Ankylosing spondylitis causes painful inflammation of the skeleton and large joints. Many medicines have been successful in controlling the symptoms. New approaches are expected to improve the lives of patients with this disease.
Ankylosing spondylitis, also known as Marie-Strümpell Disease or Bechterev Disease, is a systemic rheumatic disorder of the axial skeleton and large peripheral joints. The disease has been known for thousands of years. Egyptian mummies have been found with ankylosing changes to their skeleton. Between 1893 and 1898, Pierre Marie in France, Adolph Strümpell in Germany, and Vladimir Bechterev in Russia gave descriptions which allowed a diagnosis to be made.
Ankylosing spondylitis is a disease of the connective tissue that results in the inflammation of the joints, ligaments and tendons in the spine, the hip and the extremities. Its pathogenesis is only incompletely understood. There are strong hints for a genetic predisposition towards the development of the condition which may be triggered by an environmental factor, e.g. bacteria living in the gut. The word ankylosing refers to a status where the bones of a joint are immobile, stiff, or rigid. It is derived from the Greek word “angkylos“, meaning bent. Spondylitis describes the inflammation of the vertebrae of the backbone. The Greek word “spondylos“ means vertebra.
The most frequent presentation is back pain, but the disease can begin atypically in peripheral joints. Like most forms of arthritis, ankylosing spondylitis flares up, so patients may have periods with no symptoms alternating with periods of mild to moderate symptoms. A less common symptom is an inflammatory reaction of the iris, also known as anterior uveitis. Additional early symptoms and signs are diminished chest expansion from diffuse involvement of the vertebrae and the ribs, elevated body temperature, fatigue, weight loss, and anaemia.
Apart from back pain, morning stiffness is a likely complaint, typically relieved by activity. A flexed or bent-over posture eases back pain; thus, some degree of kyphosis is common in patients seeking medical advice for the first time. People with the disease sometimes have a stooped appearance. Eventually, the bones in the back may fuse. In some, the back ends up curved and inflexible, called “bamboo spine“, while, in others, the back is straight and stiff.
Diagnosis is confirmed by X-ray. The earliest abnormalities occur in the sacroiliac joints. Early changes in the spine are upper lumbar vertebral demineralisation, calcification of the ligaments, and one or two evolving bony outgrowths from the ligaments. Systemic manifestations occur in about 35 per cent of patients. Neurological signs can occasionally result from compression of nerves or vertebral fracture or incomplete or partial dislocation of the vertebrae.
Ankylosing spondylitis is found in fewer than one per cent of the population. About 1.5 million people within the European Union are affected with the condition. The Spondylitis Association of America estimates that between 350,000 and one million people in the USA suffer from ankylosing spondylitis. The illness is five times more frequent in men than in women, with symptoms usually occurring for the first time between the ages of 20 and 40. It is 10 to 20 times more common in first-degree relatives of patients with the disease than in the general population. In black people, the incidence of the disease is generally lower than in Caucasians.
A high prevalence of human leukocyte antigen HLA-B27 in patients with ankylosing spondylitis supports a genetic predisposition, although environmental factors are considered to contribute, as only six in ten identical twins both have the disease. The link between the condition and HLA-B27 holds in all populations: those with a low frequency of HLA-B27 have a low frequency of ankylosing spondylitis. The risk of developing the disease in individuals carrying HLA-B27 is about 20 per cent.
Joint discomfort is relieved with medicines. For proper posture and joint motion, daily exercise and other supportive measures are vital to strengthen muscle groups that oppose the direction of potential deformities, i.e. strengthening of the extensor rather than flexor muscle groups of the back. A back brace may also be needed to keep the back straight. Orthopaedic surgery is only considered in cases where the hip or knee joint is completely worn away or permanently bent.
Non-steroidal anti-inflammatory drugs (NSAIDs) facilitate exercise by suppressing inflammation of the joints, pain, and muscle spasm. Most NSAIDs are of proven value in ankylosing spondylitis. Tolerance and toxicity, rather than marginal differences in efficacy, dictate treatment choice. The daily dose of NSAIDs should be as low as possible, but maximum doses may be needed with active disease. Several new NSAIDs, referred to as COX-2 inhibitors because they inhibit cyclooxygenase-2, provide equal effectiveness. The use of COX-2 inhibitors for long periods or in patients with cardiovascular risk factors should be approached cautiously.
For acute iritis, topical corticosteroids usually are adequate. Direct injection of corticosteroids into joints may be beneficial, particularly when one or two peripheral joints are more severely inflamed than others, thereby compromising exercise and rehabilitation.
Over the past three years, clinical findings demonstrated that medicines interfering with the pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha were effective in active ankylosing spondylitis, which was a major breakthrough in the treatment of the disease. So far, two therapeutic approaches have been made available.
One compound is a murine monoclonal antibody directed against TNF-alpha, which irreversibly binds to the cytokine on the cell membrane and in the blood. The other molecule consists of a TNF-alpha fusion protein which acts as competitive inhibitor at the specific TNF-alpha receptors of white blood cells, also called T-lymphocytes. The compounds appear to act on both spinal and peripheral joints, which may retard the disease and prevent or delay spinal ankylosis. Both medicines have shown clinical effectiveness and are approved in Europe for the treatment of patients with acute disease who have responded inadequately to conventional therapy.
Recently, research groups reported data of long-term clinical studies showing a lasting clinical response including improvement of signs and symptoms in patients with active ankylosing spondylitis who had been treated with medicines acting against TNF-alpha.
In late 2005, a third TNF-alpha blocker, which is a human monoclonal antibody directed against the cytokine, was filed with the authorities to treat patients suffering from ankylosing spondylitis.
The major use of bisphosphonates has been in the treatment of osteoporosis and other bone disorders. Recent work suggests that they may suppress the formation of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6 and TNF-alpha. This treatment is under investigation in phase 2 clinical studies and could also have an effect on the osteoporosis found in ankylosing spondylitis.
Clinical studies are ongoing with a disease-modifying compound which has been used in inflammatory bowel syndromes to study the effect in patients with peripheral joint affections. Research is underway to explore how genetic predisposition may influence the severity of ankylosing spondylitis, i.e. whether some genes may cause people with the illness to have more rapid fusion of the bones of the spine, or be more likely to need orthopaedic surgery.
The crucial role which TNF-alpha plays in the development of the disease will lead to further investigations in molecules of multiple modalities. Proteins, monoclonal antibodies and small molecules which inhibit release or function of pro-inflammatory cytokines or interfere with MAP kinase to suppress the inflammation cascade are at a very early stage of research.