The article by McInnes and Schett (2017) provides an in-depth review of the pathogenetic insights gained from the treatment of rheumatoid arthritis (RA) with biologic and small molecule kinase inhibitors. RA is a chronic autoimmune disease characterized by progressive articular damage, functional loss, and comorbidities. The advent of effective therapeutics has significantly improved clinical outcomes, and these treatments have also provided valuable insights into the immune pathways driving RA. Cytokine inhibitors, particularly TNF and IL-6, have been shown to play crucial roles in disease pathogenesis, with TNF acting as a hierarchical central effector. More recently, Janus kinase inhibitors have demonstrated that cytokine receptor families, including JAK/STAT signaling, are critical for disease, adding new knowledge about the roles of other cytokines like interferons. Co-stimulatory blockade and B cell depletion have also revealed the importance of adaptive immune responses and downstream pathways initiated by these cells in synovial inflammation. Understanding the actions of specific immune interventions has elucidated molecular and cellular nodes essential for maintaining complex inflammatory networks that underlie RA. The authors discuss the genetic and environmental factors contributing to RA pathogenesis, the role of T cells and B cells, and the mechanisms of structural damage and comorbidities associated with the disease. They also explore potential future approaches for preventing disease onset and inducing tolerance, such as targeting T/B-cell responses, reducing antigen expression, and inducing antigen-specific tolerance. The article concludes by emphasizing the importance of building on these insights to achieve immunologic homeostasis and drug-free remission in RA.The article by McInnes and Schett (2017) provides an in-depth review of the pathogenetic insights gained from the treatment of rheumatoid arthritis (RA) with biologic and small molecule kinase inhibitors. RA is a chronic autoimmune disease characterized by progressive articular damage, functional loss, and comorbidities. The advent of effective therapeutics has significantly improved clinical outcomes, and these treatments have also provided valuable insights into the immune pathways driving RA. Cytokine inhibitors, particularly TNF and IL-6, have been shown to play crucial roles in disease pathogenesis, with TNF acting as a hierarchical central effector. More recently, Janus kinase inhibitors have demonstrated that cytokine receptor families, including JAK/STAT signaling, are critical for disease, adding new knowledge about the roles of other cytokines like interferons. Co-stimulatory blockade and B cell depletion have also revealed the importance of adaptive immune responses and downstream pathways initiated by these cells in synovial inflammation. Understanding the actions of specific immune interventions has elucidated molecular and cellular nodes essential for maintaining complex inflammatory networks that underlie RA. The authors discuss the genetic and environmental factors contributing to RA pathogenesis, the role of T cells and B cells, and the mechanisms of structural damage and comorbidities associated with the disease. They also explore potential future approaches for preventing disease onset and inducing tolerance, such as targeting T/B-cell responses, reducing antigen expression, and inducing antigen-specific tolerance. The article concludes by emphasizing the importance of building on these insights to achieve immunologic homeostasis and drug-free remission in RA.