0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Anti-inflammatory and Upper Gastrointestinal Effects of Celecoxib in Rheumatoid Arthritis:  A Randomized Controlled Trial FREE

Lee S. Simon, MD; Arthur L. Weaver, MD; David Y. Graham, MD; Alan J. Kivitz, MD; Peter E. Lipsky, MD; Richard C. Hubbard, MD; Peter C. Isakson, PhD; Kenneth M. Verburg, PhD; Shawn S. Yu, PhD; William W. Zhao, PhD; G. Steven Geis, PhD, MD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Division of Rheumatology and Metabolic Bone Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (Dr Simon); the Arthritis Center of Nebraska, Lincoln (Dr Weaver); Department of Medicine, Veterans Affairs Medical Center/Baylor College of Medicine, Houston, Tex (Dr Graham); Altoona Center for Clinical Research, Altoona, Pa (Dr Kivitz); Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas (Dr Lipsky); and Departments of Clinical Research (Drs Hubbard, Verburg, Yu, Zhao, and Geis) and COX-2 Technology (Dr Isakson), Searle Research and Development, Skokie, Ill.


JAMA. 1999;282(20):1921-1928. doi:10.1001/jama.282.20.1921.
Text Size: A A A
Published online

Context In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 (COX-2) but not COX-1, suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal (GI) tract effects that result from COX-1 inhibition.

Objective To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis.

Design Randomized, multicenter, placebo-controlled, double-blind trial lasting 12 weeks, with follow-up at weeks 2, 6, and 12, from September 1996 thorugh February 1998.

Setting Seventy-nine clinical sites in the United States and Canada.

Patients A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were randomized; 688 (60%) of these completed the study.

Interventions Patients were randomized to receive celecoxib, 100 mg, 200 mg, or 400 mg twice per day (n = 240, 235, and 218, respectively); naproxen, 500 mg twice per day (n = 225); or placebo (n = 231).

Main Outcome Measures Improvement in signs and symptoms of rheumatoid arthritis as assessed using standard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment, compared among treatment groups.

Results All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo. Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks. The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 (4%) of 99, and the incidences across all dosages of celecoxib were not significantly different (P>.40): 9 (6%) of 148 with 100 mg twice per day, 6 (4%) of 145 with 200 mg twice per day, and 8 (6%) of 130 with 400 mg twice per day. In contrast, the incidence with naproxen was 36 (26%) of 137, significantly greater than either placebo or celecoxib (P<.001). The overall incidences of GI tract adverse effects were 19% for placebo; 28%, 25%, and 26% for celecoxib 100 mg, 200 mg, and 400 mg twice per day, respectively; and 31% for naproxen.

Conclusion In this study, all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidenced by less frequent incidence of endoscopic ulcers compared with naproxen.

Figures in this Article

Prostanoic acids are synthesized in response to physiologic stimuli that modulate and maintain homeostasis. Prostanoic acids are also produced during acute and chronic inflammatory processes, and it is generally accepted that they mediate many of the symptoms of inflammation such as edema and pain.1,2 The 2 isoforms of cyclooxygenase (COX), COX-1 and COX-2, catalyze the committed step in the synthesis of prostanoic acids from arachidonic acid.3 Recent pharmacological evidence reinforces the likelihood that these isoenzymes mediate different biological functions.4,5 COX-1 is constitutively expressed in many tissues and produces prostanoic acids that predominantly regulate normal cellular processes.68 In contrast, COX-2 activity is typically undetectable in most tissues; however, COX-2 expression can be rapidly induced by proinflammatory cytokines or by growth factors.811

As a result of the research that characterized the role of COX-2 in prostanoic acid production,4,5,9,1214 a class of anti-inflammatory and analgesic agents that primarily inhibit COX-2 while sparing COX-1 at therapeutic dosages has been developed.1518 The clinical rationale for this effort is that by sparing COX-1 activity, COX-2–specific inhibitors are not expected to interfere with homeostatic prostanoid-dependent processes such as upper gastrointestinal (GI) tract mucosal protection and platelet aggregation. The potential clinical benefit of this strategy is important given that patients who take nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2,15 incur a 3- to 10-fold higher risk of gastroduodenal injury and death than those who do not.1922 Endoscopic studies have shown that the prevalence of gastroduodenal ulcers is 15% to 30% among users of conventional (ie, nonspecific) NSAIDs.2326 Large, randomized trials have suggested that endoscopic ulcers are surrogate markers for NSAID-induced complications such as bleeding, perforation, and obstruction.27,28 Celecoxib has been shown to inhibit COX-2 and spare COX-1 activity in vitro while possessing effective anti-inflammatory and analgesic properties when studied in vivo.8,18,2931 It is recommended for the treatment of osteoarthritis at 100 mg 2 times a day or 200 mg once daily, and for the treatment of rheumatoid arthritis (RA) at 100 to 200 mg twice per day. This randomized, placebo-controlled, double-blind, 12-week trial was conducted to test the hypothesis that celecoxib has efficacy as an anti-inflammatory and analgesic drug through COX-2 inhibition but has little effect on COX-1 activity at efficacious doses as evidenced by reduced GI tract mucosal damage defined by endoscopy. The efficacy and upper GI tract safety of celecoxib in treating RA was assessed and compared with the effects of naproxen and placebo.

Study Population

Men and women outpatients aged 18 years or older were eligible to participate in the study if they fulfilled the American College of Rheumatology (ACR-20) criteria for a diagnosis of RA evident for 3 months or longer32 and were in a functional class of I, II, or III.33 Additional selection criteria were based on disease activity.

Patients were eligible to participate if the dosages of any glucocorticoids, disease-modifying antirheumatic drugs, or methotrexate had been stable and were expected to remain constant throughout the study.

Patients were excluded from the study if they had active GI tract, renal, hepatic, or coagulation disorders; history of malignancy (unless removed surgically with no recurrence within 5 years); esophageal or gastroduodenal ulceration within the previous 30 days; or a history of gastric or duodenal surgery other than an oversew. In addition, patients were excluded if the upper GI tract endoscopy performed at baseline disclosed an esophageal, gastric, or duodenal ulcer or more than 10 erosions in the stomach or duodenum. Patients were not excluded for a history of peptic ulcer disease.

Study Protocol

This prospective, randomized, double-blind trial was conducted at 79 clinical sites in the United States and Canada in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional review board at each clinical site, and all patients were required to provide written informed consent. Quality control measures included site visits, verification of case report forms against source medical records, and site audits by sponsor personnel.

Prior to enrollment, patients completed a physical examination and clinical laboratory testing. A baseline serological antibody test for Helicobacter pylori (FlexSure, Beckman-Coulter, Palo Alto, Calif) was included. Screening or baseline clinical assessments of arthritis included patients' and physicians' global assessment of arthritis, scored on a scale of 1 (very good) to 5 (very poor); the patients' assessment of arthritis pain marked on a visual analog scale (VAS) from 0 mm (no pain) to 100 mm (severe pain); a complete count of tender/painful joints; a complete count of swollen joints (hip joints were not assessed); duration of morning stiffness; the health assessment questionnaire Functional Disability Index; and plasma levels of C-reactive protein.3438

Following a 2- to 7-day washout period of NSAIDs or any analgesic medication, symptomatic RA (flare) was confirmed at a baseline visit according to the following definition: physicians' and patients' global assessments of "fair," "poor," or "very poor" and the first 2 plus either the third or the fourth of the following: (1) the presence of at least 6 tender or painful joints with an increase of 20% or at least 2 joints; (2) a minimum of 3 swollen joints with an increase of 20% or at least 2 joints; (3) a minimum of 45 minutes of morning stiffness and increase of at least 15 minutes; or (4) patients' assessment of pain of at least 40 mm on the VAS and an increase of at least 20% or 10 mm.

An upper GI tract endoscopic evaluation was performed within 7 days prior to the first dose of study medication. The mucosae of the stomach and duodenum were evaluated separately for the presence of petechiae, erosions, and ulcers. An ulcer was defined as any break in the mucosa at least 3 mm in diameter with unequivocal depth.

Treatment

Patients were assigned by a computer-generated randomization schedule to 1 of 5 treatment groups: placebo, celecoxib 100 mg twice per day, celecoxib 200 mg twice per day, celecoxib 400 mg twice per day, or naproxen 500 mg twice per day (Figure 1). Randomization was stratified by center using a block size of 10 treatments. All treatment regimens were fully masked so that all patients took the same number of capsules, and all regimens were identical in appearance and frequency.

Figure 1. Flowchart of Patient Disposition
Graphic Jump Location
Concomitant Medications

Stable doses of aspirin no more than 325 mg/d were allowed, and acetaminophen up to 2 g/d for no longer than 3 consecutive days was also allowed except within 48 hours prior to arthritis assessments, during which no analgesics were allowed. NSAIDs, injectable corticosteroids, and anticoagulants were prohibited. Stable doses of oral glucocorticoids (up to 10 mg of prednisone per day) or disease-modifying antirheumatic drugs (DMARDs) were allowed and antiulcer drugs were prohibited.

Clinical Assessments

Clinical efficacy and safety assessments were performed at weeks 2, 6, and 12. Efficacy assessments were identical to those performed at the screening and baseline visits. Safety was evaluated according to the incidence and type of adverse reactions and clinical laboratory abnormalities. At the final treatment (or early termination) visit, each patient underwent a second upper GI tract endoscopy, and a CLO test for H pylori was performed on a tissue sample taken from the greater curvature of the stomach. In all cases, the endoscopist was blinded to the treatment a patient was receiving.

Patient demographic and baseline characteristics are shown in Table 1.

Table Graphic Jump LocationTable 1. Patient Demographic and Baseline Characteristics*
Statistical Analysis

Homogeneity of the treatment groups at baseline was analyzed using the χ2 (for sex and race), 2-way analysis of variance (for continuous demographic variables and baseline disease activity), and the Cochran-Mantel-Haenszel test (for patients' and physicians' global assessments). Differences among the treatment groups in concurrent medication use were analyzed with the Fisher exact test.

Efficacy analyses were based on the intent-to-treat cohort, defined as all patients who took at least 1 dose of study medication. In all efficacy measures, including the composite ACR-20 analysis, missing values for any assessment time were imputed by carrying forward the last observed value for any patient who discontinued the study for any reason (including treatment failure) before completing 12 weeks. Continuous efficacy variables were compared among treatment groups using analysis of covariance with treatment and center as factors and the corresponding baseline value as a covariate. Hochberg's step-up procedure was used to control for type-1 error associated with multiple-treatment comparisons at each time point within each efficacy variable.39

For categorical efficacy variables (Patient's and Physician's Global Assessments and the ACR-20 responder criteria40), the Cochran-Mantel-Haenszel test, stratified by center, was used to compare results among treatment groups. Incidence of withdrawal due to treatment failure was analyzed with the Fisher exact test.

The gastroduodenal ulcer incidences at week 12 were analyzed with Cochran-Mantel-Haenszel tests stratified by baseline status; 95% confidence intervals (CIs) for the ulcer incidences were also calculated. The overall effects of H pylori status and H pylori status by treatment interaction were examined using both analysis of covariance and Cochran-Mantel-Haenszel test. The effects of concurrent aspirin or corticosteroid use, history of gastroduodenal ulcers, and history of GI tract bleeding were analyzed in a similar manner.

The planned sample size was based on the expectation that 35% of patients receiving active treatment would show improvement compared with 20% of placebo-treated patients. A sample size of 200 patients per treatment group was sufficient to detect this difference with 80% power at an α level of .05 adjusted for 3 celecoxib doses vs placebo by the Bonferroni method. This sample size was also sufficient to detect an anticipated difference in endoscopic gastroduodenal ulcer rate of 3% (celecoxib 400 mg twice per day) vs 11% (naproxen 500 mg twice per day) at the same α level and power.

Patient Characteristics

A total of 1149 patients were enrolled. No significant differences among the treatment groups at entry were detected with respect to baseline characteristics (Table 1). The study was completed by 688 patients (60%). Figure 1 shows reasons for early discontinuation from the study and includes the numbers of patients withdrawing during each interval, indicating the extent of data extrapolation at each assessment time.

Baseline endoscopic scores were not significantly different among treatment groups. More than 50% of the patients had normal gastric and duodenal mucosae, and no patients had an ulcer. The incidence of H pylori positive serology results at baseline was also not statistically significantly different across the treatment groups, ranging from 23% to 34% of patients.

Efficacy Results

Celecoxib produced significant improvement in the signs and symptoms of RA for all efficacy measures. As shown by the reduced number of tender/painful and of swollen joints among those treated (Figure 2), celecoxib produced statistically significant and maximal effects by week 2, which were sustained through 12 weeks. All celecoxib doses generally demonstrated similar efficacy, and all were comparable to naproxen 500 mg twice per day.

Figure 2. Changes in Signs and Symptoms of Rheumatoid Arthritis
Graphic Jump Location
Mean numbers of tender/painful joints (top panel) and swollen joints (bottom panel) at 2, 6, and 12 weeks. Statistically significant effects (P<.05 vs placebo) were observed in all celecoxib-treatment groups at all assessment times, and in the naproxen group at all but 1 assessment time. Asterisk indicates P<.05 for all doses of celecoxib and naproxen vs placebo. Dagger indicates P<.05 for all doses of celecoxib vs placebo. Celecoxib and naproxen were both administered twice daily for all dosages. One patient was withdrawn from the celecoxib 400-mg group because of a protocol violation.

The percentages of patients who responded (improved) by ACR-20 criteria at weeks 2, 6, and 12 are shown in Figure 3. The results show significant and comparable treatment effects among patients in all the dose groups of celecoxib and naproxen, with maximal effect achieved by week 2.

Figure 3. Patients Responding to Treatment
Graphic Jump Location
Patients classified as responders by American College of Rheumatology (ACR-20) criteria at 2, 6, and 12 weeks. Responders were defined as those with at least 20% improvement from baseline in the number of tender/painful joints and number of swollen joints, as well as at least 20% improvement in at least 3 of the following: (1) Physician's Global Assessment, (2) Patient's Global Assessment, (3) patient's assessment of pain, (4) C-reactive protein levels, or (5) health assessment questionnaire functional disability score. All active treatments were statistically significantly superior to placebo (P<.05) at all 3 assessment times (asterisks). Dagger indicates significantly different from naproxen (P<.05). Celecoxib and naproxen were both administered twice daily for all dosages.

For other efficacy measures, week 12 results are presented in Table 2. In the patients' and physicians' global assessments, celecoxib was associated with statistically significant treatment effects compared with placebo. For patients' global assessment, all celecoxib dose groups had significantly better scores than the placebo group. However, for Physicians' Global Assessment, only those in the 200-mg and 400-mg, twice-per-day celecoxib-dose groups had significantly better scores than those in the placebo group. Naproxen was not significantly different from placebo at week 12 in either measure of efficacy. In patients' assessment of arthritis pain and duration of morning stiffness, all active treatments showed significant improvement and were statistically distinct from placebo. Improvements in the health assessment questionnaire functional disability scores were significant for those taking celecoxib 200 mg and 400 mg twice per day (P<.001 for both) and those taking naproxen compared with those taking placebo (P = .008). Neither celecoxib nor naproxen was associated with demonstrable effects on C-reactive protein levels.

Table Graphic Jump LocationTable 2. Effect of Treatment on Signs and Symptoms at 12 Weeks*

Withdrawals from the study due to treatment failure were significantly lower for all active treatment groups (P<.001 for all) than for the placebo group: 104 (45%) of placebo patients compared with 67 (28%) of patients receiving 100 mg, 50 (21%) receiving 200 mg, and 59 (27%) receiving 400 mg of celecoxib twice per day, and 65 (29%) of patients receiving naproxen (Figure 1).

Endoscopic Results

Figure 4 shows the incidences of ulceration over the 12-week course of the trial in patients who completed the study and underwent final endoscopic evaluation. Any endoscopic finding other than ulcer was categorized as unknown if the data were obtained before the 12-week visit; only patients with endoscopy results categorized as known, including all patients found to have an ulcer at any time, are included in the analysis. In 99 patients receiving placebo, gastroduodenal ulcers developed in 4 (4% [95% CI, 0.1%-7.9%]); in 148 receiving 100-mg celecoxib, ulcers developed in 9 (6% [95% CI, 2.2%-10.0%]); in 145 receiving 200-mg celecoxib, ulcers developed in 6 (4% [95% CI, 0.9%-7.3%]); and in 130 receiving 400-mg celecoxib twice daily, ulcers developed in 8 (6% [95% CI, 2.1%-10.4%]). In comparison, of 137 patients receiving naproxen, 36 developed gastroduodenal ulcers (26% [95% CI, 18.9%-33.7%]). There were no statistically significant differences in the incidence of gastroduodenal ulcers between the placebo group and any of the celecoxib groups (P>.40) and no evidence of a dose response, whereas the incidence of ulceration in the naproxen group was significantly greater than in each of the other treatment groups (P<.001). A comparison of the effects of H pylori status, concurrent aspirin or corticosteroid use, history of GI tract bleeding, or history of GI tract ulcers on the incidence of gastroduodenal ulcers within treatment groups showed that none of these factors was associated with an effect on ulceration.

Figure 4. Incidence of Gastroduodenal Ulcers Over 12 Weeks of Treatment
Graphic Jump Location
An ulcer was defined as any break in the mucosa at least 3 mm in diameter with unequivocal depth. For each patient there were 3 possible outcomes: known ulcer, known no ulcer, and unknown. Any endoscopic finding other than ulcer was categorized as unknown if the data were obtained before the 12-week visit. Naproxen-treated patients had a significantly greater incidence of gastroduodenal ulcers than did patients treated with either celecoxib or placebo (P<.001). The incidences of gastroduodenal ulcers in the celecoxib treatment groups were similar to that in placebo-treated patients (P>.40). Error bars indicate 95% confidence intervals. Asterisk indicates P<.001 vs all other treatments. Celecoxib and naproxen were both administered twice daily for all dosages.
General Safety

All doses of celecoxib were well tolerated in this study. The incidences of adverse events among the celecoxib treatment groups were generally higher than in the placebo group but did not suggest a dose response. The adverse events with the highest incidence were headache, upper respiratory tract infection, dyspepsia, diarrhea, and abdominal pain (Table 3).

Table Graphic Jump LocationTable 3. Incidence of Adverse Events*

The incidences of the most frequently reported GI tract adverse events (dyspepsia, diarrhea, abdominal pain, nausea, and flatulence) combined were 19% for placebo; 28% for 100 mg, 25% for 200 mg, and 26% for 400 mg of celecoxib twice per day; and 31% for naproxen.

No adverse renal effects of celecoxib were detected. The incidences of peripheral edema and hypertension were low (0%-2%) and were similar among all treatment groups (Table 3). As representative measures, mean blood pressures and creatinine values decreased slightly over the 12 weeks in all treatment groups (Table 4).

Table Graphic Jump LocationTable 4. Representative Measures of Renal Effects*

Serious adverse events (representing hospitalizations or malignancies detected during study participation) were reported for 5 patients (2%) receiving placebo; 4 patients (2%) receiving 100 mg, 5 (2%) receiving 200 mg, and 4 (2%) receiving 400 mg of celecoxib twice per day; and 4 patients (2%) receiving naproxen. None of these events was considered to be related to study medication.

One clinically significant upper GI tract ulcer complication occurred during the study. An 80-year-old woman who received naproxen 500 mg twice per day developed an ulcer on the superior wall of the duodenal bulb and a large postbulbar ulcer on the anterosuperior wall of the duodenum, creating a partial gastric outlet obstruction after 22 days of treatment.

We tested the hypothesis that an agent that inhibits COX-2 while sparing COX-1 will be as effective as conventional NSAIDs (that inhibit both COX-1 and COX-2) but at therapeutic doses will not interfere with other prostaglandin-dependent homeostatic processes such as upper GI tract mucosal integrity.7,8,29,30,41,42 The results of our study provide evidence supporting the hypothesis. Celecoxib demonstrated anti-inflammatory and analgesic efficacy comparable with naproxen, with a significantly lower incidence of gastroduodenal ulceration than naproxen, and not significantly different from placebo.

All doses of celecoxib were associated with anti-inflammatory and analgesic efficacy. This efficacy was reflected by improvements in all efficacy measures beginning at week 2 and sustained over 12 weeks. Total daily celecoxib doses of 200 mg to 400 mg were maximally efficacious, with no further benefit observed with the 400 mg twice per day regimen (800 mg/d). The efficacy of celecoxib was comparable with naproxen, and the improvement in patients treated with naproxen was similar to previously reported results from RA efficacy trials investigating the efficacy of naproxen and other NSAIDs.43,44

Approximately 20% to 30% of patients who take conventional NSAIDs develop persistent adverse effects, and more than 10% are estimated to discontinue treatment as a result.45 In this study, the GI tract tolerability of celecoxib was found to be intermediate between that for placebo and that for naproxen, as shown by incidences of GI tract adverse events and withdrawals due to GI tract adverse events. (Because crude incidences are not normalized for differing lengths of exposure, the ability to interpret these data is limited.) Overall, celecoxib was well tolerated.

It is well established that conventional NSAID therapy can lead to gastroduodenal ulceration and associated serious complications of perforation, hemorrhage, and gastric outlet obstruction.1926 There is evidence to suggest that NSAID-induced ulcers and their resulting complications are largely caused by NSAID-mediated inhibition of mucosal prostaglandin production, primarily mediated by COX-1 activity.45,46 Prostaglandins have been shown to modulate gastroduodenal mucosal protection by several interrelated mechanisms.47,48 In animal models, NSAID-induced GI tract toxicity has been isolated to inhibition of COX-1 activity.17,30

The results of this study provide clinical evidence for the association of celecoxib with improved endoscopic upper GI tract safety compared with naproxen. Moreover, the incidence rates of gastroduodenal ulcers associated with celecoxib, even at 4 times the recommended dose, were not significantly different from that observed with placebo. However, it should be noted that the study was not powered to show equivalence between celecoxib and placebo.

The incidence of gastroduodenal ulcers among patients receiving placebo in our study is similar to that observed in previous studies in which the point prevalence of gastroduodenal ulcers in normal asymptomatic volunteers was examined by upper GI tract endoscopy.49,50 The prevalence of gastroduodenal ulcers in untreated patients in these previous studies ranged from 1.7% to 4.3%. The incidence of gastroduodenal ulcers among patients who received naproxen in our study was 26%, which is similarly consistent with previous endoscopic studies of upper GI tract damage induced by naproxen or other NSAIDs.2326

The precise cause of the ulcers that develop in the patients treated with either placebo or celecoxib in our study is uncertain. Neither H pylori–positive status nor low-dose aspirin use (≤325 mg/d), both known ulcerogenic factors,51,52 was shown to be a factor contributing to gastroduodenal ulcer formation.

The observed differences in upper GI tract ulceration between celecoxib and naproxen are important since ulcers are generally thought to be precursors for potentially fatal ulcer complications (perforation, bleeding, or obstruction).27,28 If true, these data would indicate that drugs that inhibit COX-2 while sparing COX-1 may result in a decreased rate of ulcer complications compared with conventional NSAIDs.

Overall, these results provide evidence of the clinical benefits of celecoxib in the treatment of RA. Current therapeutic strategies for RA usually consist of combination therapy including NSAIDs together with corticosteroids and disease-modifying agents.53 In this 12-week study, celecoxib produced improvement in the signs and symptoms of RA comparable with the effects of naproxen but with a significantly reduced incidence of endoscopically identified gastroduodenal ulcers. Thus, one of the major impediments that can limit the effective use of conventional NSAIDs, upper GI tract toxic effects, may potentially be obviated by the use of celecoxib.

Vane JR, Botting RM. Biological properties of cyclooxygenase products. In: Lipid Mediators. London, England: Academic Press Ltd; 1994:61-97.
Abramson SR, Weissman G. The mechanisms of action of nonsteroidal anti-inflammatory drugs.  Arthritis Rheum.1989;32:1-9.
Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2.  Adv Immunol.1996;62:167-215.
Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS 10 prostaglandin synthase/cyclooxygenase gene.  J Biol Chem.1992;267:7991-7994.
Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.  Proc Natl Acad Sci U S A.1991;88:2692-2696.
O'Neill GP, Ford-Hutchinson AW. Expression of messenger mRNA for cyclooxgenase-1 and cyclooxygenase-2 in human tissues.  FEBS Lett.1993;330:156-160.
Kargman S, Charleson S, Cartwright M.  et al.  Characterization of prostaglandin G/H synthase 1 and 2 in rat, monkey, and human gastrointestinal tracts.  Gastroenterology.1996;111:445-454.
Seibert K, Zhang Y, Leahy K.  et al.  Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.  Proc Natl Acad Sci U S A.1994;91:12013-12017.
Fu J-Y, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes.  J Biol Chem.1990;265:16737-16740.
Crofford LJ, Wilder RL, Ristimäki AP.  et al.  Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1 , phorbol ester, and corticosteroids.  J Clin Invest.1994;93:1095-1101.
DuBois RN, Awad J, Morrow J, Roberts LJ, Bishop PR. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor and phorbol ester.  J Clin Invest.1994;93:493-498.
Raz A, Wyche A, Siegel N, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases.  Proc Natl Acad Sci U S A.1989;86:1657-1661.
Masferrer JL, Zweifel BS, Seibert K, Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice.  J Clin Invest.1990;86:1375-1379.
O'Banion MK, Sadowski HB, Winn V. A serum- and glucocorticoid-regulated 4 kilobase mRNA encodes a cyclooxygenase-related protein.  J Biol Chem.1991;266:23261-23267.
Gierse JK, Hauser SD, Creely DP.  et al.  Expression and selective inhibition of the constitutive and inducible forms of human cyclooxygenase.  Biochem J.1995;305:479-484.
Futaki N, Arai I, Hamasaki S, Takahashi S, Higuchi S, Otomo S. Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation.  J Pharm Pharmacol.1992;45:753-755.
Chan C, Boyce S, Brideau C.  et al.  Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach.  J Pharmacol Exp Ther.1995;274:1531-1537.
Penning TD, Talley JJ, Bertenshaw SR.  et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of SC-58635 (celecoxib).  J Med Chem.1997;40:1347-1365.
Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta analysis.  Ann Intern Med.1991;115:787-796.
MacDonald TM, Morant SV, Robinson GC.  et al.  Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.  BMJ.1997;315:1333-1337.
Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.  Gastroenterology.1993;105:1078-1088.
Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.  Ann Intern Med.1991;114:257-263.
Agrawal NM, Van Kerckhove HEJM, Erhardt LJ, Geis GS. Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers: a one-year study.  Dig Dis Sci.1995;40:1125-1131.
Roth SH, Bennett RE, Caldron PH, Mitchell CS, Swenson CM. Endoscopic evaluation of the long-term effects of diclofenac sodium and naproxen in elderly patients with arthritis.  Clin Drug Invest.1995;9:171-179.
Taha AS, Hudson N, Hawkey CJ.  et al.  Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs.  N Engl J Med.1996;334:1435-1439.
Cheatum DE, Arvanitakis C, Gumpel M.  et al.  An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs.  Clin Ther.1999;21:992-1003.
Silverstein FE, Graham DY, Senior JR.  et al.  Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial.  Ann Intern Med.1995;123:241-249.
Graham DY, White RH, Moreland LW.  et al.  Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs.  Ann Intern Med.1993;119:257-262.
Anderson GD, Hauser SD, McGarity KL.  et al.  Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.  J Clin Invest.1996;97:2672-2679.
Masferrer J, Zweifel B, Manning PT.  et al.  Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and non-ulcerogenic.  Proc Natl Acad Sci U S A.1994;91:3228-3232.
Simon LS, Lanza FL, Lipsky PE.  et al.  Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor.  Arthritis Rheum.1998;41:1591-1602.
Arnett FC, Edworthy SM, Bloch DA.  et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.  Arthritis Rheum.1988;31:315-324.
Hochberg MC, Chang RW, Dwosh I, Linsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis.  Arthritis Rheum.1992;35:498-502.
Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee: validation: value in comparison with other assessment tests.  Scand J Rheumatol.1987;65(suppl):85-89.
Langley GB, Sheppard H. Problems associated with pain measurement in arthritis: comparison of visual analogue and verbal rating scales.  Clin Exp Rheumatol.1984;2:231-234.
Felson DT, Anderson JJ, Boers M.  et al.  The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis trials.  Arthritis Rheum.1993;36:729-740.
Egger MJ, Huth DA, Ward JR, Reading JC, Williams HJ. Reduced joint count indices in the evaluation of rheumatoid arthritis.  Arthritis Rheum.1985;28:613-619.
Wolfe F, Kleinheksel SM, Cathey MA, Hawley DJ, Spitz PW, Fries JF. The clinical value of the Stanford health assessment questionnaire functional disability index in patients with rheumatoid arthritis.  J Rheumatol.1988;15:1480-1488.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance.  Biometrika.1988;75:800-802.
Felson DT, Anderson JJ, Boers M.  et al.  American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis.  Arthritis Rheum.1995;38:727-735
Masferrer JL, Reddy ST, Zweifel BS.  et al.  In vivo glucocorticoids regulate cyclooxygenase-2 but not cyclooxygenase-1 in peritoneal macrophages.  J Pharmacol Exp Ther.1994;270:1340-1344.
Crofford LJ, Wilder RL, Ristimäki AP.  et al.  Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues.  J Biol Chem.1990;265:16737-16740.
Gall EP, Caperton EM, McComb JE.  et al.  Clinical comparison of ibuprofen, fenoprofen calcium, naproxen and tolmetin sodium in rheumatoid arthritis.  J Rheumatol.1982;9:402-407.
Day RO, Furst DE, Dromgoole SH, Kamm B, Roe R, Paulus HE. Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis.  Clin Pharmacol Ther.1982;31:733-740.
Shoen RT, Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.  Am J Med.1989;86:449-458.
Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy.  Gastroenterology.1989;96:675-681.
Shorrock CJ, Rees WDW. Overview of gastroduodenal mucosal protection.  Am J Med.1988;84(suppl 2a):25-34.
Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal antiinflammatory drugs and peptic ulcer disease.  Ann Intern Med.1991;114:307-319.
Akdamar K, Ertan A, Agrawal NM.  et al.  Upper gastrointestinal endoscopy in normal asymptomatic volunteers.  Gastrointest Endosc.1986;32:78-80.
Ihmaki T, Varis K, Siurala M. Morphological, functional and immunological state of the gastric mucosa in gastric carcinoma families.  Scand J Gastroenterol.1979;14:801-812.
Weil J, Colin-Jones D, Langman M.  et al.  Prophylactic aspirin and risk of pepticulcer disease.  BMJ.1995;310:827-830.
Graham DY. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and ulcers: where we stand.  Am J Gastroenterol.1996;91:2080-2086.
Wilske KR, Healey LA. Remodeling the pyramid: a concept whose time has come.  J Rheumatol.1989;16:565-567.

Figures

Figure 1. Flowchart of Patient Disposition
Graphic Jump Location
Figure 2. Changes in Signs and Symptoms of Rheumatoid Arthritis
Graphic Jump Location
Mean numbers of tender/painful joints (top panel) and swollen joints (bottom panel) at 2, 6, and 12 weeks. Statistically significant effects (P<.05 vs placebo) were observed in all celecoxib-treatment groups at all assessment times, and in the naproxen group at all but 1 assessment time. Asterisk indicates P<.05 for all doses of celecoxib and naproxen vs placebo. Dagger indicates P<.05 for all doses of celecoxib vs placebo. Celecoxib and naproxen were both administered twice daily for all dosages. One patient was withdrawn from the celecoxib 400-mg group because of a protocol violation.
Figure 3. Patients Responding to Treatment
Graphic Jump Location
Patients classified as responders by American College of Rheumatology (ACR-20) criteria at 2, 6, and 12 weeks. Responders were defined as those with at least 20% improvement from baseline in the number of tender/painful joints and number of swollen joints, as well as at least 20% improvement in at least 3 of the following: (1) Physician's Global Assessment, (2) Patient's Global Assessment, (3) patient's assessment of pain, (4) C-reactive protein levels, or (5) health assessment questionnaire functional disability score. All active treatments were statistically significantly superior to placebo (P<.05) at all 3 assessment times (asterisks). Dagger indicates significantly different from naproxen (P<.05). Celecoxib and naproxen were both administered twice daily for all dosages.
Figure 4. Incidence of Gastroduodenal Ulcers Over 12 Weeks of Treatment
Graphic Jump Location
An ulcer was defined as any break in the mucosa at least 3 mm in diameter with unequivocal depth. For each patient there were 3 possible outcomes: known ulcer, known no ulcer, and unknown. Any endoscopic finding other than ulcer was categorized as unknown if the data were obtained before the 12-week visit. Naproxen-treated patients had a significantly greater incidence of gastroduodenal ulcers than did patients treated with either celecoxib or placebo (P<.001). The incidences of gastroduodenal ulcers in the celecoxib treatment groups were similar to that in placebo-treated patients (P>.40). Error bars indicate 95% confidence intervals. Asterisk indicates P<.001 vs all other treatments. Celecoxib and naproxen were both administered twice daily for all dosages.

Tables

Table Graphic Jump LocationTable 1. Patient Demographic and Baseline Characteristics*
Table Graphic Jump LocationTable 2. Effect of Treatment on Signs and Symptoms at 12 Weeks*
Table Graphic Jump LocationTable 3. Incidence of Adverse Events*
Table Graphic Jump LocationTable 4. Representative Measures of Renal Effects*

References

Vane JR, Botting RM. Biological properties of cyclooxygenase products. In: Lipid Mediators. London, England: Academic Press Ltd; 1994:61-97.
Abramson SR, Weissman G. The mechanisms of action of nonsteroidal anti-inflammatory drugs.  Arthritis Rheum.1989;32:1-9.
Smith WL, Dewitt DL. Prostaglandin endoperoxide H synthases-1 and -2.  Adv Immunol.1996;62:167-215.
Kujubu DA, Herschman HR. Dexamethasone inhibits mitogen induction of the TIS 10 prostaglandin synthase/cyclooxygenase gene.  J Biol Chem.1992;267:7991-7994.
Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons DL. Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.  Proc Natl Acad Sci U S A.1991;88:2692-2696.
O'Neill GP, Ford-Hutchinson AW. Expression of messenger mRNA for cyclooxgenase-1 and cyclooxygenase-2 in human tissues.  FEBS Lett.1993;330:156-160.
Kargman S, Charleson S, Cartwright M.  et al.  Characterization of prostaglandin G/H synthase 1 and 2 in rat, monkey, and human gastrointestinal tracts.  Gastroenterology.1996;111:445-454.
Seibert K, Zhang Y, Leahy K.  et al.  Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain.  Proc Natl Acad Sci U S A.1994;91:12013-12017.
Fu J-Y, Masferrer JL, Seibert K, Raz A, Needleman P. The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes.  J Biol Chem.1990;265:16737-16740.
Crofford LJ, Wilder RL, Ristimäki AP.  et al.  Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues: effects of interleukin-1 , phorbol ester, and corticosteroids.  J Clin Invest.1994;93:1095-1101.
DuBois RN, Awad J, Morrow J, Roberts LJ, Bishop PR. Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor and phorbol ester.  J Clin Invest.1994;93:493-498.
Raz A, Wyche A, Siegel N, Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases.  Proc Natl Acad Sci U S A.1989;86:1657-1661.
Masferrer JL, Zweifel BS, Seibert K, Needleman P. Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice.  J Clin Invest.1990;86:1375-1379.
O'Banion MK, Sadowski HB, Winn V. A serum- and glucocorticoid-regulated 4 kilobase mRNA encodes a cyclooxygenase-related protein.  J Biol Chem.1991;266:23261-23267.
Gierse JK, Hauser SD, Creely DP.  et al.  Expression and selective inhibition of the constitutive and inducible forms of human cyclooxygenase.  Biochem J.1995;305:479-484.
Futaki N, Arai I, Hamasaki S, Takahashi S, Higuchi S, Otomo S. Selective inhibition of NS-398 on prostanoid production in inflamed tissue in rat carrageenan-air-pouch inflammation.  J Pharm Pharmacol.1992;45:753-755.
Chan C, Boyce S, Brideau C.  et al.  Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach.  J Pharmacol Exp Ther.1995;274:1531-1537.
Penning TD, Talley JJ, Bertenshaw SR.  et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of SC-58635 (celecoxib).  J Med Chem.1997;40:1347-1365.
Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs: a meta analysis.  Ann Intern Med.1991;115:787-796.
MacDonald TM, Morant SV, Robinson GC.  et al.  Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study.  BMJ.1997;315:1333-1337.
Henry D, Dobson A, Turner C. Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.  Gastroenterology.1993;105:1078-1088.
Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.  Ann Intern Med.1991;114:257-263.
Agrawal NM, Van Kerckhove HEJM, Erhardt LJ, Geis GS. Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers: a one-year study.  Dig Dis Sci.1995;40:1125-1131.
Roth SH, Bennett RE, Caldron PH, Mitchell CS, Swenson CM. Endoscopic evaluation of the long-term effects of diclofenac sodium and naproxen in elderly patients with arthritis.  Clin Drug Invest.1995;9:171-179.
Taha AS, Hudson N, Hawkey CJ.  et al.  Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs.  N Engl J Med.1996;334:1435-1439.
Cheatum DE, Arvanitakis C, Gumpel M.  et al.  An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs.  Clin Ther.1999;21:992-1003.
Silverstein FE, Graham DY, Senior JR.  et al.  Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial.  Ann Intern Med.1995;123:241-249.
Graham DY, White RH, Moreland LW.  et al.  Duodenal and gastric ulcer prevention with misoprostol in arthritis patients taking NSAIDs.  Ann Intern Med.1993;119:257-262.
Anderson GD, Hauser SD, McGarity KL.  et al.  Selective inhibition of cyclooxygenase (COX)-2 reverses inflammation and expression of COX-2 and interleukin 6 in rat adjuvant arthritis.  J Clin Invest.1996;97:2672-2679.
Masferrer J, Zweifel B, Manning PT.  et al.  Selective inhibition of inducible cyclooxygenase 2 in vivo is anti-inflammatory and non-ulcerogenic.  Proc Natl Acad Sci U S A.1994;91:3228-3232.
Simon LS, Lanza FL, Lipsky PE.  et al.  Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor.  Arthritis Rheum.1998;41:1591-1602.
Arnett FC, Edworthy SM, Bloch DA.  et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.  Arthritis Rheum.1988;31:315-324.
Hochberg MC, Chang RW, Dwosh I, Linsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis.  Arthritis Rheum.1992;35:498-502.
Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee: validation: value in comparison with other assessment tests.  Scand J Rheumatol.1987;65(suppl):85-89.
Langley GB, Sheppard H. Problems associated with pain measurement in arthritis: comparison of visual analogue and verbal rating scales.  Clin Exp Rheumatol.1984;2:231-234.
Felson DT, Anderson JJ, Boers M.  et al.  The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis trials.  Arthritis Rheum.1993;36:729-740.
Egger MJ, Huth DA, Ward JR, Reading JC, Williams HJ. Reduced joint count indices in the evaluation of rheumatoid arthritis.  Arthritis Rheum.1985;28:613-619.
Wolfe F, Kleinheksel SM, Cathey MA, Hawley DJ, Spitz PW, Fries JF. The clinical value of the Stanford health assessment questionnaire functional disability index in patients with rheumatoid arthritis.  J Rheumatol.1988;15:1480-1488.
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance.  Biometrika.1988;75:800-802.
Felson DT, Anderson JJ, Boers M.  et al.  American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis.  Arthritis Rheum.1995;38:727-735
Masferrer JL, Reddy ST, Zweifel BS.  et al.  In vivo glucocorticoids regulate cyclooxygenase-2 but not cyclooxygenase-1 in peritoneal macrophages.  J Pharmacol Exp Ther.1994;270:1340-1344.
Crofford LJ, Wilder RL, Ristimäki AP.  et al.  Cyclooxygenase-1 and -2 expression in rheumatoid synovial tissues.  J Biol Chem.1990;265:16737-16740.
Gall EP, Caperton EM, McComb JE.  et al.  Clinical comparison of ibuprofen, fenoprofen calcium, naproxen and tolmetin sodium in rheumatoid arthritis.  J Rheumatol.1982;9:402-407.
Day RO, Furst DE, Dromgoole SH, Kamm B, Roe R, Paulus HE. Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis.  Clin Pharmacol Ther.1982;31:733-740.
Shoen RT, Vender RJ. Mechanisms of nonsteroidal antiinflammatory drug-induced gastric damage.  Am J Med.1989;86:449-458.
Graham DY. Prevention of gastroduodenal injury induced by chronic nonsteroidal antiinflammatory drug therapy.  Gastroenterology.1989;96:675-681.
Shorrock CJ, Rees WDW. Overview of gastroduodenal mucosal protection.  Am J Med.1988;84(suppl 2a):25-34.
Soll AH, Weinstein WM, Kurata J, McCarthy D. Nonsteroidal antiinflammatory drugs and peptic ulcer disease.  Ann Intern Med.1991;114:307-319.
Akdamar K, Ertan A, Agrawal NM.  et al.  Upper gastrointestinal endoscopy in normal asymptomatic volunteers.  Gastrointest Endosc.1986;32:78-80.
Ihmaki T, Varis K, Siurala M. Morphological, functional and immunological state of the gastric mucosa in gastric carcinoma families.  Scand J Gastroenterol.1979;14:801-812.
Weil J, Colin-Jones D, Langman M.  et al.  Prophylactic aspirin and risk of pepticulcer disease.  BMJ.1995;310:827-830.
Graham DY. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and ulcers: where we stand.  Am J Gastroenterol.1996;91:2080-2086.
Wilske KR, Healey LA. Remodeling the pyramid: a concept whose time has come.  J Rheumatol.1989;16:565-567.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 550

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles