How antirheumatic drugs protect joints from damage in rheumatoid arthritis

Therapy in rheumatoid arthritis (RA) aims forthe containment of chronic inflammation as well asstructural protection of the affected joints. Both reduc-tion of inflammation and protection of joints fromdamage are considered central therapeutic goals in RA.Virtually all therapeutic agents used and developed forthe treatment of RA have been assessed for theirpotential to reach these 2 goals and, ideally, combine anantiinflammatory effect with a structure-sparing effect.Since the molecular mechanisms of synovitis, which areresponsible for the “inflammatory” signs of disease suchas swelling, pain, and stiffness, differ from the mecha-nisms leading to structural damage, antirheumatic drugsideally have to affect both mechanisms of disease.Inflammatory signs of RA are based on a chronicinflammatory process in the synovial membrane, whichis the result of an enhanced influx of immune cells aswell as synovial hyperplasia (1,2). Physiologically, only afew cells migrate into the normal synovium through thesynovial microvessels, and few cells escape this compart-ment to move toward regional lymph nodes through thelymphoendothelial microvessels. The enhanced influx ofimmune cells in inflammatory arthritis is regulated bychemokine and adhesion molecule expression in thesynovial tissue, which is induced by inflammatory cyto-kines such as tumor necrosis factor (TNF ) andinterleukin-1 (IL-1). Thus, joints are literally flooded byimmune cells, which accumulate in the synovial spaceand overflow the efflux mechanism through the lym-phatic vessels (3). This influx of immune cells, includingmacrophages, lymphocytes, dendritic cells, neutrophils,and mast cells, is accompanied by a response of theresident synovial fibroblasts (synovial hyperplasia),which express genes rendering them resistant to apopto-tic cell death as well as angiogenesis. Importantly, how-ever, this chronic inflammatory process in the synovialmembrane leads to profound damage of the surroundingtissue, particularly cartilage and bone. These destructivemechanisms are a consequence of an imbalance betweencatabolic and anabolic pathways induced by cytokinesand mediated by matrix-degrading enzymes (aggre-canases and matrix metalloproteinases MMPs) pro-duced by effector cells, including osteoclasts, fibroblasts,leukocytes, and chondrocytes.It is evident that inflammation is the driving forcein RA and gives rise to structural damage during thecourse of disease. The greater the inflammatory load towhich joints are exposed, the more likely it is forstructural damage to occur and the faster such damagewill progress. Risk predictors of structural damage inRA are thus the parameters that quantify inflammatoryload, such as the number of swollen joints or the level ofC-reactive protein (CRP) (4–6). Another key link be-tween inflammation and structural damage is time. Thelonger inflammation lasts, the more likely structuraldamage is to occur. Disease duration and parametersthat predict chronicity of arthritis, such as the presenceof anti–cyclic citrullinated peptide antibodies and/orrheumatoid factor, are associated with structural dam-age in RA (3–6). It is thus the chronicity of inflamma-tion that gives rise to structural damage of joints, andthisiswellreflected,forexample,bytheobservationthata transitory decrease in the acute component ofinflammation upon treatment with nonsteroidal anti-inflammatory drugs is not sufficient to achieve jointprotection. Accumulation of joint damage during thecourse of RA requires the presence of synovitis, which