Ankylosing spondylitis

Contributed by Dr Andrew Cairns, consultant rheumatologist, Musgrave Park Hospital, Belfast.

Section 1: Epidemiology and aetiology

Ankylosing spondylitis is a chronic inflammatory condition that primarily affects the axial skeleton.1

Sacroilitis is its hallmark, accompanied by inflammation of the entheses (points of union between tendon, ligament or capsule and bone) and formation of syndesmophytes (bony bridges between neighbouring vertebrae), leading to spinal fusion, or ankylosis, in later stages.

The prevalence varies between 0.1 and 2 per cent in different populations.

The annual incidence in the UK has been estimated at 6.9/100,000, with around 2,300 new cases per year in England and Wales.2

The male-to-female ratio is around 5:1, and men may be more likely to develop severe spinal disease. While the disease can begin at any age, the peak age of onset is 15-35 years.

Aetiology
The aetiology of the disease is not fully understood, but it is likely to be triggered by some unknown, possibly infective, environmental factor in patients who are genetically predisposed.

Approximately 90-95 per cent of white European patients with ankylosing spondylitis have the tissue human leukocyte antigen B27 (HLA-B27), compared with around 8 per cent in the general population, although prevalences vary across different populations.

Populations with a higher frequency of HLA-B27 have higher prevalence rates of ankylosing spondylitis.

The association is complex, as there are a number of HLA-B27 subtypes, not all of which are pathogenic, and other non-HLA-B27 genes also play a role.

Ankylosing spondylitis seems to be less common among black populations, but there is a need for further epidemiological research in this area.

It should be remembered that the majority of individuals who possess HLA-B27 will never develop ankylosing spondylitis.

Section 2: Diagnosis
The key point to elicit during history taking is of inflammatory back pain. This typically presents as low back pain and stiffness of insidious onset, which is worse first thing in the morning or after rest, lasting at least 30 minutes and improving with activity. Sacroilitis 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.

Patients may also present with symptoms arising from peripheral joint synovitis or enthesitis (such as achilles enthesitis or plantar fasciitis).

Sleep disturbance and daytime fatigue are common. Clinical findings may be subtle in the early stages or in milder cases. Spinal movements and chest expansion may be generally reduced.

Plain X-ray demonstrating bilateral sacroilitis

Spinal deformity
Patients with severe disease can develop obvious spinal deformity. A number of patients will have peripheral arthritis or enthesitis, and iritis is a relatively common manifestation.

Ankylosing spondylitis overlaps with the other seronegative spondyloarthropathies and the differential diagnosis of inflammatory back pain includes psoriatic arthritis, reactive arthritis and inflammatory bowel disease-associated arthritis.

Ankylosing spondylitis is occasionally confused with diffuse idiopathic skeletal hyperostosis (DISH), although DISH is a non-inflammatory condition, and the sacroiliac joints are not involved.

Investigations
Most, but not all, patients have elevated inflammatory markers. When requesting X-rays, sacroiliac views may be helpful. Radiographic sacroilitis is the hallmark of the disease.

Initially the joint may appear blurred and indistinct, classically in the lower third, followed by bony erosions, sclerosis and the appearance of widening of the joint. This may be associated with marginal vertebral body erosions, squaring of the vertebral bodies and the formation of syndesmophytes between vertebrae.

Ossification of spinal ligaments may occur, and spinal osteopaenia is common. In severe longstanding disease, complete fusion of the vertebral column may occur (a 'bamboo spine').

Normal X-rays do not exclude the disease and further imaging, particularly MRI, plays an important role in early diagnosis. MRI of the sacroiliac joints is more sensitive than plain radiography in detecting early changes.

Specific criteria for the classification of ankylosing spondylitis have been developed (see box).3 Definite ankylosing spondylitis is said to be present when the fourth or fifth criterion presents with any clinical criteria. These criteria were published before the availability of MRI scanning.

Dagnosing ankylosing spondylitis

Modified New York criteria for ankylosing spondylitis

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 sacroilitis grade 2 or higher.

5. Unilateral sacroilitis grade 3 or higher.

Section 3: Management
Evidence-based recommendations for the management of ankylosing spondylitis have been produced by the international assessment in ankylosing spondylitis working group (ASAS) in collaboration with the European League Against Rheumatism (EULAR).4

Physiotherapy
Physiotherapy is a key element of overall management of all patients. A Cochrane review found evidence that physiotherapy had beneficial impacts on pain, stiffness, physical function and patient global assessment.5

Pharmacotherapy
NSAIDs improve spinal pain, peripheral joint pain and function in ankylosing spondylitis when compared with placebo. COX-2 inhibitors and traditional NSAIDs seem broadly comparable in efficacy. The decision on which NSAID or COX-2 inhibitor to use should be on an individual patient basis, taking into account risk factors, particularly for GI and cardiovascular side-effects.

Analgesics including paracetamol and opioids may be used, particularly when NSAIDs are contraindicated.

Sulfasalazine has inconclusive evidence for efficacy in ankylosing spondylitis.6 A Cochrane review of 12 randomised controlled trials has found some evidence of benefit in peripheral joint symptoms and reducing ESR, but no evidence of benefit in physical function, pain, spinal mobility, enthesitis, or patient or physician global assessment.

There is little evidence to support the use of methotrexate of other traditional DMARDs for spinal disease in ankylosing spondylitis.

Intra- or periarticular steroid injections for sacroilitis, and local steroid injections for peripheral arthritis and enthesitis in ankylosing spondylitis are often used in clinical practice. IV methylprednisolone is occasionally used in severe unresponsive cases.

Oral bisphosphonates are often used for fracture prevention in ankylosing spondylitis. Bisphosphonates also have an anti-inflammatory action and may have an effect on disease activity. IV pamidronate (a bisphosphonate) has been investigated in a number of studies, with variable clinical effects.

Cardiovascular risk
Patients with ankylosing spondylitis have increased rates of cardiovascular morbidity and mortality, in common with patients with other inflammatory conditions.

This may only partially be explained by traditional risk factors, and the chronic inflammatory nature of the condition may be partially responsible. Traditional modifiable cardiovascular risk factors should be identified and treated. Better control of the underlying inflammatory condition may also modify the cardiovascular risk.

Hip arthritis
A high proportion of patients develop hip arthritis. Hip replacement surgery should be considered in patients with refractory pain or disability and with radiographic evidence of structural damage, independent of age.

Spinal surgery may be of value in selected patients and is performed for a variety of reasons in patients with ankylosing spondylitis, including fusion procedures for segmental instability.

Patients with severe disease present anaesthetic difficulties, and the risks and benefits of surgery need to be carefully considered.

Section 4: Prognosis and recent advances
Ankylosing spondylitis has a variable long-term prognosis. Patients with mild or limited disease often retain good functional ability and remain in employment. Patients with severe persistent disease may develop progressive spinal fusion and functional decline.

MRI scan demonstrating unilateral sacroilitis

The prognosis for patients with moderate-to-severe disease has been revolutionised by the introduction of anti-tumour necrosis factor (TNF) agents.

Three anti-TNF drugs are currently available. Etanercept is a soluble TNF receptor fusion protein that is administered subcutaneously; infliximab is a chimeric monoclonal anti-TNF antibody administered by IV infusion; adalimumab is a human monoclonal anti-TNF antibody given subcutaneously. All three drugs have demonstrated rapid, large improvements in spinal pain, function and peripheral joint disease.7-9

Anti-TNF drugs have also demonstrated persistent reduction of spinal inflammation as detected by MRI. TNF-inhibitor therapy should be considered for patients with persistently high disease activity despite conventional treatments.

Anti-TNF guidelines
The British Society for Rheumatology has produced guidelines for the use of anti-TNF therapies in ankylosing spondylitis.10 Patients should have persistent active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index and persistent spinal pain, despite trials of two or more NSAIDs.

There have been reports of increased rates of infection with anti-TNF drugs, including the reactivation of TB. Active significant infection is a contraindication to treatment.

Long-term use of anti-TNF agents may theoretically predispose to the development of some malignancies. Other reported side-effects include demyelinating disease, lupus-like syndromes and injection site or infusion reactions.

Anti-TNF drugs are expensive; 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. Early treatment with TNF-inhibitors may also reduce the requirement for future surgery.

The Scottish Medicines Consortium approves the use of etanercept, infliximab or adalimumab for active ankylosing spondylitis in accordance with the BSR guidelines.

NICE has reviewed the use of anti-TNF drugs for ankylosing spondylitis and recommended the use of etanercept or adalimumab for active disease in patients who have not responded to two NSAIDs.2

Infliximab was not recommended on cost grounds (the dosage of infliximab used for ankylosing spondylitis is higher than that in rheumatoid arthritis - 5mg/kg versus 3mg/kg).

References

1. McVeigh C, Cairns A. Diagnosis and management of ankylosing spondylitis. BMJ 2006; 333: 581-5.

2. NICE technology appraisal guidance, TA143. Guidance on the use of adalimumab, etanercept and infliximab for ankylosing spondylitis. London: NICE, 2008.

3. Van der Linden S, Valkenburg H, 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. Zochling J, van der Heijde D, Burgos-Vargas R et al; 'Assessment in AS' international working group; European League Against Rheumatism. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis 2006; 54: 442-52.

5. Dagfinrud H, Kvein T, Hagen K. Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev 2004; (4): CD002822.

6. Chen J, Liu C. Sulphsalazine for ankylosing spondylitis. Cochrane Database Syst Rev 2005;(2): CD004800.

7. Braun J, Brandt J, Listing J et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1,187-97.

8. Calin A, Dijkmans BA, Emery P et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 2004; 63: 1,594-600.

9. Van der Heijde D, Kivitz A, Schiff M et al; ATLAS Study Group. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. 1: Arthritis Rheum 2006; 54: 2,136-46.

10. Keat A, Barkham N, Bhalla A et al; BSR Standards, Guidelines and Audit Working group. BSR guidelines for prescribing TNF-alpha blockers in adults with ankylosing spondylitis. Report of a working party of the British Society for Rheumatology. Rheumatology (Oxford) 2005; 44: 939-47.

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