Spotlight on ankylosing spondylitis

The key to optimal management of ankylosing spondylitis (AS) is early diagnosis. Whilst the typical late features of severe disease are easy to recognise, the early symptoms may be extremely difficult to differentiate from other causes of back pain; hence many AS sufferers are managed inappropriately and spend years of young adult life with disabling but unexplained symptoms.

The introduction of TNF inhibitor biologic drugs has dramatically changed the treatment of ankylosing spondylitis (AS). In spite of this, many patients still fail to achieve optimal outcomes, largely because of delayed or failed diagnosis. Estimates of the prevalence of AS vary but it is likely that the prevalence in the UK adult population is approximately 0.2%.¹

Men predominate, but with a sex ratio of 3:1, it is not the much higher ratio that was once thought to apply. Thus a Trust serving 500,000 adults should expect that 1000 people with AS live within the area. To this must be added others with related forms of spondyloarthritis and an unknown number of undiagnosed cases.

Diagnosis of ankylosing spondylitis

Ankylosing spondylitis is conventionally diagnosed using the modified New York Criteria1 (Van der Linden 1984), which include radiographic evidence of sacroiliitis. It is now clear that in some patients, especially early in the course of AS, radiographic changes are not apparent. In reality, there is a spectrum of disease ranging from inflammatory symptoms in the absence of radiographic changes to end-stage disease with extreme, irreversible X-ray changes and complications. Since the diagnostic criteria for AS require radiographic changes, the whole spectrum has been named “Axial Spondyloarthritis (SpA)”.² Diagnostic criteria for Axial SpA have not yet been agreed but classification criteria have been established by the Assessments of Ankylosing Spondylitis (ASAS) International Society.

Recognition of ankylosing spondylitis

Key symptoms

Onset of AS is usually in the late teens and twenties with buttock or back pain, which may be episodic and associated with sacroiliitis, morning stiffness and fatigue. Since back pain is such a prominent early feature of Axial SpA, the critical step in early diagnosis is recognition of characteristic inflammatory features. These characteristics are referred to as inflammatory back pain (IBP).

Physical findings

Physical examination may reveal restricted spinal segments although in early disease mobility may be normal. Tenderness on pressure over the sacrum may indicate sacroiliitis though clinical assessment is insensitive. Peripheral enthesitis, commonly affecting the Achilles’ tendon and plantar fascia insertions at the calcaneum, the patella, tendon insertion on the tibial tubercle and around the pelvis, affects 50% of patients at some point. Costovertebral and sternal tenderness is common and may cause both pain and anxiety.

Diagnostic investigations

In most but not all patients, active disease is reflected by an increased acute phase response. The HLA B27 gene is present in 95% of patients with typical AS but in a lower proportion of Axial SpA patients. The detection of this gene in people with IBP has diagnostic and prognostic value. Recognition of spinal inflammation requires appropriate spinal imaging. Plain radiographs may remain normal up to 7–10 years afer the onset of axial SpA6 so that radiography is of limited value in early diagnosis. In suspected early disease, magnetic resonance imaging (MRI) is therefore the investigation of choice. At minimum, views of the SI joints with T1, T2 and STIR (fat-suppressed) sequences are desirable.⁷

The more extensive the spinal scan the greater the likelihood of detecting diagnostic inflammatory lesions but individual spinal lesions may be indistinguishable from degenerative or malignant change.⁸ Subsequent structural changes detectable by plain radiography include sacroiliitis, vertebral squaring, syndesmophytes and obliteration of facet joints. The lesions underpinning the radiological appearances are principally enthesitis and osteitis. Doppler ultrasound may be helpful for assessment of enthesitis.⁹ The investigation of AS is well described in the ASAS Handbook.^2,4

Genetics and aetiology

AS appears to result from a combination of genetic and environmental factors. Twin studies show that monozygotic twins have a 63% concordance rate whereas that in dizygotic twins is only 24%, indicating a polygenic background.10,11 HLA-B27 remains the strongest genetic association, almost all allotypes of HLAB27, (there are more than 40) predisposing to AS but ongoing genetic studies have revealed likely links within genes in the IL-1, IL- 17, IL-12, IL-23R and ARTS-1/ ERAP-1 regions.^12,13 Potential mechanisms by which genetic factors lead to AS are discussed elsewhere.12 A role for gut bacteria has been suggested by both animal and human studies but no clear pathogenic mechanism has been demonstrated.

Measurement of disease characteristics

A number of compound indices have been devised for the measurement of aspects of AS. Of these, the most commonly used are listed below.

Management of ankylosing spondylitis

Good management of ankylosing spondylitis involves timely and appropriate treatment of each element of the disease present in the individual. Thus, treatment should be targeted specifically at spinal disease, peripheral disease, enthesitis, comorbidities and associated features, always bearing in mind the need to maintain quality of life, capacity for work and well-being. The management of comorbidities, especially acute anterior uveitis, psoriasis and inflammatory bowel disease is critically important but is out of the scope of this article.

Exercise

Regular spinal exercise, whether in the form of sport, approved gym exercises or a regime of stretches each morning, is vital both for the antagonism of ankylosis and for maintaining well-being. Physiotherapy is crucial to the planning of regular exercise and in sustaining what is often a demanding and irksome routine; breathing exercises and spinal stretching should be incorporated into a daily routine lifelong. The National Ankylosing Spondylitis Society (NASS) provides regular exercise or hydrotherapy sessions at locations throughout the country and also has recently published a new handbook and iphone app of gym exercises (www.nass.co.uk/ exercise). Swimming and piliates are often helpful.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Non-steroidal anti-inflammatory drugs remain the first-line medical treatment. Commonly used agents include naproxen, ibuprofen and diclofenac and the cox-2 selective anti-inflammatories such as celecoxib and etoricoxib. Long acting preparations have significant advantages in terms of providing overnight comfort and reduced morning stiffness.

Patients vary in responsiveness to individual NSAIDs, so finding the right NSAID and prescribing it at an adequate dosage is important. Experience with rofecoxib (Vioxx) has given appropriate prominence to potential do serelated cardiovascular toxicity of all NSAIDs and has been reviewed elsewhere14 and cardiovascular risk has been compared in a recent meta analysis.¹⁵ As a consequence, NSAIDS are contra-indicated in patients with known heart disease, renal disease, peripheral vascular disease and stroke; in practice, a careful balance must be struck between good symptom control with continuous medication and on demand NSAID usage. Bearing in mind the potential very long-term NSAID treatment, pre-treatment assessment of conventional cardiovascular risk factors and kidney function is appropriate. NSAIDS may antagonise the cardio-protective effect of aspirin.¹⁶

Disease-modifying antirheumatic drugs (DMARDs)  and corticosteroids

DMARDs are not effective in spinal disease and are not indicated for its treatment. Oral corticosteroids may provide symptomatic relief for active spondylitis but may aggravate osteoporosis in AS.¹⁷ Intramuscular corticosteroid injections may also be considered when spinal or peripheral symptoms are severe especially before a rehabilitation programme and CT guided injections into the sacro-iliac joints may be valuable when other treatment modalities cannot be used or are ineffective.

Biologic (TNF-inhibitor) therapy

The introduction of TNF inhibitor therapy has revolutionised the management of AS. Several anti- TNF agents are licensed in the UK for treatment of ankylosing spondylitis but only etanercept, adalimumab and golimumab are approved for usage by NICE (NICE technology appraisal guidance 143 and TA233). Treatment of patients with AS with TNF inhibitor drugs in the UK should be in accordance with NICE guidelines. Adalimumab and golimumab are human monoclonal antibodies binding to TNF alpha and etanercept is a fusion protein, which binds to the TNF receptor.

Although not NICE-approved for AS treatment in the UK, due to cost, infiximab is widely used throughout Europe and has been investigated in many clinical trials. TNF blocking drugs appear to share class efect with regard to both efcacy and toxicity though possible variations in toxicity and drug survival have become apparent. Most patients with axial and/or peripheral disease derive substantial clinical benefit. In trials 60% patients have been noted to have significant improvement in symptoms (BASDAI), quality of life and function (BASFI).

Remission is unusual but 30% of patients develop partial remission after three to six months of treatment. On stopping treatment, however, most patients relapse. Approximately 10% of patients per year fail treatment due to loss of efcacy or toxicity. Switching to a second anti-TNF agent may be benefcial18 but costly and is not currently recommended by NICE. The key side effects of anti-TNF drugs concern immunosuppression. Screening for TB (as per British Thoracic Society guidelines) prior to initiating treatment is mandatory, as latent TB may be activated once the patient is immunosuppressed; exclusion of viral hepatitis and HIV infection in at risk individuals is also necessary. In AS there is thus far no evidence of increased tumour risk. TNF blockers should be used cautiously in patients with NYHC stage 3 and 4 heart failure as preliminary evidence suggested that treatment may be linked to higher mortality.¹⁹

Spinal surgery

Up to a third of patients with AS have hip involvement and many of these come to hip replacement, often later requiring revision surgery.²⁰ Other large joints, especially the knee may also fail and require surgical treatment. Surgery to the spine may be immensely valuable for a small minority of patients but should only be undertaken by a specialist team with appropriate anaesthetic and post-operative care and high patient care throughout. Spinal surgery should be considered in patients with severe spinal fexion deformity who are unable to make eye contact or find difficulty with balance or field of vision. Correction of hip fexion deformities may also improve posture. With careful selection of both patients and technique²¹ the risks of surgery have reduced in recent years and patient satisfaction is high.²²

Treatment of peripheral spondyloarthritis

In addition to the symptomatic benefit of NSAIDs, sulfasalazine may be helpful in the treatment of peripheral spondyloarthritis.^17,23 Methotrexate is often used as in rheumatoid arthritis but without the convincing supportive data. Oral corticosteroids may provide symptomatic relief for active peripheral spondyloarthritis but may aggravate osteoporosis in AS.¹⁷ Intra-articular steroid injections may be helpful and local injection treatment is often the treatment of choice for peripheral monoarthritis. TNF blockade treatment is also effective and appropriate for peripheral arthritis though most trial data have focused on axial disease.

Persistent painful enthesitis may be a challenging clinical problem. For heel enthesitis conservative measures such as corrective insoles and stretching exercises may be used but in non weight-bearing sites local steroid injections may be helpful. NSAIDs may provide some relief and TNF blockade has been shown to be effective in severe refractory cases.²⁴ .

Adjunct medical treatment

Bisphosphonates

In addition to their value in treatment of post-menopausal osteoporosis, oral and intravenous bisphosphonates have been used in the treatment of AS.²⁵ Evidence of benefit is slight and their place in the treatment of AS and associated osteoporosis is not clear currently.

Tricyclics

Low dose tricyclics such as amitriptyline and nortriptyline may be valuable adjuncts in the reduction of sleep disturbance and associated fibromyalgic symptoms.

Assessing prognosis

Assessment of the prognosis is an important part of treatment planning. The presence of peripheral joint involvement, young age of onset, elevated acute phase response, hip involvement, smoking and poor response to NSAIDs predict poor outcome.^27,28 Presently there is a dearth of prognostic biomarkers though degree of intensity of sacroiliitis on initial MRI scan may predict the subsequent fulfilment of modified New York Criteria for AS.²⁹

Referral

All adult patients under 40 years with back pain of more than three months should be assessed for IBP. Those with IBP should be asked about linked factors, including family history or history of SpA comorbidities. In these individuals consideration should be given to the possibility of a spondyloarthritis and referral to a rheumatologist.

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Maria Mouyis, Rheumatology Department, Northwick Park Hospital, Harrow, Middlesex

Andrew Keat, Rheumatology Department, Northwick Park Hospital, Harrow, Middlesex Email: [email protected]

Confict of interest: none

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