1. Introduction

Rheumatoid arthritis is a chronic autoimmune disease that has adverse effects on people and healthcare systems worldwide. In the U.S., there are about 1.3 million adults with rheumatoid arthritis [12,47], whereas globally, it is between 0.5% and 1% of adults with rheumatoid arthritis. Women are 2-3 times more likely than men to have rheumatoid arthritis, with the common age range of onset being 30-60 years [12,17]. According to statistics about 35% of the patients become disabled within 10 years, and life expectancy is reduced further, up to five to ten years, that arises from complications of cardiovascular diseases [33,8].

The Pathogenesis of Rheumatoid Arthritis. Rheumatoid arthritis is characterized by synovial inflammation and hyperplasia ("swelling"), production of autoantibodies, including rheumatoid factor and anti-citrullinated protein antibodies, and progressive destruction of cartilage and bone leading to joint deformities. Systemic manifestations of RA include effects on the cardiovascular, pulmonary, psychiatric, and musculoskeletal systems [31].

Rheumatoid arthritis is an autoimmune disease involving genetic factors such as HLA-DRB1 in association with environmental risk factors: smoking and infections. These factors lead to citrullination of proteins, production of autoantibodies such as rheumatoid factors and anti-citrullinated protein antibodies. The formation of immune complexes caused by these autoantibodies activates the immune system, resulting in much chronic inflammation. The respectively inflamed joint synovial tissues cause a pannus, an invasive structure that erodes cartilage and bone. This activity is provoked by proinflammatory cytokines such as TNF-, IL-1, IL-6, and IL-17, as well as by enzymes such as matrix metalloproteinases and osteoclasts activated by RANKL. Chronic inflammation relates to its impact on concurrent cardiovascular disease and osteoporosis as systemic complications of directional immuno-dysregulation [14,46].

The role of Inflammation Biomarkers in Rheumatoid Arthritis. Early diagnosis of rheumatoid arthritis is of utmost importance to hinder the damage to joints and disease progression. Identification of these biomarkers will facilitate earlier diagnosis of RA, including circulating markers such as anti-CCP antibodies, RF, anti-MCV antibodies, and 14–3-3η proteins [43]. Biomarkers of inflammation are important in the diagnosis, target progress, and management of rheumatoid arthritis (RA). Non-specific markers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are routinely used to assess inflammation and treatment efficacy. Pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1, are responsible for joint destruction and placebo markers for RA therapy. Autoantibodies, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP), are important in the early diagnosis of RA and identifying the potential for aggression. The 14-3-3η protein has also become an important predictor of disease progression. Together, these biomarkers have propelled personalized therapeutic strategies which have led to improved clinical outcomes in RA [1,32,30].

Figure 1. Classification of Inflammatory Biomarkers in RA

Toll-like receptors (TLRs). Toll-like receptors (TLRs) are important pattern recognition receptors that are important for innate immunity since they recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In rheumatoid arthritis (RA), TLR2 and TLR4 have been recognized to be activated by endogenous ligands such as heat-shock proteins and extracellular matrix damaging patterns which induces pro-inflammatory cytokines (TNF-α, IL-1, IL-6) to be released and promote inflammation in the synovium and destruction of joints [37,22]. These receptors are abundantly expressed in synovial fibroblasts, leading to degradation of cartilage and bone by releasing matrix metalloproteinases (MMPs) and inflammatory cytokines [28]. TLR7 and TLR9 also contribute to the development of RA by inducing production of auto-antibodies (e.g., rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) that are pertinent to RA pathogenesis [29].

Toll-like receptor 2 (TLR-2) and Toll-like receptor 4 (TLR-4) recognize DAMPs in synovial tissue and lead to the secretion of pro-inflammatory cytokines including TNF-α, IL-1, and IL-6, promoting inflammation and joint damage [25]. There is high expression of TLR-2 and TLR-4 in synovial fibroblasts and macrophages, with the activation promoting the degradation of cartilage and bone by various MMPs [11]. TLR-4 directly promotes the production of various autoantibodies including RF and ACPAs, two biomarkers important in RA [42]. Cross-sectioning analysis among the genetic polymorphisms in TLR-4 suggests an increase in susceptibility and severity to RA, pointing toward their future as biomarkers for diagnosis and prognosis of the disease [44]. This fact strongly suggests that a pathway targeting either TLR-2 or TLR-4 and their downstream implementing molecules like MyD88 and NF-κB will be the most promising in limiting inflammation and disease progression [37].

Acute-phase reactants. C-reactive protein (CRP) is an important acute-phase reactant in Rheumatoid arthritis (RA). It is mainly produced by the liver in response to IL-6 and reflects systemic inflammation and disease activity. CRP furthers RA pathogenesis by promoting complement activation, enhancing phagocytosis, and regulating cytokine production, particularly of IL-6 and TNF-α [39,18]. Higher levels of CRP are associated with joint inflammation, cartilage degradation, and bone erosion and thus serve as useful biomarkers for monitoring disease progression and treatment response [3].

Autoantibodies. Anti-CCP (anti-cyclic citrullinated peptide) antibodies are crystallized highly specific biomarkers for rheumato-nid arthritis-their role is paramount in the early diagnosis and prognosis. Anti-CCP antibodies are believed to target immuno-logically undergone citrullinated protein during the process of inflammation, and they are associated with severe disease such as joint erosion or radiological progression [35,54]. They may be present before clinical symptoms emerge, proving valuable in identifying individuals at risk of developing RA [41]. Their presence correlates well with disease activity and poor treatment response; reaffirming their importance in personalized management of RA [2].

Cytokines and Chemokines. Cytokines are involved in the pathogenesis of rheumatoid arthritis (RA), contextually controlling synovial inflammation, cartilage degradation, and bone erosion, and further serve as important biomarkers and therapeutic targets for disease management.

Interleukin-1 (IL-1) is a cytokine with a molecular weight of 17 kilodaltons secreted principally by monocytes and macrophages. There are, however, two isoforms (a and p) which share -26 percent amino acid sequence homology. IL-1p is the predominant form, mainly synthesized by human monocytes. It binds to the same receptor on target cells as IL-1a and shows-like IL-1a-comparable bioactivities. Its systemic effects include induction of metabolic changes in the central nervous system (CNS), bone marrow, and vascular walls [7].

Interleukin-6 (IL-6) is a multifunctional cytokine that plays a prominent role within the complexity of the pathophysiology of rheumatoid arthritis (RA). Produced by synovial fibroblasts, macrophages, and T cells, IL-6 ultimately participates in local joint destruction and systemic manifestation as a resultant of such stimuli. It stimulates synovial inflammation through the production of acute-phase reactant cytokines like C-reactive protein (CRP) and fibrinogen as well as drives Th17 cell differentiation and autoimmune responses. In addition, IL-6 also activates osteoclasts and causes bone resorption and joint destruction [26,51].

Tumor necrosis factor-alpha (TNF-α) is one of the pro-inflammatory cytokines in rheumatoid arthritis (RA), facilitating synovial inflammation, cartilage destruction, and bone erosion. It activates endothelial cells, fibroblasts, and immune cells, which release such inflammatory mediators as interleukin 1 (IL-1), interleukin 6 (IL-6), and matrix metalloproteinases (MMPs) that will be responsible for joint destruction. TNF-α also promotes the formation of pannus, an invasive tissue attacking joint structures and causing systemic manifestations such as fatigue, anemia, and cardiovascular disease. Because of its critical role in RA pathogenesis, TNF-α is one of the prime targets for some biologic therapies; indeed, TNF inhibitors have a significant effect in controlling inflammation and slowing the disease progression [4,36].

Interleukin-8 (IL-8 or CXCL8), a chemokine that is central to RA because it recruits neutrophils and other immune cells to inflamed joints, is secreted by synovial fibroblasts and macrophages. IL-8 promotes angiogenesis, synovial hyperplasia, and cartilage degradation, contributing to the destruction of the joints [27,49]. Its increased levels in synovial fluid and serum are correlated to disease activity and radiographic progression, thus predicting its usefulness for monitoring RA severity [21,10].

Enzymes & Proteins. Calprotectin, a protein complex released from activated neutrophils and monocytes, is an indicator of inflammation in rheumatoid arthritis (RA). This indicates synovial inflammation with some correlation to disease activity, joint damage, and radiographic damage progression [6,23]. Rheumatoid arthritis is characterized by its elevation in patients in conjunction with heightened production of pro-inflammatory cytokines such as TNF-α and IL-6, thereby serving as an assay in evaluating disease activity and response to treatment [20,13]. The fact that it can predict treatment outcome, particularly for biologic therapy, gives it further clinical relevance [6].

Genetic & Epigenetic Biomarkers. miRNAs are small non-coding RNAs involved in regulating gene expression with high impact on RA. They modulate immune responses, synovial inflammation, and joint destruction by targeting key molecules such as TNF-α, IL-6, and MMPs [9,38,48]. In RA patients, dysregulated miRNAs are correlated with disease activity, joint damage, and response to therapy, suggesting their use as biomarkers and drug targets [34,16].

The contribution of inflammatory biomarkers with respect to the early diagnosis and management of rheumatoid arthritis (RA) has become the subject of continuous research interest. These biomarkers-including CRP, ESR, RF, ACPAs, and novel cytokines-are deemed competitive in assessing disease progression and severity, as well as the treatment response. Intuitively synthesizing these have made the diagnosis of RA easy and treatment more personalized. A brief description of important studies, researchers, and findings is provided below that provide insight into the work done on RA biomarkers:

• Xinping Tian and colleagues have studied some newer biomarkers like IL-34 and IL-33. Their study identifies IL-34 as a potential biomarker to predict joint damage and treatment resistance in patients with RA. These findings imply that newer cytokines could probably provide additional accuracy for RA diagnosis and prognosis [52].

• Kevin D. Deane has advanced the concept of "preventive rheumatology" by studying pre-RA phases. By examining ACPA, RF, and other biomarkers, his research shows that prediction of which high-risk subjects might go on to develop RA is enhanced, thus allowing for consequent preventive interventions [15].

• Tsutomu Takeuchi explores cytokine patterns and their use in predicting treatment responses to biologic therapy. His study identified distinct cytokine patterns in patients with better responses to TNF inhibitors and IL-6 blockers and allows for a personalized treatment approach [50].

• Peter K. Gregersen has searched for genetic and molecular bases of rheumatoid arthritis, also for the role of the interplay between genetic markers and inflammatory cytokines. Such work offered knowledge on how genetic and biomarker information can be jointly applied for disease severity and treatment response prediction [19].

• Dirkjan van Schaardenburg has studied the predictive value of autoantibodies such as ACPAs and RF in pre-RA stages. His work indicates that in individuals with arthralgia (joint pain), ACPA positivity is a strong predictor for progression into clinical RA, thus allowing early intervention [53].

2. Conclusions

Biomarkers of inflammation such as CRP, ESR, RF, ACPAs, TNF-α, and IL-6 are an essential part of the diagnostic, prognostic, and therapeutic management of rheumatoid arthritis. Toll-like receptors primarily TLR-2 and TLR-4 have furthered the understanding of mechanisms responsible for the inflammation of the synovium and subsequent joint destruction. Newer biomarkers namely calprotectin and miRNAs show promise in predicting disease progression and response to treatment. The combined efforts of these above parameters provide an enabling framework for early diagnosis, targeted therapy, and treatment approval enhanced by improved patient outcomes, thus highlighting their critical roles in providing better care for RA. Further studies of new biomarkers and their roles in clinical practice are expected to inform better management for RA.