Clinical review

Diagnosis and management of ankylosing spondylitis

¹ Department of Rheumatology, Musgrave Park Hospital, Belfast BT9 7JB

Correspondence to: A P Cairns andrew.cairns{at}greenpark.n-i.nhs.uk

	Introduction

 
Ankylosing spondylitis is a chronic inflammatory rheumatic disorder that primarily affects the axial skeleton. Sacroiliitis is its hallmark, accompanied by inflammation of the entheses (points of union between tendon, ligament, or capsule and bone) and formation of syndesmophytes, leading to spinal ankylosis in later stages. Prevalence estimates vary between 0.1% and 2% in different populations.¹ The male:female ratio is around 5:1, and the peak age of onset is at 15-35 years.

Because of its insidious nature, the diagnosis is sometimes delayed until late stages of the disease. Until recently, treatment has been limited to non-steroidal anti-inflammatory drugs and physiotherapy, but the development of cytokine inhibitors that inhibit the activity of tumour necrosis factor has been an important advance in treatment.

	Sources and selection criteria

 
We searched Medline for clinical trials and reviews using the keywords "ankylosing spondylitis," "treatment," "physiotherapy," "NSAIDs," "DMARDs," "anti-TNF," and "biologics."

	How is it diagnosed?

 
The most commonly used criteria for the classification of ankylosing spondylitis were developed in 1966 and modified in 1984.^{2 3} They are:

1. Low back pain of at least three months duration with inflammatory characteristics (improved by exercise, not relieved by rest)
   
2. Limitation of lumbar spine motion in sagittal and frontal planes
   
3. Decreased chest expansion (relative to normal values for age and sex)
   
4. Bilateral sacroiliitis grade 2 or higher
   
5. Unilateral sacroiliitis grade 3 or higher.
   

Definite ankylosing spondylitis is said to be present when the fourth or fifth criterion presents with any clinical criteria. However, radiological sacroiliitis may not develop for many years, and the development of new criteria (including magnetic resonance imaging) has been proposed to allow confirmation of the diagnosis in patients with early disease (see below).⁴

History
The key point in a patient's history is inflammatory back pain.⁵ This typically presents as low back pain and stiffness of insidious onset that is worse first thing in the morning or after rest, lasts at least 30 minutes, and improves with activity. Sacroiliitis may present as ill defined unilateral or bilateral buttock pain, with radiation sometimes felt into the upper posterior thigh. Pain may also be felt in the cervical or thoracic region or in the chest. Occasionally, patients present with symptoms arising from peripheral joint synovitis or enthesitis (such as achilles enthesitis or plantar fasciitis). Sleep disturbance and daytime fatigue are common.

A recent study to try to identify a new candidate set of criteria for inflammatory back pain found a sensitivity of 70% and specificity of 81% when at least two of the following four criteria were present?morning stiffness of more than 30 minutes duration; improvement in back pain with exercise but not with rest; waking because of back pain during the second half of the night only; and alternating buttock pain.⁶

Ankylosing spondylitis may overlap with other spondyloarthropathies?including psoriatic arthritis, reactive arthritis, and enteropathic arthropathy?which can be difficult to distinguish from ankylosing spondylitis, particularly in early stages. Clinicians should therefore have a high index of suspicion in patients presenting with inflammatory back pain and a history of iritis, psoriasis, inflammatory bowel disease, or recent infection.

Fig 1 Plain radiograph showing bilateral sacroiliitis in a patient with ankylosing spondylitis

Genetics
About 90-95% of white western European patients with ankylosing spondylitis have the tissue human leukocyte antigen B27 (HLA-B27), compared with around 8% in the general population,¹ though prevalences vary in different populations.^w3 The association is complex, as there are several subtypes of HLA-B27, not all of which are pathogenic, and other non-HLA-B27 genes also play a role. The disease is likely to be triggered by an unknown environmental factor in patients who are genetically predisposed.^w4 It should be remembered that most individuals who possess HLA-B27 will never develop ankylosing spondylitis.

Laboratory findings
Most, but not all, patients with ankylosing spondylitis will have elevated levels of C reactive protein and erythrocyte sedimentation rates. Levels of inflammatory markers are less useful for monitoring disease activity in ankylosing spondylitis than they are in other inflammatory conditions such as rheumatoid arthritis, and may relate more to disease activity in peripheral joints than axial disease. A normocytic normochromic anaemia may be present, particularly in patients with active disease.

Imaging
Sacroiliitis is the hallmark of the disease. Changes classically occur in the lower third of the sacroiliac joints. Initially the joint may seem blurred and indistinct, followed by bony erosions, sclerosis, and the apparent widening of the joint (fig 1). Complete bony fusion may occur in longstanding disease. ⁵ Spinal radiographic changes include marginal vertebral body erosions, squaring of the vertebral bodies, and the formation of bony bridges or syndesmophytes between adjacent vertebrae. Ossification of spinal ligaments may occur, and spinal osteopenia is common. In severe longstanding disease, almost complete fusion of the vertebral column may occur ("bamboo spine").

Plain radiographs may be normal in early disease, and further imaging, particularly magnetic resonance imaging, plays an important role in the early diagnosis of ankylosing spondylitis (fig 2). Magnetic resonance imaging of the sacroiliac joints has been shown to be more sensitive than either plain radiography or computed tomography in detecting sacroiliitis.⁷ It may therefore be considered in patients presenting with typical characteristics of inflammatory back pain but normal plain radiographs, particularly if they are seropositive for HLA-B27.^{w5 w6} Magnetic resonance imaging may also be used to monitor treatment in patients with active ankylosing spondylitis.^{8 9 w7} Musculoskeletal ultrasound scanning is particularly helpful in the diagnosis of enthesitis.¹⁰

Fig 2 Coronal STIR (short tau inversion recovery) magnetic resonance image showing unilateral (right) sacroiliitis

Osteoporosis and fracture
Osteoporosis and fracture are common in ankylosing spondylitis.^w8-w10 Dual energy x ray absorptiometry may underestimate the fracture risk in ankylosing spondylitis because of new bone formation, particularly in the spine. Measurement of biochemical markers of bone turnover has been used in research into ankylosing spondylitis and may be of clinical value in future.¹¹ Fractures most commonly occur at the thoracolumbar and cervicothoracic junctions and may occur with minimal trauma. Clinicians should have a low threshold of suspicion of fracture, particularly in patients with previously stable ankylosing spondylitis who present with acute persistent spinal pain.

	How is it treated?

 
New evidence based recommendations for the management of ankylosing spondylitis have been produced by the International Assessment in Ankylosing Spondylitis working group in collaboration with the European League Against Rheumatism.^{12 13}

Physiotherapy
This is a key element of the overall management of all patients. A recent Cochrane review found evidence that physiotherapy had beneficial effects for patients with ankylosing spondylitis, but it was not clear which specific treatment protocol should be followed.¹⁴ Many patients find hydrotherapy particularly beneficial.^w11

Non-steroidal anti-inflammatory drugs
Randomised controlled trials have shown that, compared with placebo, NSAIDs improve spinal pain, peripheral joint pain, and function in ankylosing spondylitis.¹³ Cyclo-oxygenase-2 selective inhibitors and traditional NSAIDs seem broadly similar in efficacy. One study has suggested that regular use of NSAIDs, starting with celecoxib, inhibits radiographic progression in ankylosing spondylitis compared with NSAID use on demand, giving some support to the regular use of NSAIDs in active ankylosing spondylitis.¹⁵ The decision on which NSAID to use should be on an individual patient basis taking into account risk factors, particularly for gastrointestinal and cardiovascular disease. Analgesics, including paracetamol and opioids, may be considered when NSAIDs are contraindicated or not tolerated.

Disease modifying antirheumatic drugs
Sulfasalazine has inconclusive evidence for efficacy in ankylosing spondylitis. A recent Cochrane review of 12 randomised controlled trials has found some evidence of benefit in peripheral joint symptoms and in reducing morning stiffness and erythrocyte sedimentation rate but no evidence of benefit in physical function, pain, spinal mobility, enthesitis, or patient or physician global assessment.¹⁶

A Cochrane review of methotrexate for treating ankylosing spondylitis concluded that there was no evidence to support its use.^w12 It included only two papers, however, and a subsequent small study of low dose methotrexate did suggest some clinical benefit in ankylosing spondylitis.^w13 There is little evidence to support the use of other traditional disease modifying antirheumatic drugs in ankylosing spondylitis.^w14

Corticosteroids
Intra-articular or periarticular corticosteroid injections for sacroiliitis have been shown to be effective in small trials.^{w15 w16} Local corticosteroid injections for peripheral arthritis and enthesitis in ankylosing spondylitis are widely used in clinical practice to good effect, but no clinical trials exist to support this use. Intravenous methylprednisolone is occasionally used in severe unresponsive cases, but this use may decline with the availability of tumour necrosis factor inhibitors.

Bisphosphonates
Oral bisphosphonates are commonly used for fracture prevention in ankylosing spondylitis.^w17 Bisphosphonates also have an anti-inflammatory action and may have an effect on disease activity. Intravenous pulses of the bisphosphonate pamidronate have been investigated in several studies and have produced significant clinical improvements in some but not all studies.^{11 17 w18 w19}

Cardiovascular risk
In common with other inflammatory rheumatic conditions, ankylosing spondylitis is associated with increased rates of cardiovascular morbidity and mortality.^w20 This may be only partially explained by traditional risk factors, and it seems likely that the chronic inflammatory nature of the condition is partially responsible. Clinicians should be alert to this and take action to identify and treat traditional modifiable cardiovascular risk factors. It has been proposed that better control of the underlying inflammatory condition may improve this risk. It is also possible that chronic use of NSAIDs may increase this risk. As well as their effect on lipids, statins also have an anti-inflammatory effect, and a recent small open study has reported that rosuvastatin treatment produced clinical improvement in ankylosing spondylitis.^w21

Surgery
A large proportion of patients with ankylosing spondylitis develop hip arthritis. Hip replacement should be considered in patients with refractory pain or disability and with radiographic evidence of structural damage, independent of age.^{12 w22 w23} Spinal surgery may be of value in selected patients and is performed for a variety of reasons in ankylosing spondylitis patients, including fusion procedures for segmental instability and wedge lumbar osteotomy for fixed kyphotic deformity.¹² Patients with severe ankylosing spondylitis present anaesthetic difficulties, and the risks and benefits of surgery need to be carefully considered.

	Tumour necrosis factor inhibitors

 
Drugs that inhibit tumour necrosis factor (TNF) have revolutionised the treatment of ankylosing spondylitis. Three different drugs are currently available?etanercept, a recombinant TNF receptor: Fc fusion protein that is administered subcutaneously; infliximab, a chimeric monoclonal antibody to TNF given by intravenous infusion; and adalimumab, a humanised monoclonal antibody to TNF given subcutaneously. These drugs have been widely used in the treatment of severe rheumatoid arthritis.^w24

Evidence from randomised controlled studies supports the use of etanercept^18-20 and infliximab^{21 22} to treat ankylosing spondylitis for spinal pain, function, and peripheral joint disease. More recently adalimumab has also been shown to be effective.^{23 w25} The drugs have rapid and substantial clinical effects. Recent studies have also shown marked persistent reduction of spinal inflammation as detected by magnetic resonance imaging.^{9 24} Treatment with TNF inhibitors should be considered for patients with persistently high disease activity despite conventional treatments.¹²

The case for using these drugs in ankylosing spondylitis is perhaps even more compelling than in rheumatoid arthritis: they are at least as effective in treating ankylosing spondylitis as they are in rheumatoid arthritis,^w26 whereas the evidence to support the use of other disease modifying antirheumatic drugs in ankylosing spondylitis is much weaker. The British Society for Rheumatology has produced guidelines for the use of TNF inhibitors in ankylosing spondylitis.²⁵ Patients should have persistent active disease as defined by the Bath ankylosing spondylitis disease activity index (BASDAI)²⁶ and persistent spinal pain despite trials of two or more NSAIDs.

TNF inhibitors seem to achieve higher rates of remission in patients with shorter duration of disease: in one study, remission occurred in 35% of patients with less than 10 years since first symptoms, in 24% of those with disease duration of 10-20 years, but in none of those who had had the condition for more than 20 years.²⁷ The possibility that treatment early in the disease course improves remission rates needs confirmation, but it underlines the importance of diagnosing ankylosing spondylitis early, before established radiological changes are evident.

Stopping treatment with TNF inhibitors results in rapid relapse for most patients with longstanding disease.^w27 However, in patients with early rheumatoid arthritis (< 1 year duration) remission induction with infliximab plus methotrexate significantly reduced joint inflammation and erosion (shown by magnetic resonance imaging) at one year, and the functional and quality of life benefits were sustained at two years despite stopping infliximab treatment.²⁸ Further study is required to determine whether treating patients with early ankylosing spondylitis with a TNF inhibitor could produce remission that is sustained on withdrawal of treatment. If so, then it would be logical to treat patients with a short course of TNF inhibitor at an early stage (perhaps at diagnosis) rather than later in the disease course, when the treatment needs to be continued long term, perhaps for life (though long term data are lacking).

TNF inhibitors are powerful drugs and carry the risk of significant adverse effects. Increased rates of infection have been reported, including tuberculosis, and pretreatment screening is carried out routinely as part of assessment.^{w28 w29} Active infection is a contraindication to treatment, and patients taking the drugs are warned to stop treatment and consult their doctor immediately if they develop any symptoms suggestive of infection.²⁹ If any patient receiving a TNF inhibitor presents feeling unwell the possibility of infection should always be considered. If there is doubt the drug should be withheld and advice sought from a rheumatology department. It is also possible that long term use of the drugs may predispose patients to the development of some malignancies.^w29 Other reported side effects include demyelinating disease, lupus-like syndromes, and worsening of pre-existing congestive cardiac failure, as well as injection site or infusion reactions.

TNF inhibitors are also expensive, and formal cost benefit analyses are complex. However, the large improvements in pain and function may outweigh the initial high financial costs, particularly if patients can remain in employment and out of hospital.^w30 Early treatment with the drugs may also reduce later requirement for surgery. The availability of funding for the drugs varies between the different countries of the United Kingdom. At the time of writing, the National Institute for Health and Clinical Excellence (NICE) is reviewing the clinical and cost effectiveness of these drugs for ankylosing spondylitis for England and Wales. It is expected to issue guidance in 2007. The Scottish Medicines Consortium has approved the use of etanercept and infliximab in NHS Scotland for ankylosing spondylitis according to the British Society for Rheumatology guidelines. In Northern Ireland patients meeting these guidelines are also eligible for treatment, but funding is restricted and a waiting list has developed.^w31

Extra references w1-w31 are on bmj.com.

We thank David Taylor, consultant radiologist, Musgrave Park Hospital, Belfast, for providing the images.

Contributors: CMMcV performed the literature search and wrote the initial draft of the paper. APC planned the review, wrote the outline, and the final version. Both approved the final version.

Competing interests: CMMcV has received funding to attend meetings from MSD, Pfizer, Sanofi-Aventis, Novartis, Schering-Plough, Wyeth and Roche. She has given talks for Sanofi-Aventis. APC has received funding to attend meetings from MSD, Pfizer, Abbott, Schering-Plough, Wyeth and Roche. He has given talks for MSD, Pfizer, Sanofi-Aventis, and Abbott, and has received an equipment grant from Wyeth.

	References

 

1. Gran JT, Husby G. Epidemiology of ankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 3 rd ed. London: Mosby, 2003: 1153-9.
2. Moll JM, Wright V. New York clinical criteria for ankylosing spondylitis: a statistical evaluation. Ann Rheum Dis 1973;32: 354-63.
3. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 1984;27: 361-8.
4. Rudwaleit M, Khan MA, Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? Arthritis Rheum 2005;52: 1000-8.
5. Khan MA. Clinical features of ankylosing spondylitis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 3 rd ed. London: Mosby, 2003: 1161-81.
6. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondylitis: a reassessment of the clinical history for application as classification and diagnostic criteria. Arthritis Rheum 2006;54: 569-78.
7. Yu W, Feng F, Dion E, Yang H, Jiang M, Genant HK. Comparison of radiography, computed tomography and magnetic resonance imaging in the detection of sacroileitis accompanying ankylosing spondylitis. Skeletal Radiol 1998;27: 311-20.
8. Braun J, Landewe R, Hermann KG, Han J, Yan S, Williamson P, et al. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: Results of a multicentre, randomised, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum 2006;54: 1646-52.
9. Baraliakos X, Brandt J, Listing J, Haibel H, Sorensen H, Rudwaleit M, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 2005;53: 856-63.
10. Balint PV, Kane D, Wilson H, McInnes IB, Sturrock RD. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61: 905-10.
11. Cairns AP, Wright SA, Taggart AJ, Coward SM, Wright GD. An open study of pulse pamidronate treatment in severe ankylosing spondylitis, and its effect on biochemical markers of bone turnover. Ann Rheum Dis 2005;64: 338-9.
12. Zochling J, van der Heijde D, Burgos-Vargas R, Collantes E, Davis J, Dijkmans B, et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2006;54: 442-52.
13. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis. Ann Rheum Dis 2006;65: 423-32.
14. Dagfinrud H, Kvein TK, Hagen K. Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev 2004;(4):CD002822.
15. Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, et al. Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis. Arthritis Rheum 2005;52: 1756-65.
16. Chen J, Liu C. Sulphasalazine for ankylosing spondylitis. Cochrane Database Syst Rev 2005;(2):CD004800.
17. Maksymowych WP, Jhangri GS, Fitzgerald AA, LeClerq S, Chiu P, Yan A, et al. A six-month randomised, controlled, double-blind, dose-response comparison of intravenous pamidronate (60 mg versus 10 mg) in the treatment of nonsteroidal anti-inflammatory drug-refractory ankylosing spondylitis. Arthritis Rheum 2002;46: 766-73.
18. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumour necrosis factor alpha. N Engl J Med 2002;346: 1349-56.
19. Davis JC Jr, Van Der Heijde D, Braun J, Dougados M, Cush J, Clegg DO, et al. Recombinant human tumour necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomised, controlled trial. Arthritis Rheum 2003;48: 3230-6.
20. Calin A, Dijkmans BA, Emery P, Hakala M, Kalden J, Leirisalo-Repo M, et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2004;63: 1594-600.
21. Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359: 1187-97.
22. Van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis. Results of a randomised controlled trial (ASSERT). Arthritis Rheum 2005;52: 582-91.
23. Van der Heijde D, Kivitz A, Schiff M, Sieper J, Dijkmans B, Braun J, et al. Adalimumab therapy significantly reduces signs and symptoms in patients with ankylosing spondylitis (AS): results of the ATLAS trial. [abstract] Rheumatology (Oxford) 2006;45(suppl 1): OP15.
24. Sieper J, Baraliakos X, Listing J, Brandt J, Haibel H, Rudwaleit M, et al. Persistent reduction of spinal inflammation as assessed by magnetic resonance imaging in patients with ankylosing spondylitis after 2 years of treatment with the anti-tumour necrosis factor agent infliximab. Rheumatology (Oxford) 2005;44: 1525-30.
25. Keat A, Barkham N, Bhalla A, Gaffney K, Marzo-Ortega H, Paul S, et al. BSR guidelines for prescribing TNF- blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for Rheumatology. Rheumatology (Oxford) 2005;44: 939-47.
26. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath ankylosing spondylitis disease activity index. J Rheumatol 1994;21: 2286-91.
27. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 2004;63: 665-70.
28. Quinn MA, Conaghan PG, O'Connor PJ, Karim Z, Greenstein A, Brown A, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52: 27-35.
29. Cairns AP, Taggart AJ. Tumour necrosis factor inhibitors: maximizing patient safety. Rheumatology (Oxford) 2003;42: 188-9.