Ankylosing spondylitis (Bechterew’s disease)

01Definition and overview

Ankylosing spondylitis, also called Bechterew's disease after the Russian neurologist who described it in 1893, is a chronic inflammatory disease of the sacroiliac joints and the spine. Its name means a stiffening (ankylosis) inflammation of the vertebrae. It belongs to the spondyloarthritides, a family of inflammatory diseases that share HLA-B27, inflammation of the entheses, a tendency to new bone formation, the same extra-articular features and no rheumatoid factor:

The family is also split by where it shows: axial (sacroiliac joints and spine) or peripheral (arthritis, enthesitis, dactylitis), with much overlap.

Today the axial disease is seen as one condition with two stages. Axial spondyloarthritis is the whole; when the sacroiliac joints show definite damage on X-ray it is radiographic axial spondyloarthritis, the same as ankylosing spondylitis; before that, with inflammation seen only on MRI or suspected from HLA-B27 and the clinical picture, it is non-radiographic. A minority of non-radiographic patients progress to the radiographic form, and some never do. Symptoms, quality of life and response to treatment are similar in both.

02Etiology and pathophysiology

Genes

• HLA-B27 is carried by 80 to 95 per cent of white Europeans with ankylosing spondylitis, against about 8 per cent of the general population (more in Scandinavia, fewer in southern Europe). Only about 1 to 5 per cent of HLA-B27 carriers develop the disease, more if a first-degree relative has it. The disease is rare where HLA-B27 is rare, as in sub-Saharan Africa.
• Identical twins are concordant in up to about 60 to 70 per cent if HLA-B27 positive, far more than non-identical twins, so heredity explains most of the risk.
• HLA-B27 accounts for only part of the inherited risk. Genome-wide studies add variants in ERAP1 (an enzyme that trims peptides before they are loaded onto HLA class I, whose effect is seen mainly in HLA-B27-positive people) and in the IL-23 receptor and other genes of the IL-23 and IL-17 pathway.

How HLA-B27 might cause disease

No single mechanism is proven. Three ideas are studied, and they may all contribute:

The gut probably matters: up to about half of patients have microscopic inflammation of the ileum or colon, a few develop Crohn's disease, and the gut microbiome differs from that of healthy people.

From enthesitis to new bone

1. 1

   Trigger at the enthesis

   Mechanical stress at the entheses, where ligaments, tendons and the joint capsule attach to bone, and possibly bacterial products from the gut, act on resident immune cells that respond to IL-23.
2. 2

   IL-23 and IL-17

   These cells, including Th17 cells, γδ T cells and innate lymphoid cells, release IL-17 and TNF, which bring in neutrophils, inflame the adjacent bone marrow (seen as oedema on MRI) and drive osteoclasts to erode the bone.
3. 3

   Repair with new bone

   As the inflammation settles, the eroded corners of the vertebrae heal with fat and then new bone. Bony bridges, the syndesmophytes, grow vertically along the outer fibres of the discs and join neighbouring vertebrae.
4. 4

   Ankylosis

   The sacroiliac joints fuse, the facet joints and costovertebral joints fuse, the spinal ligaments ossify, and the spine stiffens into a single bony column, the bamboo spine, while the trabecular bone inside thins.

03Clinical features

Inflammatory back pain

The disease usually begins in the late teens or twenties, rarely after 45. The pain is felt low in the back and in one or both buttocks, sometimes alternating from side to side, and comes with stiffness.

By the ASAS definition, chronic back pain that began before 40 is inflammatory if it has four of five features (slow onset, improvement with exercise, no improvement with rest, pain at night and improvement on getting up). About 70 to 80 per cent of patients with axial spondyloarthritis have it, but so do some people without the disease, so it is a reason to refer, not a diagnosis.

In the UK, a person whose low back pain began before 45 and has lasted more than 3 months is referred if four or more of these features are present (onset before 35, waking in the second half of the night, buttock pain, better with movement, better within 48 hours of an NSAID, a first-degree relative with spondyloarthritis, past or present arthritis, enthesitis or psoriasis), or if three are present and an HLA-B27 test is positive.

The spine and chest

• Early: loss of the lumbar lordosis, tenderness over the sacroiliac joints, limited spinal movement in all directions.
• Schober test: a mark is made at the lumbosacral junction (the level of the dimples of Venus), with one 10 cm above and one 5 cm below; an increase of less than 5 cm in the 15 cm between them on full forward flexion shows lumbar stiffness.
• Chest expansion is reduced (normally 5 cm or more at the fourth intercostal space) when the costovertebral joints fuse, and costochondral enthesitis causes anterior chest pain.
• Late: fixed thoracic kyphosis, a flat lumbar spine, a stooped "question mark" posture with the neck flexed forward, and wasting of the paraspinal muscles. The patient cannot look ahead without bending the hips and knees.

Outside the spine

• Peripheral arthritis, in about a third: an asymmetric oligoarthritis of large joints, mostly in the legs. Hip disease is common, often bilateral, and a major cause of disability; shoulders are affected too.
• Enthesitis: heel pain at the Achilles tendon and plantar fascia insertions, also at the pelvis, chest wall and spine. Dactylitis (a whole swollen "sausage" digit) is less common than in psoriatic arthritis.
• Acute anterior uveitis, in about a third over the course of the disease, more in HLA-B27-positive patients: a painful red eye with photophobia and blurred vision, usually one eye at a time, often recurring, sometimes the first sign. Acute anterior uveitis needs an ophthalmologist the same day; untreated it can cause synechiae, glaucoma and loss of vision.
• Skin and gut: psoriasis in about 10 per cent, clinical inflammatory bowel disease in about 5 to 10 per cent.
• Heart: aortic regurgitation from aortitis of the aortic root, in about 1 per cent of long-standing disease, and conduction block; cardiovascular risk is raised overall.
• Lungs: a restrictive defect from the rigid chest wall, and rarely upper-lobe fibrosis.
• Bone: osteoporosis of the spine in about a quarter, with vertebral fractures; it is easily missed because syndesmophytes falsely raise the spinal bone density.
• Kidneys: IgA nephropathy, kidney damage from long-term NSAIDs, and rarely secondary AA amyloidosis.

Fracture of the fused spine

A fused spine breaks like a long bone, after minor trauma such as a fall from standing, most often at the lower cervical spine and the cervicothoracic junction. The fracture usually crosses all three columns and is unstable; in a large review two thirds of patients had a neurological deficit on arrival, and diagnosis was often delayed. A change in the pattern of pain, particularly new localised neck or back pain after any trauma, is investigated with CT and MRI of the whole spine, because plain X-rays often miss it. The neck is immobilised in the patient's usual posture, not forced straight.

Measuring activity

ASDAS is the preferred measure in European recommendations, because it includes the CRP.

04Diagnosis and management

Tests

• CRP and ESR: raised in only about half of patients, so normal values do not exclude the disease. A raised CRP predicts progression and a good response to biologics.
• HLA-B27: supports the diagnosis in a patient with suggestive symptoms, but is not a diagnosis, because most carriers are healthy. Rheumatoid factor and anti-CCP antibodies are usually negative.
• X-ray of the pelvis: sacroiliitis is graded 0 to 4, from blurred joint margins through erosions and sclerosis (looking like a widened joint) to complete fusion. In the spine: squaring of the vertebral bodies, shiny corners (Romanus lesions), syndesmophytes and, late, the bamboo spine, with fused facet joints and ossified ligaments. Changes take years to appear.
• MRI of the sacroiliac joints (with fat-suppressed sequences such as STIR): bone marrow oedema beside the joint shows active inflammation; erosions, fat deposition and bone bridges show structural damage. It is the test for early disease and for patients with a normal X-ray. Bone marrow oedema alone is not specific: it is also seen after childbirth, in athletes and in mechanical back pain.

The ASAS classification criteria

The ASAS criteria apply to patients with back pain for at least 3 months that began before the age of 45. They classify axial spondyloarthritis by one of two arms:

The spondyloarthritis features are inflammatory back pain, arthritis, heel enthesitis, uveitis, dactylitis, psoriasis, Crohn's disease or ulcerative colitis, a good response to NSAIDs, a family history of spondyloarthritis, HLA-B27 and a raised CRP. The criteria have a sensitivity of about 83 per cent and a specificity of about 84 per cent. Ankylosing spondylitis itself is still defined by the older modified New York criteria: radiographic sacroiliitis (at least grade 2 on both sides, or grade 3 or 4 on one side) with a clinical feature (inflammatory back pain, limited lumbar movement or limited chest expansion).

Treatment

The goal is the best quality of life through control of symptoms and inflammation, prevention of structural damage and preservation of function and work, by shared decision with the patient.

1. 1

   Everyone

   Education, regular exercise for posture, spinal mobility and chest expansion, often supervised physiotherapy and hydrotherapy at first, and stopping smoking, which speeds new bone formation.
2. 2

   NSAIDs first

   An NSAID at the full dose, such as naproxen 500 mg twice daily, etoricoxib or ibuprofen, taken continuously while it is needed to control symptoms, with gastroprotection where indicated and checks of blood pressure and kidney function. A good response supports the diagnosis. Two NSAIDs that fail over at least 4 weeks in total count as NSAID failure.
3. 3

   Local measures

   A glucocorticoid injection into an inflamed joint or enthesis, never into the Achilles tendon itself. Analgesics such as paracetamol or opioids only for pain that remains.
4. 4

   Biologics or a JAK inhibitor

   If the ASDAS stays at 2.1 or more despite at least two NSAIDs (the BASDAI at 4 or more where the ASDAS cannot be used), and the CRP is raised, the MRI positive or the X-ray shows sacroiliitis, a TNF, IL-17 or JAK inhibitor is considered; current practice is to start with a TNF or IL-17 inhibitor. The effect is judged after at least 12 weeks: a fall in ASDAS of 1.1 or more is a response.
5. 5

   If it fails

   The diagnosis and other causes of pain, such as fibromyalgia, are reconsidered; then a switch to another TNF or IL-17 inhibitor or to a JAK inhibitor. In sustained remission a biologic can be tapered, by lengthening the interval; stopping it usually brings a relapse.

Patients with purely axial disease are not treated with conventional DMARDs or long-term systemic glucocorticoids. Methotrexate, sulfasalazine and leflunomide do not work on the spine. Sulfasalazine may be used for peripheral arthritis.

Before any of them, patients are screened for tuberculosis and hepatitis B and C (and HIV), and vaccines are brought up to date. TNF and IL-17 inhibitors work in both the radiographic and the non-radiographic form. They relieve pain and stiffness quickly and improve function and quality of life; evidence that they slow new bone formation comes from long-term observational studies, especially with early and sustained use.

Surgery and other care

• Total hip replacement for a damaged, painful hip, at any age.
• Corrective spinal osteotomy in specialised centres for a severe, disabling kyphosis.
• Same-day ophthalmology for uveitis, treated with steroid and dilating eye drops.
• Attention to osteoporosis, cardiovascular risk and depression; the fracture risk of the fused spine taught to the patient.

05Epidemiology

Ankylosing spondylitis affects about 0.2 to 0.3 per cent of adults in Europe, and axial spondyloarthritis as a whole, including the non-radiographic form, up to about 1 per cent. Prevalence follows HLA-B27: highest in northern Europe and in some Indigenous peoples of the Arctic and North America, lowest in sub-Saharan Africa and Japan. Onset peaks in the twenties.

Ankylosing spondylitis is two to three times commoner in men, but non-radiographic disease affects men and women about equally. Women tend to have less radiographic progression and are diagnosed later. Across studies, the average delay from the first symptoms to the diagnosis is about seven years, longer when there are no extra-articular features to raise the suspicion. Pooled studies show it has not shortened over the years, which is why earlier MRI and clear referral pathways are pushed.

06Prognosis

The disease runs a course of flares and quieter periods over decades. Many patients keep good function and work, especially with regular exercise and modern treatment, but a minority develop marked spinal restriction. Progression is faster with male sex, smoking, a high CRP, existing syndesmophytes and early hip involvement. Among patients with non-radiographic disease, most studies find that about 10 to 40 per cent reach the radiographic stage over 2 to 10 years, more often men and those with a raised CRP or active inflammation on MRI.

Long-standing disease brings osteoporosis, spinal fractures, hip damage, aortic regurgitation and a higher cardiovascular and overall mortality than in the general population. Follow-up checks disease activity (ASDAS or BASDAI with the CRP), mobility and function, the eyes, bowel and skin, kidney function and blood pressure on NSAIDs, bone density and cardiovascular risk.