Rheumatoid Arthritis: Schnitzer TJ

Schnitzer TJ, Hochberg MC. · Office of Clinical Research and Training, Northwestern University School of Medicine, Chicago, IL 60611, USA. · Cleve Clin J Med. · Pubmed #12086290 links to  free full text

Abstract: Therapy with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has long been the cornerstone of pharmacologic management of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Many patients with OA or RA, however, are at increased risk of developing clinically significant adverse events associated with NSAID therapy, particularly upper gastrointestinal (GI) complications including symptomatic and complicated ulcers. The introduction of cyclooxygenase (COX)-2-selective inhibitors (coxibs) represents a major advance in the pharmacologic approach to the signs and symptoms of arthritis. In addition to the first two members of this class, celecoxib and rofecoxib, other coxibs have been introduced or are in development (valdecoxib, etoricoxib). In numerous clinical trials, coxibs have been shown to be as effective as nonselective NSAIDs in relieving pain and inflammation associated with OA and RA, and notably, with a significantly lower risk of NSAID-type adverse events. The use of coxibs to treat OA and RA is recommended as first-line therapy when symptoms of pain and inflammation are present in patients vulnerable to potential NSAID-associated GI toxicity.

Laine L, Connors LG, Reicin A, Hawkey CJ, Burgos-Vargas R, Schnitzer TJ, Yu Q, Bombardier C. · University of Southern California School of Medicine, Los Angeles 90033, USA. · Gastroenterology. · Pubmed #12557133 No free full text.

Abstract: BACKGROUND & AIMS: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2-selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2-selective agent in a prospective, double-blind, randomized GI outcomes trial. METHODS: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. RESULTS: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22-0.93; P = 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. CONCLUSIONS: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.

Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, Anonymous00004. · Institute for Work and Health, Mount Sinai Hospital, and the University Health Network, Toronto, ON, Canada. · N Engl J Med. · Pubmed #11087881 links to  free full text

Abstract: BACKGROUND: Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS: We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS: Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

Yocum DE, Allard S, Cohen SB, Emery P, Flipo RM, Goobar J, Jayawardena S, Job-Deslandre C, Jubb RW, Krüger K, Lopes Vaz A, Manger B, Mur E, Nygaard H, Weiner SM, Rainer F, Sack MR, Schiff MH, Schnitzer TJ, Trigg LB, Whatmough I, Schmidt AG. · Arizona Arthritis Center, University of Arizona, Tucson, Arizona, USA. · Rheumatology (Oxford). · Pubmed #10725065 links to  free full text

Abstract: OBJECTIVE: To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral) and the original CyA formulation (Sandimmun), in patients with severe active rheumatoid arthritis (RA), over a 12-month period. METHODS: In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients' assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals. RESULTS: Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients' assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups. CONCLUSION: These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.

Schnitzer TJ, Truitt K, Fleischmann R, Dalgin P, Block J, Zeng Q, Bolognese J, Seidenberg B, Ehrich EW. · Office of Clinical Research and Training, Northwestern University School of Medicine, Chicago, Illinois, USA. · Clin Ther. · Pubmed #10566565 No free full text.

Abstract: Nonsteroidal anti-inflammatory drugs. (NSAIDs) inhibit both cyclooxygenase (COX)-1 and COX-2 isoenzymes and are effective in the treatment of inflammatory disorders. This 8-week, double-masked, placebo-controlled trial was undertaken to assess the safety profile, tolerability, and effective dose range of once-daily rofecoxib, a COX-2-specific inhibitor, in the treatment of rheumatoid arthritis (RA). After a 3- to 15-day washout of prior NSAID therapy, 658 patients were randomly allocated to receive placebo or rofecoxib 5 mg, 25 mg, or 50 mg once daily. Safety profile, tolerability, and efficacy were evaluated after 2, 4, and 8 weeks of therapy. Six hundred fifty-eight patients (168, 158, 171, and 161 in the placebo and 5-mg, 25-mg, and 50-mg rofecoxib groups, respectively) were enrolled at 79 clinical centers in the United States. Mean age was 55 years, mean duration of RA was 10 years, and 506 (77%) of the 658 patients were female. All groups had similar baseline demographic characteristics. Patients taking rofecoxib 25 and 50 mg showed significant clinical improvement compared with those taking placebo; 43.9% in the rofecoxib 25-mg group and 49.7% in the rofecoxib 50-mg group completed the treatment period and achieved an American College of Rheumatology 20 response (P = 0.025 and 0.001 vs. placebo, respectively). The 5-mg dose of rofecoxib did not differ significantly from placebo. Patients in the rofecoxib 25- and 50-mg groups showed significant improvement in key individual efficacy measurements, including patient global assessment of pain, patient and investigator global assessment of disease activity, and Stanford Health Assessment Questionnaire Disability Index (P<0.05 vs placebo). Compared with placebo, significantly fewer patients in the 25-mg and 50-mg rofecoxib groups discontinued therapy because of lack of efficacy (P = 0.02 and P = 0.032, respectively). Our results show that rofecoxib 25 and 50 mg once daily was effective and generally well-tolerated in patients with RA.

Schnitzer TJ, Gitton X, Jayawardene S, Sloan VS. · Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Curr Med Res Opin. · Pubmed #15881487 No free full text.

Abstract: OBJECTIVES: Overview of three dose-response studies demonstrating the efficacy of lumiracoxib, a novel COX-2 selective inhibitor, for chronic pain associated with osteoarthritis (0A), or rheumatoid arthritis (RA) and acute pain following dental extraction. METHODS: OA and RA: 4-week, randomized, placebo- and active-controlled studies of similar design. Patients (OA, n = 583; RA, n = 571) received lumiracoxib 50 mg, 100 mg or 200 mg twice daily (bid), lumiracoxib 400 mg once daily (od), diclofenac 75 mg bid or placebo. Dental: 12-h, single-center, randomized, placebo- and active-controlled study. Patients (n = 202) received single oral doses of lumiracoxib 100 mg or 400 mg, ibuprofen 400 mg or placebo. Main outcome measures: OA: pain intensity (PI) in the target joint (visual analogue scale [VAS]) and WOMAC score at Week 4; RA: overall PI (VAS) and ACR20 response at Week 4; Dental: difference (PID, categorical and VAS) score over 12h post dose, time to onset of analgesia. RESULTS: Throughout the OA study, all lumiracoxib doses provided superior reductions in PI versus placebo and at Week 4, all lumiracoxib doses provided efficacy similar to each other and to diclofenac. In the RA study, lumiracoxib 100 mg bid, 200 mg bid and 400mg od were significantly better than placebo in PI at Weeks 1 and 2 (all p < 0.05) but demonstrated borderline significance at Week 4 (lumiracoxib 400 mg od, p = 0.06). In pain following dental surgery, PID scores for both lumiracoxib doses were superior to placebo from 1.5 h onwards and always comparable, or superior, to ibuprofen. Lumiracoxib 400 mg had the fastest onset of analgesia, measured as median time to confirmed first perceptible pain relief using the two-stopwatch method (37.4 min, superiority versus placebo, p < 0.001). Lumiracoxib was well tolerated in all studies. CONCLUSIONS: These studies provide initial evidence that lumiracoxib is an effective, well-tolerated agent for the treatment of chronic and acute pain.

Schnitzer TJ, Kong SX, Mitchell JH, Mavros P, Watson DJ, Pellissier JM, Straus WL. · Northwestern Center for Clinical Research, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA. · Clin Ther. · Pubmed #14749154 No free full text.

Abstract: OBJECTIVE: This study assessed prescribing patterns for rofecoxib and celecoxib in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA), as well as differences in prescribing patterns across physician specialties. METHODS: This was an observational, retrospective, cohort study of a large, US pharmacy claims database. Eligible patients were initiating therapy with rofecoxib or celecoxib and had succeeds, equals 90 days' supply of medication, as well as > or =1 medical claim specific to OA or RA between June 1, 2000, and May 31, 2001. Analyses were stratified according to diagnosis, prescribing physician specialty, and patient demographics. The main outcome measure was mean daily usage (ie, mean daily dose [milligrams]; mean number of pills per day; and mean daily consumption [denoted as DACON], calculated as daily dose divided by most frequently prescribed strength). This was primarily a descriptive study. Tests of statistical significance were not performed because the large sample size would have rendered small differences significant. RESULTS: A total of 58,574 patients with OA (81.8% [n=47,935]) or RA (18.2% [n=10,639]) received 220,627 prescriptions for rofecoxib or celecoxib (47.7% [n=27, 924] and 52.3% [n=30, 650] of patients, respectively) during the study period. Overall, the most frequently prescribed strengths were rofecoxib 25 mg and celecoxib 200 mg. In both OA and RA, the most frequently prescribed mean daily dose of rofecoxib was 25 mg. In OA, the most frequently prescribed mean daily dose of celecoxib was 200 mg; in RA, it was 400 mg. Both pills per day and DACON were higher for celecoxib than rofecoxib. The DACON for rofecoxib was unrelated to physician specialty. Rheumatologists prescribed celecoxib at 20% to 40% higher mean daily doses than did primary care physicians, orthopedic specialists, or other specialists. Regardless of physician specialty, the DACON appeared higher for patients with RA than OA, for men than women, and for younger (aged <65 years) than older patients. CONCLUSIONS: In this analysis, relative to the most frequently prescribed strength, celecoxib-treated patients with OA and RA had higher DACONs than rofecoxib-treated OA and RA patients across all subgroups. These observations may have economic implications in terms of direct effects on cost and the need for formularies to consider overall use patterns in addition to pill costs. However, these conclusions are limited by lack of clinical information (other than an OA or RA diagnosis), inability to ascertain actual use, and potential for selection bias.

Bombardier C, Laine L, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, Weaver A. · No affiliation provided · N Engl J Med. · Pubmed #16495387 No free full text.

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