ANKYLOSING SPONDYLITIS

by Dr Andrei Calin MD, FRCP, Consultant Rheumatologist, Royal National Hospital for Rheumatic Diseases, Bath

Ankylosing spondylitis has affected mankind for several millennia, but there is now increasing information about the genetic background of the condition, and in recent years we have gained greater understanding of the factors affecting prognosis.

Prevalence

A recent German study found the prevalence of spondylarthritis to be 1.8% and that of ankylosing spondylitis to be 0.8%. The prevalence of ankylosing spondylitis mirrors the distribution of the HLA-B27 antigen. In the UK, HLA-B27 occurs in about 8% of the Caucasian population, and of these around 10% of men and 4% of women develop ankylosing spondylitis. Thus, almost one in 100 Caucasian men and one in 250 Caucasian women develop the disease.

HLA-B27 is less common in the Afro-Caribbean population, and the disease is less prevalent in this group.

Pathogenesis and genetics

There is a complex interplay between environmental and genetic factors in the disease pathogenesis.

The specific role of HLA-B27 remains unclear, but presumably it has an impact on the patient's susceptibility to an infective trigger.

Environmental triggers

The environmental triggers for ankylosing spondylitis remain unknown.

Gram-negative organisms such as salmonella, Shigella flexneri, campylobacter and Yersinia precipitate reactive arthropathy, a closely related condition that
is also related to HLA-B27. However, there is no clear evidence that any of these, or klebsiella, another putative agent, is involved in the pathogenesis of ankylosing spondylitis.

Protective factors

HLA-B*2705, an indicator of susceptibility to ankylosing spondylitis in Caucasians, is present in the Gambia, west Africa, yet the disease appears to be extraordinarily rare in the population. This raises several questions:

• Is there some environmental protective mechanism?
• Do the chronic parasitic infections that are prevalent in that country prevent the development of disease by suppressing the necessary immune mechanism?
• Do dietary or other factors play a role?

In some communities, certain subtypes of HLA-B27 have a protective role. For example, in Sardinia, HLA-B*2709 appears in healthy but not diseased individuals. In Thailand and Indonesia, B*2706 is negatively associated with ankylosing spondylitis.

Presentation and diagnosis

Ankylosing spondylitis is one of the spondylarthritides (Box 1), a group of conditions that also includes spondylitis secondary to psoriasis or inflammatory bowel disease and reactive arthritis.

It presents in young adulthood or childhood, predominantly with buttock pain and lower limb arthropathy and persists indefinitely.

The criteria for diagnosing ankylosing spondylitis have been clarified in recent years. A simple definition is the presence of symptomatic sacroiliitis - persistent back pain and stiffness for over 3 months, associated with morning stiffness, improvement with exercise and becoming worse with rest.

Alternatively, the diagnosis can be based on more formal criteria (Boxes 2 and 3).(1)

Clinical presentation

The diagnosis is suggested by:

• onset before the age of 40 years;
• persistence for longer than 3 months;
• associated with morning stiffness;
• improvement with exercise.

Ankylosing spondylitis does not burn out, but continues to be active more or less continuously. Flares occur, but what precipitates these remains unclear. Fatigue is a major symptom of this disease and is often more difficult to manage than the pain or stiffness.

No system in the body escapes the ravages of ankylosing spondylitis - cardiac, lung and neurological involvement all occur. Indeed there are symptoms and signs in virtually every part of the body.

Sacroiliac joint involvement

The characteristic early sign of ankylosing spondylitis is radiological evidence of sacroiliac joint arthritis. Biopsies at different stages of the disease provide information about the distribution of HLA-B27 and various cytokines.

Spine involvement

Spinal examination may reveal muscle spasm and loss of normal lordosis. In contrast to mechanical spinal disease, mobility is usually equally decreased symmetrically in both anterior and lateral planes. Complications of severe spinal disease include fractures and spondylodiscitis - collapse of the vertebral endplate.

Peripheral joint involvement

Peripheral joints, particularly in the legs, are involved at some stage in about 20-30% of cases. The frequency increases with the severity of the disease.

Inflammatory disease of the hip and shoulder may produce progressive disability. About 20% of patients with ankylosing spondylitis that starts before the age of 16 years develop endstage hip disease, requiring total hip replacement within 15-20 years. Often both hips will need to be replaced. The rate of endstage hip disease falls with increasing age of disease onset. The rate is about 10% if onset occurs in the patient's late teens, and endstage disease is particularly rare among those who develop ankylosing spondylitis in their late 20s or 30s.

Enthesopathic - disease at the site of the ligament insertion into bone - features include plantar fasciitis, costochondritis and Achilles tendinitis.

Age and sex differences

There are recognised differences between men and women, and between young and old patients, in their experience of ankylosing spondylitis.

Women tend to have more peripheral joint involvement, while men have more severe spinal disease. Women are more likely to have inflammatory bowel disease, whereas men are more likely to have psoriatic spondylitis.

The sex distribution in teenage patients appears to be similar to the overall pattern. However, in paediatric patients, more boys than girls appear to be affected (in a ratio of 4-5:1.

There is still no explanation for the higher prevalence among men.

Useful investigations

X-rays and laboratory tests are useful investigations in the diagnosis of ankylosing spondylitis.

Radiology

Sacroiliitis visible on x-rays confirms ankylosing spondylitis. The severity of sacroiliitis is graded from 0 to IV, according to the amount of joint distortion observed. In many patients, the disease does not progress beyond grade II or III.

Early change in the lumbar spine is seen as squaring of the superior and inferior margins of the vertebral body. This is caused by inflammatory disease at the site of insertion of the outer fibres of the annulus fibrosus. Later changes result in the classic, though uncommon, bamboo spine.

Radionuclide and CT scans, and other specialised radiological techniques can be used to evaluate the sacroiliac joints, but a anteroposterior radiograph is usually sufficient.

Laboratory findings

HLA-B27 testing should not be used for routine screening because it is expensive and usually unnecessary. The antigen is present in over 95% of white patients with ankylosing spondylitis.

ESR is raised in 50% of patients, but may be normal despite severe disease. Elevation of serum immunoglobulin A and the presence of immune complexes suggest aberrant immunity and/or persistent antigenaemia.

Serum creatinine phosphokinase and alkaline phosphatase may be raised.

Clinical assessment

The Bath ankylosing spondylitis metrology index, an expression of spinal mobility can help in assessing the severity of the disease.(2)

Alternatively, function or disease activity can be assessed through self-administered questionnaires,(3,4) and global status and radiology indexes to give a full definition of the disorder(5-7)

Prognosis

If ankylosing spondylitis is recognised early, much can be done to ameliorate the symptoms and, perhaps, prevent spinal deformity.

The course of the disease for any individual is difficult to predict. Some patients have minimal symptoms, with pelvic involvement and little or no spinal or extraspinal disease. In others, progressive, widespread disease results in poor functional outcome and even death.

Apart from hip involvement and cervical spine disease, which are both associated with earlier age at onset, it is not understood why some patients do better than others. Recent data suggest an inverse relation between social/educational status and disease severity.

The disease is less severe in patients with familial ankylosing spondylitis - which represents about 20% of cases. It is also less severe in patients with HLA-B*60. HLA-B27 homozygosity is not associated with worse disease.

Overall, the outcome in terms of employment is good and over 80% of patients continue in full-time work.

Management

The main approaches to management include:

• patient education;
• family education;
• genetic counselling;
• pain relief;
• physiotherapy;
• occupational therapy;
• possible surgery.

Genetic counselling

Most patients with ankylosing spondylitis are HLA-B27 positive, and need to be aware that the risk of transmitting the antigen to their children is 50%.

Children who are HLA-B27-positive have a 1 in 3 chance of developing the condition. The overall risk for the children of affected patients is 1 in 6.

Specialist help should be sought if any child of a patient with ankylosing spondylitis develops symptoms such as swollen joints or painful eyes.

Drug treatment

NSAIDs such as indomethacin (Artracin SR, Flexin Continus, Indocid, Indomod) are indicated. Intra-articular steroids may be tried for persistent local inflammatory disease.

Sulphasalazine may be useful, but only for those with major peripheral joint involvement and systemic disease.

Lifestyle advice

The patient should be advised to avoid smoking and to take regular exercise. Swimming is a good form of exercise because it exercises the muscles and protects the joints.

Surgery

Surgery is most often used in patients with hip involvement. In rare cases, spinal osteotomy is used for severe spinal curvature.

Physiotherapy and occupational therapy

The patient should be taught exercises that can be performed daily at home.

An occupational therapist can advise on useful aids to daily living.

What treatments are effective?

An intensive rehabilitation programme with physiotherapy, hydrotherapy, group therapy and counselling is the hallmark of good clinical practice.

Drug therapy has relatively disappointing results, apart from nonsteroidal anti-inflammatory drugs, which clearly decrease inflammation and pain.

The disease-modifying agents that are helpful in rheumatoid disease are less effective in ankylosing spondylitis. Even methotrexate has little to offer in this disease. Sulphasalazine may help peripheral joint pain, but, has virtually no effect on spinal symptoms.

Low-dose amitriptyline 10-30 mg at 8 pm not only eases the pain and stiffness of ankylosing spondylitis, but also improves sleep pattern and fatigue.(8) Moreover, disease activity decreases and function improves. However, this was a short-term study, and we need to evaluate long-term use of this safe medication.

Referral criteria

There is no such thing as an inappropriate referral. If the GP believes the patient would benefit from referral, or if the patient asks to see a specialist, then it is absolutely appropriate that the case should be referred.

Any patient whose symptoms are worsening, is losing confidence or at risk of losing their job should be sent to a specialist unit, for consideration for admission to an intensive 2-week rehabilitation programme.

All patients should be encouraged to join the National Ankylosing Spondylitis Society.

Follow-up

Follow-up must be tailored to individual needs. A rheumatologist may need to see the patient once every 10 years, or once every 6 months, or more often if there are complications.

I use the Bath outcome measurements (BASRI, BASDAI and BASFI) to monitor my patients.

Conclusion

Ankylosing spondylitis is a frequent cause of disability in young men and women. Early recognition and referral is mandatory.

Box 1. Characteristics of the spondylarthritides

• Involvement of sacroiliac joints
• Peripheral arthropathy
• Absence of rheumatoid factor
• Pathological changes at the sites of insertion of ligaments or tendons into the bone (enthesopathy)
• Inflammatory eye disease (iritis)
• Involvement of heart, lung and skin
• Clinical evidence of overlap between the different spondylarthritides - for example a patient with psoriatic arthropathy may develop uveitis or sacroiliitis
• A tendency towards inheritance
• An association with HLA-B27, ranging from about 50% (psoriatic and enteropathic spondylitis) to over 95%, depending on ethnic group

Box 2. New York criteria for diagnosing ankylosing spondylitis
Clinical

• Limited movement of lumbar spine in three planes
• Pain in lumbar spine or at dorsolum bar junction
• Chest expansion

Radiological

• Bilateral sacroiliitis (grade 2 disease)
• Unilateral sacroiliitis (grade 3 disease)

Box 3. ESSG criteria for diagnosing ankylosing spondylitis

• Inflammatory spinal pain or synovitis (asymmetrical or predominantly in the lower limbs)
• One of more of:
• positive family history
• psoriasis
• inflammatory bowel disease
• alternate buttock pain
• enthesopathy
• sacroiliitis* Without sacroiliitis, sensitivity is 77% and specificity 89%. With sacroiliitis, sensitivity is 86% and specificity 87%

References

1. Calin A, Taurog J, eds. The spondylarthritides. Oxford: Oxford University Press, 1998, p 1-353.
2. Jenkinson T, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis: the Bath ankylosing spondylitis metrology index (BASMI). J Rheumatol 1994; 21: 1694-8.
3. Calin A, Garrett SL, Whitelock HC et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath ankylosing spondylitis functional index (BASFI). J Rheumatol 1994; 21: 2281-5.
4. Garrett SL, Jenkinson TR, Whitelock HC, Kennedy LG, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath ankylosing spondylitis disease activity index (BASDAI). J Rheumatol 1994; 21: 2286-91.
5. Jones SD, Steiner A, Garrett SL, Calin A. The Bath ankylosing spondylitis (AS) patient global score (BAS-G). Brit J Rheum 1995; 34 Suppl 1: 114.
6. Mackay K, Mack CS, Brophy S, Calin A. The Bath ankylosing spondylitis radiology index (BASRI): a new validated approach to disease assessment. Arthritis and Rheumatism 1998. In press.
7. Taylor A, Balakrishnan C, Calin A. The development of a severity index in ankylosing spondylitis. Br J Rheum 1997: 36 Suppl 1: 128.
8. Koh W-H, Pande I, Samuels A, Jones SD, Calin A. Low dose amitriptyline in ankylosing spondylitis: a short-term, double-blind, placebo-controlled study. J Rheumatol 1997; 24(11): 2158-21.