Rheumatoid Arthritis (RA) is a chronic inflammatory disorder and systemic autoimmune disease where the immune system mistakenly attacks its own tissues, primarily within the joints. Pathophysiology describes the biological mechanisms that initiate this process and perpetuate tissue damage. Understanding these mechanisms, from genetic susceptibility to chronic inflammation and physical destruction, is key to understanding RA and its treatments.
The Role of Genetic and Environmental Factors
The development of RA begins with genetic predisposition combined with environmental exposures that trigger the loss of immune tolerance. The most significant genetic factor is the Human Leukocyte Antigen (HLA) complex, specifically the HLA-DRB1 gene, which contains the “shared epitope” (SE). Carrying the SE makes individuals more susceptible to developing RA, particularly the form associated with autoantibodies.
This genetic vulnerability is often activated by external factors, with cigarette smoking being the most clearly defined environmental trigger. Smoking can increase the risk of RA up to three times, especially in genetically predisposed individuals whose disease is characterized by autoantibodies. Another factor is chronic infection, such as periodontitis, which is also linked to an increased risk of RA. These environmental factors are hypothesized to create a local inflammatory environment, often in the lungs or gums, which initiates a process called citrullination.
Citrullination is a natural process where the amino acid arginine is converted into citrulline, altering protein structure and making them appear foreign. The genetic risk conferred by HLA-DRB1 primes the immune system to recognize these citrullinated proteins as threats. This molecular mimicry breaks immune tolerance, initiating the generation of autoantibodies against the body’s own citrullinated proteins, which is the first step in the autoimmune attack.
The Immune System’s Misdirected Attack
Once immune tolerance is broken, the autoimmune response is driven by various immune cells and signaling molecules. Activated B-cells differentiate into plasma cells that produce autoantibodies. The two main types are Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA), often measured as anti-cyclic citrullinated peptide (anti-CCP) antibodies.
These autoantibodies, especially ACPA, are specific markers for RA and often appear years before joint symptoms manifest. They form immune complexes that activate macrophages, which are powerful effector cells in the joint space. Macrophages are the most abundant immune cell type in the inflamed joint lining and produce destructive pro-inflammatory signaling molecules.
The signaling molecules, known as cytokines, form a dense network that sustains and amplifies the inflammatory cycle. Tumor Necrosis Factor-alpha (TNF-\(\alpha\)) is a central mediator, activating endothelial cells and recruiting inflammatory cells into the synovium. Interleukin-6 (IL-6) acts both locally and systemically, driving acute-phase proteins and contributing to disease progression. These cytokines, along with Interleukin-1 (IL-1), maintain chronic inflammation, causing local cell proliferation and attracting a continuous influx of T-cells and B-cells to the joint.
How Inflammation Damages the Joints
The localized consequence of this cytokine-driven immune attack is concentrated within the synovial membrane, or joint lining. The initial phase is synovitis, which is the inflammation and thickening of this tissue. In RA, the synovial lining layer, normally one to three cells thick, becomes greatly hypertrophied, increasing to eight to ten cells thick.
This excessive proliferation of synovial cells, combined with the continuous infiltration of T-cells, B-cells, and macrophages, leads to the formation of the pannus. The pannus is a highly vascularized tissue mass that grows over the joint cartilage and invades the underlying bone. The fibroblast-like synoviocytes within the pannus acquire an altered, destructive phenotype.
The physical destruction of the joint is mediated by enzymes released by the pannus tissue, including matrix metalloproteinases (MMPs) and collagenase. These enzymes actively degrade the cartilage matrix, leading to cartilage erosion and loss of function. Furthermore, inflammatory cytokines, particularly TNF-\(\alpha\) and IL-1, drive the activation of osteoclasts, which are the bone-resorbing cells.
Osteoclasts are activated via a signaling pathway involving the interaction between RANK and its ligand (RANKL), expressed by inflammatory cells and fibroblasts in the synovium. The resulting bone resorption causes characteristic erosions visible on X-rays, undermining joint integrity and leading to instability and progressive deformation.
Effects Beyond the Joints
While RA is primarily known for its effect on the joints, the systemic nature of the disease means chronic inflammation extends its reach to other organ systems. This is driven by the persistent circulation of pro-inflammatory cytokines, such as TNF-\(\alpha\) and IL-6. These extra-articular manifestations can be a significant source of morbidity and mortality for patients with RA.
One serious effect is on the cardiovascular system, where chronic inflammation accelerates atherosclerosis, increasing the risk of heart disease and stroke. Persistent cytokine signaling also affects the lungs, causing inflammation and scarring known as interstitial lung disease. Furthermore, the chronic inflammatory state interferes with the body’s ability to utilize iron, leading to anemia of chronic disease, a common finding in RA patients.