Rheumatoid Arthritis: Lefkowith JB

Lefkowith JB. · Research and Development, G.D. Searle and Company, Research and Development, Chicago, Illinois 60077, USA. · Am J Med. · Pubmed #10390127 No free full text.

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by inhibiting the synthesis of prostanoids. However, these drugs inhibit both cyclooxygenase-1 (COX-1), which is essential for the regulation of homeostasis in many tissues, as well as COX-2, which is an important mediator of pain and inflammation. Disruption of COX-1 enzymatic activity by NSAIDs leads to such side effects as interference with platelet functions and gastric ulcers. The recent development of COX-2-specific inhibitors, such as celecoxib, raises the possibility of relieving pain and inflammation with reduced risk of gastrointestinal complications. In Phase II and III studies, celecoxib has demonstrated efficacy in alleviating dental pain and the signs and symptoms of osteoarthritis and rheumatoid arthritis. This COX-2-specific inhibitor was also associated with a markedly lower rate of gastroduodenal injury than is seen typically with NSAIDs. Incidence of most adverse events (including gastrointestinal) and withdrawal rates resulting from adverse events with celecoxib were similar to placebo. Celecoxib appears to be both safe and effective in the treatment of osteoarthritis and rheumatoid arthritis. Its COX-2-specific inhibitory properties thus introduce the possibility of effective relief of arthritic and other types of pain and inflammation with less risk of the mechanism-based toxicities observed with conventional NSAIDs.

Tindall EA, Sharp JT, Burr A, Katz TK, Wallemark CB, Verburg K, Lefkowith JB. · Department of Medicine, Oregon Health and Science University, Portland, Oregon 97224, USA. · Clin Ther. · Pubmed #12581544 No free full text.

Abstract: BACKGROUND: Studies have suggested that nonspecific nonsteroidal anti-inflammatory drugs may inhibit matrix biosynthesis by articular cartilage, thereby accelerating the progression of osteoarthritis (OA). OBJECTIVE: The objective of this analysis was to determine whether 1-year treatment with the cyclooxygenase-2-specific inhibitor celecoxib at up to twice the recommended and maximally effective dose for OA had any deleterious effects on OA progression by assessing radiographic changes in knee or hip joint morphology in patients with OA. METHODS: In a 12-month, multicenter, prospective, open-label trial, patients with OA of the knee or hip or rheumatoid arthritis received celecoxib at doses ranging from that recommended for the treatment of OA (200 mg/d) to twice the recommended daily dosage (400 mg/d). Available radiographs showing baseline and end-of-treatment status were analyzed using semiquantitative measures of index joint morphology in patients with mild to moderate OA. The morphologic scores were then subjected to mean change and shift-table analysis to determine the extent and rate of disease progression. RESULTS: A total of 2,327 patients (796 with OA of the knee, 1,531 with OA of the hip) were included. A subset of 344 patients (160 with OA of the knee, 184 with OA of the hip) had radiographs from both before and after 12 months' celecoxib treatment. One hundred forty-seven and 158 pairs of knee and hip radiographs, respectively, were available for analysis. These revealed that, with the exception of significant hip joint-space narrowing (P = 0.029), no evidence of disease progression with long-term celecoxib treatment could be detected. The observed increase in hip joint-space narrowing was small (0.14 units/y) (95% CI, 0.08-0.20), was observed prior to celecoxib exposure (by mean change or shift-table analysis), and was not dose related. CONCLUSION: These results are consistent with the hypothesis that long-term therapy with celecoxib does not accelerate progression of OA of the knee or hip.

Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS. · Pharmacia Clinical Research and Development, 4901 Searle Pkwy, Bldg A3E, Skokie, IL 60077, USA. · JAMA. · Pubmed #10979111 links to  free full text

Abstract: CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (</=325 mg/d) was permitted. MAIN OUTCOME MEASURES: Incidence of prospectively defined symptomatic upper GI ulcers and ulcer complications (bleeding, perforation, and obstruction) and other adverse effects during the 6-month treatment period. RESULTS: For all patients, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76% vs 1.45% (P =.09) and 2. 08% vs 3.54% (P =.02), respectively. For patients not taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P =.04) and 1.40% vs 2.91% (P =.02). For patients taking aspirin, the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01% vs 2.12% (P =.92) and 4.70% vs 6.00% (P =.49). Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal toxicity. No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs, irrespective of aspirin use. CONCLUSIONS: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly. JAMA. 2000;284:1247-1255