Rheumatoid arthritis is an auto-immune, chronic (long-term) condition that causes pain, swelling and stiffness in the (synovial) joints e.g. hands, feet and wrists- affecting more than 400,000 people within the UK (1). Similarly to other auto-immune diseases, (e.g. Myasthenia Gravis), the immune system will produce antibodies against its own tissues- joints in rheumatoid arthritis. The sex differences with the disease is also well documented with a 3:1 female to male ratio suffering with the condition, also backed by the fact that disease activity and function is much worse in females compared to males (linked to sex hormones) (8). Although there is no known cure for it, treatment options such as biological therapy (monoclonal antibodies) can be used to treat the condition successfully. Initially, to reduce swelling, anti-inflammatory drugs can be used to try and reduce swelling however, this isn’t the only treatment option. Examples of these drugs include DMARDs (disease-modifying antirheumatic drugs), which act on the immune system to prevent the effects of molecules that are released when the immune system attacks the joints e.g. Methotrexate (1). As stated before, the use of drugs is not the only treatment, if drugs alone aren’t effective biological treatments can be used. This essay outlines how biological therapy (the use of monoclonal antibodies) can be used in treatment of rheumatoid arthritis. It also explores the importance of biological therapy in clinical practice.
Pathogenesis of Rheumatoid arthritis
Rheumatoid arthritis is believed to be caused by an imbalance of pro-inflammatory cytokines such as Interleukin 1 (IL-1) and Tumor Necrosis Factor alpha (TNFα) (2). As with most immunological diseases, the balance of immune cells and what they secrete is important. In rheumatoid arthritis, antigen presenting cells such as B cells and T helper cells (CD4+ T) can present foreign antigens on their surface (specific antigens may bind to T cells). This results in the activation of macrophages, which secrete large amounts of cytokines- IL-1 and TNFα. An imbalance of these cytokines is thought to of stimulate synovial fibroblasts that secrete enzymes which degrade collagen and proteoglycans (component of connective tissue) leading to tissue destruction in joints (2). Usually, the immune system releases maintained levels of cytokines which bring out an inflammatory response which can be done by the complement system. However, in this situation abnormal levels of these cytokines are produced which in turn causes damage to the joints. Apart from TNFα and IL-1 there are many other cytokines that are involved in causing rheumatoid arthritis and drugs can be used to target these. Other examples of cytokines involved are: IL-6, IL-7, IL-15 etc (3).
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The uncontrollable production of pro-inflammatory cytokines plays a major role in pathogenesis of rheumatoid arthritis. However, as stated before, rheumatoid arthritis is an autoimmune disease. This autoimmunity can be caused by post-translational modifications of proteins. The proteins are modified through citrullination (substitution of amino acid arginine to citrulline) and carbamylation (protein modification through exposure to urea) (12). Due to these modifications in protein structure, immune cells identify the cells of proteins (e.g. collagen) in joints as ‘foreign’ and produce antibodies against these cells (autoantibodies). It is through this mechanism that destruction of the synovial joints can occur. These antibodies can also be identified in the blood when diagnosing rheumatoid arthritis.
There are many triggers for a rheumatoid arthritis flair: Stress, infection, overexertion (through frequent motion) and lack of sleep (11). To reduce the effect of these flairs, treatment is required. Modern treatments include the use antibodies against these cytokines. This essay focuses on the use of therapeutic monoclonal antibodies such as adalimumab.
Mechanism of action for Adalimumab
Antibodies (immunoglobins) are proteins released by cells such as plasma B cells which cause the destruction of foreign pathogens (bacteria and viruses)- for example by cell lysis. Antibodies consist of a light chain, heavy chain and an antigen binding site which is very specific. Antibodies may be polyclonal or monoclonal. Monoclonal antibodies are released by identical immune cells which are clones of a specific parent cell and so will have affinity for the same antigen and epitope. On the other hand, polyclonal antibodies are made from different immune cells and have affinity for the same antigen but different epitopes. As mentioned before, rheumatoid arthritis uses monoclonal antibodies- specificity is higher. Alongside DMARDs, biologics are used. Biologics are however still classed as DMARDs (bDMARD) (3). The first bDMARD used was infliximab which was a chimeric (contains DNA from mice which is combined with human amino acid sequences) monoclonal antibody against TNFα. However, today Adalimumab (pharmaceutically known as Humira) is used instead which also acts against TNFα but is a full human antibody and is used alongside Methotrexate (3). A full human antibody is much more effective than a chimeric one as with infliximab there could be a chance of rejection by immune cells as the antibody is recognised as ‘foreign.’ Therefore, the development of Adalimumab was very important as a long-term treatment option for a patient as there is less chance a patient’s body will reject it compared to a chimeric monoclonal antibody. Although, the precise mechanism of how this treatment works is relatively unknown some aspects are now better understood. Generally, Adalimumab will act to reduce the effects of high levels of TNFα. It is made by recombinant DNA technology which uses the cell expression system of mammals. It may be taken intravenously or subcutaneously (4). It is an anti-TNF monoclonal antibody which acts by binding to TNFα, blocking the interaction of TNF with p55 and p75 cell surface TNF receptors (5). As the functioning of TNFα is reduced, high levels of it within the body will cause less deterioration of the joints and therefore, reducing the symptoms of rheumatoid arthritis such as swelling and joint pain. Adalimumab is a monoclonal antibody, so it will only be specific to this cytokine and will not target others. There are many reasons as to why Adalimumab is generally, a long-term viable treatment option for rheumatoid arthritis. It is indistinguishable in its structure and functions compared to other human antibodies allowing it to be used as a treatment in chronic arthritis with high efficacy and low chance of rejection rates from the body’s immune system. This also coupled with the fact that it has a comparable half-life to other human immunoglobins makes it an effective treatment (5).
Although targeting cytokines such as TNFα have proven to be effective, in some patients this is not the case and they will develop refractory disease (not responding to disease treatment) so other treatments can be used which target different cytokines such as IL-6 (9). There are conflicted views on how IL-6 is involved in the pathogenesis of rheumatoid arhritis. On one hand, IL-6 is thought to have a role in regulation of inflammation in rheumatoid arthritis by controlling the amount of IL-1 and TNFα produced by the body. As IL-6 is present in high numbers in synovial fluid, it can promote joint destruction and synovitis by stimulating neutrophil migration and osteoclast maturation. On the other hand, it is thought to have mediate rheumatoid arthritis by inducing osteoperosis (through its effects on osteoclasts) and the acute-phase reaction where proteins are produced in response to inflammation. Overall, this means that IL-6 blockade can be used as a desirable therapeutic option (13). The monoclonal antibody used to target IL-6 is called tocilizumab which has shown efficacy in clinical trials and is a licensed treatment treatment option (10). This shows how another monoclonal antibody which targets a different cytokine can also be used as a biological treatment for rheumatoid arthritis.
Adalimumab in clinical trials
In clinical trials, the use of Adalimumab alongside the drug Methotrexate has been proven to be successful and therefore, is now implemented as one of the main treatment options for rheumatoid arthritis. In fact, the drug Humira generated the most money from prescription drug sales in 2015 sales alone around the world, generating approximately $8.2 billion USD (6). In a clinical trial called ARMADA (Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab), 271 patients were given Adalimumab alongside Methotrexate for a duration of 24 weeks (placebo was also given every other week) which lead to immediate and long-term positive therapeutic effects- 52% had clinical remission and 28% with no physical limitation within 5 years (5). Although this sample size may not reflect the efficacy of this treatment option for larger groups with rheumatoid arthritis, it still shows how the use of monoclonal antibodies can deliver long-term positive therapeutic effects for patients. This is also only one type of monoclonal antibody, as mentioned before there are many others that can be used which target different cytokines.
Indication and adverse effects
Adalimumab can be used in treatment of other diseases apart from rheumatoid arthritis. This can include: Crohn’s disease, psoriatic arthritis, ulcerative colitis and ankylosing spondylitis (7). These diseases generally are associated with symptoms of inflammation and therefore, Adalimumab can be used to treat them as it will reduce inflammation through preventing the adverse effects of excess proinflammatory cytokines (TNFα).
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Although adverse effects of using Adalimumab are not common, it may still occur (5). Side effects may include chest pain, fever, redness, skin reactions (rash), dizziness, vomiting and cough. Some people also have developed serious infections through the interactions of Adalimumab and Methotrexate/corticosteroids. Adalimumab is also known to interact with vaccines such as influenza and MMR (measles, mumps and rubella) causing the patient to have an increase risk of infection due to the severity of the interaction (7). To counteract these serious infections or to identify them at an early stage, patients can be monitored e.g. blood tests. One has to also consider the fact that the use of these monoclonal antibodies may also weaken the immune system making it prone to infections. As with all medication, the circumstances of the patient must be taken into consideration. If the person is pregnant or breastfeeding it is advised to avoid taking the drug. There may also be implications on contraception and conception (7).
Immunosuppressant drugs are commonly given to patients with auto-immune diseases. However, in this instance, this will not be the case. This is due to the fact that Adalimumab is a full human antibody meaning that the immune system is unlikely to produce an immune response against it (indistinguishable)- no immunogenicity. Therefore, patients will be less exposed to immunosuppressant drugs and their potential toxic side effects.
It is important that new treatments and drugs are developed regularly to counteract long-term effects of rheumatoid arthritis. Adalimumab is only one of many other monoclonal antibodies that can be used to treat rheumatoid arthritis. This outlines the potential of the use of biological treatment not just in arthritis related diseases but in also in the world of medicine.
The use of monoclonal antibodies in treatment for rheumatoid arthritis outlines the importance of how biological treatments can be used alongside drugs. Traditionally, for many diseases only drug treatments were present. However, as our understanding of the immune system and molecular biology improves, more treatments (biological) can be developed. For patients with rheumatoid arthritis, it is important to consider their quality of life. Symptoms such as pain in the joints of the body may prevent people from doing day to day tasks such as walking and climbing stairs- decreases quality of life and may reduce social activity. In this instance, the use of monoclonal antibodies in clinical practice allows healthcare professionals to provide patients with better outcomes. This is highlighted by the fact that treatment (Adalimumab) is specific and causes immediate effects alongside long-term effects. Biological therapy is also of great economic importance in clinical practice as it will reduce the need for surgical procedures to be done- saving money. Overall, the use of monoclonal antibodies in treatment of rheumatoid arthritis has proven to be a relatively safe treatment option with long-term benefits.
By Mubashar Nadeem