Rheumatoid Arthritis

Author: Brandon Eden

Rheumatoid arthritis (RA) is a systemic autoimmune disorder that affects 1% of the world’s population and is characterized by joint inflammation, swelling, pain, and loss of function (Trier et al, 2017). The immune system launches an attack on cells of synovial joints. Activated T-cells and macrophages rush to the joint and secrete cytokines that cause an inflammatory response (Begovich et al 2004). The increase in immune cells and cytokines causes synovial cells to proliferate, resulting in swelling of the synovial joint and eventually bone erosion and damage to the cartilage (Lefévre et al 2009). Rheumatoid arthritis usually starts in one joint and then spreads to other synovial joints throughout the body (Lefévre et al 2009). Research in the past couple of decades has led to a greater understanding of RA pathology and identification of key antibodies, antigens, and cytokines involved in RA progression. Better patient care has resulted due to more efficient drugs that target key players in RA that have been determined due to this research.

Many genetic and several environmental factors such as cigarette smoke and bacteria can trigger RA by modifying the patient’s antibodies and collagen found in synovial joints (Glant et al 2014). A major focus in RA research revolves around a modification of collagen and fibrinogen proteins called citrullination. Peptidylarginine deiminase enzymes catalyze the citrullination of collagen protein, the transformation of arginine residues into citrulline residues (Suzuki et al, 2003). Citrullinated proteins play a role in RA since they have been found to generate antibodies (Suzuke et al 2003). Many patients with RA have been found to have anti-citrullinated protein antibodies (ACPAs), which stimulate inflammatory responses and the synovial enlargement found in RA (Trier et al, 2018). After research labs have confirmed the presence of ACPAs in RA patients, research has shifted towards understanding the IgG antibodies that bind citrullinated proteins (Amara et al 2013), different haplotypes of peptidyl deiminase enzymes that may be more involved in RA pathogenesis (Suzuki et al 2003), and even improved detection of ACPAs to diagnose RA early on and achieve a better prognosis (Trier et al 2018).

Another high yield area of RA research shifts gears from studying the antigen to studying the activation and proliferation of B-cells and T-cells that work to create the RA associated inflammation. Research on T-cell regulation has ranged from kinase signaling pathways involving protein tyrosine phosphatase (Begovitch et al 2004) and MEK/ERK/MAP (Thiel et al 2007) to T-cell surface glycoprotein ligands that require binding its respective protein ligand to activate the T-cell (Berner et al 2000). These findings have led to drug discovery research that aims to block the interaction of the T-cell ligands to decrease the number of autoimmune collagen antibodies (Choi et al 2018). Other forms of treatment explored targeting the cytokines produced by activated T-cells such as interleukin-6 to suppress inflammation and joint destruction (Mihara et al 2001).

Research has focused on citrullinated antigens and the immune response cells, and another major research theme involves synovial fibroblasts, which are the cells responsible for the production of collagen. Studies about the involvement of synovial fibroblasts in RA pathology have concluded that synovial fibroblasts in RA patients can bind cartilage and degrade it with proteases, then spread to other joints in the body (Lefévre et al 2009). Drug discovery research that targets inflammation of synovial fibroblasts in RA patients still needs further attention due to cross talk between kinase signaling pathways that causes another inflammatory pathway to be stimulated when another is blocked, making synovial fibroblast inflammation difficult to drug (Jones et al 2018).

Rheumatoid arthritis has genetic underpinnings, and studies have been done to locate risk loci for RA. Genome wide association tests were conducted to identify various single nucleotide polymorphisms in genes involved in immune function, and researchers have presented a list of genes that are risk factors for RA (Stahl et al 2010). In addition, epigenetics has been determined to play a role in RA by up-regulating proinflammatory genes such as aurora kinases that recruit transcription factor NF-kB which promotes cytokine genes (Gland et al 2014).

Rheumatoid arthritis research has revolved around a few major themes. The genetic underpinnings of RA have been studied to determine genetic risk factors. Knowledge of the citrullinated antigens that trigger RA, the activation process of T-cells and B-cells, and kinase pathways involved in synovial fibroblast inflammation have greatly aided the development of drugs that target known cytokines and cells involved in RA pathogenesis. Knowledge of the types of antibodies involved in RA pathogenesis have also allowed for early detection and better patient outcomes (Trier et al 2018).





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