Rheumatoid arthritis (RA) is a progressive disease of the immune system that begins with inflammation in the joints and can spread to other systems, causing a myriad of complications that can lead to bone deterioration. It is estimated that anywhere from 0.5 to 1.5 per cent of our global population suffers from RA (Clancy and Hasthorpe 29). Although it is known that RA is a form of inflammatory arthritis and an autoimmune disease, it is not fully understood why the immune system , which is supposed to protect our health by attacking foreign cells like viruses and bacteria, instead attacks the body’s healthy tissue, specifically synovium, a thin membrane that lines the joints (Arthritis Foundation). This can result in the accumulation of fluid in the joints, causing systemic pain in and inflammation (see Appendix A) (Arthritis Foundation). This analysis will discuss the symptoms of RA, the mechanism, pathology, and histology, provide a brief description of immunology and autoimmune features of RA, and discuss treatments of RA, focusing on the drug Enbrel and its mechanism for treatment.
Symptoms of RA
The cause of rheumatoid arthritis is unknown, but with RA, the immune system begins to damage the joints (Enbrel® etanercept). Symptoms of RA may include:
- joint stiffness in the morning that lasts at least 60 minutes
- joint pain
- swelling of the joints, commonly observed in the hands
- fatigue (Enbrel® etanercept)
The stiffness experienced in the joints can lead to loss of function and permanent joint damage (Enbrel® etanercept). Systemic features include fever, fatigue, weight loss, “nodules, anemia, Sjogren’s syndrome (dry eyes and mouth), Raynaud’s phenomenon, Splenomegaly, Pulmonary fibrosis, pleuritis, Pericarditis, 2–3 fold increased risk of cardiovascular disease, Episcleritis, scleritis, keratoconjunctivitis, Polyneuropathy, mononeuropathy, mononeuritis multiplex, Myopathy, polymyopathy, Cutaneous or systemic vasculitis (inflammation of the blood vessels)
Glomerulonephritis, Amyloidosis” (Firth, Diagnosis 1180). Furthermore, the threat of inflammation spreading to attack the heart, lungs and eyes has increased co-morbidity and mortality rates of the disease (Firth, Diagnosis 1179). Although the disease can occur at any time in a person’s life, it usually occurs from about 30 years of age and is most common between 50 and 60 years of age (Clancy and Hasthorpe 29). It has also been determined that females are significantly more prone to the disease than males, suggesting a correlation between the development of RA and female hormones (Clancy and Hasthorpe 29).
RA is a progressive and chronic disease that does not currently have a cure, although there is the possibility of controlling the disease with aggressive therapy the instant the disease is detected. Some afflicted with RA may experience intermittent bouts of intense disease activity, called flares, which may sustain continuous activity and worsen over time (Arthritis Foundation). Others may enjoy long periods of remission, in which the disease is not active and they are asymptomatic followed by bouts of painful symptoms and flares (Arthritis Foundation). Research has shown that early diagnosis and aggressive treatment are the only ways to drive the disease into remission which can potentially avoid joint destruction, organ damage and disability (Arthritis Foundation). RA affects the body symmetrically, which means that if a joint on one side of the body is affected; the corresponding joint on the other side of the body is also affected, which may present as feelings of fatigue, anemia, loss of appetite, and a low-grade fever (Arthritis Foundation). Effective management of RA may require a range of biological and non-pharmacological interventions (Firth, Diagnosis 1182).
The Mechanism of RA
RA is primarily a homeostatic imbalance commonly referred to as an autoimmune disease and is of unknown etiology, diverse in its severity and progressiveness (Clancy and Hasthorpe 30). One of the most disruptive side effects of RA is its debilitating effect on the body. It is for this reason that most people with RA tend to avoid physical activity for fear of exacerbating their condition and causing a painful flare up (Breedland et al. 879). However, avoiding physical activities results in decreased muscle strength and aerobic capacity, which further restricts the abilities of the patient (Breedland et al. 879). In comparison to people without RA, people with RA have significantly diminished muscle strength, muscular endurance, and aerobic capacity and are at greater risk for cardiovascular morbidity and mortality (Breedland et al. 879). It has also been determined that those suffering from active RA have an abundance of a protein called tumor necrosis factor (TNF) (Clancy and Hasthorpe 30).
Even though TNF is naturally created in our immune system, increased levels of active TNF are thought to play a role in the inflammation of RA (Enbrel® etanercept). Female patients have also reported remission of their RA symptoms during pregnancy, which has been speculatively linked to the surge in hormones that occurs during this time (Clancy and Hasthorpe 30). However, after birth when hormones decline, symptoms flare up significantly and require immediate care (Clancy and Hasthorpe 30). Additionally, international studies have indicated that there may be an ethnic prevalence, with increased incidence in Native Americans compared to those of African decent. Further studies have acknowledged “psychosocial, cultural and financial influences on the development of RA in individuals” (Clancy and Hasthorpe 30).
Furthermore, etiological studies of depression in patients with RA have identified a complex multitude of factors that may facilitate interactions among clinical, biological, psychological and demographic characteristics (Ho et al. 38). These factors have indicated that there is a relationship “between depression and RA to clinical events such as RA flares and hospitalization” (Ho et al. 38). While this correlation between depression and RA appears to be weak in cases of mild to moderate RA, the incidence of relationship is much stronger in severe RA (Ho et al. 38). It has also “been observed that non-clinical factors such as functional disability, maladaptive coping, social stresses, reduction in social activities and high education are associated with depression in RA” (Ho et al. 38). These relational factors are all congruent with the known procession of the disease.
Pathologic Histology of RA
Pathologic histology is the scientific study of the nature of disease and its causes, processes, development, and consequences. This includes an understanding of the nature of diseased tissues. In the case of RA, patients can present acutely or have sporadic symptoms that relapse with one or more painful joints (Oliver 462). As Oliver (462) indicates, “…classic presentation is that of multiple, symmetrical joint involvement commonly of the metacarpophalangeal or metatarsophalangeal”. Additionally, a major aspect in establishing a diagnosis of rheumatoid arthritis is taking a thorough clinical history and musculoskeletal examination of the patient to determine what their ‘normal’ threshold is (Oliver 462). These symptoms may be accompanied by early morning stiffness, fatigue, low mood, pain on movement and at rest and/or warm, swollen joints (Oliver 462).
Measuring disease activity in RA
- Assessment of joint swelling and tenderness by examination
- Visual analogue scores of overall wellbeing*, pain and fatigue
- Inflammatory blood markers (C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR))
- Duration of early morning stiffness
- Questionnaires to evaluate function/quality of life
- X-rays to measure progression of erosions (ultrasound/magnetic resonance imaging (MRI)) (Firth, Treatment 1242)
Bone erosion is a clinical endpoint for various diseases including rheumatoid arthritis. In assessing bone quality, three primary criterion are examined to quantify the magnitude of bone loss, which are “the volume of bone remaining (bone volume, BV), the total mass of bone remaining (bone mineral content, BMC), and then the average density of the bone (bone mineral density, BMD)” (Chao 642). The magnitude of bone erosion was linked to the duration of inflammation and cellular changes in severely inflamed joints for an increasing number of weeks were evaluated for various histological parameters like leukocyte infiltrate, pannus formation, cartilage damage, and bone erosion (Chao 642). Additionally, Suzuki et al. (7) determined that “…hematoxylin and eosin staining showed that the synovium of the RA patients who underwent etanercept therapy showed significantly greater vascular proliferation than that of the MTX control group”.
Immunology and Autoimmune Features of RA
In acute inflammation, the immune system responds by destroying foreign bodies or antigens, such as viruses or cancer cells, through the production of white blood cells comprising lymphocytes, macrophages and neutrophils (Firth and Critchley 1284). T cells make up the bulk of circulating lymphocytes and work primarily to enhance the production of antibodies by B cells to defeat antigens (Firth and Critchley 1284). Furthermore, as discussed in Firth and Critchley (1284), “T-helper cells produce cytokines which signal to the B cells to produce more antibody, and later T-suppressor cells damp down the immune response when appropriate”, like when bacteria has been eliminated from the body. Autoimmunity means that T cells are not able to recognize the difference between the body’s tissue and foreign tissue, which means that cytokines generate and maintain inflammation primarily in synovial tissue inappropriately, as in the case of RA (Firth and Critchley 1284). Disease-modifying therapies such as methotrexate and sulphasalazine are thought to reduce pro-inflammatory cytokine production and increase anti-inflammatory cytokine activity, but the precise mechanism of action at a cellular level is unknown (Firth and Critchley 1284).
Treatments for RA
A multilateral approach to treating RA has been traditionally used, incorporating analgesia and non-steroidal anti-inflammatory drugs and DMARDs were introduced later (Enbrel® etanercept). It is vital that patients are immediately referred to a rheumatologist to facilitate early initiation of DMARD therapy, which has been proven to exponentially increase the likelihood of disease control and improve the prognosis in cases of RA (Enbrel® etanercept). Patients that start treatment within three months of the onset of the disease tend to respond better to treatment (Firth, Treatment 1242). Early treatment of RA allows symptom management, improvement of function, and helps stop progressive joint damage (Enbrel® etanercept).
Painful rheumatoid joints are often treated with corticosteroid injections to reduce inflammation via stabilizing membranes of cellular lysosomes (Clancy and Hasthorpe 34). This decreases the secretion of the destructive enzymes lysozymes which causes less cellular destruction in the joints, alleviating pain and stiffness (Clancy and Hasthorpe 34). However, corticosteroids can potentially increase risk factors associated with atherosclerosis, including hyperglycaemia leading to type 2 diabetes, obesity and hypertension in genetically susceptible patient (Clancy and Hasthorpe 34). Biologic drugs have been developed based on greater understanding of the pathogenesis of RA and target specific cells or molecules that are thought to responsible for driving the disease process (Firth and Critchley 1284). They are aimed at “the pro-inflammatory cytokines, notably Tumour necrosis factor alpha (TNF-α), B cells, Interleukin 1 (IL-1) and Interleukin 6 (lL-6)” (Firth and Critchley 1284).
Additionally, “biologic drugs currently licensed for the management of RA are all given by injection or infusion and work in one of four ways” (Firth and Critchley 1284). The primary biological therapies are “Adalimumab (Humera), Certolizumab Pegol (C’imzia), Etanercept (Enbrel), Infliximab (Remicade), and Golimumab (Siniponi)’ and they all inhibit TNF activity (Firth and Critchley 1284). Unless contraindicated, methotrexate is normally continued alongside biologic drugs, as combination therapy has been shown to be significantly better at improving clinical outcomes and reducing radiographie progression (Firth and Critchley 1284). Other disease-modifying drugs may be continued or introduced based on individual assessment, but biologic drugs themselves are not combined. Licensed biologic drugs for RA, Adalimumab (Humira), Certoiizumab pegoi (Cimzia), Etanercept (Enbrel), Infliximab (Remicade), Rituximab (Mabthera), Tocilizumab (RoActemra), Abatacept (Orencia), Goiimumab (Simponi) (Firth and Critchley 1284). All have been approved by NICE for the management of RA (Firth and Critchley 1284)
Etanercept plus methotrexate combination therapy was generally superior to either monotherapy in reducing disease activity and structural joint damage, as well as improving health-related quality of life (HR-QOL) (Dhillon, Lyseng-Williamson and Scott 1212). Furthermore, etanercept monotherapy was superior to placebo and at least as effective as methotrexate therapy in reducing disease activity and improving HR-QOL in patients with early or refractory disease (Dhillon, Lyseng-Williamson and Scott 1212). The beneficial effects of etanercept monotherapy or combination therapy were sustained in the long term Elevated serum and synovial fluid levels of TNF in patients with rheumatoid arthritis play a central role in the inflammatory process underlying this condition (Dhillon, Lyseng-Williamson and Scott 1212). Etanercept, a soluble fusion protein, binds to both TNFα and TNFβ (lymphotoxin), thereby blocking the interaction of TNF with receptors on the cell surface, preventing TNF-mediated inflammatory cellular responses and modulating the effects of other TNF-induced or -regulated molecules (Dhillon, Lyseng-Williamson and Scott 1212). Subcutaneous etanercept is absorbed slowly and has a long elimination half-life, allowing once- or twice-weekly administration and resulting in a smooth steady-state concentration-time profile. It is distributed widely into tissues, including the synovium (Dhillon, Lyseng-Williamson and Scott 1212).
Enbrel® and its Mechanism for Treatment
Although TNF is a normal part of immune response, increased levels of TNF play a role in the inflammation associated with certain rheumatic conditions (Eustice). Etanercept (Enbrel®) is a human TNF-α receptor fusion protein mechanically produced by recombinant DNA technology to bind TNF-α and prevent interaction with cell surface receptors, which interferes with the inflammatory cascade (Wade et al. 1). Enbrel® etanercept can be used to treat active, moderate, or severe RA, either in conjunction with “methotrexate when the response to standard disease modifying antirheumatic drugs (DMARDs) is inadequate, or as monotherapy, if methotrexate cannot be tolerated or if the disease is severe, active and progressive” (Wade et al. 1). Anti-TNF therapies like etanercept can hinder the progression of joint damage, reduce joint pain and swelling, and improve mobility and physical functioning (Wade et al. 1). As discussed in Wade et al. (1), “etanercept is also used to treat other inflammatory conditions such as psoriasis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis (JIA) in patients who have had an inadequate response to standard therapy”.
Enbrel reduces the levels of active TNF and works on your immune system to reduce inflammation and help manage certain rheumatic conditions (Enbrel® etanercept). Enbrel is not approved to treat all rheumatic conditions and is indicated to treat rheumatic conditions like ankylosing spondylitis, psoriatic arthritis, and moderately to severely active RA and JIA (Enbrel® etanercept). Because Enbrel works on your immune system, it can lower the ability of your immune system to fight other infections like tuberculosis, pneumonia, and may cause fatality through infection (Enbrel® etanercept). Treating to target is an established concept in the management of diabetes, hypertension and hyperlipidaemia (Firth, Treatment 1240). This approach embodies measurable targets, the formulation of evidence based recommendations for assessment criteria and the adjustment of drug therapy in accordance with these targets (Firth, Treatment 1240). Recommendations for treating to target in RA include:
- “The target for treatment of RA is remission, defined as an absence of signs/symptoms of disease activity
- Low disease activity may be an acceptable alternative target, particularly in longstanding disease
- Disease activity should be measured at regular intervals in patients with active disease to inform treatment decisions
- Functional impairment and joint damage should be considered
- Until the desired target is reached, drug therapy should be adjusted at least every 3 months
- The patient should be appropriately informed about the treatment target and strategy planned to reach the target” (Firth, Treatment 1240)
Rheumatoid arthritis is a progressive debilitating disease that can cause tremendous physical pain and permanent disabilities if it is not properly treated and maintained. Early diagnosis and an aggressive treatment plan is the only hope most patients have of stopping the progression of the disease and managing the pain. This enables people afflicted with RA to maintain an active lifestyle and prevent the spread of the disease to other organ systems. Without treatment and care using pharmaceuticals like Enbrel®, those afflicted with RA would suffer tremendous pain, deterioration of their joints, bone, and the synovium in between them, and would become disabled. In addition, RA can lead to cardiovascular problems, obesity, and a myriad of other health problems. Immediate efforts to control and maintain the best possible state of health for the patient is always the immediate treatment plan and there are a variety of options that can be used to accomplish this.
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Visualization of a healthy joint versus one affected by Rheumatoid Arthritis Healthy Joint Joint Affected by Moderate to Severe RA
RA usually begins with inflammation of the joints, but it can progress to serious joint damage. (Enbrel® etanercept).