Treating 'Bad' Chronic Arthritis with Biologic Drugs: A New Era of Target Therapy
by Arvind Chopra, MD

There are several forms of arthritis and rheumatism. Rheumatism is a more broad based term used by the community and focuses on all kinds of aches and pains of the joints and related soft tissues as well. Arthritis may attract attention to the joints only. A low back ache is often a form of rheumatism but is generally not labeled asarthritis. However, in a true medical sense, arthritis and rheumatism are synonymous terms and mean the same. Rheumatology as a medical specialty includes non-injury disorders of joints, spine and connected soft tissues and several multisystem disorders with an underlying immune system dysfunction. Rheumatologist is a specialist physician who deals with all forms of arthritis and rheumatism.

What is bad arthritis? To begin with, all arthritis is bad because invariably there is pain and difficulty in day to day function. But many forms of arthritis and especially those related to viral infections are self limiting and last for a short period and need only symptomatic drugs like pain killers. In recent times, chikungunya has been a common cause of severe painful arthritis and body aches in millions of patients in India. In the large majority of patients, chikungunya arthritis only lasts for a week or 10 days. But there are arthritis like rheumatoid arthritis (RA) and osteoarthritis (OA) which become chronic and may last a life time. OA is generally associated with age and wear and tear of cartilage in few joints like the knees and spine and is more of a life style disorder. On the other hand, RA is an inflammatory arthritis with several bad complications and damage. RA can be considered a truly 'bad chronic arthritis'. In this article, the focus is on chronic inflammatory forms of arthritis.

Inflammation is a common physiological body response to injury and infections and is characterized by pain, swelling, local warmth and tenderness, red in appearance and some loss of function. In case of many infections, there is also fever and some constitutional symptoms like loss of appetite and feeling weak. However, the human body has a tremendous capacity to overcome infections and its component of inflammation and healing and repair take place to restore good health. Sometimes, in the case of chronic arthritis, this inflammation continues uncontrolled and leads to several complications and damage to the joints.

Inflammation is a characteristic feature of several arthritis. Patients present with painful swollen joints. Multiple joints may be involved and patients often have severe restriction of daily activities. Patients feel ill, weak and tired easily, and often lose appetite and body weight. Rheumatoid arthritis (RA) is a classical example of inflammatory polyarthritis. RA is a bad arthritis because it is a lifelong disorder, deteriorates quality of life, imposes several restrictions on daily activities of living, causes crippling joint deformities, can affect multiple body systems (including heart) and is difficult to treat. Another bad arthritis is ankylosing spondylitis (AS) which predominantly causes inflammatory damage in several parts of the spine. Psoriasis of the skin and infections of the gut and urinary system can sometimes cause bad inflammatory forms of arthritis and which are collectively called seronegative spondyloarthritis (SSA). No age is exempt. Children can also suffer from bad forms of arthritis called juvenile idiopathic arthritis (JIA). It is well known today that several forms of inflammatory arthritis including RA and AS can lead to premature heart and blood circulation disorders.

We do not know the precise cause of these bad forms of arthritis. They are caused by an abnormal function of the immune system. The disorders are generated within the body without any direct external insult like infections and trauma and are called autoimmune disorders. Patients usually have some genetic predisposition though hereditary factors are often complex and there may be no case in several generations. Several risk factors like excessive mental stress, infections, trauma and use of tobacco contribute to the onset and progression. The body's immune system is meant to fight infections (through inflammation) and promote healing. It is tightly controlled and regulated by its own mechanisms and those of the nervous system and hormones. 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 and damage. There is a breakdown of control and regulation. An inflammatory autoimmune rheumatism disorder like lupus (SLE) can effect several body systems and patients often present with skin rash, mouth ulcers, loss of hair and multiple joint pains. Sometimes the attack is targeted to a single organ like the 'joint' in RA and 'thyroid' in thyroid disorders. In RA, it is the synovial membrane inside a joint capsule which is the initial target of immune inflammation and damage but later involves all structure in the joint.

Several types of immune cells (T cells, B cells, macrophages) and chemical mediators (prostaglandins, histamine, cytokines) operate in close liaison in both health and disease. T cells are considered to be hyper functional in bad arthritis like RA. T cells regulate function of several other immune cells like macrophages and B cells. B cells produce antibodies which are protective against infections but if in excess or unchecked can also participate in immune mediated inflammation and damage. Other type of white blood cells like neutrophils and scavenger cells like macrophages are trained to take part in the immune processes during in utero development of baby and following the birth throughout life. Several chemical agents mentioned above are secreted by these immune cells and in turn influence the function of their source cell and other neighboring cells. Therefore, there are several pathways of inflammation and damage in bad forms of arthritis and no single drug is capable of stopping these pathways.

Cytokines are powerful local hormones 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 are important regulators in the immune system. In health, there is a delicate balance between cytokines with opposite effect. Some cytokines lead to intense inflammation and others may participate in healing. Cytokines operate through complex pathways and mechanism inside a cell and to begin with work on the cell surface in a 'key and lock' manner. Each cytokine (key) has a specific receptor (lock) on the surface of a cell. Once a key fits into a lock, a cascade of molecular events begin in the cell. There are several checks and counterchecks in the cytokine action pathways. Several physiological actions required for good health are served by cytokines and their other immune counterparts. These physiological actions include inflammation, anti-inflammation, cell repair, healing, cell death and cell regeneration. Several cytokines help in maintaining bone health.

We will take an example of RA to highlight the recent advances in the treatment with the newer biologic agents.
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 chloroquine, 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. Once their efficacy appears, the requirement for pain killers, anti-inflammatory drugs and even steroids become less. In fact, with good control of disease, several patients only continue DMARD and stop all other medication including pain killers and steroids. 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' has been recently discovered. Unlike conventional DMARD these agents are more precise in hitting the target which is usually a component of the uncontrolled immune system that is damaging the joint. The target can be a cytokine or its receptor (either on a cell surface or in the blood circulation) or even the immune cell itself. Biological DMARDs are proteins and behave like antibodies. In the chain of events leading ultimately to intense inflammation and damage, biologic DMARD can target an initial disease process event to cause early intense clinical improvement and arrest of the disease process. Not only do they prevent and heal bone damage, other disease processes like osteoporosis and atherosclerosis (thickening of blood vessels caused by fatty substances in blood) are also reduced. They have been called magic bullets because of a quick and excellent disease control. 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.

Should all patients of inflammatory bad arthritis be given biologics? No! These medicines should be used with great care and caution. They should ideally be given when the disease is severe and rapidly progressive and the response to conventional treatment supervised by a rheumatologist is unsatisfactory. The diagnosis of bad arthritis should be confirmed by a rheumatologist as soon as possible. Once confirmed, aggressive treatment must be started and response monitored. All patients of RA need to be begun on conventional DMARD. Conventional DMARD when begun early in the illness can often cause a remission which can sometimes last for years. Therefore hit early and hit hard. Don't wait for the joint deformities to begin. If the response to conventional DMARD is not satisfactory, Biologic drugs should be considered. The opinion is divided on how early can one begin Biologic drugs in RA? Several studies indicate a waiting period of 6 months to one year after the onset. Newer research studies have begun to evaluate the role of a biologic drug as the first choice in patients with bad arthritis.

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 need utmost care. 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 some very critical components of the immune system and this may make patients prone to infections. Of course, one can take adequate steps to protect oneself against infections. Unfortunately, hygiene and sanitation conditions in our country are often poor and infections are 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 neurological 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.

Biologic DMARDs are also effective in all other types of bad arthritis that include AS, SSA, Psoriasis arthritis and JIA (childhood onset inflammatory arthritis). These drugs are especially effective in AS and SSA. After a short period (3-4 months) of intensive Biologic therapy with Infliximab , almost 70 % patients with AS in CRD, Pune, were found to enjoy a complete disease control with little or absent pain for several months to years. A similar excellent response has been observed with tocilizumab in case of RA.

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 good control or remission. This could then be followed with long term conventional DMARD to maintain remission. Short courses of Biologic DMARDs can be repeated in case of a relapse of severe flare of arthritis. Another attractive economical strategy in RA patients is to give two rituximab infusion at 15 days interval once in 6-12 months. We have been following this kind of a treatment strategy in Center for Rheumatic Diseases, Pune, with good success.

Without doubt, biologic DMARD have made a big difference in the management of several difficult to treat bad 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 and several bad types of arthritis will rest on biologic drugs. But as of now, we somehow need to bring down their cost so that several more patients can afford. Several companies have begun to bring down the cost in recent years and are now offering special schemes.

SUMMARY POINTS:

• Biologic DMARD are very effective anti-arthritis drugs and can produce complete control/remission in several patients.
• Biologic DMARD target the specific components of the body's immune system that are responsible for the severity and complications of bad arthritis.
• The decision to start biologic DMARD is taken with utmost care by the rheumatologist after detail evaluation of several clinical , investigation and socioeconomic factors.
• RA and many such bad arthritis are lifelong disorders and need long term medication and therefore the rheumatologist will carefully decide how long to take biologic DMARD as per an individual case.
• Biologic DMARD can be used for a short course to quickly control the disease flare and severity but this needs expert handling by the rheumatologist. Single or few injections for just symptomatic relief are not recommended.
• Patients on biologic DMARD may also require several other medicines (such as pain killers, anti-inflammatory, iron-calcium supplements etc.) to begin with but will become lesser in time as arthritis improves.
• Biologic DMARDs produce anti-arthritic effect much faster than routine DMARD.
• All patients on Biologic DMARD need to be closely monitored to ensure improvement and detect early any drug side effects; this often requires repeated laboratory blood tests.
• Biologic DMARD are not pain killers but once they show efficacy the requirement of pain killers and even steroids becomes less or even nil.
• Biologic DMARDs may make patients prone to infections including tuberculosis.
• Compared to routine DMARD and steroids, biologic DMARDs are much more safer; side effects of stomach, liver, lungs and heart are extremely uncommon.
• Biologic DMARD, especially if begun early, effectively prevent or at least reduce the chances of several bad complications of rheumatoid arthritis and other inflammatory arthritis such as joint deformities, weak bones (osteoporosis), and problems of heart and blood circulation.
• Only rheumatologists are authorized to prescribe and use biologic DMARD.
• Biologic DMARD are expensive drugs but there are several schemes announced by the manufacturers from time to time to enable some patients to afford them.