Rheumatoid arthritis leads to inflamed and painful joints. It causes disability in a lot of people. Medicines can reduce the inflammation and the pain. This helps people to stay mobile and get on with their lives. Research is continuing to develop even better therapies.
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease. Persistent inflammation initially affects the movable joints of the skeleton. With the passage of time, the synovium thickens to form pannus tissue which invades cartilage and bone. Among the earliest joints affected in many people are those of the hand, where small cavities can be detected using microfocal X-ray methods. As well as affecting the joints, RA can damage connective tissue in many other body systems such as the skin, lungs, nerves, blood vesselsand heart.
The rate of progression of RA is very variable: a few people have an aggressive form of the disease, leading to disability in months, while in most people it takes years. Ultimately, the cartilage is destroyed, causing pain, as bone grates against bone, and bleeding into the joint. There is loss of function as tendons become displaced from their normal position and shorten, causing the characteristic joint deformities of the disease.
RA is the most common rheumatic disease in the world. It affects about 1 in 100 adults, or more than 50 per cent of people aged over 65. The incidence rate in Western Europe is estimated at 1 per 10,000 population, i.e. some 37,000 new cases every year. RA is about three times as frequent in women as in men, and tends to start between the ages of 35 and 50.
RA is an autoimmune disease, in which damage is caused by the body’s immune system mistakenly attacking its own tissue. Some kinds of infection seem to trigger this attack, especially in people with a family history of RA, suggesting that they have predisposing genes.
Three aspects of RA can be distinguished that are relevant for treatment: Firstly, inflammation arises through a number of interrelated biochemical and cellular events, culminating in the release of prostaglandins, complement, and other inflammatory substances in the synovium that cause pain, tenderness and swelling around the joints.
Over time, the immune system is chronically stimulated and white blood cells (lymphocytes, neutrophils and macrophages) enter the joint. They release substances which are involved in the regulation of the growth and maturation of cells, and cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha. Secondly, this causes cellular proliferation, resulting in synovial thickening and pannus formation. Finally, enzymes (metalloproteases, serine proteases) in the joint and at the pannus-cartilage interface lead to destruction of the cartilage and underlying bone.
An area of early success for medicines research was the development of compounds to treat the inflammation in RA. Analgesics were shown to work through inhibition of the enzyme cyclo-oxygenase(COX), now known to exist in two forms: COX-1 and COX-2. Inhibiting COX reduces the formation of inflammatory prostaglandins. The new medicines designed to do this, called non-steroidal anti-inflammatory drugs (NSAIDs), greatly improved the quality of life for RA patients.
Individuals differ in their response to NSAIDS and as there are many different types, several can be tried until the most suitable one is found. Older, non-selective NSAIDS irritate the intestines and can cause serious stomach bleeding. About 20 per cent of gastric ulcers are caused by NSAIDs. It is now known that COX-1 protects the lining of the stomach, while COX-2 causes inflammation. COX-2 selective NSAIDs are also available for the treatment of RA.
Attempts to find medicines that slow or halt proliferation have been disappointing. Several DMARDs (Disease Modifying Anti-Rheumatic Drugs) have been available for many years. Recently, it has been recognised that they are most beneficial when given together with an NSAID early in the disease process. Used in this way, the combination damps down inflammation and slows down, but does not entirely prevent, the growth of pannus and thickening of tendons.
More recently launched DMARDs are of value in tackling severe active disease. The newest anti-proliferative medicines inhibit TNF-alpha, an important inflammatory mediator. The active principles are either a soluble TNF receptor that binds to and inactivates TNF-alpha, or an anti-TNF-alpha monoclonal antibody (mAb). They are authorised for use late in the disease, in patients who have failed to respond to other DMARDs, and are given by injection. Further products are a PEGylated humanised anti-TNF mAb fragment, and a PEGylated sTNF-receptor inhibitor. Both are intended for use in moderate to severe RA.
However, blocking TNF-alpha also has an immunosuppressive effect and there have been reports of increased infection and cases of lymphoma. Finally, an inhibitor of IL-1 is available for treating RA that does not adequately respond to DMARDs.
Interleukin 6 (IL-6) is a different cytokine from that in the inflammatory cascade targeted by TNF-alpha inhibitors. MAbs which block the IL-6 receptor have been shown to produce remarkable reductions in symptoms in patients with early-stage disease when injected every four weeks.
There are no medicines currently on the market which could control tissue destruction in late-stage RA.
A new approach to treat the disease may be the blocking of SYK. SYK stands for “Spleen Tyrosine Kinase”, an enzyme which is part of the signalling pathway between macrophages, neutrophil granulocytes, monocytes and B-lymphocytes. An oral SYK inhibitor has been shown to improve outcomes of patients with RA who responded inadequately to ongoing treatment with DMARDs.
Patients with average to severely active RA have responded well to the treatment with an oral JAK inhibitor. JAK is the acronym for Janus Kinases. They interfere with the cytokines of the intracellular communication in white blood cells thus damping the inflammatory process.
Cryopyrin-associated periodic syndrome, or CAPS, is a rare, inherited disorder caused by a mutation in a single gene. The mutation causes the body to overproduce IL-1 which leads to inflammation and tissue damage, causing chronic rash, fever, and joint pain. Since 2009, the genetic cause of disease can be treated.