among Caucasian populations in the United States and United Kingdom, but the data is sparse. In Haida Native Americans in Northern Canada, the prevalence is around 6%.
AS correlates well with the histocompatibility antigen HLA-B27. More than 90% of patients with AS have inherited HLA-B27. In North American Caucasians, the prevalence of HLA-B27 is 7%. Of those who have inherited HLA-B27, it is estimated that only 1-6% actually develop AS. Therefore, HLA B-27 is not used a diagnostic test. In families of patients with AS, the prevalence may be nearly 30% in first-degree relatives with HLA-B27. The concordance rate among identical twins is 65%, which supports the presumed genetic component.
AS is more common in men than in women. The male: female ratio is estimated at 2:1 although, there is thought to be an under-estimation of women with AS.
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Inflammatory bowel disease
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Psoriasis
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Reactive arthritis
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Rheumatoid arthritis
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Osteoarthritis
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Tendonitis
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Plantar fasciitis
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Fibromyalgia
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Vertebral compression fracture
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Sacroiliac joint infection
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Familial Mediterranean fever
AS is distinguished by the appearance of symptoms at a young age. It may be associated with symptoms and features of inflammatory bowel disease and psoriasis. The average age of onset is 26 years. A key historical component of AS is that the back pain persists for more than 3 months, and is worsened by rest and improved by exercise.
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As a sign of sacroiliitis, some patients may have pain in the buttocks when pushing on the sacrum. Many patients have limited spinal mobility. This can be seen with flexion, and extension of the lumbar spine. The modified Schober test may be used to determine lumbar spine flexion.
The modified Schober test is performed by making two horizontal lines at 5cm below, and 10cm above the lumbosacral junction. Lumbosacral junction as identified by a horizontal line between the posterosuperior iliac spines. While standing erect with heels firmly planted together, the patient bends forward as far as possible with knees fully extended and the distance between the two lines is measured. If the distance increases by 5cm, this is normal. If the distance increases by less than 4 cm, this is abnormal and a sign of limited spinal mobility.
Signs of synovitis and enthesitis are common as well. This often presents with joint tenderness or bony tenderness over tendon insertion sites.
Otherwise, the physical exam for AS is highly variable.
No laboratory test is diagnostic of AS. CRP and ESR are often, but not always elevated. It currently remains a clinical diagnosis although imaging to establish sacroiliitis is helpful.
Following are the diagnostic steps adapted from 2013 ASAS modified Berlin algorithm to help the establish the diagnosis.
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Step 1 – In a patient with chronic back pain (at least 3 months) with onset age <45 years, obtain a plain X-ray of pelvis to examine the SI joints. AS diagnosis can be made if it meets the modified New York criteria. No further investigation is required.
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Step 2 – In a patient with a negative SI joint X-ray, review history for the 11 features of SpA. Presence of 4 out of 11 characteristic features of SpA is diagnostic of non- radiographic axial spondyloarthritis (nr-AxSpA). No additional testing is needed.
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Step 3 – In a patient with fewer than 4 SpA features and a negative SI joint X-ray undergo HLA B-27 testing. A positive HLA-B27 test may generally indicate a diagnosis of non-radiographic axial spondyloarthritis (nr-AxSpA).
However, a patient with 2 or 3 features and negative HLA-B27 and no sacroiliitis on X-ray has low likelihood of SpA. If the clinical suspicion remains high, MRI of SI joints should be done to support the diagnosis of nr-AxSpA.
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Step 4 – A patient with zero or one feature of SpA but +HLA-B27 should have a MRI of SI joints. An MRI that is positive for sacroiliitis supports the diagnosis of non-radiographic spondyloarthritis.
The diagnosis of AS is a clinical diagnosis. The role of HLA-B27 in establishing the diagnosis is unclear and under investigation. HLAB27 has utility in patients who have intermediate probability. An erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be used to help determine disease activity, but are not diagnostic. Serum alkaline phosphatase is often elevated in an advanced disease. Elevated IgA levels are common. Rheumatoid factor, anti-CCP antibodies, ANA and ANCA are usually with in normal range, and may be abnormal if these diseases coexist.
Anterioposterior radiographs of the pelvis may show pseudo widening of the sacroiliac joint as well as sclerosis, erosions and ankylosing. In a patient with high clinical suspicion and negative pelvic X-ray, MRI with T1-weighted plus STIR sequences or T2-weighted images with fat suppression are the most sensitive. Bone marrow edema in the subchondral areas on STIR or on T2-weighted images with fat suppression is a defining observation of active inflammation of the SI joints. These MRI findings alone are not diagnostic, and should be interpreted in the context of other clinical and laboratory findings. Contrast-enhancement is not required.
CT scan has a very limited utility because it is nonspecific, and does not provide information about inflammation of the joints. It also results in greater radiation exposure.
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CT scan, bone scan
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Disease activity should be determined by using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Unlike the BASDAI, the ankylosing spondylitis disease activity score (ASDAS) takes into account acute phase reactants. General assessment should include physical function, pain, spinal mobility, stiffness, fatigue, peripheral joint disease, patient global assessment, and acute phase reactants. Initial treatment for all patients should include physical therapy, exercise, and patient education.
All patients who are symptomatic should be given a trial of non-steroidal anti-inflammatory drugs (NSAIDs) for relief of musculoskeletal symptoms. To assess the usefulness of the NSAID, it should be given at a sustained dose on a regular basis for at least 4 weeks. The recommendation is to try at least two different NSAIDs before declaring this class of drugs ineffective.
Other analgesics and opioids are seldom affective during an active AS when used alone.
Patients with a BASDAI of 4 or above and a physician global score of 2 or above, and NSAID- resistant disease are considered to have moderate disease, and should receive additional therapy.
Sulfasalazine (2 to 3 g daily) may benefit the patient with mainly peripheral arthritis. For patients with axial symptoms, an anti-tumor necrosis factor (anti-TNF) agent, such as etanercept or the monoclonal antibodies such as infliximab, golimumab, or adalimubab should be prescribed. For AS patients with inflammatory bowel disease, a monoclonal antibody is preferred over etanercept.
Disease-modifying antirheumatic drugs (DMARDs), with the exception of sulfasalazine as mentioned above, are not recommended for treatment of ankylosing spondylitis per the Assessment of Spondyloarthritis International Society (ASAS) guidelines.
Corticosteroids have a minimal impact on arthritis and particularly spondylitis, and can worsen osteopenia.
Methotrexate and leflunomide has no benefit in the disease.
Tocilizumab monoclonal antibody against IL-6 receptor and abatacept which blocks the T cell costimulation has not been found to be beneficial.
Secukinumab, an Interleukin (IL)-17A monoclonal antibody, has a beneficial role in active AS in patients who have inadequate response to other therapies, including TNF-inhibitors.
Ustekinumab is a monoclonal antibody against p40 protein subunit shared by IL-12, IL-23.
Amitryptyline has been shown to benefit patients with AS with sleep disturbances, and fatigue.
Pamidronate (60 mg monthly intravenously) has decreased disease activity and produced measurable improvements in function.
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Acute anterior uveitis is the most common extra-articular manifestation of AS and can be the presenting symptom of the disease. Uveitis can be managed with local glucocorticoids, and mydriatic agents. Occasionally, systemic corticosteroids or immunosuppressive medications may be needed in refractory cases.
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Disease activity should be determined by using the BASDAI. Physical function can be determined by using the Bath Ankylosing Spondylitis Functional Index (BASFI).
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ESR and CRP can be used to follow disease activity.
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Long-term management for all patients should include physical therapy, exercise, and patient education. Extended periods of immobilization should be kept to a minimum.
Cessation of smoking is strongly encouraged.
Immunosuppressive agents, such as etanercept and infliximab, have been associated with infections (tuberculosis), pancytopenia, demyelinating disease, exacerbations of congestive heart failure, and injection site reactions. Drug-induced lupus may also be seen with these medications.
Pamidronate may cause transient lymphopenia.
Long-term use of NSAIDs should be avoided in patients with chronic kidney disease, a recent history of peptic ulcer disease, and a moderate risk of coronary artery disease.
NSAID use is cautioned with methotrexate. NSAIDs may increase the serum levels of methotrexate.
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Avoid NSAIDs and methotrexate.
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Caution with the use of anti-TNF agents, especially in patients who are chronic carriers of hepatitis B.
Anti-TNF agents have been associated with exacerbations of congestive heart failure. Caution is advised.
Avoid long-term use of NSAIDs.
Caution with the use of systemic glucocorticoids, which are generally not recommended for the treatment of AS.
Anti-TNF agents are associated with an increased risk of lymphoma.
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Caution with the use of additional immunosuppressive agents, especially anti-TNF medications.
No change in standard management.
Avoid NSAIDs in patients with recent upper GI bleeds.
Anti-TNF agents and methotrexate may cause bone marrow suppression.
No change in standard management.
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Monitor for infusion site reactions or side effects of anti-TNF medications.
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The majority of this illness is treated as an outpatient. The duration of inpatient treatment is unclear.
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Close follow-up with a rheumatologist is recommended.
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Rheumatologist within 2 weeks (if admitted for primary complications of AS)
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Primary care physician
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If AS is severe enough to require hospital admission, inpatient physical therapy may be required if the patient does not improve quickly. An assessment by physical medicine, and rehabilitation may be necessary. If the patient is severely debilitated, nursing home placement may be appropriate. A functional assessment and purified protein derivative (PPD) is usually required for nursing home placement.
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Ren, L, Li, J, Renkuan, T. “Efficacy of Antitumor Necrosis Factor (α) Agents on Patients with Ankylosing Spondylitis”. Am J Med Sci. vol. 6. 2013. pp. 455-461.
Rudwaleit, M. “The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection”. Ann of Rheum Dis. vol. 68. 2009. pp. 777
Beaten, D. “Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial”. Lancet. vol. 382. 2013. pp. 1705
Poddubnyy, D. “Ustekinumab for the treatment of patients with active ankylosing spondylitis”. Ann Rheum Dis. vol. 73. 2014. pp. 817
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