Biologic Drugs: A New Way To Treat Rheumatoid Arthritis

by Dr. Arvind Chopra

Several types of arthritis are characterized by multiple painful swollen joints which sometimes progress to crippling deformities. This leads to poor functioning of daily activities and impaired quality of life. Rheumatoid arthritis (RA) is one such important form of arthritis which predominantly affects more women than men. WHO COPCORD (community oriented program for control of rheumatic diseases) survey studies from the Pune region indicate that almost 0.5% community may be suffering from RA. Besides arthritis, RA also causes general constitutional symptoms of fever, loss of body weight and fatigue. Uncommonly, RA can affect other body systems like eyes, lungs, skin, nerves etc. Children can also rarely suffer from RA like arthritis.

Despite major advances in understanding the disease process and treatment of RA in this decade, we do not know the precise cause. Several factors pertaining to genetics, environment, life style and personal habits, occupation and infections are likely to cause and aggravate disease in a genetically prone individual. The joint swellings are primarily due to inflammation of the synovium (an inner lining of the joint) with excess synovial fluid collection. Sooner or later, all components of the joint ( bone, cartilage, blood vessels, nerves, ligaments and supporting soft tissue structures) get involved. The main role of the immune system is to fight infections (through inflammation) and promote healing. Though there is no clear cut evidence to suggest infection as the cause of RA, joints become inflamed due to an autoimmune process. During the baby's development in the mother's womb, immune cells are trained to recognize their own body cells (called tolerance). In an autoimmune process, the immune cells fail to recognize the body's cells and mount an attack causing progressive inflammation. In the case of RA, synovium is the target and the attack is driven by a disorderly and unregulated immune system. .

Several types of immune cells (T cells, B cells, macrophages) and chemical mediators (prostaglandins, histamine, cytokines) jointly damage the joint through several pathways of inflammation. T cells are considered to be hyper functional in RA and considered to be the chief culprit cells for driving the disease process. T cells regulate function of several other immune cells like macrophages and B cells. B cells produce antibodies which are protective against infections but can also participate in immune mediated inflammation. Cytokines are powerful local hormones that are produced by several types of cells but most importantly by the cells of the immune system. Cytokines mediate and regulate several functions of the immune system. Cytokines act as messengers between various cells and can cause both inflammation and healing. In health, there is a delicate balance between cytokines with opposite effect. In RA several cytokines are abnormal but the important ones are anti-tumor necrosis factor (TNF), interleukin 1 (IL 1) and interleukin 6 (IL 6). TNF causes intense inflammation and along with other cytokines (especially IL-1) causes damage to bone and cartilage in the joint. TNF and IL-6 together attracts several immune and inflammatory cells to the site of inflammation and further over stimulates their function (e.g. further increase in cytokine and prostaglandin production). In health, TNF is essential to fight infections.

RA is characterized by pain, swelling, loss of function, deformities and poor general health and is often complicated by anemia and osteoporosis (thinning of bones). RA also predisposes to atherosclerosis (thickening and hardening of blood vessels with blockade of lumen due to deposits mostly containing fat, fibrosis and calcium) which is the cause for premature heart and vascular disorders like heart attacks and strokes. Therefore, RA cannot be just treated by analgesics (pain killers) and anti-inflammatory (reduce swelling) drugs. Other treatment targets (disease process, deformities, anemia, osteoporosis and atherosclerosis) also need to be managed.

Disease modifying anti rheumatic drugs, also called DMARD, are used to control the disease process and can even arrest it at an early stage. Oral choloroquin, methotrexate, sulfasalazine and leflunomide are conventional DMARD that are popularly used to treat RA and other inflammatory arthritis. DMARD work on the immune system and essentially suppress it. This leads to a stage called 'remission' wherein the patients is free of pain and joint swellings and does not require pain killers and the blood picture shows absence of disease process activity ( like normal ESR) . Even the X-Rays will show reduction or healing of bone damage. This is not a cure but close enough. The disease process can get activated in the future due to stopping DMARD, loss of effect of DMARD or sometimes precipitated by other concurrent severe illnesses and infections. DMARD are not pain killers but may take about 8-12 weeks to produce their optimum clinical effect. They differ in their efficacy and importantly need close monitoring for their toxicity. Toxicity of DMARD includes effects on skin, eyes, liver, bone marrow (blood cells) and kidneys and is uncommon when used under expert supervision and care. They do make the patients prone for infections. However, though extremely useful, DMARD are often not able to completely control RA. Though DMARD lead to improved quality of life and lesser requirement of other medicines (including pain killers and steroids), they are sometimes not able to prevent joint deformities and other complications in patients with bad RA (which sometimes is not easily visible). In particular, the conventional DMARD often fail to prevent bone damage (seen in X-Rays or modern scans like MRI) in RA. So, there is a need to find better DMARD.

A new class of DMARD called 'Biologic DMARD' have been recently discovered. They are called biologic drugs because unlike chemical molecules they are antibodies which are capable of hitting precise disease targets. These targets can be chemical molecules, cytokines and immune cells involved in causing arthritis or its complications as described above. In the chain of events leading ultimately to intense inflammation and damage in RA and other inflammatory arthritis, biologic DMARD can stop the initial disease process event and cause early immense clinical improvement and arrest of the disease process. Not only do they prevent and heal bone damage, other disease processes like osteoporosis and atherosclerosis are also reduced. Therefore, unlike conventional DMARD, biologics have a more widespread intense benefit. They have been called magic bullets because we have never witnessed such quick and excellent disease control in patients with really bad RA with the conventional DMARD. It is important to add that fixed joint deformities cannot be reversed by biologics though they may be reduced at times. A functionally and structurally bad hip or knee may still need joint replacement surgery but the disease process would be better controlled by biologics.

The Table below shows the different kinds of biologic agents available in India and some special features. Several more are available in US and Europe and probably more than two dozen biologics are in advanced stage of clinical research and drug trials. It is one of the most rapidly emerging markets. Biologic agents are finding increasing use in several other diseases especially in cancer medicine.

Should all patients of RA be given biologics? No! RA is a spectrum of different grades of severity of arthritis illness. Some patients have relatively mild illness while some may suffer from life threatening complication of severe RA. All patients do not need aggressive therapy or at least in the beginning. It is firmly believed that almost every patient of RA will need some DMARD therapy at some stage of the disease and all patients do not progress to deformities. Conventional DMARD when begun early in the illness can often cause a remission which can sometimes last for years. Though the benefits of DMARD far outweigh their side effects, they need care and caution by the treating doctor. The diagnosis of RA must be confirmed and an assessment (clinical and investigations) of its disease activity and process carried out prior to beginning DMARD. It is also advised that the patient be evaluated for general health including cardiac and lipid status. If RA is severe and progressive, DMARD should be begun as soon as possible. Hit early and hit hard. Don't wait for the deformities to begin. The question of when to begin biologic DMARD is still not easy to answer. Possibly, the first line of therapy in our patients should be conventional DMARD and if the effect is less than optimal during a closely supervised and monitored observation period, biologic DMARD should be considered. In an early severe progressive disease, biologic drug may be considered as the first choice.

Why can't we give biologics to each patient as they are more effective than conventional DMARD? Though biologics have made the treatment of RA highly successful, they are to be handled very cautiously like fire. It must be remembered that biologics produce profound effects on the immune system. Not all effects are good. Immune system is a very complex system that has evolved over thousands of years of human evolution to effectively protect against thousands of bacteria and viruses. When controlling RA, we are suppressing very critical components of the immune system which may make patients prone to infections. Of course, one can take adequate steps to protect oneself against infections but hygiene and sanitation conditions in our country are bad and infections are fairly common. One of the major concerns with biologic agents is an increased chance of tuberculosis. Prior to beginning biologic treatment, the patient is carefully checked for past, hidden or current tuberculosis, and special blood and scan tests are required. On the other hand, the evidence gathered from several 100,000 patients of RA all over the World indicates that biologics are otherwise remarkably safe. They have very little problem, if any, with the kidney, liver, stomach, heart and lungs. Unfortunately, biologics are not to be given to any patient with significant heart ailment. A caution is required in case of certain neurologica disorders. Some studies have suggested an increased chance of certain types of tumors but this is not adequately proven. Whatever may be the present case, the World experience with biologic DMARDs is limited to less than a decade of use and we are still learning about their mechanism of action, effects on the body and toxicity..

In India, the most important problem with biologics is the cost. Basically, RA is a lifelong disease. Biologics prove to be an extremely expensive option especially if they have to be given for prolonged periods. Probably, a good socio economic strategy in suitable and affording patients would be to give biologic DMARD initially for a limited period to quickly reduce the disease and induce remission. This could then be followed with a conventional DMARD regimen to maintain the remission. We have been following this kind of a treatment strategy in Center for Rheumatic Diseases, Pune, with good success. Our experience today is based on almost 90 patients with different kinds of inflammatory arthritis (including RA) who have been treated with biologic DMARDs.

Without doubt, biologic DMARD have made a big difference in the management of several difficult to treat arthritis including RA. Some patients after suffering for several years are once again able to experience freedom from pain and disability. But today, it is unfortunate that very few patients can afford these drugs. Even the Government has refused to exempt the tax on the medicine as it is not a life saving drug. This is a 'quality of life' drug which is equally important. The future treatment of RA will rest on biologics. But as of now, we somehow need to bring down their cost.