Rheumatoid Arthritis 1. Introduction
Rheumatoid arthritis (RA) is best characterized as a systemic, chronic, inflammatory disorder that has a tendency to attack the joints. RA is also distinguished by inflammation in the lining of the joint, which will cause pain, stiffness, swelling, warmth, and potential loss of function of the joint. This is the simplest definition of this complex disease. Systemic means it can attack the whole body. It most commonly affects the joints of the hands and feet and will often affect the same joints on both sides of the body. This is one way in which RA differs from other types of polyarthritis. RA can affect other parts of the body, not just the joints. This is called systemic disease. Because RA is a symmetrical disease, this can help distinguish RA from other disorders. For example, if the right knee is affected, often the left knee will be too. RA may also cause damage to the skin, eyes, lungs, heart, blood, or nerves. This is one reason why it is called systemic. Onset of RA generally occurs between the ages of 30 and 60, and the likelihood of developing the condition increases with age. Children and the elderly can still develop RA, but it is much less common. Women are approximately 2-3 times more likely to have RA than men. I think people are finally starting to realize that RA is not just an old person's disease. Many cases of juvenile RA can now be diagnosed as different types of RA that occur in adults. Early and aggressive treatment of RA can prevent permanent damage to the joints and will often lead to remission of the disease. In cases of juvenile RA, the chance of remission is high. I was diagnosed at age 11 and was in remission by age 13. But there is no cure for RA, and the disease process can never be predicted for certain.
1.1 What is Rheumatoid Arthritis?
Rheumatoid arthritis, often considered the most disabling of the more than 100 types of arthritis, is a disease that affects the joints. It is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, lungs, and the muscles. This chronic arthritis is characterized by the inflammation of the lining, or synovium, of the joints. Rheumatoid arthritis is also an autoimmune disease, which means that the immune system of the body mistakenly attacks healthy tissue. In rheumatoid arthritis, the immune system primarily attacks the synovium, which it perceives as a foreign invader. As a result of the attack, the synovium becomes inflamed and swollen. In turn, the inflammation causes damage to the synovium, resulting in a loss of function of the affected joint. During the course of the disease, the damage to the joint may become permanent and the loss of function may be disabling. The distinctive feature of rheumatoid arthritis is the pattern of joint involvement. The joint problems associated with rheumatoid arthritis are usually symmetrical – if one knee or hand is affected, the other one is also. The disease often affects the wrist joints and the finger joints closest to the hand. It can also affect other parts of the body besides the joints. In some individuals, the skin as well as the joints may be affected. Anemia is a common feature of the disease, often resulting from the chronic inflammation. The autoimmune process can cause generalized feelings of fatigue and occasional fevers. It also may affect the lungs and the heart.
1.2 Causes and Risk Factors
Rheumatoid arthritis is a systemic autoimmune disease, which means that the immune system attacks the healthy cells of the body. This disease is one of the common arthritis diseases that affect areas of the joints in the hands and feet. Over time, the disease can affect other parts of the body including the skin, eyes, lungs, heart, and blood vessels. The synovium is a lining that surrounds joints and it becomes inflamed due to the immune system attacking the body. This inflammation thickens the synovium over time and can destroy the bone and cartilage in the joint. The tendons and ligaments that hold the joint together weaken and stretch, which causes the joint to lose its shape and alignment. During the inflammation process, the immune system produces cells that cause these changes. When the synovium is inflamed, it gives off enzymes that can diffuse into the bone and cartilage and cause damage. The cause of rheumatoid arthritis is not completely known. It is understood that the interaction between genes and the environment plays a large role in the development of the disease. This is shown by the large amount of research that has been conducted, which has provided a number of potential causes for the disease. The major advancement in the understanding of the disease cause is the study of the immune system, which has provided various new treatments. As stated above, the disease is the result of the immune system attacking the body. This system is controlled by genes, and immune system problems may be inherited. This statement is supported by the fact that the disease is more common in specific families and by the identification of specific genes that are related to the disease.
1.3 Symptoms and Diagnosis
X-Rays X-rays are used to help make initial diagnoses and to follow disease progression. Typical findings include loss of joint space, erosions, and in advanced cases, bone deformity.
Lab Tests Patients with RA often show anemia, and a slight elevation in white blood cell count. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly elevated. Although these findings are non-specific, they help to determine the presence of an inflammatory process. A positive rheumatoid factor can be found in the majority of patients, but sometimes may not appear for a year after the onset of symptoms. A newer test for the presence of antibodies to cyclic citrullinated peptide (anti-CCP) is superior to rheumatoid factor testing.
Physical Examination RA can make diagnosis a tough process because it often starts with nonspecific symptoms that are followed by periods of remission. Often in the early stages of RA, there is little distinction between different types of polyarthritis. Increased disease activity usually defines the differentiation.
Medical History Many people with RA first seek medical aid due to painful, swollen, and stiff joints. Onset can be gradual or sudden. The age of onset, pattern of joint involvement, and the presence of extra-articular disease help narrow the differential diagnosis.
Only about 2/3 of people with RA feel pain or functional problems that will lead to a diagnosis within 2 years of symptom onset. 1/4 will be disabled within 5 years and 1/3 will die. Due to these drastic consequences, early detection and diagnosis is crucial. However, there is no single test to determine the presence of RA. Instead, diagnosis is based on a number of factors including medical history, physical examination, lab tests, and x-rays.
1.4 Treatment Options
Drug therapy is used to relieve symptoms and to slow the progression of the disease and joint damage. The first choice in drug treatment is usually a nonsteroidal anti-inflammatory drug (NSAID). While they are effective in reducing inflammation and symptoms of RA, they do not prevent joint damage and NSAIDs have a number of side effects. It is not uncommon to use low-dose or short-term oral steroids to relieve symptoms, but the long-term use of steroids can have many side effects and disease-modifying antirheumatic drugs (DMARDs) are utilized to prevent joint damage. DMARDs can be effective in that they can induce partial or complete remission of the disease, which is rare with other types of treatment. If such a state is achieved, then it is possible to reduce drug therapy. More recently, biologics have become available for those with severe rheumatoid arthritis unresponsive to other treatment. These drugs are a subclass of DMARDs and can be very effective in the treatment of RA, but also have a number of adverse effects. In general, drug therapy needs to be monitored very carefully by a physician with regular assessments of the disease activity and medication toxicity.
Exercise or physical therapy can be an effective way to relieve pain and prevent or improve functional ability without causing further damage to the joints. Occupational therapy can also lessen the strain on the joints to help conserve energy and reduce pain. Rest is still important in the active stage of the disease, but prolonged rest can cause joint damage and deformities and needs to be balanced with exercise.
There are many methods of treatment for rheumatoid arthritis. The main goal of treatment is to reduce pain, prevent any additional damage to joints, and to get the patient to the point where they can function normally and independently. The treatment that is most effective is something that can be determined by a physician, but can often fluctuate between the different options. Sometimes a combination of various methods can be utilized to effectively control the disease. Patient education and the involvement of the patient are important, as it has been shown that patients who are well informed and who play an active role in their treatment have a better outcome.
2. Living with Rheumatoid Arthritis
Even though RA is not helped by physical activity, avoiding inactivity can help joint symptoms and fatigue. A proper balance between rest and exercise is essential. Too much rest can weaken muscles, and damage can reduce range of motion in joints. Range of motion exercises should be done daily to prevent weakening of the joints. If these exercises are painful, this pain can be decreased using heat. Otherwise, during acute phases of joint inflammation, rest is also essential to decrease stress on the joints. Modalities such as hot or cold packs, or paraffin baths may be used. It is best to avoid activities that stress the joints, such as climbing and long-distance running. Immobilization of joints affected with RA has been shown in producing calcium deposits. A physiotherapist can prescribe the best exercise program. Swimming is often recommended, as it is not a strenuous exercise, and the buoyancy of the water relieves stress on the joints. Patients should be taught joint protection techniques, as this can greatly improve their ability to function independently. This can involve adaptive equipment, such as using a cane, long-handled reachers, or specially designed utensils. These devices can compensate for deformed hands, or decrease stress on affected joints. Patients can also be taught positions or methods to reduce extra stress on the joints during daily activities. An occupational therapist can be helpful in addressing the patient's individual needs.
2.1 Managing Pain and Inflammation
Rheumatoid arthritis is a disease with varying symptoms that can be different from person to person. This is important to come up with a strategy that can help minimize pain and damage to your joints and allow you to live an active life. Pain has been identified as the most common symptom that affects individuals with RA. At least 50% of individuals with RA report that they have recently experienced persistent pain and have visited a healthcare professional for treatment of pain. Reducing pain is an important part of the RA treatment strategy and there is a form of medication to help decrease inflammation and/or pain. Nonsteroidal anti-inflammatory drugs and corticosteroids are often prescribed to reduce pain and inflammation. Although long-term use of corticosteroids is not recommended as they are associated with further joint damage. If the inflammation in the joint is left unchecked, it can cause damage to the cartilage and bone within the joint as well as the ligaments and tendons surrounding the joint. This damage cannot be undone and leads to chronic problems with pain and difficulty moving the joint. In recent years, there has been an emergence of a class of medications called disease-modifying antirheumatic drugs. These medications have been successful in decreasing pain and inflammation as well as preventing progression of the joint damage. DMARDs often take up to 6 weeks to have an effect and during that time, it is important that concomitant treatment is used to control pain and inflammation.
2.2 Exercise and Physical Activity
There are occasional times when exercise or increased activity can exacerbate disease symptoms such as pain, swollen joints, fatigue, and stiffness. In these instances, it is best to rest the affected joints until the symptoms subside. It is important, however, not to abandon exercise altogether. If your symptoms are fluctuating, adjust your exercise program to accommodate this by exercising less often but for longer each time, or by alternating between different types of exercises. Always ensure that you rest when you need to, but resume exercise when your symptoms are more manageable.
Exercise comes in many forms and varieties, and there is no one type that suits everyone. It is important to find the right exercise for you. At one end of the scale, if you have mild to moderate symptoms with few joint problems, playing a sport such as tennis or running may be a suitable form of exercise. At the other end of the scale, even those with severe symptoms or mobility problems can benefit from such activity as seated exercises or tai chi. These are very gentle forms of exercise that are joint-friendly and help to improve flexibility, coordination, and balance. Water-based exercise can also be helpful. The buoyancy of the water reduces the load on the joint and can make exercising easier and less painful.
Regular exercise is important for arthritis sufferers. It helps to keep your joints supple and helps to strengthen the muscles around the joints, which can help to reduce the load placed on the joint, thus reducing pain. Exercise also has a vital role in maintaining general health and well-being. There are many compelling reasons to exercise regularly, some of which include the prevention of developing other chronic conditions, such as heart disease, stroke, and diabetes. Making the decision to start a new exercise program can be a daunting task, especially if you have never exercised before, or if symptoms of pain and restricted movement make even thinking about exercise an unattractive one. It is, however, possible for everyone to benefit from exercise. It is simply a case of finding the right type and level of exercise.
2.3 Diet and Nutrition
Diet can play a crucial role in the management of rheumatoid arthritis. This is significant for two reasons. Firstly, many people with rheumatoid arthritis are overweight, and even small degrees of overweight can lead to more joint stress. Excessive weight can decrease the effectiveness of RA medications, increase the rate of joint damage, and increase the risk of other comorbid conditions such as cardiovascular disease. These comorbid conditions are more likely to cause premature death in those with rheumatoid arthritis. Therefore, weight reduction as appropriate and avoidance of excessive weight gain is a significant part of the management of rheumatoid arthritis. Secondly, it is now recognized that the chronic inflammation in rheumatoid arthritis has an effect on the entire body and can lead to abnormalities in energy metabolism and changes in the levels of key substances in the blood, some of which can cause premature atherosclerosis (heart disease). This is why it's important to take NSAIDs, corticosteroids, and DMARDs correctly and in the smallest effective doses to try to control disease activity. It also suggests that diet and nutrition can affect the course of the disease, and this has led to increasing interest in studying the effects of specific dietary manipulations on RA activity.
2.4 Coping Strategies
It is one thing to familiarize yourself with all the information available on rheumatoid arthritis. It is quite another to anticipate its effects and take decisions on how to deal with the changes to keep the most control and quality in your life. Listening to others for their descriptions of how they deal with their limitations can be helpful and encouraging. They may not all work for you but it is important to remember "As long as it is legal, safe, and does no harm to yourself or others, it is a potential coping strategy" - Deardoff, Woods & Muir (R.A. & Juvenile Arthritis: Facts & Management). For the majority of people, daily life is where the impact of the disease is most keenly felt. The task may seem overwhelming, dealing constantly with limited physical ability, fatigue, and the emotional burden of the disease. Breaking it down to specific problems and possible solutions may help make it more manageable. One of the most successful tactics in dealing with the limitations disease is learning to balance activity and rest in a way that minimizes joint pain and fatigue. This means becoming more conscious of how you do things and learning to pace yourself. Trying to ignore the disease and doing too much on good days can lead to flare-ups and pushes you into an emotional low when payback comes in increased symptoms. On the other hand, taking a "wait and see" attitude and doing too little on both good and bad days can lead to progressive loss of function and increased joint deformities. Planning your activities and looking for ways to do things with less stress on your joints can help. For example: alternate sitting and standing tasks, simplify and organize your work place, and take advantage of labor saving devices.
3. Complications and Related Conditions
Joint deformities are the most common complications of RA, affecting up to 70% of patients within 10-20 years of disease onset. Deformities develop as a result of at least four interrelated factors: anatomic site of disease, local and systemic bone loss, muscle atrophy, and ligamentous laxity. Disease in the joint synovium, which is predominantly erosive, leads to destruction of articular cartilage and periarticular bone, resulting in shortening of the digit and the characteristic ulnar deviation of the digits at the metacarpophalangeal joints. Muscle atrophy and weakness and associated tendon rupture contribute to the deformity. Loss of ligamentous support and deforming forces at the joint construct a backdrop that makes joint realignment interventions of only marginal long-term benefit. Deformities are painful and engender loss of function. (However, attempts to demonstrate an association between specific types of deformities and functional limitations have not been widely successful.) Anecdotally, patients make adjustments in habits of daily living to avoid pain associated with use of a deformed limb. Joint deformities have also been shown to be associated with increased mortality. In one study, patients with severe joint deformities had a fourfold increase in mortality compared with the general population.
3.1 Joint Deformities
Rheumatoid arthritis is a chronic, autoimmune disorder that causes the body to attack its own tissues, aiming at the synovium, the thin membrane that lines the joints. This results in inflammation of the synovium, causing swelling, pain, stiffness, redness, and warmth around the affected joint. If inflammation goes unchecked, it can damage the cartilage, causing it to wear away and lead to joint deformity. There are quite a few joint deformities that can occur in RA, they are PEM: swan-neck deformity, Boutonnière deformity, and the most frequently seen, ulnar deviation. Ulnar deviation occurs when the tendons on the sides of the fingers and metacarpophalangeal (MCP) joints slide off their original position as a result of their cut off blood supply from the inflammation of the synovium. This causes the fingers to become bent towards the little finger and the MCP joints to become prominent on the knuckle, as the rest of the fingers slowly start to curl towards the middle one. Moreover, the tendons on top of the hand weaken, making it difficult to make a fist. PIPJ and DIPJ joint erosions result in the loss of ability to straighten the fingers and affect grip strength. All these deformities in the hand(s) may develop in the early stages of RA and can cause some loss of function. In severe cases, particularly if there has been prior damage to the extensor tendons from rheumatoid inflammation, the fingers can become fixed in a bent position.
3.2 Osteoporosis
The exact mechanism of bone loss in rheumatoid arthritis is unknown, but it occurs as a result of increased bone resorption and decreased bone formation. The balance between these dictates the rate of bone loss. Researchers have discovered that the actual inflammation from RA spreads to the membranes lining the joints, which in turn causes chemicals to be released. This, in turn, is what will eventually cause damage to the bone and cartilage around the joint. With damage to the ends of the bones, ligaments, and the joint capsule, the bone has little support and may shift. When the bones move from their positions, this is what causes the deformities associated with RA. Talonus (heel bone), hallux valgus (big toe), and ulnar deviation at the wrists are examples of joint deformity. This ultimately causes huge amounts of pain and loss of movement and function of the joint. Joint deformities are considered irreversible, but if drug treatments to control disease activity are given early during diagnosis, it may be possible to prevent any damage occurring. If any damage occurs, it may be possible that orthopedic surgery is required to fuse or replace the joint. This would only be considered, however, when the disease has been controlled and the procedure is to replace the joint which is severely damaged, not just to relieve pain. RA patients have a higher infection rate after surgery, so it is not the most suitable option for everyone.
3.3 Cardiovascular Disease
Traditional risk factors do not fully account for this increase and it has been clearly demonstrated that even when controlling for these, patients with RA are at higher risk of developing CVD. It appears that there is a gradient of increased risk correlating with disease severity and the presence of RA specific factors. RA disease duration is an independent risk factor for CVD; a study has shown that after controlling for sex and hyperlipidemia CVD risk increased by 1% for each year of RA. There was also a correlation between the degree of functional impairment or joint damage and likelihood of developing CVD. However, the greatest step up in risk comes with the presence of vasculitis or extra-articular disease. A meta-analysis has shown that the relative risk for CVD is 2.0 compared with 1.3 for non-extra-articular RA. This link between systemic inflammation and CVD has led to the theory that RA is an independent CVD risk factor akin to diabetes. This has prompted research into the use of medications such as statins for cardiovascular risk reduction in RA patients.
It is well documented that individuals with RA are at significantly increased risk of developing CVD. The relative risk for CVD in RA patients compared with the general population is 50%. Different studies show that CVD causes 40-50% of all deaths in RA patients. This is due in part to an increased prevalence of traditional risk factors (hypertension, hyperlipidemia, diabetes, smoking and obesity) but also due to RA specific factors which contribute to accelerated atherosclerosis. It is now believed that chronic inflammation is the major player in the pathogenesis of atherosclerosis and is responsible for the decreased life expectancy seen in RA patients.
3.4 Lung Involvement
Interstitial lung disease is the most common form of lung involvement in rheumatoid arthritis. This, in simple terms, is a scarring process that occurs in the tissue surrounding the lungs, the pleura, and the lung itself. It can cause progressive massive fibrosis and even cause the lung to collapse. More worryingly, it often has no symptoms and the diagnosis is made after the lung has been significantly damaged, as an x-ray is the only way to confirm it. Dyspnea and a dry cough are the most common symptoms of lung involvement, and they occur in 5-10% of patients with rheumatoid arthritis. Doctors suspecting lung disease will listen to the patient's chest using a stethoscope, and if they hear a Velcro-like sound coming from the lungs, this suggests the presence of interstitial lung disease. Rheumatoid arthritis can also cause nodules to form in the lungs. This will result in dark spots on a lung x-ray and occurs in approximately 20% of RA patients, although the vast majority have no symptoms. A small number of people may develop pleuritis, an inflammation of the lining of the lung. Symptoms include sharp pain on breathing, shortness of breath, and a dry cough. A very small number of people will develop pulmonary vasculitis, inflammation and damage to blood vessels in the lungs. This can be potentially fatal. High-resolution CT scanning can now identify each of the lung problems and what part of the lung is affected. This is important as it can guide treatment and management of the condition.
4. Research and Future Developments
It is a known fact that research on rheumatoid arthritis (RA) is ongoing. In the proceeding chapters, I will discuss three important points that underline the anticipated future developments in rheumatoid arthritis. Although a cure for RA is not definitively on the horizon, the goals of research are to understand the disease better, to learn how to control it more effectively with medicines and other treatments, and to minimize the impact of RA on the lives of people who have it. Research continues to focus on identifying the early stage of RA when the disease first begins to develop. Studies have shown that people who are at a high risk of developing RA can be identified with blood tests that detect antibodies to certain proteins. This preclinical phase represents a crucial time for applying interventions to prevent the development of inflammatory arthritis. If effective and safe treatments can be identified for this stage of the disease, it is hoped that it will be possible to delay or even prevent the onset of RA. This could have a major impact on reducing the overall public health impact of RA, by reducing the number of people who develop RA and diminishing the severity of the disease for individuals who are affected by it. These studies are on the leading edge of RA research and hold great promise for the future.
4.1 Current Research Studies
Rheumatoid arthritis (RA) is an autoimmune disorder which affects the joints and surrounding muscles and tendons. Recent studies of the pathogenesis of RA have added to our understanding of the environmental, genetic, and immunoregulatory factors which contribute to the development and persistence of the inflammatory response in the synovium. Identification of the latter has helped to delineate the intracellular pathways which lead to the abnormal release of proinflammatory cytokines, chemokines, and proteolytic enzymes, and provided potential targets for future drug therapies. These signal transduction pathways can be modulated by small and large molecules, many of which are already in use or development for other disorders such as cancer. The potential for their use in RA is being explored in current animal models and human clinical trials. An area of ongoing research is the identification of individuals who are in the preclinical phase of RA but are at high risk of developing symptomatic disease, with the aim of intervention to prevent its onset. At present, the most widely used strategies to achieve disease modification are aggressive use of conventional synthetic disease modifying anti-rheumatic drugs (DMARDs) and early intervention with the combination of methotrexate and a biologic DMARD, or a treatment to target approach with a biologic agent. The choice of therapy and the extent of its intensification are frequently determined by trial and error, as there are no adequate predictive markers for drug response or long-term outcome. During recent years, advances in genetic and epigenetic profiling techniques have enabled significant progress in stratified medicine for other autoimmune and inflammatory diseases. This has potential applications to RA and its therapy with respect to identification of the best treatment for an individual patient at the onset of disease and prediction of future treatment responses and disease outcomes. Data from such studies could also facilitate informed discussions between patients and rheumatology teams about the risks and benefits of therapy.
4.2 New Treatment Approaches
Stem cell treatment: There are defined networks of abnormalities that can damage bone and cartilage in rheumatoid arthritis, and it has been shown that mesenchymal stem cells have the ability to alter these networks and, in turn, repair damaged tissue. Research has been ongoing to determine whether mesenchymal stem cells from patients or from donors can be transplanted and if so, to what effect. A phase I/IIa trial published in 2017 involving 48 patients and comparing it to a control of infusion of saline showed that there was a good safety profile along with some clinical benefit from the infusion of a single dose of 2 million allogenic mesenchymal stem cells at 6 weeks post-infusion. This is a rapidly evolving area, and thus more trials and further understanding of the effects will develop over the next few years.
Targeted treatment of inflammation: Research is steadily improving our understanding of the inflammatory process that occurs in rheumatoid arthritis. This has led to a new approach to treatment, known as "biological therapies" or "biological agents". These drugs are designed to target precise steps in the inflammatory process and they have been shown to be highly effective in many patients. Biological therapies are either given alone or in combination with methotrexate and can be effective in controlling the progression of rheumatoid arthritis, lessening joint damage, and relieving other symptoms. There are several types of biological therapies, including anti-TNF medication, which targets an inflammatory protein called TNF; T-cell costimulation blocker; and B-cell depletion therapy. In recent years, it has become apparent that the traditional conventional synthetic DMARDs such as methotrexate are also effective in halting the progression of undifferentiated arthritis to rheumatoid arthritis and thus treating rheumatoid arthritis at a much earlier stage, improving long-term outcomes for patients. This has led to the continuation of research to find beneficial effects of the combination of conventional synthetic DMARDs with biological therapies along with researching the possibility of using conventional synthetic DMARDs in combination with much earlier biological agents to achieve improved clinical outcomes. These treatments can be very effective in achieving the goal of remission or low disease activity.
4.3 Potential Breakthroughs
Preventative therapy in the form of agents which will stop the development of arthritis in individuals with undifferentiated arthritis or those with evidence of pre-clinical disease is the ultimate goal. This is likely to be achieved using predictive and sustained therapeutic strategies. An example is the calibration sub study attached to the 'BeSt' trial of early aggressive therapy. In this sub study MRI of the hands and feet will be used to predict radiological damage and the feasibility of a sustained DMARD free remission.
There are a number of potential drug treatments mentioned in Table 1.2.2.1 of the full BSR guidelines. Owing to the expected licensing dates for these agents, most will not be available for routine use for several years. The exception to this is rituximab, a B-cell depleting agent which is due to be licensed in 2006. This is currently in late stage phase III trials. It is generally not intended to be used as a first line biological agent. An overall treatment strategy has been proposed. In the early phase of disease the use of agents such as rituximab which have a slow onset of action is not a desirable approach.
Most of the drugs currently being used for the control of rheumatoid arthritis were developed many years ago. "They range from those developed early in the 20th century such as aspirin to drugs developed in the 1980s such as Enbrel. None were developed with a detailed understanding of the cause of rheumatoid arthritis and the way they work is not fully understood," added Professor Emery. These agents are relatively toxic and the prospect of enhanced understanding of the disease leading to development of safer and more effective drugs is an exciting one. The implications for patients are enormous. Full remission is a realistic goal for the majority with the ideal combination of drugs.