Diagnosis , Epidemiology and Pathophysiology of Rheumatoid Arthritis - Duniya Health
Rheumatoid arthritis (RA) is one of the more common autoimmune disorders affecting about 1% of the population worldwide. The exact cause of RA is not known; However, disease onset occurs as a result of interactions between genetic susceptibility, environmental triggers, and coincidence. RA is characterized by degranulated inflammatory processes in the synovial joint that eventually leads to destruction of the cartilaginous and bony elements of the joints, resulting in pain and disability. Systemic inflammation associated with RA is associated with a number of extra-articular combiditis, including cardiovascular disease, resulting in increased mortality in patients with RA. RA is also associated with several psychosocial disorders. Classification criteria for RA that were promulgated jointly by the American College of Rheumatology and the European League Against Rheumatism in 2010 emphasize early detection of RA so that effective management can be initiated before the disease becomes irreversible.
Arthritis (RA), a more common chronic inflammatory disease, is characterized by inflammation and swelling of the synovial joint, followed by destruction of the articular structures. Patients with active RA also experience systemic inflammation that is associated with a variety of conditions. Compared with the general population, cardiovascular disease is the most important increase in morbidity and mortality noted in this group.The pain, fatigue, and disability associated with RA leads to a significant decrease in health-related quality of life. Additionally, RA places considerable economic burden on patients, both due to rising costs of medical care and loss or loss of employment. Often.5,6 during peak working years
This article is the first in a 3-article supplement that will review the pathophysiology, treatment, and managed care implications of RA. This article will examine the epidemiology and pathophysiology of RA and provide guidance regarding diagnosis based on current disease classification criteria.
Epidemiology of Rheumatoid Arthritis
Although the exact cause of RA is unknown, disease initiation arises from interactions between genetic susceptibility, environmental triggers, and coinfection. 9. In a study of monozygotic and dizygotic twins, the genetic contribution to variance in RA liability, which is equivalent to RA's heredity, was estimated to be 53% based on data from the United Kingdom and 65% based on data from Finland. Genetic factors associated with RA susceptibility are differences in human leukocyte antigen (HLA -DRB1). Alleles, especially in patients who are positive for rheumatoid factor (RF) and anti-citrinoated protein antibodies (ACPA). 11 The presence of a common amino acid motif (QKRAA) in these alleles seems to be accompanied by a particular susceptibility to RA. Known as a shared epitope. 9 There is also evidence of gene – environment interactions; For example, RA is increased in HLA-DRB1 individuals who smoke cigarettes. Chromosome 6, which contains genes for HLA-DRB1, also contains genes that affect multiple immune processes, including modulation of tumor necrosis factor (TNF) .13
Various environmental factors have been implicated as potential triggers for RA. Hormonal effects on RA in women have been an area of active research, noting that RA is more frequent in women. For example, in a case – control study, oral contraceptive use was not associated with a lower risk of RA; However, breastfeeding for 13 or more months was associated with a lower risk of RA compared with never having breastfed (difference ratio, 0.61; 95% CI, 0.24–0.91).
In an analysis of data from nurses' health studies, the risk of RA in women with a "shared epitope", a series of AAL of the third hypereversible region of the HLA-DRB1 molecule that is associated with RA, is increased in a cumulative smoking. With a history of. 12 Other potential environmental triggers that have been associated with RA include infectious agents (eg, Epstein-Barr virus, cytomegalovirus, Proteus species, Escherichia coli) and their products (eg, heat-shock proteins). 9. These entities have often been associated with RA, even if the cause of the disease is not clear. Proposed mechanisms include molecular mimicry, potential adjuvant effects of pathogens in priming autoreactive immune responses, and biodysor activation of autoreactive cells.
Pathophysiology of Rheumatoid Arthritis
When T-cell activation occurs, naïve T helper (Th) cells differentiate into 3 major subtotals (Th1, Th2 and Th17) with distinct cytokine production profiles and functions.25 Although RA is prolonged Seen to be a disease that is mediated by Th1 cells, recent interest has been focused on the Th17 subfamily. Both dendritic cells and macrophages secrete the transforming growth factor inter, interleukin (IL) -1 6, IL-6, IL-21, and IL-23, which support Th17 differentiation and the production of regulatory T cells. Presses, thus transferring homeostatic equilibrium. Inflammation towards synovial 9. In turn, Th17 cells produce IL-17A, IL-17F, IL-22, IL-26, interferon-G, chemokine CCL20 and the transcription factor ROR-g.2.22 IL-17A. Stimulates fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes to increase production of IL-26, which induces production of inflammatory cytokines IL-1β, IL-6 and TNF-α by monocytes; These cytokines stimulate further differentiation of Th17 cells. 27 In addition to antigen-driven inflammatory pathways, inflammation via antigen-redundant pathways initiated by cell-to-cell contact between activated T cells and macrophages and fibroblasts. Can be mediated.Synovitis, inflammation, and joint damage that characterize active RA are the end result of complex autoimmune and inflammatory processes, which involve components of both the innate and adaptive immune systems. 9 In a susceptible individual, harm is caused by the interaction of environment and genus. Tolerance of self-proteins that contain citraline residues. These proteins are generated through posttranslational modification of arginine residues to citrline residues by the enzyme peptidylarginine deiminase.9. Citrullinated peptides are produced in patients with shared epitopes that are not identified as "self" by the immune system, resulting in the development of ACP against them. Comparison of magnetic resonance imaging (MRI) and synovial biopsy data from healthy individuals with MRI and biopsy data from patients positive for RF and / or ACPA shows systemic autoantibody production that leads to inflammatory and adhesive molecule formation in the mucosa, Which implies that perhaps some secondary event. Required to initiate synovium involvement in RA.17. In a study of 79 patients with RA, the initial presence of RF and ACPA involved the development of clinical RA in the middle of 4.5 years.
Synovitis occurs as a result of leukocyte infiltration into the mucosa. Accumulation of leukocytes in the synovium does not result from local cellular proliferation, but rather as a result of migration of leukocytes from distant sites of formation in response to expression of adhesion molecules and chemokines by activated endothelial cells of the synovial microbes. The inner part of the inflamed synovium is hypoxic, as a result of the proliferation of 19 synovial cells and a decrease in synovial capillary flow as a result of a decrease in synovial capillary flow. Hypoxia, in turn, stimulates angiogenesis in the mucosa, perhaps by inducing the formation of factors. Stimulate vascular endothelial growth factor such as vessel formation. 2
Immune activation and RA disease progression is a complex process involving interactions between components of both the adaptive and innate immune pathways. The nature of these interactions is strongly influenced by the local cytokine and cenovine in the chemokine environment in which they take place. In established RA, the synovial membrane is inhabited by a variety of inflammatory cell types that work together to cause joint destruction. 9
The importance of the adaptive immune pathway in RA is revealed by the presence of dendritic cells, a major class of antigen-presenting cells that express cytokines, HLA class II molecules, and costimulatory molecules in close proximity to groups of T cells. Does. Synovium. Dendritic cells present antigens to T cells that are present in the synovium and also serve as a component of the T-cell activation process. Activation of T cells requires 2 signals. The first signal is antigen presentation of the T-cell receptor. The second signal, costimulatory signal, requires the CD28 protein on the antigen-presenting (dendritic) cell of the cell surface protein CD80 / 86, along with the T28 cell CD3. With T-cell activation and downstream events.24 Effectiveness of CD80 / 86 blockade as a treatment for RA validates the concept that T cells play an active role in the pathophysiology of RA.
Humoral adaptive immunity also plays an integral role in the pathogenesis of RA. The contribution of B cells to autoimmune disease can be mediated through several possible mechanisms. Defects at B-cell tolerance outposts can result in autoreactive B cells that act as antigen-presenting cells capable of activating T cells. B cells can produce both pro- and antiinflammatory cytokines. Finally, B cells can act as antibody-producing cells. Separately or in combination, these mechanisms may contribute to RA pathogenesis. 30 Additional support for the involvement of B cells in RA is provided by the successful use of agents that eliminate specific B-cell populations for the management of RA. Rituximab, a monoclonal antibody directed against CD20-positive B cells, has demonstrated success in RA clinical trials and is currently approved for use in patients with RA who are refractory to TNF inhibitors.
Cells of the innate immune system, including macrophages, mast cells, and natural killer cells, are located in the synovial membrane, while neutrophils are typically found in the synovial fluid. Macrophages, in particular, are important factors of synovitis that act through phagocytosis; Antigen presentation; And the release of pro-inflammatory cytokines, reactive oxygen intermediates, prostenoids, and matrix-degrading enzymes. Tollift receptors (TLRs) on monocytes, macrophages, and dendritic serve to initiate inflammatory and immune responses upon exposure to an immunogenic stimulus. Such as a microbial pathogen. Activation of TLRs leads to rapid expression of proinflammatory cytokines that mediate an immune response that recruits neutrophils, monocytes, and lymphocytes. Macrophages and dendritic cells accumulate processed antigens and migrate to peripheral lymphoid tissue where antigens are presented to cells of the adaptive immune system with activation of cellular immunity and production of antibodies. In most cases, a combination of innate and adaptive immune system responses will abolish the pathogen, leading to the termination of the immune response. In the setting of RA, however, the inflammatory response is not abolished after pathogen clearance, but rather remains chronologically active.
Pathogenesis of RA also involves intracellular signaling pathways. All of the various cytokines, chemokines, antibodies and antigens that contribute to bind inflammation in receptors on the cell surface of specific target cells. Receptor binding usually results in a cascade of intracellular signaling events that eventually transform into the nucleus of the cell and alter gene expression in ways that affect cell function. In particular, changes in gene expression in immune cells are often associated with the production and secretion of inflammatory mediators in response to a particular stimulus. The secretion of these mediators into additional mediators is the result of further amplification and / or modification of the original signal. Examples of intracellular signaling pathways include mitogen-activated protein kinase (MAPK) pathway, Janus kinase (JAK) pathway, signal transducers and activator of transcription (STAT) pathway, spleen tyrosine kinase (Syk) signaling, and nuclear factor ell. Activated B cells (NF-) B) enhance the light chain of pathway. The differences between the pathways are reported.
Intracellular signaling pathways are essential for a normal immune response, and these pathways may contribute to autoimmune disease. The first generation of small molecules directed against 34 intracellular targets is now being used for the treatment of RA.3.3. Possibility to identify additional therapeutic targets. Inflammation of RA is also associated with characteristic changes in mesenchymal tissue. FLS, which usually reside in the synovium, become indifferent and alter their phenotype in the setting of RA.9. In the inflammatory simonium, cell contact between FLS and T cells involves a variety of inflammatory mediators and adhesion molecules, including IL-6, TNF, interferon-G, intracellular adhesion molecule-1, and vascular cell adhesion molecules. -1.36 Altered FLs invade the cartilage of the joint and produce a variety of protons that contribute to joint destruction.
Disease Activity Assessment
Several tools have been developed for the assessment of disease activity for use in clinical trials and office settings. They are used to standardize definitions and direct treatment. In particular, the development of standardized measures of disease activity, which define demonetization, low disease activity, and high disease activity, is essential for the use of a "treatment-to-target" strategy using pharmacologic therapy. In the "treatment-to-target" paradigm, a patient's baseline disease activity is determined and therapy is initiated with the primary goal of maximizing long-term health-related quality of life. After therapy begins, progress toward the goal is rescheduled at regular intervals and therapy is adjusted based on the attainment of the goal.
Disease activity score using 28 joints (DAS28) is one of the most commonly used assessments of disease activity in RA clinical trials. In DAS28, the physician's evaluation of 28 joints for inflammation and tenderness, individual physician and patient assessment of global disease activity, and laboratory evaluation of inflammation (either erythrocyte sedimentation rate [ESR] or plasma level of C-reactive protein] CRP]). The resulting numbers are added to an empirical formula to generate the DAS28 value. The DAS28 score has been used to define the level of disease activity in clinical trials. Definitions of disease activity, which were calculated using the DAS28 (ESR) formula, were low (DAS28 <3.2), moderate (3.2 <DAS28) 5.1), and high (DAS28> 5.1). DAS less than 2.6 corresponds to the exemption condition according to the American Rheumatism Association criteria. There is some discrepancy between the DAS28 values calculated using 329 CRP and ESR. Given the more common current use of CRP for DAS28 counts, disease activity reductions were developed in 2010 for DAS28 (CRP). In this schema, disease remission is defined as 2.3 less than DAS28, with low disease activity ranging from 2.3 to 3.8. Moderate disease activity ranges from 3.8 to 4.9, and high disease activity exceeds 4.9 in both clinical trials and clinical practice. DAS evaluation is used.
Other commonly used scales in clinical trials and clinical practice include the Simplified Disease Activity Index (SDAI), which measures 5 measured parameters (numerical and combined counts of disease, physician and global assessments of disease, and CRP), and regular assessment of Patient Index Data 3 (RAPID 3), which is a measure of physical function, pain, and global status. 4,1,42 Other scales commonly used in clinical trials include the ACR response, which is the percentage improvement from baseline, and the Clinical Disease Activity Index (CDAI), which is called inflammation and tender joint count, and physician and patient global Is calculated as the sum of the assessments. 4,3,44 CDAI is probably the easiest scale to use, as it is only an arithmetic sum of 4. Measured parameters. As a result of its simplicity, it is probably the most widely used scale in clinical practice. Based on the limitations of current measurements of disease activity, there is considerable interest in developing novel markers for early RA.
Patient reported outcomes are also routinely used to assess current patient status and treatment outcome of RA, particularly functional status and quality of life. Functional status is usually measured with the Health Assessment Questionnaire (HAQ) or one of its many variants. The HAQ consists of a series of 41 questions in 8 categories that evaluate a patient's difficulties with activities of daily living in the past week. The general quality of life in patients with RA has generally been evaluated with the short form 36, while the disease-specific quality of life can be measured with the Rheumatoid Arthritis Quality of Life Instrument. 45,46
In 2011, a joint committee of the ACR and the European League Against Rheumatism (EULAR) suggested 2 possible approaches to define clinical remission in clinical trials of RA. A patient may be considered in remission when scores on the tender joint count, joint count, CRP (in mg / dL), and patient global assessment (0–10 scale) are all 1 or less than or equal to. , When the score on SDAI is less than or equal to 3.3.47
An estimate of the real-world remission rate during treatment was obtained by applying the 2011 ACR / EULAR criterion to 2 large cohorts of patients in clinical practice. The probability of remission on a visit to a given clinic using the ACR / EULAR criterion was 7.5% in one cohort and 8.9% in another. For patients who received remission, the probability of remaining in remission after 2 years ranged from 6.0% to 14.1%. Based on this 2011 analysis, 3% of all RA patients can be expected to experience a remission lasting 2 years or longer. In addition, MRI has been noted to show radiographic evidence of disease progression or synovitis in some patients with clinical remission or ultrasound examination. ४
Analysis of clinical and radiological follow-up data for 290 patients with RA showed that patients who experienced rapid radiologic progression in the first year after RA diagnosis compared with patients without rapid progression for 8 years Were more likely to experience functional disability over a period of. 50 Although radiographic imaging is a useful and specific method for evaluating disease progression and treatment effectiveness, it is less useful for routine monitoring in an office setting, and thus for the controversial previously discussed ACR / EULAR Criteria do not include. The 2012 update of the RCR RA treatment recommendations reviewed other indicators of poor prognosis in patients with RA, including standardized health questionnaires, extra-articular disease, positive RF, positive ACPA, and bony erosion performed by radiographs. Are included.
Disease Burden
In a radiographic study of 42 patients with early RA, 45% of patients experienced bone erosion of the joints within 4 months after diagnosis. In addition to the loss of joints that result from pain, disability, and functioning, RA is a systemic disease. Expression can occur even after controlling joint damage. A more complete consideration of the burden of RA should include comorbidities, psychosocial deficits, and loss of health-related quality of life with extra-articular manifestations of RA (Figure). 53
Systemic comorbidity associated with RA includes heart disease, pulmonary disease, gastrointestinal disease, cancer, and psychiatric disease. Heart disease has attracted special interest, as it appears to be an important source of mortality in RA. The results of a 2008 meta-analysis that included more than 110,000 patients from 24 observational studies stated that patients with RA have a 50% higher risk of heart disease than the general population. Mortality rates for ischemic heart disease and cerebrovascular accident increased by 59% and 52%, respectively.
RA is also associated with a heavy burden of psychosocial comorbidities, which have received significantly less attention than other comorbidities. RA is associated with decreased health-related quality of life, increased fatigue and depression, and impaired cognitive function. 5 Assuming that clinical trials of RA for clinical trials typically focus on joint symptoms There is currently treatment potential for RA. The psychosocial aspects of RA are unclear.
Symptoms and Diagnosis of Rheumatoid Arthritis
The most recent classification criteria for RA were developed by the Joint Committee of ACR and EULAR and published in 2010.55. These classification criteria can be applied to any patient who has at least 1 active active mucositis in the joint that is not explained by a non-RA diagnosis. . Numerical scores are evaluated in 4 domains of RA: joint involvement, serology, acute phase reactants, and duration of symptoms. A patient with a score of 6 or more out of 10 can be classified as RA.55. The 2010 ACR / EULAR classification criteria replaced the ACR criteria promulgated in 1987; Its primary weakness was the failure to identify patients with early disease who may benefit from early initiation of therapy. Although the 2010 classification criteria were formulated to identify patients with RA for clinical trials, there is also a cutoff score of 6 or higher based on these criteria. RA is the clinically preferred method for testing RA clinically 5. Validity of classification criteria for diagnosis.
According to the 2010 ACR / EULAR classification criteria, the markers for autoimmune dysfunction, RF and ACPA, are scored according to the range of values, where normal is defined as lower than the upper limit of normal for laboratory or assay (ULN) Is defined, is less homogenous between ULNs and 3 times less than ULNs, and more than 3 times higher than high-positive ULNs. ESR and CRP levels are scored on the basis that they are normal or abnormal according to reference laboratory standards. The 2010 classification criteria factor duration of therapy, but not the presence or absence of radiographic changes in the final score. The authors of the 2010 ACR / EULAR classification criteria recommend that guidelines for assessment of current and future patients should be used to facilitate earlier use of therapies capable of changing disease progression.
The Conclusion of Rheumatoid Arthritis
RA, a common autoimmune disease, is associated with synovial inflammation and inflammation of the joint and, if left untreated, often leads to destruction of both the bony and cartilaginous elements of the joint and the resulting disability. Several types of comorbidity associated with systemic inflammation contribute to the mortality observed in patients with RA compared with the general population. Although the pathophysiology of RA has not been fully understood, the process typically involves diseased inflammation, including antigen presentation, T-cell activation, and autoantibind production that all act as mediators in the inflammatory process. Diagnosis of RA is based on the patient's history and physical examination demonstrating synovitis in many joints. Indications for disease activity have been developed to guide treatment-to-target approaches to pharmacological interventions.
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