Remicade has transformed the treatment of Rheumatoid Arthritis. Discuss the role of antibodies within the immune response and describe, giving examples how monoclonal antibodies are now being utilised for the treatment of a range of diseases.
It is true to state that Remicade has transformed the treatment of Rheumatoid arthritis, but more accurate to describe that the large scale production of monoclonal antibodies has transformed the treatment of a range of diseases, particularly Rheumatoid Arthritis. In this essay, I intend to explore the disease of Rheumatoid arthritis, focusing on how it was discovered, how the immune system is compromised in a disease such as this and treatments and modern advances in therapy for such autoimmune diseases.
A Historical View of Immunology
To introduce Immunology, which is a relatively new science, one must first consider the finding of immunology as a branch of medicine, but it is debatable who the proper godfather of immunology really is. For example, do we take Antony Van Leeuwenhoek (1632 - 1723), who discovered the first microscope, a critical step in discovering bacteria as disease causing pathogens.(1)The Golden age of microbiology brought many scientists together in the debate of Spontaneous Generation, of which Louis Pasteur's (1822 - 1895) work with swan neck flasks disproved this theory. Robert Koch (1843 - 1910) designed the first direct demonstration of the role of bacteria causing disease with the study of Anthracis Bacillus and the link with Anthrax,(2) another major step in microbiology but paving the way to immunological discovery. We now know individual classes or categories of disease causing microorganisms based on their pathology - Viruses, bacteria, fungi and a major class, parasites. (3) However, the title of Godfather of immunology is usually attributed to Edward Jenner (1749 - 1823), (4) who in his studies of disease and resistance to disease developed the first vaccination in 1796, the vaccination against smallpox, which was successfully eradicated worldwide by 1980. "Vacca" meaning cow, was kept as the name for vaccination, based on Jenner's groundbreaking discoveries. It is with his work that I shall use as the opening to my essay.
Others who are more relevant to the title include Paul Ehrlich (1854 - 1915) who worked with Robert Koch and discovered antitoxin and Haemolysis - he uncovered the side chain theory of antibody formation - this credits the idea of the innate immune defence mechanism (antibody mediated)(5). Elie Metchnikoff (1847 - 1916) found phagocytosis while studying starfish development; this marked the birth of cellular immunology and proved the existence of a second immune defence mechanism, the Adaptive response (T - Cell mediated). (6)Both shared the Nobel Prize in medicine in 1908 for their discoveries. It is particularly significant that both were right in their theories, which gives us the core branches of the immune system today; the Innate (non specific/non adaptive, B cell mediated) immune response and the Adaptive (specific/ adaptive, T cell response.
Our immune system is a series of very complex mechanisms which hasn't been fully discovered yet, but groundbreaking discoveries are being made rapidly in the space of 100 years. Immunology is the study of physiological mechanisms that humans and other animals use to defend from invading organisms. Organisms need to pierce through a number of barriers in the first and second lines of defence before causing infection. There is a final third line of defence which is more specific and will provide memory if the same organism is found again. There are two types of immunity, innate immunity which is rapid and non - specific, and adaptive which takes longer and is more specific to the antigen, vaccination is based on memory cell ability to divide and replicated to allow rapid antibody production should re exposure to the same antigen occur a second time.
Antibodies are core within the immune response; they interact with a various number of antigens and foreign molecules to trigger an immune response. It is important that we cover the antibody structure and how it relates to function as later I will talk about auto antigens and auto antibodies and their role in autoimmune diseases, with reference to immune tolerance and breakdown of immune tolerance.
As Figure 1 depicts the structure of an antibody,(7) one can see the different portions adapted for antigen recognition. The N terminus which is also called the "fab" region, is highly variable to interact with a number of foreign molecules. Diversity of this region is very wide, it is estimated that humans have 7.2 X 107 different antibodies to recognise antigens.(8) The C terminus shown here, is the "Fc" portion of the antibody is used for the effector function of the antibody. The antibody has heavy and light chains and is held together by disulphide bonds and covalent bonds, this stabilises the structure.
On recognition of an antigen, the antibody binds the antigen and enters cells to be processed, these are then presented on the MHC class 2 to T helper cells. The T cells analyse the antigen structure and produce cytokines in response, which will stimulate B cells to turn on antibody production. The B and T cell will undergo differentiation and clonal expansion.
There are many classes of antibodies which are adapted to each function in the immune response. Firstly, the most common serum antibody is IgG, the most versatile antibody being able to carry out a range of functions. This is the only class of antibody which crosses the placenta , loading the newborn baby with just enough immunity to last three to five months.
The second most common antibody is IgA, and it can have serum and secreted forms. It is found in bodily secretions such as saliva, tears, mucus etc. The importance of this antibody is that it is cabable of physically blocking toxin entry and neutralising toxins, by forming a dimer using a J - chain and secretory piece.(9)
Monoclonal antibodies are a relevantly new discovery within immunology - they were developed by Milstein, Jerne and Kohler who won the Nobel prize in 1984 for their contribution to immunologic therapy in production of monoclonal antibodies. Basically, myeloma cells are fused with spleen cells which have been previously immunized by a given antigen taken from a mouse. These can be either put in vitro or in vivo and can be utilised to churn out a line of antibodies of which new treatments such as Remicade have been made to act as treatment for autoimmune diseases. Monoclonal antibodies in new treatments will be covered later in my section of Therapy for autoimmunity.
The term "Autoimmunity" can cover a number of various diseases. Autoimmunity is when the immune system acts inappropriately, this could involve the development of autoantibodies and immune complexes. Paul Ehrlich suggested that instead of the immune system acting properly and defeating "foreign" antigens, there would be some cases where it would react against "self antigens," this he named "Horror autotoxicus." (10) Paul Ehrlich and Morgenroth first described the concept of immune "tolerance" in 1905, by experimenting with goats - they watched as they injected a goat with RBC's from another goat and seen how antibodies were mounted to make a response, whereas when they injected the goat with its own RBC's, it did not mount a response (8). Autoimmunity is described as a result of the breakdown of normal immune tolerance, by what I understand of immune tolerance is that we have certain mechanisms in our immune system that defend us from breaking down our own antigens, that is why in this goat sample the goat when injected with his own cells did not mount an immune response, though in autoimmunity breakdown in self tolerance leads to destructive self reactive antigens/self reactive antibodies. Tolerance is achieved in immune regulation of the body - ie immune responses are regulated, there must be a feedback mechanism in place to limit the way in which the body responds to infection - self regulatory. Sufficient amount of antibodies and antigens play a particular role in regulation of the immune system - when there is an increased amount of IgM, the body senses that is enough production of antibody and leads to a negative feedback loop, which down regulates the response. To avoid accumulation of unnecessary amounts of antibody or immune cells, there are ways in which the body deals with regulation - the first one is AICD (activation induced cell death) in which T cells in excess will be killed by apoptosis. There are regulatory cells (T - regs) which naturally overlook the immune system and suppress the actions of other immune cells, they will watch over the actions of Natural killer cells for example. Another way of inhibiting stimulation is by CTLA - 4 present on T cells which will bind to B7 competing with CD28 - competition within co - stimulatory molecules which will also downregulate the immune response (9). The idea here is to get across the fact that there are mechanisms in place which will regulate the immune response and switch the response off if need be. Immune Tolerance by definition is;
"Immunological tolerance is a phenomenon by which the autoreactive cells are either eliminated or neutralized to provide the immune system the ability to distinguish between self and nonself (10)."
Tolerance can be based on the structure of receptors on surface of antigens, there is a wide variety of antigen antibody receptors in play in the immune system, during cell development there will be some random problems within the development of these receptors and some will react against own self antigens. There are three categories of tolerance, 1 - Central Tolerance, in which immature T cells which act strongly against self antigens are deleted by clonal deletion, 2- Peripheral Tolerance, if the self reactive cells escape central tolerance they enter peripheral tolerance where encountering occurs by B cells which will delete the cell or the cell will become Anergic (unresponsive.) 3 - Aquired tolerance can be naturally acquired as in pregnancy, the foetus is "tolerated" for nine months even though it is non - self, or acquired tolerance can be induced as in immunosuppressive therapy being received in post - organ transplantation. It is important to note that T cell tolerance is harder to break than B cell tolerance - there are a lot of layers in our immune regulation of tolerance, and if breakdown in this tolerance occurs, autoimmunity results.
Autoimmunity can be divided into two main groups (the spectrum of autoimmunity.) The first group is Organ specific Autoimmune diseases, which by the name suggests, are localised to a particular organ. For example, a very common organ specific autoimmune disease is type 1 Diabetes mellitus, with 1 in 22 of the population will have it at the age of 20. (11) This is a direct autoimmune attack on the pancreas, where insulin producing "beta" cells in the Islets of langerhans are attacked and destroyed, leading to decreased amount of insulin produced and increased levels of blood glucose. (12)
Another example of an organ specific autoimmune disease is Multiple Sclerosis, which affects the CNS, brain and spinal cord. In systemic Autoimmune diseases, Rheumatoid Arthritis (RA) is one of the many systemic autoimmune diseases in which I will be focus on. Rheumatoid arthritis is a systemic, autoimmune disease. It is particularly focused with the disease of the joints, an immune mediated inflammation of the synovium. (13) The most noticeable characteristic of Rheumatoid arthritis is the abnormal shape and swelling of the hands, knees, feet. In RA, which is an autoimmune disease, (auto which indicates targeting against self componants) progresses when cells of the immune system are activated against self components and travel to the synovium of joints and cause inflammation. Note that inflammation arises and causes most of the damage due to immune complex production. The prolonging of this disorder can also promote tissue damage, in which the cartilage is damaged and leads to reduced mobility. Symptoms in Rheumatoid arthritis are not always but nearly always "symmetrical" (14) Typical symptoms include -
- Morning stiffness
- Stiffness after short periods of inactivity
- Weight loss
- Redness/warmth of the affected area
- Rheumatoid Nodules ****
I have especially highlighted here Rheumatoid nodules as they are extremely common in Rheumatoid arthritis, small lumps under the skin can be seen, usually around the knuckles on the hands. Spontaneous remission is a term I have came across a number of times, it is a condition which according to most text books does rarely occur, and can result in destruction of joint tissues, it advances to total joint deformity and severe disability.(15)
Statistics reveal that this autoimmune disease, (RA) has a gender bias, and effects women five times more often than men, it is also five times more common in smokers than in non smokers. (16) The median age of onset of this disease is from 40 years old to 50 years old, and it does not tend to have a genetic predisposition. (17) Although, journals say otherwise;
"Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q."(18)
In this quote, taken from a journal disagrees with the genetic predisposition of autoimmune diseases. They argue throughout the journal that regions between STAT1 and STAT4 contain a haplotype associated with susceptibility of RA and Systemic Lupus Erythematosus. (19)
Their conclusion was that;
"A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses." (20)
This discovery concludes that there is a genetic factor influencing the passing on of this illness to future generations. Twin studies show that if one twin has the disease then the other must have the disease also.
The most common onset of RA is the presence of IgM antibodies against determinants on the Fc portion of IgG, this autoantibody is known as the infamous Rheumatoid Factor. 80% of patients with RA have the Rheumatoid Factor,(RF) although RF presence does not always indicate the patient has RA, as other diseases such as Chronic Liver Disease, Sarcoidosis, and Chronic Pulmonary disease possess the RF, therefore RF alone is not diagnostic of RA disease, and also, the amount of RF in a serum sample does not correlate with disease severity, ie the more RF does not always mean the more severe the disease is. (21) Serology is carried out in the laboratory to detect the presence of RF in a patients serum sample. The most common test is carried out using Nephelometry, in which serum and anti - IgG are mixed, small aggregates form and the amount of light which passes through the tube is measured and compared against scatter.
In RA, there are a number of ideas which have been postulated as to the cause, but there doesn't seem to be a definite cause which initiates the disease directly.
This picture depicts the difference in a normal joint and a RA patients joint. As one can clearly see, there is definite erosion around the cartilage, and actual cartilage loss. The whole joint area seems to be inflamed, swollen and looks "rough". The bones look demineralised and weak, the picture depicts how pain can be generated from this situation. Histologically, there is a T cell rich infiltrate into the synovium of the joints, the synovial membrane thickens as cells proliferate and expand abnormally, out of control, and enlarge in response to stimulation by inflammatory cytokines. (23) Fibrin, as a result of the "wear and tear" damage, develops in place of where the damage was done, this develops into granulation tissue, termed the "panus" and greatly reduces joint mobility, this is characteristically felt by joint stiffness in RA patients. (24)
Immune complexes are another typical presence in RA joint fluid. Immune complexes are such things which are created when an immune response happens, in response to a given antigen. They are usually cleared after the threat by RBCs and other immune cells, immune cells of the complement system and usually cause no damage to other tissue, however in RA patients, there is a significant lowering of complement levels, so in fairness there could not be regulated breakdown of these complexes. The bigger or more the immune complexes results from how much antigen is present, which can be overwhelming. Another way in which immune complexes can be extremely hard to break down is within bacterial infections as in Endocarditis, when a bacterial infection takes place on the valve of the heart, and bacterial antigens are persistently leaking out into the blood stream, where immune complexes are built up (25). This can be applied to any autoimmune disease, if there is constant leakage of antigen (or as in RA Self antigen) then there will be a mounted immune response to the individuals own tissue, a terrible disease.
The initial factor or the causative agent leading to self reactive cells in autoimmune illnesses such as Rheumatoid arthritis is unknown, but there have been many postulates. Such as Environmental cofactors, genetic factors, inflammatory injury and crossing of the placenta of autoantibodies. I will explain these in a little detail. Such "causes" need to be explained in order to prescribe treatment for the individual, and understanding of these causes paved the way toward the new monoclonal antibodies used in the treatment of such autoimmune diseases.
Environmental factors include outside agents such as bacterial infections, viral infections etc, but this does not mean that RA is contagious, it is dependent on the person's immune reaction towards these outside agents, but some scientist argue that an outside agent MUST be present in the pathogenesis of the disease.
Genetic factors I have already explained, that there is experimental evidence that regions along STAT1 - STAT4 have some sort of link toward RA, and the passing on of the disease to future generations.
Crossing the placenta in pregnancy is another way in which auto antibodies can emerge. This would result in the child having the same disease as the mother, all due to auto antibodies passing across the placenta. Although if this causes a major problem, the child will have to have a full plasma transfusion, called plasmapheresis.(26)
Inflammatory injury is a big postulate in the cause of RA. This is the postulate I strongly believe in. The idea that when, for example, a person falls and breaks a bone, some of the cartilage or bone is damages and I believe that this can in some form or way generate the production of autoantibodies toward the site of the wound during the cascade of events in inflammation, and maybe spread the generation of autoantibodies to other joints. In the normal functioning of growing bone, osteoblasts produce bone and osteoclasts ingest bone, both work together to maintain proper growth of bone. But following injury, in RA, Th17 cells promote production of osteoclasts by secreting cytokine IL-17, this induces expression of RANKL on osteoblasts, RANKL binds to RANK on osteoclast precursor cells and stimulates differentiation into osteoclasts which digest bone, proinflammatory cytokines such as TNF - a and IL - 1 also contribute to the productions of osteoclasts. (27) New treatments try to block TH17 cells from secreting IL 23, which is characteristic of severe inflammation in RA.
It can be therefore deduced that the work of osteoclasts, if overproduced can degrade bone tissue, the involvement of TNF - a is core in RA, and is what many modern treatment ideas are based on.
The treatment I am exploring is the treatment called Remicade, which was derived from the discovery of monoclonal antibodies and has had a profound effect on RA, and other autoimmune diseases.
In my research, statements stood out to me that really shocked me, I did not know previously that treatment in RA is usually just to improve the persons quality of life, rather than cure the disease. There are three groups of standard treatments used today, they include;
- NSAIDS (non - steroidal anti - inflammatory drugs)
- DMARDS (disease modifying anti - rheumatic drugs)
The group we are concerned with and the group that Remicade belongs to is the third group, DMARDS. NSAIDS reduce inflammation and pain, and can give a better quality of life then, DMARDS have actually been known to do this, but also maintain the proper mobility and functioning of the joint, they are slow to respond taking initially around 4weeks - 2 months to work, but new therapies based on DMARDS like Remicade, include antibodies which block TNF- a reducing inflammation and actually promote the healing of eroded joints. (28)
Remicade, or Infliximab as is its generic name, is a TNF blocker, which created by monoclonal antibody production has been known to stop the inflammation and destruction of joints in RA patients. In autoimmune diseases such as RA, T and B cell proliferation is rapid and breakdown in self tolerance occurs as a result of no negative feedback system but a positive feedback loop in which autoreactive cells keep proliferating and leukocytes infiltrate target organs. Monoclonal antibodies are used to target specific immune cells, and can either delete or manipulate them cells to bring about change in the autoimmune disease (29). TNF - alpha has been extensively researched and has been proven to be the driver of the inflammatory cytokine cascade, there are two TNF receptors, TNFR1 and TNFR2 and by selectively blocking these factors, can eliminate the severity of RA and other autoimmune diseases (30). A blocking antagonist can be used to maybe block the binding of TNF and therefore stop the cascade of events in inflammation, therefore reducing immune complex deposition and promoting the effect of joint mobility.
Remicade consists of the antigen binding region of mouse anti - TNF monoclonal antibodies and the human region of IgG1, in which it binds with high affinity, targeting both soluble and transmembrane TNF (31). It is usually given to patients with RA who have not shown good responding to Methotrexate alone. Remicade is usually treated intravenously, taken from the journal Eular, it outlines experimental procedures in which individuals with RA were tested with Remicade intravenously for 1 year, to obtain results:
"The osteoclast-activating protein RANKL showed a linear decrease during the treatment with infliximab. This resulted in a favourable change in the RANKL/OPG ratio (32)."
Here it states that RANKL decreased during the treatment, meaning that it did not bind to osteoclast as much as before treatment and did not promote differentiation and proliferation of osteoclasts which degrade bone. It can be seen then that Remicade has truely transformed the treatment in RA, but also in Sjorgens syndrome and Crohns disease also.
The only problem with such treatments is that patients are susceptible to opportunistic infections ie; when the immune system is compromised, and we are blocking TNF and other cytokine agents, there is not a full immune response which works 100%. It was found that in patients treated with such TNF blocking treatments, tuberculosis re emerging is a massive fear when being treated, reactivation of latent tuberculosis would occur within the first couple of months of therapy, and it is therefore recommended that screening take place for tuberculosis prior to treatment (33).
Not only has Remicade (infliximab) transformed the treatment of RA and other autoimmune diseases, it has also "revolutionised the management of malignancies(34)" and inflammatory bowel disease also. Adalimumab (Humira) is another example of a monoclonal antibody treatment therapy for RA, when Remicade doesn't suit the individual, other treatments will be tried out such as this one. Humira is injected into the individual, and is also a TNF blocker, it reduces the pain and immobility of RA patients, leading them to a better quality of life(35).
Etanercept (Embrel) is another example of monoclonal antibody therapy also, it has been proven to relieve the effects of RA in patients being used alone or in combination with Methotrexate over a period of two years (36). This treatment can be used in a number of situations/ diseases, such as prolonged RA, polyarticular juvenile arthritis, ankylosing sponditis etc. From the National Institute of Health journal, I took this quote;
"a TNF receptor p75 Fc fusion protein (TNFR:Fc), is a soluble recombinant form of the extracellular domain of human TNFR2 receptor fused to the Fc fragment of human immunoglobulin G1 (IgG1). It binds to soluble TNF and LT-a, effectively neutralizing the biologic activity of TNF (37)."
This statement shows that by using HUMAN antibodies now instead of mouse antibodies as in other treatments like Humira, the same effects are achieved, TNF is blocked and neutralised which stops the massive cascade of inflammation events that follow.
This can therefore pave the steps needed to find more treatment that can influence activity in RA, and maybe someday there could be a treatment based on these principles and findings which can possibly promote bone healing more than treatments do today, maybe there will be a way of defining how to prevent diseases such as RA, and maybe there will be a direct link to a cause, instead of many hypotheses. Overall, Remicade HAS transformed the treatment of lots of inflammatory diseases, autoimmune diseases, and monoclonal antibody development paves the way for more extensive research and discovery.