Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy Medication

  • Author: Lawrence H Brent, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Apr 16, 2012
 

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and to prevent complications—specifically, by reducing the pain and inflammation associated with ankylosing spondylitis (AS). At present, no disease-modifying medications are available for the treatment of AS.

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Nonsteroidal Anti-inflammatory Drugs

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for reducing pain secondary to inflammation and systemic symptoms in AS patients. These agents reduce inflammatory symptoms of spinal and peripheral joint pain and morning stiffness and appear to have a modest disease-modifying effect on spinal disease. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as traditional NSAIDs.

NSAIDs and COX-2 inhibitors may increase the risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. They also increase the risk of serious adverse gastrointestinal (GI) effects, including stomach or intestinal bleeding, ulceration, and perforation, which can also be fatal. Elderly patients are at greater risk for serious GI events.

Sulfasalazine is also useful in improving symptoms, most notably peripheral arthritis.

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Indomethacin (Indocin)

 

Indomethacin is thought to be the most effective NSAID for the treatment of AS, although no scientific evidence supports this claim. It is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

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Ibuprofen (Ibu-200, Motrin, Advil, NeoProfen)

 

Ibuprofen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

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Naproxen (Naprosyn, Naprelan, Aleve, Anaprox)

 

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of COX, which results in a decrease of prostaglandin synthesis.

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Diclofenac (Voltaren, Cataflam XR, Zipsor, Cambia)

 

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

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5-Aminosalicylic Acid Derivatives

Class Summary

5-Aminosalicylic acid derivatives inhibit prostaglandin synthesis and reduce the inflammatory response to tissue injury.

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Sulfasalazine (Azulfidine, Azulfidine EN-tabs)

 

Sulfasalazine has been shown to reduce the inflammatory symptoms of AS in controlled studies; its most common toxicities include nausea, diarrhea, and hypersensitivity reactions (rash).

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DMARDs, TNF Inhibitors

Class Summary

Tumor necrosis factor alpha (TNF-α) antagonists are biologic agents and include etanercept, infliximab, and adalimumab. These agents inhibit TNF-α and have been shown to improve symptoms and function in AS patients in clinical trials. All have been approved for the treatment of AS. These agents are also all approved for the treatment of rheumatoid arthritis and psoriatic arthritis (PsA).

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Etanercept (Enbrel)

 

Etanercept consists of a fusion protein of the extracellular portion of the p75 TNF-α receptor and the Fc portion of immunoglobulin G (IgG). It inhibits TNF-α, reducing inflammation and symptoms of ankylosing spondylitis. It is given as a subcutaneous (SC) injection and is available in a prefilled syringe, an autoinjector, or lyophilized powder. It is also approved for rheumatoid arthritis, PsA, psoriasis, and juvenile idiopathic arthritis.

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Infliximab (Remicade)

 

Infliximab is a chimeric IgG1κ monoclonal antibody (mAb) directed against TNF-α. The variable regions of heavy and light chains are murine in origin, and the constant regions are human. Infliximab inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an intravenous (IV) infusion. It is also approved for rheumatoid arthritis, PsA, psoriasis, and Crohn disease.

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Adalimumab (Humira)

 

Adalimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis, PsA, psoriasis, juvenile idiopathic arthritis, and Crohn disease.

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Golimumab (Simponi)

 

Golimumab is a human IgG1κ mAb directed against TNF-α. It inhibits TNF-α, reducing inflammation and symptoms of AS. It is given as an SC injection and is available in a prefilled syringe or an autoinjector. It is also approved for rheumatoid arthritis and PsA.

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Immunosuppressants

Class Summary

Immunosuppressants inhibit key factors in the immune system that are responsible for inflammatory responses.

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Methotrexate (Trexall, Rheumatrex)

 

Methotrexate has an unknown mechanism of action in AS; it may affect immune function. Effects are observed in the 3-6 weeks following administration. Methotrexate ameliorates symptoms (eg, pain, swelling, stiffness), but there is no evidence that it induces remission. Adjust the dose gradually to obtain a satisfactory response.

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Contributor Information and Disclosures
Author

Lawrence H Brent, MD  Associate Professor of Medicine, Jefferson Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, and American College of Rheumatology

Disclosure: Abbott Honoraria Speaking and teaching; Centocor Consulting fee Consulting; Genentech Grant/research funds Other; HGS/GSK Honoraria Speaking and teaching; Omnicare Consulting fee Consulting; Pfizer Honoraria Speaking and teaching; Roche Speaking and teaching; Savient Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching

Coauthor(s)

Rajni Kalagate, MD  Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Rajni Kalagate, MD is a member of the following medical societies: American Academy of Pediatrics and Indian Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

Additional Contributors

Jason C Eck, DO, MS Assistant Professor, Department of Orthopedics and Physical Rehabilitation, UMass Memorial Medical Center

Jason C Eck, DO, MS is a member of the following medical societies: American Osteopathic Academy of Orthopedics, American Osteopathic Association, International Society for the Study of the Lumbar Spine, and North American Spine Society

Disclosure: Medtronic Honoraria Speaking and teaching

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Scott D Hodges, DO Consulting Surgeon, Department of Orthopedic Surgery, Center for Sports Medicine and Orthopedics

Scott D Hodges, DO is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Medical Association, American Osteopathic Association, American Spinal Injury Association, North American Spine Society, Southern Medical Association, Southern Orthopaedic Association, and Tennessee Medical Association

Disclosure: Medtronic Royalty Consulting; Biomet Spine Royalty Consulting

S Craig Humphreys, MD Orthopedic Spine Surgeon, Department of Orthopedic Surgery, Center for Sports Medicine and Orthopedics

S Craig Humphreys, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Orthopaedic Surgeons, American Medical Association, American Spinal Injury Association, North American Spine Society, Southern Medical Association, Southern Orthopaedic Association, and Tennessee Medical Association

Disclosure: Nothing to disclose.

James F Kellam, MD Vice-Chair, Department of Orthopedic Surgery, Director of Orthopedic Trauma and Education, Carolinas Medical Center

James F Kellam, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, Orthopaedic Trauma Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

William O Shaffer, MD Professor, Vice-Chairman and Residency Program Director, Department of Orthopedic Surgery, University of Kentucky at Lexington

William O Shaffer, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Association, International Society for the Study of the Lumbar Spine, Kentucky Medical Association, Kentucky Orthopaedic Society, North American Spine Society, Southern Medical Association, and Southern Orthopaedic Association

Disclosure: DePuySpine 1997-2007 (not presently) Royalty Consulting; DePuySpine 2002-2007 (closed) Grant/research funds SacroPelvic Instrumentation Biomechanical Study; DePuyBiologics 2005-2008 (closed) Grant/research funds Healos study just closed; DePuySpine 2009 Consulting fee Design of Offset Modification of Expedium

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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  92. Clegg DO, Reda DJ, Weisman MH, Blackburn WD, Cush JJ, Cannon GW, et al. Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheum. Dec 1996;39(12):2004-12. [Medline].

  93. Clegg DO, Reda DJ, Abdellatif M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study. Arthritis Rheum. Nov 1999;42(11):2325-9. [Medline].

  94. Braun J, Pavelka K, Ramos-Remus C, Dimic A, Vlahos B, Freundlich B, et al. Clinical efficacy of etanercept versus sulfasalazine in ankylosing spondylitis subjects with peripheral joint involvement. J Rheumatol. Apr 2012;39(4):836-40. [Medline].

  95. Inman RD, Maksymowych WP. A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol. Jun 2010;37(6):1203-10. [Medline].

  96. Braun J, Davis J, Dougados M, et al. First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis. Mar 2006;65(3):316-20. [Medline].

  97. Braun J, Baraliakos X, Golder W, et al. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis, before and after successful therapy with infliximab: evaluation of a new scoring system. Arthritis Rheum. Apr 2003;48(4):1126-36. [Medline].

  98. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med. May 2 2002;346(18):1349-56. [Medline].

  99. Davis JC, Van Der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum. Nov 2003;48(11):3230-6. [Medline].

  100. [Best Evidence] van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. Feb 2005;52(2):582-91. [Medline].

  101. Braun J, Landewé R, Hermann KG, et al. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum. May 2006;54(5):1646-52. [Medline].

  102. Gengenbacher M, Sebald HJ, Villiger PM, Hofstetter W, Seitz M. Infliximab inhibits bone resorption by circulating osteoclast precursor cells in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis. May 2008;67(5):620-4. [Medline].

  103. van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. Jul 2006;54(7):2136-46. [Medline].

  104. Inman RD, Davis JC Jr, Heijde D, Diekman L, Sieper J, Kim SI, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. Nov 2008;58(11):3402-12. [Medline].

  105. Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Emery P, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006. Ann Rheum Dis. Nov 2006;65 Suppl 3:iii2-15. [Medline].

  106. [Best Evidence] Chen J, Liu C, Lin J. Methotrexate for ankylosing spondylitis. Cochrane Database Syst Rev. Oct 18 2006;CD004524. [Medline].

  107. [Best Evidence] van Denderen JC, van der Paardt M, Nurmohamed MT, de Ryck YM, Dijkmans BA, van der Horst-Bruinsma IE. Double blind, randomised, placebo controlled study of leflunomide in the treatment of active ankylosing spondylitis. Ann Rheum Dis. Dec 2005;64(12):1761-4. [Medline].

  108. van der Heijde D, Dougados M, Davis J, Weisman MH, Maksymowych W, Braun J, et al. ASsessment in Ankylosing Spondylitis International Working Group/Spondylitis Association of America recommendations for conducting clinical trials in ankylosing spondylitis. Arthritis Rheum. Feb 2005;52(2):386-94. [Medline].

  109. Zochling J, Braun J. Assessments in ankylosing spondylitis. Best Pract Res Clin Rheumatol. Aug 2007;21(4):699-712. [Medline].

  110. Zochling J. Assessment and treatment of ankylosing spondylitis: current status and future directions. Curr Opin Rheumatol. Jul 2008;20(4):398-403. [Medline].

  111. Van Royen BJ, De Gast A. Lumbar osteotomy for correction of thoracolumbar kyphotic deformity in ankylosing spondylitis. A structured review of three methods of treatment. Ann Rheum Dis. Jul 1999;58(7):399-406. [Medline]. [Full Text].

  112. Shih LY, Chen TH, Lo WH, Yang DJ. Total hip arthroplasty in patients with ankylosing spondylitis: longterm followup. J Rheumatol. Sep 1995;22(9):1704-9. [Medline].

  113. Dagfinrud H, Kvien TK, Hagen KB. The Cochrane review of physiotherapy interventions for ankylosing spondylitis. J Rheumatol. Oct 2005;32(10):1899-906. [Medline].

  114. [Best Evidence] Dagfinrud H, Kvien TK, Hagen KB. Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev. Jan 23 2008;CD002822. [Medline].

  115. Hidding A, van der Linden S, Gielen X, et al. Continuation of group physical therapy is necessary in ankylosing spondylitis: results of a randomized controlled trial. Arthritis Care Res. Jun 1994;7(2):90-6. [Medline].

  116. Kraag G, Stokes B, Groh J, Helewa A, Goldsmith C. The effects of comprehensive home physiotherapy and supervision on patients with ankylosing spondylitis--a randomized controlled trial. J Rheumatol. Feb 1990;17(2):228-33. [Medline].

  117. Kisacik B, Tufan A, Kalyoncu U, et al. Mean platelet volume (MPV) as an inflammatory marker in ankylosing spondylitis and rheumatoid arthritis. Joint Bone Spine. May 2008;75(3):291-4. [Medline].

 
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The family of spondyloarthropathies
This radiograph of the pelvis of a patient with ankylosing spondylitis shows bilateral sacroiliitis with sclerosis and narrowing of the sacroiliac joints.
This radiograph of the lumbar spine of a patient with ankylosing spondylitis shows sclerosis of vertebral margins, which are referred to as shining corners.
This radiograph of the lumbar spine of a patient with end-stage ankylosing spondylitis shows bridging syndesmophytes, resulting in bamboo spine.
This radiograph of the cervical spine of a patient with ankylosing spondylitis shows fusion of vertebral bodies due to bridging syndesmophytes.
This radiograph of the heel of a patient with undifferentiated spondyloarthropathy shows bony changes secondary to enthesitis, with an erosion at the insertion of the Achilles tendon and periosteal new-bone formation at the insertion of the plantar fascia on the calcaneus.
This 15-year-old female patient presented with recent onset of right-sided low back pain. Plain radiography findings were normal.
MRI of the same patient whose radiography findings were normal (Picture 7). She underwent further evaluation, including MRI. The MRI (short tau inversion recovery [STIR]) showed increased sinal intensity in the right sacroiliac joint, revealing sacroiliitis. Other laboratory study findings were essentially normal. The patient was started on indomethacin and rapidly improved.
Patient with ankylosing spondylitis affecting cervical and upper thoracic spine. Patient's spine has been fused in flexed position.
Posterior view of patient with ankylosing spondylitis affecting cervical and upper thoracic spine. Patient's spine has been fused in flexed position.
Anteroposterior radiograph of sacroiliac joint of patient with ankylosing spondylitis. Bilateral sacroiliitis with sclerosis can be observed.
Anteroposterior radiograph of spine of patient with ankylosing spondylitis. Ossification of anulus fibrosus can be observed at multiple levels, which has led to fusion of spine with abnormal curvature.
Anteroposterior radiograph of spine of patient with ankylosing spondylitis. Ossification of anulus fibrosus at multiple levels and squaring of vertebral bodies can be observed.
Anteroposterior radiograph of spine of patient with ankylosing spondylitis.
Anteroposterior (left) and lateral (right) radiographs of patient with ankylosing spondylitis.
Radiographs of hand (top) and arm (bottom) of patient with peripheral involvement of ankylosing spondylitis. Fusion of joint spaces and deformity can be observed.
Sagittal MRI of thoracolumbar spine of a patient with ankylosing spondylitis. Degenerative disc disease and bridging osteophytes can be observed at multiple levels.
Radiograph shows vertebral fracture in patient with ankylosing spondylitis.
Table 1. Association of Spondyloarthropathies With HLA-B27
Population or Disease EntityHLA-B27 –Positive
Healthy whites8%
Healthy African Americans4%
Ankylosing spondylitis (whites)92%
Ankylosing spondylitis (African Americans)50%
Reactive arthritis60-80%
Psoriasis associated with spondylitis60%
IBD associated with spondylitis60%
Isolated acute anterior uveitis50%
Undifferentiated spondyloarthropathy20-25%
Table 2. Genetics of Ankylosing Spondylitis
GenesChromosome LocationGene Product/Function
Definitely associated



HLA-B27



IL-1 gene cluster



CYP 2D6



ARTS1 (ERAP1)



IL23R



6p21.3



2q12.1



22q13.2



5q15



1p31.1



Antigen presentation



Modulator of inflammation



Metabolism of xenobiotics



ER aminopeptidase 1



IL-23 receptor



Possibly associated



ANKH



HLA-DRB1



5p15



6p21.3



Ectopic mineralization



Antigen presentation



Not associated



TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc



MultipleMultiple
Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria
Inclusion CriteriaExclusion Criteria
Inflammatory back pain1 pointDiagnosis of specific spondyloarthropathy
Unilateral buttock pain1 pointSacroiliitis on radiograph = grade 2
Alternating buttock pain2 pointsPrecipitating genitourinary/gastrointestinal infection
Enthesitis2 pointsPsoriasis
Peripheral arthritis2 pointsKeratoderma blennorrhagicum
Dactylitis (sausage digit)2 pointsInflammatory bowel disease (Crohn disease or ulcerative colitis)
Acute anterior uveitis2 pointsPositive rheumatoid factor
HLA-B27 –positive or family history of spondyloarthropathy2 pointsPositive antinuclear antibody, titer > 1:80
Good response to nonsteroidal anti-inflammatory drugs2 points
Diagnosis of spondyloarthropathy with 6 or more points
Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy
Clinical or Laboratory FeatureFrequency
Inflammatory back pain90%
Buttock pain80%
Enthesitis75%
Peripheral arthritis40%
Dactylitis (sausage digits)20%
Acute anterior uveitis1-2%
Fatigue55%
Elevated ESR32%
HLA-B27 –positive25%
ESR = erythrocyte sedimentation rate.
Table 5. ESSG and Amor Criteria for Diagnosis of Spondyloarthropathy
ESSG CriteriaAmor Criteria*
Inflammatory spinal pain or synovitis and one of the following:Inflammatory back pain1 point
Alternating buttock painUnilateral buttock pain1 point
EnthesitisAlternating buttock pain2 points
SacroiliitisEnthesitis2 points
IBDPeripheral arthritis2 points
Positive family history of spondyloarthropathyDactylitis (sausage digit)2 points
Acute anterior uveitis2 points
HLA-B27 –positive or family history of spondyloarthropathy2 points
Good response to NSAIDs2 points
*Diagnosis of spondyloarthropathy with 6 or more points.



European Spondyloarthropathy Study Group (ESSG); IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug.



Table 6. New York and Rome Criteria for Diagnosis of Ankylosing Spondylitis
New York CriteriaRome Criteria
  • Low back pain with inflammatory characteristics
  • Limitation of lumbar spine motion in sagittal and frontal planes
  • Decreased chest expansion
  • Bilateral sacroiliitis grade 2 or higher
  • Unilateral sacroiliitis grade 3 or higher
  • Low back pain and stiffness for >3 months that is not relieved by rest
  • Pain and stiffness in the thoracic region
  • Limited motion in the lumbar spine
  • Limited chest expansion
  • History of uveitis
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteriaDiagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2 or higher
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