Essentials of Pathology

Rheumatoid arthritis is a disease which is chronic and it is classified as an autoimmune in nature (Generali et al., 2018). Generally, it is understood as a disease which affects the bone and joints of the body but it affects other parts of the body and organs. It can cause damage to the skin, eyes, lungs, heart and even blood vessels. The pathology of the disease is related to the fact that there is a presence of autoantibody which attacks the cells of the body and cause the disease. In contrast to osteoarthritis which is the result of wear and tear of the bones leading to pain and discomfort, in rheumatoid arthritis their inflammation of the lining of the joint (Generali et al., 2018). This inflammation causes the erosion of the associated bones and even deforms the joint. The cause of inflammation of the lining is due to the presence of antibodies which are produced by the body to destroy the cells of its own (Hanaoka et al., 2019). These antibodies are called autoantibodies. The antibodies which are responsible for the pathophysiology of the disease are called rheumatoid factor and anti-citrullinated protein antibodies (Derksen et al., 2017). Since the historic times along with the advancements in the medicine and other elements have led to the discovery of other factors and antibodies which can cause the disease. The aim of the present literature review is to explore the diagnostic value of autoantibodies in the pathophysiology of rheumatoid arthritis with an argument for and against the use of autoantibodies in the diagnosis of the disease.

Role of Diagnosis

Rheumatoid arthritis is the disease which is an inflammatory disease which is progressive in nature and late diagnosis and lack of appropriate treatment can cause destruction of the joint by the erosion of the bone and can cause disability (Guo et al., 2018). The symptoms of the disease are not specific to the disease and can be seen other conditions which is one of the reasons for delayed diagnosis and treatment. Symptoms include pain, swelling and stiffness in the joints and the joints that are affected the most are the small joints like that of wrists, hands and feet. The discomfort should be long and for over at least six weeks and the patients have morning stiffness of at least 30 minutes and often complain of fatigue and there is the loss of appetite (van Steenbergen and van der Helm-van Mil 2016). There are various tests which are conducted for the diagnosis of rheumatoid arthritis. There can family history of the disease which is followed by the physical examination and radiographs. The most important tests that the healthcare professional or the specialist doctor advises generally are the ones to explore the presence of autoantibodies (Derksen et al., 2017). These antibodies due to changes in the chemical response and other things are formed and they perceive cells of self as foreign and they attack them and cause an inflammatory reaction. There is also a need for other blood tests.

Broadly there are two schools of thoughts regarding the involvement of rheumatic factor which consists of autoantibodies in the pathophysiology of the disease causation and progression. The first school of thought is that the presence of autoantibodies like rheumatic factor and anti-citrullinated protein antibodies which are responsible for the disease if identified earlier can have an impact on the disease outcome. While the other school of thought is influenced by the fact that there are other factors in the blood other than just the antibodies which are responsible for the disease. This is supported by the fact that not all the patients who have rheumatoid arthritis test positive for the autoantibodies. Hence, the credibility of autoantibodies as diagnostic value is questionable.

The researchers, as well as healthcare professionals, stress on the diagnostic test of the autoantibodies so that the disease can be identified in the earlier stages. There are various documents in the literature which is suggestive of the presence of the autoantibodies in the blood. The disease is a chronic and progressive one and there is no known treatment and there is no reversal but an early diagnosis can help in changing the course and rate of disease progression. The earlier the identification or diagnosis of the disease can help in the earlier start of the palliative care which can help the patients to have a better quality of life. Early diagnosis can help in starting the preventative measures earlier which can help in the prevention of extensive erosion of the joints and subsequent deformity. The diagnostic value of autoantibodies should be established so that the presence of these antibodies means that disease is absolutely present or if it is present in a particular percentage or concentration should demarcate the stage of the disease. This is one of the drawbacks of the diagnostic value of autoantibodies as it can produce inconclusive results as it is also documented that there can be presence and development of the disease even without the presence of autoantibodies.

Autoantibodies as A Diagnostic Tool for Rheumatoid Arthritis

There are various factors which are associated with the pathogenesis of rheumatoid arthritis and they are immunological, genetic and environmental (Sun et al., 2017). As the disease progresses further it is seen that there are many autoantibodies are present in the serum of the patient. Along with the clinical manifestation of the disease, it is seen that the most associated factors in the development of the disease are a rheumatic factor and highly disease-specific anti-cyclic citrullinated peptide. Early studies which have been conducted for the antibody profiling showed that it was helpful in the accurate diagnosis and prognosis of the disease. As the diagnostic tests have developed it is seen that there are other antibodies along with the ones mentioned and they are antibodies to mutated citrullinated vimentin (MCV), anti-keratin antibodies (AKA), anti-perinuclear factor (APF), and antibodies to Ig heavy chain binding protein (BIP) and others (Besada et al., 2011; Abedian et al., 2015).

A study was conducted by Sun et al. (2016) to get the best combination of the diagnostics related to the presence of autoantibodies. The study was conducted with an aim to get the best combination as a result there can be good specificity and higher sensitivity to the detection which can have an accurate diagnosis. When a diagnostic test is formed it has two components and they are screening and confirmatory which have higher specificity and higher sensitivity respectively. In a diagnostic test, it is not possible to have a hundred per cent sensitivity and specificity as they are inversely proportional to each other. So to get the best possible result it is required that a balance is struck between specificity and sensitivity which will help in having diagnostic accuracy. In this study, the authors selected six autoantibodies which were combined in various combinations to be detected arbitrarily.

These combinations were formed and calculated for the sensitivity, specificity, test accuracy, predictive values, diagnostic agreement rate and Youden’s index. The result of the study reflected that the anti-cyclic citrullinated peptide had the highest specificity of 86.73% and it had good sensitivity as well which was 75.14% (Sun et al., 2017). From the results, the authors concluded that anti-cyclic citrullinated peptide was a good prognostic marker for rheumatoid arthritis. It had the ability to differentiate between the erosive and non-erosive stages of the disease with more accuracy compared to other autoantibodies. This along with other autoantibodies like rheumatic factors provided less sensitive results as they are present in other conditions as well.

The level of autoantibodies is also not only valuable in the early diagnosis but they are also helpful in knowing the level of remission if it has occurred. The effectiveness of the treatment that is being provided to the patient which is pertaining to the reduction in the autoantibodies in the plasma can also is verified by the level of autoantibodies. The diagnostic value of the rheumatic factor is not only helpful in the early stages but also in cases with remission as lower levels are seen in cases with remission (Bugatti et al., 2018).

The main aim behind the identification of the autoantibodies in the blood plasma or serum is that these antibodies are normally are not present in the system and anti-cyclic citrullinated peptide gets cleaved and is removed from the body. Due to the defect in the immune system, it is seen that these factors or antibodies are not destructed or removed from the body. These factors increase in concentration and get accumulated in the synovial membrane of the joints and cause an adverse inflammatory reaction. There are other factors which have their own roles in the disease causation and progression but the most prominent ones are anti-cyclic citrullinated peptide and rheumatic factor (Fang et al., 2019). The presence of these factors is suggestive of the fact that there is an underlying inflammatory response which is related to the pathogenesis of rheumatoid arthritis.

 Autoantibodies as A Diagnostic Tool for Rheumatoid Arthritis Are Not Valuable

It is a fact that for the proper treatment of a disease it is required that it is diagnosed early so that appropriate treatment can be provided to the relevant population. In a disease like rheumatoid arthritis which is a progressive and chronic one and the associated symptoms are debilitating and can result in deformation and disability diagnosis play an important role. Since it has been identified that autoantibodies are responsible for the causation and progression of disease researches have been carried out to explore the related antibodies. The presence of these factors in the blood are known to have diagnostic value for the disease but at the same time, there is more number of factors both internal and external which are related to the disease.

The disease has a significant amount of genetic linkage and also due to external environment like stress the disease is known to occur. The diagnostic test should be robust in such a way that the result of the test and the occurrence of the disease both coincide. In a study conducted by Doğan et al. (2014) it was seen that a combination of tests for the identification of autoantibodies has proved to be beneficial in diagnosing rheumatoid arthritis. In the same study is it reported that anti-cyclic citrullinated peptide along with rheumatoid factor has high specificity and positive predictive value. This is beneficial when the disease is also present otherwise it can provide a large number of false-positive which might not be beneficial to the healthcare organization as it may waste time. 

Another study was conducted with an aim to update the knowledge of the healthcare professionals on the clinical and diagnostic values of autoantibodies in the plasma (de Brito Rocha et al., 2019). It was seen that testing of rheumatoid factor in patients with rheumatoid arthritis had mediocre sensitivity with relatively higher specificity (Ingegnoli et al., 2013). It is because of this reason that even patient who is healthy might test positive for rheumatoid arthritis. There are other diseases which might have a similar outlook but they can be either autoimmune as well as non-autoimmune diseases but these autoantibodies might be found in raised quantity (Verheul et al., 2015). For example, in the case of systematic lupus erythematosus and systemic sclerosis rheumatoid factor is tested positive but the patient is not actually suffering from the disease. Immunoglobulins of rheumatoid factor are IgM and IgA and former is the one which is most commonly associated with rheumatoid arthritis and is associated 65% (Verheul et al., 2015). In other connective tissue disorders also it can be seen that this factor specifically IgM is prevalent and the sensitivity of the diagnostic test becomes questionable (Ingegnoli et al., 2013).

The anti-cyclic citrullinated peptide is positive in a maximum of the patient to such an extent that it is associated with the disease is the highest sensitivity (Song and Kang 2010). Although, it is seen that the disease process is not simultaneous with the level of anti-cyclic citrullinated peptide and it cannot be used for the diagnosis of the erosive and non-erosive stages which is the progression of the disease (Willemze et al., 2012). Also, if the patient is asymptomatic it is seen that the test for anti-cyclic citrullinated peptide can produce inconclusive results. It is seen that the overall sensitivity of the test of anti-cyclic citrullinated peptide assay is similar to that of rheumatoid factor but it is also seen to show a positive result in 20-30% of the patients who are actually negative (Szekanecz et al., 2013).

Considerations for Rheumatoid Arthritis

For the current literature review essay the articles that have been selected from last ten years though it has been made sure that all the sources are peer-reviewed but the credibility and the currency of the articles are not same. To tackle this information of relatively older articles are taken and compared with the current data that is available to arrive at the conclusion. Diagnosis of a disease is an important aspect of disease identification and which determines the treatment process. In order to make sure that the quality of life of the patients is maintained it is required that the disease is diagnosed early and appropriate interventions are given immediately. in case of rheumatoid arthritis, it is seen that this is required for the prevention or rather retardation of the radiographic progression, functional disability and deformity of the joint.

Rheumatoid arthritis has biomarkers which are present in the blood and the identification of them can be used as a diagnostic tool. The biomarkers for this disease are C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) and autoantibodies like rheumatoid factor (RF) and anti-cyclic citrullinated peptide (ACCP) (Nakken et al., 2017). The presence of these autoantibodies are most commonly used for the diagnosis of the disease but it is seen that the specificity and sensitivity of the tests are not a hundred per cent. There are other diseases also wherein these factors test positive but the disease is actually absent and in such cases the diagnostic value is questionable. In recent times, combinations of tests for more than single biomarkers are being done which are better than single-factor tests (Nakken et al., 2017).

Conclusion on Essentials of Pathology

Autoimmune disease is the kind of disease which attacks the cells of self and as a result disease occurs and rheumatoid arthritis is one of them. It is a chronic and progressive disease in which there is the formation of autoantibodies which attack the synovial membrane of the joint and cause inflammation and there is resultant erosion of bone and deformity of the joint. These autoantibodies are used as biomarkers so that the disease can be detected early and treatment is started earlier so that there can be an improvement in the quality of life. The present literature review essay was done to know the diagnostic value of the autoantibodies in rheumatoid arthritis. It was seen that the tests of individual factors of autoantibodies are less sensitive and can be false positive as there are other diseases as well where these factors can be seen. In the recent times, there has been the development of tests which are by the combination of multiple factors which are more sensitive and specific and their diagnostic value is more and required and is valuable in early diagnosis.

References for Essentials of Pathology

Abedian, Z., Sagafi, M., Kenari, S.A. and Abedian, F. 2015. Anti-perinuclear factor as diagnostic marker in rheumatoid arthritis. Journal of Clinical and Diagnostic Research: JCDR9(9), p.OC13. https://doi.org/10.7860/JCDR/2015/14962.6456.

Aletaha, D. and Blüml, S., 2016. Therapeutic implications of autoantibodies in rheumatoid arthritis. RMD Open2(1). https://doi.org/10.1136/rmdopen-2014-000009.

Besada, E., Nikolaisen, C. and Nossent, J.C. 2011. Diagnostic value of antibodies against mutated citrullinated vimentin for rheumatoid arthritis. UiT The Arctic University of Norway. https://hdl.handle.net/10037/5634.

Bugatti, S., Manzo, A., Montecucco, C. and Caporali, R. 2018. The clinical value of autoantibodies in rheumatoid arthritis. Frontiers in Medicine5, p.339. https://doi.org/10.3389/fmed.2018.00339.

de Brito Rocha, S., Baldo, D.C. and Andrade, L.E.C. 2019. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Advances in Rheumatology59(1), pp.1-13. https://doi.org/10.1186/s42358-018-0042-8.

Derksen, V.F.A.M., Huizinga, T.W.J. and van der Woude, D. 2017. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. In Seminars in immunopathology, 39(4), pp. 437-446. Springer Berlin Heidelberg. https://doi.org/10.1007/s00281-017-0627-z.

Doğan, M., Küçüksaraç, S., Tüfekçi, O., Feyzioğlu, B., Özdemir, M., Baykan, M. and Baysal, B. 2014. Comparison of the diagnostic values in rheumatoid arthritis: Anti-CCP antibodies and other serological tests. Biomedical Research (0970-938X)25(3). https://www.alliedacademies.org/articles/comparison-of-the-diagnostic-values-in-rheumatoid-arthritis-anticcpantibodies-and-other-serological-tests.html.

Fang, Q., Ou, J. and Nandakumar, K.S. 2019. Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis. Mediators of Inflammation2019.

Generali, E., Bose, T., Selmi, C., Voncken, J.W. and Damoiseaux, J.G. 2018. Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmunity Reviews17(9), pp.935-941. https://doi.org/10.1016/j.autrev.2018.04.002.

Guo, Q., Wang, Y., Xu, D., Nossent, J., Pavlos, N.J. and Xu, J. 2018. Rheumatoid arthritis: Pathological mechanisms and modern pharmacologic therapies. Bone Research6(1), pp.1-14. https://doi.org/10.1038/s41413-018-0016-9.

Hanaoka, B.Y., Ithurburn, M.P., Rigsbee, C.A., Bridges Jr, S.L., Moellering, D.R., Gower, B. and Bamman, M. 2019. Chronic inflammation in rheumatoid arthritis and mediators of skeletal muscle pathology and physical impairment: A review. Arthritis Care & Research71(2), pp.173-177. https://doi.org/10.1002/acr.23775.

Ingegnoli, F., Castelli, R. and Gualtierotti, R. 2013. Rheumatoid factors: Clinical applications. Disease Markers35(6), pp.727-734. https://doi.org/10.1155/2013/726598.

Nakken, B., Papp, G., Bosnes, V., Zeher, M., Nagy, G. and Szodoray, P. 2017. Biomarkers for rheumatoid arthritis: From molecular processes to diagnostic applications-current concepts and future perspectives. Immunology Letters189, pp.13-18. https://doi.org/10.1016/j.imlet.2017.05.010.

Song, Y.W. and Kang, E.H. 2010. Autoantibodies in rheumatoid arthritis: Rheumatoid factors and anticitrullinated protein antibodies. QJM: An International Journal of Medicine103(3), pp.139-146. https://doi.org/10.1093/qjmed/hcp165.

Sun, P., Wang, W., Chen, L., Li, N., Meng, X., Bian, J., Yang, J., Wang, X.N., Zhu, W. and Ming, L. 2017. Diagnostic value of autoantibodies combined detection for rheumatoid arthritis. Journal of Clinical Laboratory Analysis31(5), p.e22086. https://doi.org/ 10.1002/jcla.22086.

Szekanecz, Z., Szabó, Z., Zeher, M., Soós, L., Dankó, K., Horváth, I. and Lakos, G. 2013. Superior performance of the CCP3. 1 test compared to CCP2 and MCV in the rheumatoid factor-negative RA population. Immunologic Research56(2-3), pp.439-443. https://doi.org/10.1007/s12026-013-8425-8.

Tracy, A., Buckley, C.D. and Raza, K., 2017, June. Pre-symptomatic autoimmunity in rheumatoid arthritis: When does the disease start?. In Seminars in immunopathology, 39(4), pp. 423-435. Springer Berlin Heidelberg. https://doi.org/10.1007/s00281-017-0620-6.

van Steenbergen, H.W. and van der Helm-van Mil, A.H., 2016. Clinical expertise and its accuracy in differentiating arthralgia patients at risk for rheumatoid arthritis from other patients presenting with joint symptoms. Rheumatology55(6), pp.1140-1141. https://doi.org/10.1093/rheumatology/kev431.

Verheul, M.K., Fearon, U., Trouw, L.A. and Veale, D.J. 2015. Biomarkers for rheumatoid and psoriatic arthritis. Clinical Immunology161(1), pp.2-10. https://doi.org/10.1016/j.clim.2015.04.005.

Willemze, A., Trouw, L.A., Toes, R.E. and Huizinga, T.W. 2012. The influence of ACPA status and characteristics on the course of RA. Nature Reviews Rheumatology8(3), pp.144-152. https://doi.org/10.1038/nrrheum.2011.204.

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