musculoskeletal and connective tissue disorders
Rheumatoid Arthritis (RA)
Pathophysiology of Rheumatoid Arthritis
 T cells. Macrophages and lymphocytes produce pro-inflammatory cytokines and chemokines (eg, tumor necrosis factor [TNF]-alpha, granulocyte-macrophage colony-stimulating factor [GM-CSF], various interleukins, interferon-gamma) in the synovium. Released inflammatory mediators and various enzymes contribute to the systemic and joint manifestations of rheumatoid arthritis, including cartilage and bone destruction ( Pathophysiology references ). In seropositive rheumatoid arthritis, accumulating evidence suggests that anti-CCP antibodies appear long before any signs of inflammation ( Pathophysiology references ). Additionally, anti-carbamylated protein (anti-CarP) antibodies ( In chronically affected joints, the normally thin synovium proliferates, thickens, and develops many villous folds. The synovial lining cells produce various materials, includingcollagenaseand stromelysin, which contribute to cartilage destruction, and interleukin-1 (IL-1) and TNF-alpha, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins (which potentiate inflammation). Fibrin deposition, fibrosis, and necrosis are also present. Hyperplastic synovial tissue (pannus) releases these inflammatory mediators, which erode cartilage, subchondral bone, articular capsule, and ligaments. Polymorphonuclear leukocytes on average make up about 60% of white blood cells in the synovial fluid. Rheumatoid nodules develop in about 30% of patients with rheumatoid arthritis. They are granulomas consisting of a central necrotic area surrounded by palisaded histiocytic macrophages, all enveloped by lymphocytes, plasma cells, and fibroblasts. Nodules can also develop in visceral organs. 1.McInnes IB, Schett G: The pathogenesis of rheumatoid arthritis.N Engl J Med365(23):2205–2219, 2011. doi:10.1056/NEJMra1004965 2.Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al: Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis.Arthritis Rheum48:2741–2749, 2003. doi: 10.1002/art.11223 3.Brink M, Verheul MK, Rönnelid J, et al: Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage.Arthritis Res Ther17:25, 2015. doi: 10.1186/s13075-015-0536-2 4.Sokolove J, Bromberg R, Deane KD, et al: Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis.PLoS ONE7(5):e35296, 2012. doi: 10.1371/journal.pone.0035296 