RHEUMATOID ARTHRITIS

What is rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints. Persistent inflammation initially affects the synovium of the movable joints of the skeleton (Figure 1). 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 (Figure 2). As well as affecting the joints, RA can damage connective tissue in many other body systems, such as the skin, lungs, nerves, blood vessels and heart. For that reason, it is often referred to as rheumatoid disease. A study of a group of people with RA who were monitored for 40 years showed that RA reduced average life expectancy by about 10 years as compared with people who did not have RA, with the leading cause of death being cardiovascular disease.

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 causing bleeding into the joint. There is loss of function as tendons become displaced from their normal position, shorten, and cause the characteristic joint deformities of the disease.

The cause of RA remains unclear, but it may be 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 who have a family history of RA, suggesting that they have predisposing genes.

Who does rheumatoid arthritis affect and what does it cost?

RA affects about 0.8 per cent of the adult population in the UK, or 387,000 people. It is over twice as frequent in women as in men, and starts most often in the child-bearing years. In addition, 12,000 children in the UK have the related inflammatory disease juvenile idiopathic arthritis. The Office of Health Economics estimates that treatment of rheumatoid arthritis and related conditions cost the NHS £792 million in 2002/03, but this figure does not include lost earnings, and costs of non-professional carers, social services etc, so that the total cost to society is likely to exceed £1 billion per year.

Present treatments and shortcomings

Rheumatoid arthritis involves three processes that are targets for treatment. For some reason, RA causes chronic activation of the immune system, resulting in production of an autoantibody called 'rheumatoid factor', which can be found in the circulation and in affected joints. White blood cells then enter the joint and release substances including interferon gamma (IFN-γ) and cytokines, especially IL-1, IL-6, and TNF-α (Figure 3), that cause cell proliferation, resulting in synovial thickening and pannus formation. Cytokines are a product of cells of the immune system that stimulate immunity. Cytokine-induced inflammation causes the release of further substances in the synovium that cause pain, tenderness and swelling around the joints. Finally, enzymes in the joint and at the pannus-cartilage interface cause 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. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors work by inhibiting the enzyme cyclo-oxygenase (COX), now known to exist in two forms: COX-1 and COX-2. This reduces the formation of inflammatory prostaglandins. Individuals differ in their response to NSAIDs and, as there are many different types, several can be tried until the best one is found. Some of the best known NSAIDs are diclofenac (Voltarol, Novartis), flurbiprofen (Froben, Abbott), ibuprofen (Brufen, Abbott), meloxicam (Mobic, Boehringer Ingelheim) and naproxen (Naprosyn, Roche). All are available for use in the more commonly occurring osteoarthritis as well as in RA.

Older, non-selective NSAIDS can cause serious stomach bleeding. About 20 per cent of gastroduodenal ulcers are caused by NSAIDs and the cost to the NHS of treating their side-effects has been estimated to be as much as £1 million per day. It is now known that prostaglandins produced by COX-1 protect the stomach, while those formed by COX-2 cause inflammation. Hence, compounds that specifically block the action of COX-2 but not COX-1 should control inflammation without harming the stomach. Two selective COX-2 inhibitors, celecoxib (Celebrex, Pfizer) and etoricoxib (Arcoxia, Merck Sharp & Dohme), are available for use in RA. However, caution is recommended in their use, as some earlier selective COX-2 inhibitors, now withdrawn, have been shown to be associated with an increased risk of complications such as heart attack and stroke./p>

Attempts to find medicines that slow or halt proliferation have, however, been less successful. Disease Modifying Anti-Rheumatic Drugs (DMARDs), of which the most often used are methotrexate (Maxtrex, Pfizer) and sulfasalazine (Salazopyrin, Pfizer), have been available for many years, but are not always effective. The newer leflunomide (Arava, sanofi-aventis) and cyclosporin (Neoral, Novartis) are of value in severe disease, but may cause serious side-effects. Recently, it has been recognised that DMARDs are most beneficial when given early in the disease process, together with an NSAID. Used in this way, the combination damps down inflammation and slows down the growth of pannus and thickening of tendons, but does not entirely prevent them.

The newest anti-proliferative medicines are three that inhibit tumour necrosis factor alpha (TNF-α), which has an important role in inflammation. Etanercept (Enbrel, Wyeth) is a soluble TNF-α receptor that binds to and inactivates TNF-α, and infliximab (Remicade, Schering-Plough) and adalimumab (Humira, Abbott) are anti-TNF-α monoclonal antibodies. They are available for use late in the disease, in patients who have failed to respond to other DMARDs, and are given by injection. However, blocking TNF-α also has an immunosuppressive effect and there have been reports of increased infection rates with their use. Patients will normally be screened for latent tuberculosis and treatment will also be withheld if there is evidence of other active infections. Infliximab has also been found to contribute to heart failure and is unsuitable for those at risk.

Those with severe active RA who have not responded to DMARDs and anti-TNF-α agents can be given rituximab (MabThera, Roche), which is also used to treat non-Hodgkin's lymphoma. In a Phase 3 study, 51 per cent of those treated with rituximab experienced at least a 20 per cent improvement in clinical signs of disease activity, as compared with 18 per cent of those treated with placebo.

Finally, anakinra (Kineret, Amgen) an inhibitor of the pro-inflammatory cytokine interleukin-1, is available for treating RA that does not respond adequately to the DMARD methotrexate alone. However, NICE has recommended that it should only be used in the context of a clinical study.

There are no medicines currently on the market which control tissue destruction in late-stage RA.

What's in the development pipeline?

Efforts to develop alternative NSAIDs and selective COX-2 inhibitors have essentially ceased, but there are ongoing projects to develop other medicines that interact with TNF-α. Two are at the Phase 3 stage: certolizumab pegol (Cimzia, UCB), and golimumab (Centocor/Schering-Plough). Both are intended for use in moderate to severe RA. A so-called TACE inhibitor (BMS-561392) from Bristol-Myers Squibb is at Phase 2. At Phase 1, Targeted Genetics is exploring another approach with tgAAC94 - a gene therapy product that seeks to introduce the gene for soluble TNF-α receptor protein into affected joints.

A variety of other projects aim to block one or more of the other cytokines that fuel the inflammatory reaction in RA. Amgen's AMG-108 (at Phase 2) is a monoclonal antibody that binds to IL-1 itself and is thus a complement to anakinra, which binds to the IL-1 receptor. A similar monoclonal antibody from Novartis (ACZ 885) and one from Eli Lilly are also both at Phase 2. More advanced is tocilizumab (MRA), an anti-IL-6 receptor monoclonal antibody being developed by Roche and Chugai, which is in Phase 3 trials. In a first Phase 3 trial, this antibody produced striking reductions in symptoms in patients with earlystage disease when injected once every four weeks, proving more effective than conventional DMARDs.

Other monoclonals in development target the cytokines IL-15 (AMG 714, Amgen, Phase 2), IFN-α fontolizumab, Biogen Idec, Phase 2), and IL-17 (AIN 457, Novartis, Phase 1), Serono has an IL-18-binding protein (tadekinig-alpha) in Phase 2, Synta Pharma has an oral IL-12 inhibitor (STA-5326, apilimod mesylate, Phase 2) and Kowa is working on an oral inhibitor (K-832) of the production of several cytokines, also at Phase 2.

A large number of compounds are in Phase 2 development that aim to inhibit the cascade of cytokine production and release provoked by TNF-α and IL-1. This is achieved by blocking one of the common signalling pathways following activation of TNF-α and IL-1 receptors on the cell surface. Most of these compounds have been selected to inhibit an enzyme called p38 MAP kinase, which is found in synovial cells in affected joints (Figure 4). Kinase inhibitors are in development by Boehringer Ingelheim (BIBR 796 BS, doramapimod), GlaxoSmithKline (GSK 681323 and 856553), Pfizer (CP-690550 and PH-797804), Roche (R1503), Scios (SCIO-469) and Vertex (VX-702).

Other companies have chosen to target cell adhesion molecules, which influence the infiltration of the synovium and synovial cavity by inflammatory cells. Examples include MLN 3897 (Millennium Pharma) and AVE 9897 from sanofi-aventis at Phase 2 and Millennium's MLN 3701, AVE 1701 (sanofi-aventis) and UCB's CDP 323, all at the Phase 1 stage.

Several other compounds are in development that, like rituximab, target B cells, which play a role in the immune system. These include ocrelizumab (R1594) of Roche (Phase 3) and GSK/Genmab's ofatumumab, Wyeth's TRU-015 and belimumab (LymphoStat-B, Human Genome Sciences), all at Phase 2. T-cell activation may also be important in some cases of RA, and Bristol-Myers Squibb has abatacept (Orencia) that blocks this process. It may provide an alternative to rituximab in those who have not responded adequately to DMARDs and anti-TNF-α inhibitors.

The longer-term future

There are so many processes involved in inflammation and tissue destruction in RA that there are many more compounds under investigation than can be mentioned here. Other types of compounds are being studied by Astellas, AstraZeneca, Dainippon- Sumitomo, Eli Lilly, GW Pharmaceuticals, Pfizer, Serono, Toyama, Wyeth and ZymoGenetics, among others. With such intense research activity, it is likely that the situation of people with RA will be considerably improved over the next decade, with more selective treatments that can slow or stop disease progress and prevent much of the deformity, pain and loss of function that are all too common now.

FOR FURTHER INFORMATION CONTACT:

ARTHRITIS CARE
18 Stephenson Way
London, NW1 2HD
Phone: 0808 800 4050 (helpline)
Website: www.arthritiscare.org.uk