Pathophysiology of Metabolic Diseases: Rheumatoid Arthritis

Epidemiology/Etiology

Rheumatoid arthritis (RA) is a systemic chronic autoimmune (AI) disease, that causes chronic inflammation to joints. It is an inflammation arthritis, that affects the synovial fluid in the joints. Subsequent pannus formation may lead to cartilage destruction and bone erosion¹. The destruction process is caused by the body over producing cytokines. The increase in cytokines are a factor in the inflammation of the joints as well, two key pro-inflammatory cytokines in RA are IL-1 (interlukin-1) and TNFα (tumor necrosis factor). There are suggestions that TNFα was an inflammatory mediator and by itself not destructive, but together with IL-1 it could create more damage, as it can enhance the destructiveness of IL-1². IL-1 and TNF activate innate responses which leads to the release of C-reactive protein (CRP)³. These cytokines are produced by T cells that become activated by the engagement of a second signal it receives. T cells and cytokines activate B cells; B cells along with plasma cells can be found in rheumatoid synovium. They also produce more cytokine and are antigen-presenting cells to T cells. The antigen-presenting cells are dendritic cells (DC) and these activate CD4 T cells in the lymph. In the synovium, DC-CD4 T cells infiltrate this area causing the autoimmune response. Part of RA is the presence of autoantibodies, which is a characteristic of autoimmune diseases. The autoantibodies found in RA are called rheumatoid factors (RF) and anti-citrullinated peptide antibodies (ACPA). Autoantigens targeted by autoantibodies found in RA display a wide spectrum of cartilage components, stress proteins, enzymes, nuclear proteins and citrullinated proteins, this demonstrates that RA is not characterized by only one autoreactivity to a single autoantigen but by accumulated autoreactivities in B and T cells⁴.

Risk Factors

 There are several risk factors involved with RA. The most common ones are older in age, Female, family history of illnesses, and smoker or previous smoker. A genome-wide DNA methylation profiling study in peripheral blood mononuclear cells reported differentially methylated regions in the major histocompatibility complex loci that make a significant contribution to the genetic risk of developing RA⁵. The same study discusses several meta-analyses have identified approximately 40 genetic variations that could increase the risk for the ACPA of RA. The study on genetics and epigenetics and how RA is developing is still expanding, however like smoking, genetic risk factors also are associated with ACPA-positive RA.  There are other risk factors besides age, gender, history, smoking, or genetics. Environmental factors and diet also play a large part in the risk of developing RA. One environmental factor that is the strongest thus far is smoking. Most RA patients are ACPA-positive are often RF-positive, which shows an overall risk of RA for smokers. Some other environmental factors that are being studied in their association with RA is some agriculture exposures. Agricultural settings confer a variety of other potentially immune-modulating exposures that may be associated with RA and systemic autoimmune diseases, such as sunlight, inorganic dusts, and endotoxins⁶. A person’s diet can be an intervention and a risk to developing RA. The gastrointestinal (GI) microbiota plays a part in the pathogenesis of systemic inflammation diseases. RA is a systemic inflammation disease, that is why the diet and GI health is important when talking about risk factors. Changes in diet have been known to lead to imbalances within the body, including immune system imbalances. As an autoimmune (AI) disease, when is influenced by the damage done to the immune system from poor dieting. Dysbiosis (the change in microbiome due to lifestyle and dietary habits) impacts the innate immunological pathways which lead to the production of pro-inflammatory cytokines IL-1, IL-18, IL-17, IFNϒ, TNF, and others⁷. These dietary impacts the intestinal microbiome, leading to local inflammation and increased permeability, causing release of the cytokines and lymphocytes into the system. The release of cytokines and lymphocytes into the system could cause a spread of inflammation to sites such as joints, which is where the most common points of inflammation and pain are noticed.

Assessment

 Visually patients with RA can see swelling around the joints, which is typical with stiffness and pain in those joints. The hands and the feet are most susceptible to joint swelling. There is stiffness and sluggish movement in the morning that would be prevalent when pain and inflammation are presented in the patient. Some diagnostic tests look for autoantibodies which are rheumatic factors, but not all patients have rheumatic factors, some do if they have other diseases. A proper baseline of blood work would be the most important with a patient, this is to rate the progression and create a good starting point for treatment and monitoring. After the baseline is completed the patient should have their CRP levels and erythrocyte sedimentation rate monitored because they often increase with RA, the testing for these levels can also assist in showing how the disease is progressing. Progressing with medication, with a dietary change, or following the disease to see if it becomes more aggressive and damages more joints. Part of the assessment to determine the severity or complications the patient is having in their daily life, they should discuss things as: does it impede your work, are you able to complete daily functions (walking, eating, etc.), are you able to perform necessary hygiene acts; with each of these the questions of no help needed, rarely/minimal help needed, occasionally/moderate help needed, always/complete help needed – cannot function without assistance. Answering a questionnaire like this would assist in determining pain levels, functionality, and could assist in finding out the progression of the disease. An assessment of needs from the patient, the physician and rheumatologist should be in great consideration. If the patient wants reduction in pain, then the assessment from the physician and rheumatologist should coincide with the patients request, but also discuss the importance of further joint damage, fatigue⁸ and reducing the risk of developing other diseases. This assessment is important in determining what the patient wants, what is best for the patient, and what is treatable or manageable. While there is no cure for the disease it is often looked at on how to treat the symptoms and manage the disease.

Intervention

 Intervention and RA is more about manageability and treatment of symptoms that can be controlled. The disease has not been cured yet, but there are many options in the ways of improving the quality of life for a patient with RA. A doctor or rheumatologist may prescribe medications and/or infusion treatments to help with management of symptoms of RA. There are a few things that can help with pain and inflammation that does not require a doctor though, quitting smoking, reducing coffee consumption, diet, and moderate consumption of red wine⁹. Coffee has been added as a risk due to its association with smoking, and smoking is one of the preventable risks that is best-studied. Smoking cessation has shown to lower the risk of RA; however, it is not right away, it takes some time after quitting for the effects of being a non-smoker to activate. A person who is already a non-smoker will have a lower risk than of someone who just quit smoking or still smokes. Moderate consumption of red wine falls into the diet category of a Mediterranean diet.  Red wine possibly could protect against coronary heart disease because of its antioxidant properties, and antioxidants have demonstrated to help in protecting the systemic review⁹. Antioxidants have been shown, with use over time to reduce stiffness, reduce pain and decrease swelling in the joints. Some antioxidant rich foods that can help with inflammation and pain are garlic, ginger, walnuts (also a good source of Omega-3), berries and a couple more. The Mediterranean diet is recommended because the diet is high in Omega-3 and low in red meats, and dairy. Red meat and dairy are two factors that have been known to increase inflammation in the GI, while Omega-3 has been identified as one way to decrease inflammation. Low-fat vegan diet and diets rich in unsaturated fat or probiotics have a positive effect at alleviating pain and on inflammation markers¹⁰ as well. Omega-3 fatty acids has been found to alter disease progression. Omega-3 can reduce the proinflammatories that are being overproduced and can influence the immune system, both innate and adaptive by inhibiting T cell proliferation.  Recent studies have shown DHA-derived resolvins to be protective against leucocyte infiltration, swelling and severity in murine models of inflammation arthritis; EPA-derived resolvins have been shown to be associated with a reduced pain score in persons with inflammation arthritis¹¹.  Omega-3 (DHA and EPA) fatty acids can be found in many founds that have the capability of reducing inflammation and pain. The Mediterranean diet has items like olive oil, and fish, while there is also nuts soybeans have a good amount of Omega-3. Supplementation of Omega-3 should only be done with the consent from the patient’s doctor, this is to ensure that the dosage will not affect any medication or treatment that is already undergoing. Antioxidant foods and Omega-3 foods combined with a proper clean nutritional diet can help with reducing inflammation and pain. Eating processed foods, high in fat foods, large amounts of alcohol and caffeine, and sugary foods should be avoided as they can irritate the GI causing disruption to the system creating additional inflammation possibilities.

Conclusion

 In conclusion, rheumatoid arthritis is a systemic inflammation disease that the origin of it is still being researched. It is known to have genetic background fueled by an improper diet, improper healthy weight, heavy drinking, smoking, gender and age. The disease can progressively get worse over time if action is not taking to intervene, treat and manage. Currently there is no cure for the disease, as the exact origin is not confirmed yet. It is however treatable, preventable (in some cases) and manageable with proper dieting, check-ups with the patient’s physician and reducing the intake of factors that contribute to inflammation and poor gastrointestinal health. Without intervening the disease can deteriorate the cartilage increasing the inflammation and lack of movement within the joints. With more cartilage damage, the more cytokines are released which creates more inflammation, more pain and less movement. Despite the inflammation, pain and movement issues, rheumatoid arthritis as an autoimmune disease increases the chances of a person contracting another illness if not monitored or taken care of. Poor dieting can decrease the immune systems ability to react. In a patient that is already in an immune deficiency capacity, this could magnify the changes significantly of the patient contracting a disease. With certain illnesses (i.e. pneumonia) a person may not survive the illness due to complications within the body and the body unable to defend itself against foreign antigens. It may not be rheumatoid arthritis that is the culprit of death, but the lack of immune system could cause the chance of survival to not exist for the patient.

References

1. Wasserman, A. (2011). Diagnosis and Management of Rheumatoid Arthritis. American Family Physician, [online] 84(11), pp.1245-1252. Available at: https://www.aafp.org/afp/2011/1201/p1245.html [Accessed 19 Nov. 2018].
2. Lubberts E, Berg WBVD. Cytokines in the Pathogenesis of Rheumatoid Arthritis and Collagen-Induced Arthritis. Advances in Experimental Medicine and Biology Cytokines and Chemokines in Autoimmune Disease. 2003:194-202. doi:10.1007/978-1-4615-0171-8_11
3. Lutzky, V., Hannawi, S., & Thomas, R. (2007). Cells of the synovium in rheumatoid arthritis. Dendritic cells. Arthritis research & therapy, 9(4), 219.
4. Song, Y. W., & Kang, E. H. (2009). Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies. QJM: monthly journal of the Association of Physicians, 103(3), 139-46.
5. Liu Y, Aryee MJ, Padyukov L, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142-7.
6. Parks CG, Hoppin JA, De Roos AJ, Costenbader KH, Alavanja MC, Sandler DP. Rheumatoid Arthritis in Agricultural Health Study Spouses: Associations with Pesticides and Other Farm Exposures. Environ Health Perspect. 2016;124(11):1728-1734.
7. Badsha H. Role of Diet in Influencing Rheumatoid Arthritis Disease Activity. The Open Rheumatology Journal. 2018;12(1):19-28. doi:10.2174/1874312901812010019
8. Gibofsky A, Galloway J, Kekow J, et al. Comparison of patient and physician perspectives in the management of rheumatoid arthritis: results from global physician- and patient-based surveys. Health and Quality of Life Outcomes. 2018;16(1). doi:10.1186/s12955-018-1035-3
9. Lahiri M, Morgan C, Symmons DPM, Bruce IN. Modifiable risk factors for RA: prevention, better than cure? Rheumatology. 2011;51(3):499-512. doi:10.1093/rheumatology/ker299
10. Winkvist A, Bärebring L, Gjertsson I, Ellegård L, Lindqvist HM. A randomized controlled cross-over trial investigating the effect of anti-inflammatory diet on disease activity and quality of life in rheumatoid arthritis: The Anti-inflammatory Diet In Rheumatoid Arthritis (ADIRA) study protocol. Nutrition Journal. 2018;17(1). doi:10.1186/s12937-018-0354-x
11. Gan RW, Bemis EA, Demoruelle MK, et al. The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology. 2017;56(12):2229-2236. doi:10.1093/rheumatology/kex360