WORKUP	Section 5 of 11
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Lab Studies:

• The diagnosis of AS is not dependent on laboratory data.

• Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are found in approximately 75% of patients and are used as markers of disease activity and response to treatment.

• Other laboratory values, including alkaline phosphatase and creatine kinase, may be elevated; however, these values are generally not used to assess disease activity.

• While HLA-B27 is present in most patients with AS, its presence is not necessary to establish the diagnosis.

Imaging Studies:

• Radiographs

• Radiographic evidence of inflammatory changes both in the SI joints and the spine are useful in the diagnosis and ongoing evaluation of the disease process.

• Involvement of the SI joint is a requirement for the diagnosis of AS. Sacroiliitis is a bilateral inflammatory condition leading to bony erosions and sclerosis of the joints (see Image 3).

• Involvement of the spine is observed radiographically with squaring of the vertebral bodies and ossification of the annulus fibrosis, leading to bridging or syndesmophytes (see Images 4-7). This disease generally begins in the distal portions of the spine and progresses more proximally with time.

• Plain radiographs of the peripheral skeleton can demonstrate inflammatory changes in some patients, including loss of joint spaces, sclerosis, and deformation (see Image 8).

• MRI

• In most patients, plain radiographs are sufficient to visualize and track the disease progression. However, MRI can be used as an adjunct to evaluate the inflammatory changes and to assess neural compromise (see Image 9).

• Immediately perform MRI on patients who develop bowel or bladder dysfunction to assess for possible cauda equina syndrome secondary to spinal stenosis (see Surgical care).

• CT scans may be useful in patients with suspected spinal fracture with equivocal radiographs.

Other Tests:

• Diagnosis of AS generally is based on clinical presentation.

• The New York Criteria for the diagnosis of AS, which is based on clinical and radiographic findings, are as follows:

• Limitation of motion of the lumbar spine in all 3 planes

• History of pain or presence of pain at the thoracolumbar junction or in the lumbar spine

• Limitation of chest expansion to 1 inch or less measured at the fourth intercostal space

• Radiographic sacroiliac changes are as follows:

• Normal

• Suspicious

• Minimal sacroiliitis

• Moderate sacroiliitis

• Ankylosis

• Definite AS if (1) grade 3-4 bilateral sacroiliitis with at least 1 clinical criterion or (2) grade 3-4 unilateral or grade 2 bilateral sacroiliitis with clinical criterion 1 or with both clinical criteria 2 and 3. Probable AS if grade 3-4 bilateral sacroiliitis exists without any signs or symptoms satisfying the clinical criteria.

• As noted in the New York Criteria, radiographic evidence of SI changes is graded from a normal SI joint (grade 0) to evidence of complete ankylosis (grade 4). The disease progression is a gradual process, and the grading is somewhat subjective.

Biopsy and histologic analysis is not indicated for individuals with AS.

	TREATMENT	Section 6 of 11
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Medical Care:

• No preventative measure or definitive treatment exists for individuals with AS. Early diagnosis and proper patient education are important.

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are used commonly to reduce pain and decrease inflammation. Aspirin has been reported to have limited benefit. Oral steroids are not used for long-term management of AS because of the high risk of adverse effects.

• Sulfasalazine has been reported to be effective in some patients with peripheral involvement. Sulfasalazine is also useful in patients with coexisting inflammatory bowel disease.

• Laboratory values, including ESR and CRP, are used commonly to monitor the progression of the disease and the effectiveness of treatment.

• After identifying persons with extra-articular manifestations, provide proper treatment or refer them to the appropriate specialist. These extra-articular manifestations include acute iritis, aortitis, heart block, pulmonary fibrosis, amyloidosis, and neurologic deficits including cauda equina.

• Genetic counseling and patient support groups are useful in further educating patients about the disease process and in identifying individuals at increased risk.

Surgical Care:

• Surgical treatment is geared toward resolution of complications related to AS. No curative surgical treatment exists.

• Patients with fusion of the cervical or upper thoracic spine may have significant impairment in line of sight, eating, and psychosocial well-being. These patients may benefit from extension osteotomy of the cervical spine. This procedure is difficult and hazardous; however, if successful, it allows the patient to return to a more functional life.

• Patients with fusion of the spine secondary to AS who report a change in position of the spine should cautiously be treated and should be considered to have sustained a spinal fracture. Surgical intervention may be necessary to stabilize the fracture and prevent neurologic deficit.

• Patients who develop bowel or bladder dysfunction should be evaluated immediately with MRI to assess for possible cauda equina syndrome secondary to spinal stenosis. The presence of cauda equina syndrome is a surgical emergency requiring decompression within 48 hours to prevent permanent loss of function.

• Patients with significant involvement of the hips may benefit from total hip arthroplasty. Following surgery, heterotropic bone formation can be reduced with use of indomethacin or radiation therapy.

Consultations:

• Rheumatologist: Consult a rheumatologist for evaluation and management of ongoing medical treatment of patients with AS. Additional coexisting seronegative spondyloarthropathies can be assessed.

• Gastroenterologist: Refer patients with symptoms suggesting coexisting inflammatory bowel disease to a gastroenterologist for evaluation.

• Cardiologist: Refer patients with cardiac involvement, including aortitis or heart block, to a cardiologist for evaluation.

• Physical therapist or physical medicine and rehabilitation specialist: Refer all patients to a physical therapist or rehabilitation specialist. Symptoms of AS are worse with inactivity and are relieved with exercise. As a result, a proper exercise program is a crucial element of treatment.

• Geneticist: Patients may be referred for genetic counseling to assess questions regarding probabilities of relatives developing the disease.

• Support groups: Many patients benefit from various support groups, which can provide further education on the disease process and available treatment options.

Diet:

• Generally, no dietary restrictions are implemented for patients with AS; however, patients with coexisting diseases, such as inflammatory bowel disease, have dietary restrictions.

Activity:

• A proper exercise program is a crucial component in the treatment of AS. Patients obtain a significant reduction in symptoms following exercising. Referral to physical therapy or rehabilitation specialist is useful in assisting patients to develop an appropriate exercise program.

	MEDICATION	Section 7 of 11
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Pharmacotherapy generally is aimed at reducing pain and inflammation associated with the disease. Currently, no disease-modifying medications are available for the treatment of AS.

Drug Category: Nonsteroidal anti-inflammatory drugs -- Useful in reducing pain and inflammation associated with AS.

Drug Name	Indomethacin (Indocin, Indochron ER) -- Rapidly absorbed. Metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation. Inhibits prostaglandin synthesis.
Adult Dose	25-50 mg PO bid/tid 75 mg SR PO bid; not to exceed 200 mg/d
Pediatric Dose	1-2 mg/kg/d divided PO bid/qid; not to exceed 4 mg/kg/d or 150-200 mg/d
Contraindications	Documented hypersensitivity; GI bleeding; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia exists)

Drug Name	Diclofenac (Voltaren, Cataflam) -- Inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which, in turn, decreases formation of prostaglandin precursors.
Adult Dose	25 mg PO bid/tid; if well tolerated, increase by 25 mg or 50 mg at weekly intervals until satisfactory response is obtained or total daily dose of 150-200 mg is reached; higher doses generally do not increase effectiveness
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; do not administer into CNS; do not give to patients with peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; low white blood cell counts occur rarely and usually return to normal in ongoing therapy; discontinuation of therapy may be necessary if persistent leukopenia, granulocytopenia, or thrombocytopenia exists

Drug Name	Naproxen (Aleve, Naprelan, Anaprox) -- For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.
Adult Dose	250-500 mg PO bid; may increase to 1.5 g/d for limited periods
Pediatric Dose	<2 years: Not established >2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Drug Category: Aminosalicylic acid derivatives -- Inhibit inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis.

Drug Name	Sulfasalazine (Azulfidine, EN-tabs) -- Useful in management of ulcerative colitis. Acts locally in colon to decrease inflammatory response. Systemically inhibits prostaglandin synthesis.
Adult Dose	1 g PO tid/qid initially, followed by maintenance dose of 2 g/d in divided doses
Pediatric Dose	<2 years: Not established >2 years: 40-60 mg/kg/d PO in 3-6 divided doses; follow by maintenance dose of 20-30 mg/kg/d divided qid
Contraindications	Documented hypersensitivity; sulfa drugs or any component of sulfa drugs; those diagnosed with GI or GU obstruction
Interactions	Decreases effects of iron, digoxin, and folic acid; conversely, increases effect of oral anticoagulants, oral hypoglycemic agents, and methotrexate
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction

Drug Category: Immunosuppressants -- Inhibit key factors in the immune system responsible for inflammatory responses.

Drug Name	Methotrexate (Folex PFS, Rheumatrex) -- Unknown mechanism of action in AS; may affect immune function. Effects observed in 3-6 weeks following administration. Ameliorates symptoms (eg, pain, swelling, stiffness) but has no evidence of inducing remission. Adjust dose gradually to attain satisfactory response.
Adult Dose	30-40 mg/m2/wk PO/IM to 100-7500 mg/m2 with leucovorin rescue
Pediatric Dose	5-15 mg/m2/wk PO/IM as single dose or as 3 divided doses given q12h
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides (including TMP-SMZ) can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBC counts monthly, and monitor liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, during dose adjustments, or when risk of elevated MTX levels [eg, dehydration] exists); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs

Drug Category: Tumor necrosis factor (TNF) inhibitors -- TNF is a cytokine of which 2 forms have been identified with similar biological properties. TNF-alpha or cachectin is produced predominantly by macrophages, and TNF-beta or lymphotoxin is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to symptoms.

Drug Name	Infliximab (Remicade) -- Neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Mix in 250 mL normal saline for infusion over 2 h. Must use with low-protein–binding filter (<1.2 mm). Indicated to reduce signs and symptoms of active ankylosing spondylitis.
Adult Dose	5 mg/kg IV infusion at 0, 2, and 6 wk as induction regimen, then 5 mg/kg q6wk for maintenance IV infusion must be administered over at least 2 h; must use infusion set with in-line, sterile, nonpyrogenic, low-protein–binding filter (pore size <1.2 mm)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	TNF-alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF alpha-blockers compared with control groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections

	FOLLOW-UP	Section 8 of 11
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Further Inpatient Care:

• Inpatient care generally is not necessary for patients with AS. The exceptions to this include patients with coexisting or extra-articular disease or those requiring surgery.

Further Outpatient Care:

• Outpatient care should be aimed toward providing adequate pain control and maximizing motion and functional ability. Outpatient care includes pain medication, exercise programs, recreational therapy, and vocational therapy.

• Disease progress and response to therapy can be monitored by laboratory values, including CRP and ESR.

In/Out Patient Meds:

• NSAIDs routinely are used for pain control and anti-inflammatory effects.

• Local steroid injections are useful for persistent synovitis and enthesitis.

• Sulfasalazine is useful in patients who do not respond to or who have contraindications to NSAIDs. Sulfasalazine is also useful for patients with coexisting inflammatory bowel disease.

• MTX is reserved for patients with symptoms that are not adequately controlled with NSAIDs or sulfasalazine.

Deterrence/Prevention:

• Currently, no accepted methods exist for the prevention of AS. Regular exercise is useful in reducing the symptoms and may slow the progress of the disease.

Complications:

• The most common complications of AS include pain, stiffness, and limited functional disability. All of these complications can be reduced through a proper treatment plan consisting of medications, exercise, and education.

• Patients with AS often have additional coexisting diseases including other seronegative spondyloarthropathies. Inflammatory bowel disease is also more common in these individuals.

• Fractures

• The most serious complication related to AS is a vertebral fracture. For a patient with advanced AS, minor trauma is capable of producing an unstable spinal injury with risk of neurologic injury or death.

• Vertebral fractures are more likely to produce spinal instability in an individual with AS than in an individual without AS because in advanced AS, the fracture occurs as in a long bone fracture. The fracture disrupts not only the bony elements but also the ligamentous supports that have become ossified. Without the ligamentous support, the spine becomes grossly unstable, which can lead to severe neurologic injury including paralysis and death.

• Vertebral fractures associated with AS are most common in the cervical spine and are most commonly the result of a minor fall.

• Proper diagnosis of a vertebral fracture often is delayed because of the patient not realizing the need to seek medical help, failure of the physician to consider vertebral fracture following minor trauma, or difficulty in radiographic visualization of the fracture.

• Radiographic diagnosis is difficult in some cases because of the presence of osteopenia and spinal deformity. Additionally, immobility of the glenohumeral joint can interfere with the patients ability to obtain an adequate "swimmer's view" to visualize the lower cervical spine.

• In many cases, CT scans are required to better assess the spine. The possibility of fractures in the transverse plane suggests the need for sagittal reformatting of the images. If visualization is still inadequate, MRI and bone scans may be helpful.

• Spondylodiscitis

• Spondylodiscitis is also referred to as Andersson lesions, which are named after the physician who first reported on them. An Andersson lesion is a destructive discovertebral lesion with an estimated symptomatic prevalence of 1-10% in patients with AS. The prevalence in asymptomatic patients is unknown.

• The etiology of spondylodiscitis is debatable. Some authors argue that these lesions are the result of mechanical factors, while other authors believe the inflammation caused by AS is the source. Each of these possible etiologies is likely capable of producing similar lesions.

• Spondylodiscitis can occur at any time, regardless of the severity of AS. Patients generally present with localized pain with an acute onset. Pain is exacerbated with movement and is alleviated with rest. These symptoms can be easily differentiated from the normal pain pattern of AS, which is insidious in onset and relieved with motion.

• Radiologic evidence of spondylodiscitis varies with the disease progression but can include destructive foci throughout the discovertebral junction, bony sclerosis on both sides of the affected disc level, widening or narrowing of the disc space, and osteolysis of the vertebral bodies.

• Plain radiographs are not always sufficient to identify spondylodiscitis. CT scan, MRI, and bone scan often are helpful in confirming the diagnosis.

• Prognosis is generally good with conservative therapy including rest, administrations of NSAIDs, and physical therapy. Surgical treatment is only indicated in cases with evidence of spinal instability of neurologic injury.

Prognosis:

• Life expectancy generally is not affected by AS unless the patient has other significant coexisting diseases.

• At the onset of the disease, symptoms generally are unilateral and intermittent. As the disease progresses, pain and stiffness generally become more severe and more constant. Adequate exercise can improve symptoms and ROM.

• Most patients are able to remain fully functional and continue working. Some patients may need to find employment that is less physically demanding as the symptoms increase. Vocational therapy is useful in assisting patients with these issues.

Patient Education:

• Patient education is essential in disease management. Inform patients that proper exercise programs are useful in reducing symptoms and increasing ROM. Various patient support groups are available to assist in the education of these patients.

• Genetic counseling is useful in assisting patients with questions regarding the risk of family members developing AS or other seronegative spondyloarthropathies.

• For excellent patient education resources, visit eMedicine's Muscle Disorders Center. Also, see eMedicine's patient education article Chronic Pain.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Patients with a history of AS who report any recent trauma or an increased level of back or neck pain should be fully evaluated for the possibility of a vertebral fracture and subsequent spinal instability (see Image 10).

Special Concerns:

• Many patients with advanced disease have fusion of the spine. As discussed above, if these patients report any change in position or movement of the spine, they should be assumed to have a spinal fracture since this is the only method for the spine to move. Patients should be treated cautiously until fracture has been ruled out. If spinal fracture is present, surgical stabilization may be necessary.

• Symptoms generally are not affected by pregnancy or childbirth. Medical management of the disease, including medications, must be adjusted during pregnancy based on the specific pregnancy profiles of the medications.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Patient with ankylosing spondylitis affecting the cervical and upper thoracic spine. The patient's spine has been fused in a flexed position.
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Caption: Picture 2. Back view of a patient with ankylosing spondylitis affecting the cervical and upper thoracic spine. The patient's spine has been fused in a flexed position.
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Caption: Picture 3. Anteroposterior radiograph of the sacroiliac joint of a patient with ankylosing spondylitis. Bilateral sacroiliitis with sclerosis can be observed.
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Caption: Picture 4. Anteroposterior radiograph of the spine of a patient with ankylosing spondylitis. Ossification of the annulus fibrosis can be observed at multiple levels, which has led to fusion of the spine with abnormal curvature.
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Caption: Picture 5. Anteroposterior radiograph of the spine of a patient with ankylosing spondylitis. Ossification of the annulus fibrosis at multiple levels and squaring of the vertebral bodies can be observed.
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Caption: Picture 6. Anteroposterior radiograph of the spine of a patient with ankylosing spondylitis.
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Caption: Picture 7. Anteroposterior and lateral radiographs of a patient with ankylosing spondylitis.
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Caption: Picture 8. Radiographs of a hand and an arm of a patient with peripheral involvement of ankylosing spondylitis. Fusion of the joint spaces and deformity can be observed.
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Caption: Picture 9. Sagittal MRI of the thoracolumbar spine of a patient with ankylosing spondylitis. Degenerative disc disease and bridging osteophytes can be observed at multiple levels.
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Caption: Picture 10. Radiograph showing a vertebral fracture in a patient with ankylosing spondylitis.
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	BIBLIOGRAPHY	Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Ankylosing Spondylitis excerpt