Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease. Although the precise cause of RA is not clearly elucidated, both genetic and environmental factors have been implicated in susceptibility to developing RA. Repeated and persistent activation of the innate and adaptive immune system occurs with RA, which over time, results in a cascade of immune tolerance failures, autoantibody production, and overproduction of inflammatory cytokines. This, in turn, results in inflammation of the joints, eventually leading to permanent and disabling cartilage and bone damage. Patients with RA may also experience systemic inflammatory conditions of the lungs and heart.
Prior to autoantibody positivity, pre-RA is characterized by altered levels of inflammatory cytokines, including interleukin-1 (IL-1), IL-6, and IL-10. IL-6, and fellow cytokine type II interferon (IFN-γ), predominantly activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. This is a crucial moderator of downstream signaling for numerous inflammatory cytokines, and has crosstalk with other immune-related pathways, such as the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. While IL-1 and IL-6 increase the inflammatory response, IL-10 is inhibitory. Nevertheless, this chronic inflammatory response leads to compromised T cell and B cell tolerance, and autoimmunity manifests.
One of the early and central cytokines involved in RA pathogenesis is tumor necrosis factor alpha (TNF-α). TNF-α is a pleiotropic cytokine produced by numerous cell types, and critical to the immune cascade. It also activates JAK/STAT signaling, in addition to mainly driving stress-activated protein kinase/mitogen-activated protein kinase (SAPK/MAPK) pathway signaling, and is one of the main instigators of both inflammation and joint damage in RA. Dendritic cells release a host of cytokines, including TNF-α, which initiate the differentiation of T cells and B cells. B cells transition into plasma cells and plasmablasts, which produce anti-citrullinated protein antibodies (ACPA), rheumatoid factors (RF), and an immune complement, furthering the autoimmune response.
Triggered by inflammatory cytokines such as transforming growth factor beta (TGF-β), IFN-γ, IL-2, IL-12, and IL-21, T cells differentiate into Th1 and Th17 cells, and produce and release a host of inflammatory molecules. T regulatory cells (Treg) and Th2 cells can produce anti-inflammatory cytokines such as IL-2, IL-4, and IL-10, however in RA this anti-inflammatory response is insufficient. Th1 and Th17 cells release additional inflammatory molecules, and signal through RANKL and CD40L to trigger immune responses in macrophages and synovial fibroblasts. RANKL is a ligand associated with the NF-κB signaling pathway, which is recognized as one of the primary inflammation pathways in RA. Macrophages amplify the inflammatory response, secreting a swarm of inflammatory molecules, to which T cells, osteoclasts, and chondrocytes respond, perpetuating the inflammatory setting.
At this point, the synovium has become a highly immune responsive environment, and additional cell types such as mast cells and neutrophils are activated. Neutrophils produce cytokines, proteases, reactive oxygen species (ROS), reactive nitrogen species (RNS), and neutrophil extracellular traps (NETs), ultimately contributing to destruction of cartilage and bone. Simultaneously, synovial fibroblasts, in response to inflammatory input from multiple sources, initiate production of several metalloproteinases, cyclooxygenase-2 (COX2), prostaglandin E2 (PGE2), and cadherin-11, which promote inflammation and tissue damage. Cadherin-11 drives remodeling of the actin cytoskeleton in synovial fibroblasts, resulting in enhanced invasion of, and damage to, the cartilage. Chondrocytes also produce metalloproteinases, leading to the production of ROS and RNS that damage the cartilage and bone. These inflammatory cycles persist, resulting in destruction of bone and cartilage from multiple angles, and making RA a disease with no single solution.
RA pathogenesis involves a complex network of interactions, and it is therefore unsurprising that RA therapies have correspondingly numerous varied targets, with investigations for novel treatment mechanisms and avenues ongoing. Traditional treatment of RA begins with medications that aim to reduce damage to bone and cartilage, broadly known as disease-modifying antirheumatic drugs (DMARDs). Amongst the most critical DMARDs are TNF inhibitors (TNFi). In particular, TNF-α inhibitors have become a cornerstone of treating RA, as the large majority of joint damage from RA occurs within the first two years, and TNF-α is a key driver of both inflammation and the consequent damage. Unsurprisingly, other therapies take aim specifically at the inflammatory response associated with RA. Another line of DMARDs, JAK inhibitors, result in a reduction of the inflammatory cascade, interfering in downstream signaling for many pro-inflammatory cytokines, such as IL-6. IL-6 is a crucial cytokine in RA pathogenesis, and inhibitors of IL-6 and its receptor are important for reducing the inflammatory cascade. Similarly, RANKL inhibitors interfere with NF-κB signaling, also reducing and blocking the inflammatory cascade. Also highly effective are CD20 antibodies, which deplete the levels of circulating B cells and inhibit T cell activation, reducing cytokine production.
However, RA treatment typically involves a combination of therapeutics to manage the disease on multiple fronts. Co-stimulatory factors help the immune system parse the stimuli it encounters, and triage immune response accordingly. In RA, these various co-stimulatory receptors and factors contribute to the large-scale inflammatory response. More recently developed therapeutics target co-stimulatory factors such as those that regulate the CD28 and TNF pathways. These interventions have become very effective tools in the RA treatment arsenal, reducing T cell activation, proliferation, and cytokine production. Research focused on identifying and understanding these molecules is ongoing, and critical to better treating RA. Overall, a broader understanding of the various genetic and environmental factors that induce and affect the pathogenesis of RA is necessary to improve current therapeutics and identify novel avenues of treatment for this complicated disease.
We would like to thank Salah-uddin Ahmed, Ph.D., Washington State University College of Pharmacy & Pharmaceutical Sciences for reviewing this diagram.
Created August 2022.