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Targeted therapies for patients with rheumatoid arthritis

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Rheumatoid arthritis (RA) is an auto-immune disease that results in a debilitating inflammatory arthritis with no known cure. The immune system treats the body’s own synovial tissue, which lines the articular surfaces of moveable joints, as foreign and launches an immune response against it. When inflammation persists or fails to respond to treatment, destruction of nearby cartilage, bone, tendons and ligaments can occur, leading to permanent disability.

Susan Oliver, MSc.

Clinical Nurse Specialist Rheumatology, Northern Devon Health-care Trust, Barnstaple


The effects of this continuing disease activity are also seen in synovial joint swelling, stiffness, pain and fatigue. The auto-immune nature of the disease can have significant multi-system effects on extra-articular features, including subcutaneous nodules, scleritis, pericarditis, pleural effusions, vasculitis and skin ulceration. The consequences are significant, with 42% of patients registered as disabled within three years of diagnosis and many requiring joint replacements.

Survival rates for patients with severe RA are comparable to Hodgkin’s disease, diabetes mellitus and triple-vessel coronary artery disease (Pincus and Callahan, 1993). RA is a major consumer of health-care resources and a major contributor to morbidity, disability and mortality. The daily consequences of the disease not only place a significant burden on the individual but also make high demands of health-care resources.

The immune response
The principles of the accepted normal immune response are sometimes taken for granted. Although health-care professionals are aware of this in practical terms, there is often little need for close scrutiny of the underlying theoretical concepts. In recent years, research has helped us understand more about the cell interactions involved in the normal immune response, which has led to new treatments that have the potential to block or ‘disarm’ cell interactions in the early stages of an immune response. These potentially powerful interventions have raised awareness of many auto-immune diseases.

This paper will give a simple explanation of auto-immune disease and the resulting inflammatory response. Tumour necrosis factor alpha (TNFa) is one of many powerful chemical messengers (cytokines) involved in a normal inflammatory response. The role of new treatments with anti-TNFa is addressed in the treatment of RA or idiopathic juvenile chronic arthritis.

In the past decade research has helped us understand more about immunology. A number of chronic illnesses are known to have an auto-immune component that results in the self-destruction of vital tissues. The consequences of the disease will depend on which tissues are damaged as a result of the body’s ‘malfunction’.

RA is a good example of an auto-immune disease. An abnormal immune response is ‘triggered’ by the body’s faulty recognition of the synovial tissues that line moveable joints as ‘foreign’. Similar responses are seen in other ‘faulty’ immune responses, for example the immune system of a patient with diabetes mellitus sees pancreatic cells as ‘foreign’ and, as a result, ‘triggers’ an immune response that causes cell damage to the pancreas.

Understanding immunity
To understand immunity it is useful to think of the immune system working as an army (Isenberg and Morrow, 1995). An antigen is a foreign substance that invades the body. The response to these ‘invaders’ is to launch a response by lymphocytes, which develop in bone marrow and are initially called stem cells. The stem cells are similar to new recruits, and the bone marrow can be thought of as a headquarters and recruitment centre.

The young stem cells are developed and trained as general soldiers - the B-lymphocyte cells. Some are sent to ‘base camps’ around the body, situated in lymphoid tissue in the tonsils, adenoids, lymph nodes, spleen, lymphatic vessels and patches of lymphoid tissue in the intestines. The system is very efficient with a good communication system and means of travel (via lymphatic vessels) between lymphoid tissue. One-quarter of all developed B cells are present in the lymphoid tissues. Some stem cells, however, become specialist cells in the thymus gland. Those that originate in the thymus are known as T-lymphocyte cells.

T-lymphocytes and B-lymphocytes
Although T cells and B cells have their unique roles in arming the immune system, they also have common characteristics.

A clear difference between the two is that T-lymphocytes need ‘invader’ cells to be presented to them in a specific way. T cells will identify an antigen after an antigen-presenting cell (APC) has shown it to them. APCs will often be macrophages, which are cells distributed throughout the body in tissues and blood. They have the potential to consume passing antigens and immune complexes by cleaning up debris throughout the immune system. When a macrophage works as an APC, it uses enzymes to partially break down the proteins in the antigen before presenting it to the T cell. The role of the APC and how it presents the antigen to the T cell will also help the T cell know what type of attack to launch.

Both types of cell are capable of ‘clonal expansion’, that is, they have the ability to reproduce themselves rapidly when needed. They have ‘receptors’ that enable good communication and contact with antigens. Another important role of T cells is the ability to secrete potent chemical messengers (cytokines) that trigger a response from other cells, particularly in response to an ‘invader’ or antigens. B cells can also secrete cytokines, although this is predominantly the role of T cells.

Research continues to identify a wide range of cytokines, some of which are grouped into families such as interleukins and tumour necrosis factors to name a few.

Each cytokine has a specific role in the immune system. The cytokine or messenger can be released into the blood or lymphatic systems. When this occurs, it needs to ‘lock into’ a T cell receptor. Once this occurs, it can launch a number of responses. One is that of a ‘killer’ T cell: these are powerful cells that deliver a lethal dose of chemical directly on to the antigen killing it. This is of particular relevance when thinking of an antigen that could be a virus or rogue cancer-type cell.

Sometimes the T cell will recognise the need to launch a response from a ‘suppressor’ T cell, which causes a reduction of the normal attack or immune response. It is this process that tells the T cells to cease attack: this occurs when an antigen is no longer functioning, when the immune response has had the desired effect.

B-lymphocytes, although less highly specialised than T cells, are the memory of the immune system. B cells can be thought of as the intelligence corp and, as noted above, are mainly based in lymphoid tissues. They have the ability to remember previous antigens (foreign invaders) and have a tailor-made immune response that can destroy them. The B cells will respond quickly to requests from T cells that recognise the initial attack from an antigen. The B cell memory results in a tailor-made decisive ‘bullet’ or attack on the antigen released through the lymphatic or blood system. This tailor-made response is an immunoglobulin.

An immunoglobulin is almost always a Y-shaped structure (Figure 1). The significance of this shape is essential to understanding some of the new treatments used to control auto-immune disease. One section of the Y-shape is fixed, while others can change. The V-part is the flexible part that can be manipulated in the laboratory. The V-section is where the antigen sticks when trapped by the immunoglobulin.

When a B cell recognises an antigen, it sends out an immunoglobulin specifically made to match the known antigen. The immunoglobulin has jigsaw-like sections (Figure 1) that fit the shape of the antigen exactly, thus acting like a lock and key. If an immunoglobulin and antigen match perfectly, they are said to have a shared epitope and this is what brings an effective immune response. If the antigen is a new one, the B cell rapidly develops an immunoglobulin to deal with it. The pattern remains as part of the ‘memory’ of a B cell for future immune responses.

The immune response in RA
When the T cell activates a response in RA, it releases the cytokine TNFa, which locks into a T cell receptor that can be circulating either in the blood, the lymphatic system, or tissue bound in cells such as synovial tissue. Cytokine activation or ‘locking in’ results in a burst of activity from other T cells and other cytokines, causing activation of various processes in the body. This response is called the inflammatory cascade (Figure 2).

Although this paper focuses on RA, patients with other diseases known to have an auto-immune component have been shown to benefit from therapeutic interventions to reduce or block the normal immune responses (for example, infliximab is licensed for treating Crohn’s disease).

Immunosuppressive therapies have evolved, sometimes without a clear understanding of the mechanisms that reduce the immune response. It was by chance that researchers, who believed that RA and tuberculosis were similar diseases (Forestier, 1929), discovered that Myocrisin (gold injections) was effective in controlling the destructive process in RA.

The use of immunosuppressive agents, which have some effect on controlling the disease process, are not without a range of serious side-effects and still fail to adequately suppress the auto-immune disease (Brooks, 1998).

Treatment of RA relies heavily on pharmacological therapies such as non-steroidal anti-inflammatory drugs (NSAIDs), steroids, disease-modifying anti-rheumatic drugs (DMARDs), cytotoxic agents and, more recently, anti-TNFa treatments. Methotrexate (MTX) has been recognised as being the most efficacious in treating RA and is the most commonly used disease-modifying drug (Wilkens, 1990; Weinblatt et al, 1992). Many patients remain on DMARDs for a few years only, because of lack of efficacy or because of toxicity (Cash and Klippel, 1994). Studies show that MTX can be tolerated for longer, up to 10 years, and it is the cornerstone of most combination therapies (Kremer, 1995). In recent years, leflunomide has been introduced as a DMARD with properties similar to MTX. This has increased the armoury in managing patients with RA (Smolen et al, 1999). But there remains a need for treatments that significantly reduce the overall impact of aggressive RA.

Not all patients, however, respond to MTX or combination therapy: they are a treatment challenge and many rely on the use of steroids. Today, the development of TNFa agents offers them an opportunity for disease suppression and an improved quality of life. Once the key role of cytokine TNFa in effecting the inflammatory cascade was identified, research focused on developing an immunoglobulin to ‘lock into or block’ the cytokine from connecting to the T cell receptor.

Two new anti-TNFa drugs - infliximab and etanercept - have been developed along these principles and are available for treating active RA (Box 1). Although both treatments are anti-TNFa products their characteristics are different.

Etanercept is licensed for the treatment of juvenile arthritis and RA, while infliximab is licensed for use with RA and Crohn’s disease. The average costs per patient per year are £6000-£10 000, depending on the method of administration. RA patients should be considered eligible for anti-TNFa treatment assessment only if he or she has failed to benefit from two conventional DMARDs, at target dose, one of which must have been MTX.

The British Society of Rheumatology (2000) has clear criteria for the selection, documentation and administration of anti-TNFa treatments. It has also established a register of patients having these treatments to evaluate response and monitor adverse events. This is important, as the long-term effects of these drugs are unknown. These factors mean that the drugs are recommended for use in patients with uncontrolled disease who have failed to benefit from conventional therapy (National Institute for Clinical Excellence, 2002).

According to Keane et al (2001), 147 000 patients have received anti-TNFa treatments worldwide. There is evidence that 70% of patients have a good response to this therapy (Emery et al, 1999), but it is expensive compared with conventional treatment. What counts as a good response remains an area of close scrutiny in research and clinical practice. However, the most important factor for both drugs has been the reduction in erosions to joints on radiographic evidence.

Etanercept (Enbrel) is a soluble fusion protein anti-TNFa receptor. It is administered by subcutaneous injection at a dose of 25mg twice a week. Patients can be taught to self-administer at home, reducing their need to attend hospital. The most common unwanted side-effects are injection-site reactions. More rarely, the therapy has also been associated with leucopenia, pancytopenia and aplastic anaemia or with onset of demyelinating diseases such as multiple sclerosis. Regular review of the patient is essential to monitor the benefits of therapy and to detect side-effects.

Infliximab (Remicade) is a chimeric human-murine monoclonal antibody - that is, it consists of part human, part mouse immunoglobulin. Because part of the antibody is developed using mouse cells, patients with a known sensitivity to murine proteins should not be given infliximab.

It is administered by intravenous infusion at initial intervals of 0, 2 and 6 weeks at a dose of 3mg/kg, followed by a maintenance dose every eight weeks. It is given in combination with MTX, because of its complementary effect on treatment; in addition, research evidence has shown that in patients co-prescribed MTX there is a reduction in developing antibodies to infliximab. The most common side-effects include infections (Box 1) and infusion reactions that tend to resolve if the infusion is slowed or temporarily interrupted.

Although additional treatment is rare, it is essential that antihistamine, corticosteroid and adrenaline are accessible in the event of anaphylaxis. Infusion reactions are more likely to occur during the first infusions.

Infliximab has been associated with acute infusion reactions that can occur within a few seconds or a few hours of administration. Data on reactions include cardiopulmonary reaction; less severe reactions include urticaria, pruritis, or fever and chills. Some patients can have a delayed hypersensitivity reaction - for example, myalgia, arthralgia, fever, rash or hand or lip oedema - up to 12 days after the infusion.

It is essential to monitor patients regularly to assess the treatment benefits and any side-effects. If the patient is receiving infliximab, the standard criteria for monitoring MTX should apply. General guidance for patients receiving etanercept is that they should be monitored monthly.

Assessment of the response to treatment and level of disease activity should be undertaken and reviewed after three months of therapy, and if the patient fails to adequately respond within this period, the treatment should be stopped.

Although blood disorders are less common with the use of both these drugs, routine monitoring should continue. A range of blood disorders have been identified (pancytopenia, anaemia, leucopenia, neutropenia, thrombocytopenia and elevated liver function tests), but patients will have active and sometimes complex diseases. Although those receiving infliximab will have blood tests before any infusions there is, as yet, no consensus on how regularly blood tests should be done and the significance of some of the results, such as elevated liver function tests.

RA is a debilitating disease that has major personal, social and economic repercussions for both the individual and society. Of the estimated 600 000 people affected by RA in the UK, 80% will be disabled within 20 years of developing the disease (Scott, 1998; Choy and Panayi, 2001). The development of cytokine-blocking agents brings renewed hope for treatment of RA, although not every patient will fulfil the criteria for therapy.

If such targeted therapies continue to prove as successful in clinical practice as the research evidence suggests, patients will benefit from improved disease control. This will not only improve their quality of life, but also reduce the need for joint replacement surgery, provision of equipment and aids, and may even reduce emergency admissions for patients with complex uncontrolled disease who experience side-effects either before treatment or as a result of aggressive disease.

The long-term benefits and side-effects of these drugs are unknown, but early evidence demonstrates the value of both drugs in treating RA (Moreland et al, 1999; Maini et al, 1999). Significant improvements have been observed for a range of criteria set out by the American College of Rheumatology (Felson, 1995). These evaluate percentage improvements in a range of disease activity measures such as tender and swollen joint counts, early morning stiffness and reductions in inflammatory markers in the blood (such as C-reactive protein and erythrocyte sedimentation rate).

Confirmation of the long-term safety and efficacy of these drugs would signal the start of exciting developments in the treatment and care of patients with RA. Potential benefits to patients include a reduction in joint destruction and the subsequent need for joint replacements, and improvements in functional ability and the social consequences of patients being able to take a more active part in society. The role of the nurse is to ensure that patients are informed, and that they are assessed, monitored and managed carefully while receiving these new treatments.


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