Development and Clinical Application of COX-2-Selective Inhibitors for the Treatment of Osteoarthritis and Rheumatoid Arthritis

Insight into the structure, biochemistry, and molecular pharmacology of the COX isoenzymes has provided the opportunity to design new NSAIDs, coxibs, that selectively inhibit COX-2 (4) . Two of these drugs, rofecoxib and celecoxib, have been shown to have no clinically relevant inhibition of COX-1 activity.(5) These agents have efficacy similar to that of nonselective NSAIDs but with a low potential for mucosal injury and GI complications.(6,7) In addition, one new COX-2, valdecoxib, has recently received FDA approval for OA, RA, and menstrual pain; several COX-2 inhibitors are in clinical development. The development and clinical application of COX- 2-specific inhibitors are reviewed here.

Arthropathies and Inflammation

Osteoarthritis

Osteoarthritis is the most common of articular disorders. Though the etiology of OA remains unknown, it is increasingly appreciated that inflammation is a component of this disease.(8) Fundamentally, OA is a process of cartilage degradation accompanied by incomplete repair. This cascade of events is usually initiated by biomechanical insult or intrinsic factors such as genetic, metabolic, endocrine, or neuropathic disorders.(9)

Prostaglandins are central to the pathophysiology of arthritides. In healthy joint cartilage, prostaglandins likely contribute to homeostasis.(10) In the arthritic joint, the overproduction of prostaglandins may lead to inflammatory and degradative processes.(10) As OA progresses, chronic inflammation ensues, characterized by the disproportionate activities of growth factors and cytokines.(9) Synovial fibroblasts, macrophages, and chondrocytes become activated, and multiple proinflammatory mediators are released into the synovial fluid. With further disease progression, chondrocytes fail and proteolytic enzymes overwhelm matrix defenses. Cartilage degradation occurs as proteoglycans are lost, and cartilage becomes less elastic. Cartilage fibrillation and subchondral sclerosis is seen; osteophytes and subchondral bony cysts develop.(11)

A major role of prostaglandin E2 (PGE2) in the pathogenesis of OA is supported by in vitro data, which show that chondrocytes isolated from patients with OA produce 50-fold more PGE2 than chondrocytes from patients without OA.(12) PGE2 appears to have an autocrine effect on chondrocytes, increasing proteoglycan production. High concentrations of prostaglandins can inhibit collagen synthesis, and the inhibitory effects of interleukin 1 (IL-1) on collagen transcription may be mediated in part by prostaglandins.(13) Prostaglandins also have significant effects on osteoclasts and osteoblasts, participating in the regulation of bone generation and resorption. Degradation of the joint may also result from prostaglandin-stimulated release of matrix metalloproteinases (MMPs).(14)

Rheumatoid arthritis

Initiation of RA begins with an immune event in the form of antigen presentation to T cells, leading to activation, with TH1 responses predominating.(15) The activation of macrophages by TH1 cytokines and their release of proinflammatory cytokines, including tumor necrosis factor- (TNF ) and IL-1, lead to further activation of cells in the synovium including synovial fibroblasts and endothelial cells. Cytokines released by the accumulated cells regulate growth, differentiation, and activation of other cells in the environment, including chondrocytes and osteoclasts. The result is mediator generation- MMPs including collagenase, prostaglandins, and nitric oxide-with eventual destruction of bone and cartilage.(16)

Prostaglandins are involved in a number of biologic activities relevant to the pathogenesis of RA. Prostaglandins are found in elevated levels in rheumatoid synovial fluid, and the bone-resorbing activity produced by rheumatoid synovial tissues was shown to be mediated in part by PGE2.(17) Fibroblasts from patients with either OA or RA release greater amounts of PGE2 compared with normal fibroblasts.(18) Increased proliferative responses to PGE2 may occur similarly for both OA and RA, mediated by the proinflammatory cytokine, IL- 1.(18)

It is likely that many of the PGE2 effects on bone and cartilage potentially involved in OA are also important in RA.(13,19) In addition, prostaglandins probably contribute to such symptoms as swelling, redness, fever, and pain. By interacting with bradykinin and IL-1 , PGE1 and PGE2 may enhance vasopermeability and are thought to be hyperalgesic.(12)

Bingham CO III. Development and clinical application of COX-2-selective inhibitors for the treatment of osteoarthritis and rheumatoid arthritis. Cleve Clin J Med 2002;69:SI5-12.