Faculty Bibliography

The production of nitric oxide (NO) by chondrocytes is increased in human osteoarthritis. The excessive production of NO inhibits matrix synthesis and promotes its degradation. Furthermore, by reacting with oxidants such as superoxide anion, NO promotes cellular injury and renders the chondrocyte susceptible to cytokine-induced apoptosis. Thus, NO produced by activated chondrocytes in diseased cartilage may modulate disease progression in osteoarthritis and should therefore be considered a potential target for therapeutic intervention.

Colchicine is the only drug known to effectively prevent familial Mediterranean fever (FMF) attacks, as well as FMF-associated amyloidosis. Unfortunately, colchicine is neither always effective nor always well tolerated, leaving some patients and their physicians with inadequate weaponry to fight this hazardous disease. We present a patient with recurrent episodes of abdominal, scrotal, and joint attacks, who was diagnosed with FMF and advised to take colchicine. Diarrhea prevented optimal treatment with this drug and led to a trial of etanercept, with resolution of FMF manifestations. This case adds to a growing body of evidence suggesting that tumor necrosis factor (TNF) blockade may result in resolution and prevention of further FMF attacks

Traditional NSAIDs and some cyclooxygenase (COX)-2 inhibitors used to treat persons with osteoarthritis (OA) have adverse effects. However, traditional NSAIDs remain first-line therapy for some patients. The toxicities (eg, renal and GI effects) mostly are the result of COX inhibition. The ideal NSAID would inhibit COX-2 while sparing COX-1. The mechanisms for increased COX-2 cardiovascular toxicity remain less than fully understood. Several conservative strategies may help physicians use these agents effectively and safely. OA therapies under investigation (eg, inhibition of prostaglandin E synthases and disease-modifying osteoarthritis drugs) may render NSAIDs and COX-2 inhibitors obsolete

Both selective cyclooxygenase (COX)-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) have been beneficial pharmacological agents for many patients suffering from arthritis pain and inflammation. However, selective COX-2 inhibitors and traditional NSAIDs are both associated with heightened risk of myocardial infarction. Possible pro-atherogenic mechanisms of these inhibitors have been suggested, including an imbalance in prostanoid production leaving the pro-aggregatory prostaglandins unopposed, but the precise mechanisms involved have not been elucidated. We explored the possibility that downregulation of proteins involved in reverse cholesterol transport away from atheromatous plaques contributes to increased atherogenesis associated with COX inhibition. The reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP-binding cassette transporter A1 (ABCA1) export cholesterol from macrophages. When mechanisms to process lipid load are inadequate, uncontrolled cholesterol deposition in macrophages transforms them into foam cells, a key element of atheromatous plaques. We showed that in cultured THP-1 human monocytes/macrophages, inhibition of COX-1, COX-2, or both reduced expression of 27-hydroxylase and ABCA1 message (real-time reverse transcription-polymerase chain reaction) and protein (immunoblot). The selective COX-2 inhibitor N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide (NS398) significantly reduced 27-hydroxylase and ABCA1 message (to 62.4% +/- 2.2% and 71.1% +/- 3.9% of control, respectively). Incubation with prostaglandin (PG) E2 or PGD2 reversed reductions in both of these cholesterol transport proteins induced by NS398. Cholesterol-loaded THP-1 macrophages showed significantly increased foam cell transformation in the presence of NS398 versus control (42.7% +/- 6.6% versus 20.1% +/- 3.4%, p = 0.04) as determined by oil red O staining. Pharmacological inhibition of COX in monocytes is involved in downregulation of two proteins that mediate cholesterol efflux: cholesterol 27-hydroxylase and ABCA1. Because these proteins are anti-atherogenic, their downregulation may contribute to increased incidence of cardiac events in patients treated with COX inhibitors. Reversal of inhibitory effects on 27-hydroxylase and ABCA1 expression by PGD2 and PGE2 suggests involvement of their respective signaling pathways. NS398-treated THP-1 macrophages show greater vulnerability to form foam cells. Increased cardiovascular risk with COX inhibition may be ascribed at least in part to altered cholesterol metabolism

Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed

Over the past decade, significant advances have been made regarding the pathogenesis, clinical implications, and treatment of hyperuricemia. While physicians have understood for at least a century that uric acid causes gout, we are now beginning to address the question of why hyperuricemia exists and the mechanisms by which uric acid acts to stimulate inflammation. This review focuses on (1) previously unknown biological roles of uric acid; (2) why the loss of the uricase gene and resultant hyperuricemia may have provided an evolutionary advantage to primates and, in particular, to humans; (3) the molecular effects of uric acid on inflammatory cells; and (4) novel antihyperuricemic agents currently under study