Safety and Efficacy of Oral Nonsteroidal Anti-Inflammatory Drugs in Patients with Rheumatoid Arthritis Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial. Comparison of the efficacy and safety profiles of a pelubiprofen versus celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, phase III, non-inferiority clinical trial Celecoxib and Diclofenac Plus Omeprazole are Similarly Effective in the Treatment of Arthritis in Patients at High GI Risk in the CONDOR Trial§ Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Do non-steroidal anti-inflammatory drugs have a significant effect on detection and grading of ultrasound-detected synovitis in patients with rheumatoid arthritis? Results from a randomised study Evaluation of health-related quality of life of rheumatoid arthritis patients treated with celecoxib. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. An endoscopic study of gastroduodenal lesions induced by nonsteroidal anti-inflammatory drugs. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis Dyspepsia tolerability from the patients' perspective: a comparison of celecoxib with diclofenac Reduced incidence of gastroduodenal ulcers associated with lumiracoxib compared with ibuprofen in patients with rheumatoid arthritis Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: results of a randomized double-blind trial. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. Upper gastrointestinal tolerability of celecoxib, a COX-2 specific inhibitor, compared to naproxen and placebo. Efficacy and safety of celecoxib versus diclofenac and omeprazole in elderly arthritis patients: a subgroup analysis of the CONDOR trial Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial
Abstract Objective : To monitor the safety and efficacy profile of long-term treatment with diclofenac , nabumetone , meloxicam and celecoxib in patients with rheumatoid arthritis . Design and methods : This r and omised , prospect i ve clinical trial included a total of 461 subjects ( 313 females and 148 males ) with clinical ly diagnosed rheumatoid arthritis . Their average age was 46.9 ± 14.4 years ( range 20–69 years ) , and the average disease duration was 1333.7 ± 992.85 days . Subjects were r and omly assigned daily administration of one of the following : diclofenac 75–100 mg , meloxicam 15 mg , nabumetone l000 mg or celecoxib 200 mg . During the 6-month treatment period , a monthly patient interview was conducted to evaluate drug efficacy and safety . Results : 407 subjects successfully completed the 6-month treatment . Sixteen patients ( 12.2 % ) withdrew from the diclofenac group , 16 ( 12.2 % ) from the nabumetone group , 17 ( 11.8 % ) from the meloxicam group and five ( 9.1 % ) from the celecoxib group . Most withdrawals occurred during the first 3 months of treatment . Reasons for withdrawals in the first three groups were lack of efficacy ( 44.9 % ) and adverse effects ( 38.8 % ) . For the celecoxib group , high cost ( 80 % ) was the main reason for withdrawal . Adverse drug reactions to NSAIDs mostly occurred at an early stage of treatment , with an incidence rate of 31.9 % for the diclofenac group , 19.9 % for the nabumetone group , 25.2 % for the meloxicam group , and 7.27 % for the celecoxib group . Clinical efficacy rates for the four NSAIDs were positively related to the length of treatment . During the first 4 months , diclofenac , meloxicam and celecoxib showed better efficacy than nabumetone . There were no significant differences in efficacy during the fifth and sixth months . The overall 6-month effectiveness rates were 68.8 % for diclofenac , 59.8 % for nabumetone , 67.6 % for meloxicam and 69.1 % for celecoxib . Conclusions : Adverse drug reactions and their related withdrawals occurred mostly at an early stage of NSAID treatment , so it is crucial to strengthen pharmacovigilance during this period . Among the investigated NSAIDs , celecoxib did not prove to be superior to diclofenac , nabumetone or meloxicam with respect to its efficacy in the treatment of rheumatoid arthritis ; however , it did show good patient compliance and safety profiles BACKGROUND SKI306X , which consists of biologically active ingredients from Clematis m and sburica , Tricbosantbes kirilowii , and Prunella vulgaris , was developed and tested in pre clinical trials in Korea . Those studies found that SKI306X was associated with an anti-inflammatory and analgesic effect , and that it can delay the destruction of cartilage in rheumatoid arthritis ( RA ) . OBJECTIVE The aim of this study was to compare the pain relief and tolerability of SKI306X and celecoxib in patients with RA . METHODS This study was a 6-week , multicenter , r and omized , double-blind , double-dummy , Phase III , noninferiority clinical trial . Eligible patients were aged 18 to 80 years , had a history of RA with a disease duration of > or =3 months , and were functional American College of Rheumatology ( ACR ) class I , II , or III before entry . After a washout period of 2 weeks , patients were r and omized to SKI306X 200 mg TID or celecoxib 200 mg BID for 6 weeks . The primary end point was a change in patient assessment of pain intensity using a visual analog scale ( VAS ) . The secondary end points were a 20 % improvement in response rate as defined by the ACR ( ACR20 ) and the frequency of rescue medication use . Results after 3 and 6 weeks of treatment were compared with baseline and between treatment groups , and all patients were assessed for adverse events ( AEs ) , clinical laboratory data , and vital signs . AEs were identified based on spontaneous reports by patients during interviews conducted by the investigators and the study coordinator . RESULTS Two hundred twenty-two Korean patients from 7 medical centers were assessed and 183 were enrolled and r and omized to 1 of 2 treatment groups . Ninety-one patients ( 10 male , 81 female ; mean [ SD ] age , 52.13 [ 12.64 ] years ; mean [ SD ] duration of RA , 9.08 [ 10.23 ] years ; no. [ % ] of ACR class I , II , and III , 13 [ 14.29 ] , 44 [ 48.35 ] and 34 [ 37.36 ] patients , respectively ) received SKI306X 200 mg TID and 92 patients ( 10 male , 82 female ; mean [ SD ] age , 51.78 [ 10.94 ] years ; mean [ SD ] duration of RA , 8.78 [ 7.78 ] years ; no. [ % ] of ACR class I , II , and III , 14 [ 15.22 ] , 44 [ 47.83 ] , and 34 [ 36.96 ] patients , respectively ) received celecoxib 200 mg BID . An analysis of the change in reported pain intensity as determined by VAS ( mm ) score between baseline and week 3 ( mean [ SD ] , 13.64 [ 16.62 ] vs 14.45 [ 15.89 ] ) , and between baseline and week 6 ( 18.4 [ 20.8 ] vs 17.9 [ 19.1 ] , respectively ) suggested that SKI306X was not inferior to celecoxib . The number of patients who achieved ACR20 response rate was not significantly different between the SKI306X group and the celecoxib group at week 3 ( 16/87 [ 18.4 % ] vs 24/87 [ 27.6 % ] , respectively ) and at week 6 ( 29/87 [ 33.3 % ] vs 29/87 [ 33.3 % ] ) . The frequency of rescue medication use was not significantly different between the SKI306X group and celecoxib group at week 3 ( 54/87 [ 62.1 % ] vs 47/87 [ 54.0 % ] , respectively ) or week 6 ( 57/87 [ 65.5 % ] vs 49/87 [ 56.3 % ] ) . Drug-related AEs were reported by 27 ( 29.7 % ) patients in the SKI306X group and 22 ( 23.9 % ) patients in the celecoxib group . The most frequent drug-related AEs were epigastric pain ( 9/91 [ 9.9 % ] ) in the SKI306X group and glutamyltranferase elevation ( 4/92 [ 4.3 % ] ) in the celecoxib group . No significant between-group differences were observed in the prevalence of drug-related clinical - or laboratory-determined AEs . CONCLUSION The results of this study suggest that SKI306X was generally well tolerated and not inferior to celecoxib in regard to pain relief in these Korean patients with RA Background Pelubiprofen is a prodrug of 2-arylpropionic acid with relatively selective effects on cyclooxygenase-2 activity . The aim of this study was to compare the efficacy and safety profiles of pelubiprofen with those of celecoxib in patients with rheumatoid arthritis . Methods This was a 6-week , multicenter , r and omized , double-blind , double-dummy , parallel-group , phase III , non-inferiority clinical trial . The primary end point was non-inferiority of pain decrease from baseline to week-6 as determined using a 100 mm pain visual analog scale ( VAS ) . Pelubiprofen was considered non-inferior to celecoxib if the lower limit of the 97.5 % confidence interval for treatment difference [ ( pain reduction in pelubiprofen group ) – ( pain reduction in celecoxib group ) ] was more than −10 mm . The secondary end points were as follows : non-inferiority of ( 1 ) reduction of Korean health assessment question naire ( KHAQ ) score ; ( 2 ) decreased duration of morning stiffness ; and ( 3 ) decrease in the frequency and total dose of rescue drugs after 6 weeks of treatment . Results Seventy-seven patients in the pelubiprofen group and 68 patients in the celecoxib group started the study medication . Pelubiprofen was non-inferior to celecoxib with regard to reduction in VAS pain severity ( difference , mean ± SD 5.0 ± 20.1 ; 97.5 % CI , −2.3 to ∞ ) . Pelubiprofen was also non-inferior to celecoxib in terms of the secondary end points , such as , decrease in KHAQ score ( 0.0 ± 0.5 , 97.5 % CI −0.2 to ∞ ) , decrease in duration of morning stiffness ( median 0.0 minute in both groups ) , and decrease in the frequency ( 0.7 ± 3.5 , 97.5 % CI −0.6 to ∞ ) and total amount ( 0.7 ± 3.6 , 97.5 % CI −0.6 to ∞ ) of rescue medication uses during the 6 week study period . Safety analysis revealed 31.2 % patients in the pelubiprofen group and 20.6 % patients in the celecoxib  group experienced an adverse drug reaction ( ADR ) . The frequency of gastrointestinal ADRs was 20.8 % and 8.8 % , respectively . Conclusions Pelubiprofen was found to be as effective as celecoxib at pain reduction and for relieving stiffness in RA patients . However , more patients in the pelubiprofen group experienced ADR and the frequency of gastrointestinal ADRs was higher in the pelubiprofen group . ClinialTrials.gov identifier : NCT01781702 Objective : Compare effectiveness of celecoxib versus diclofenac plus omeprazole in improving arthritis signs and symptoms in patients at high gastrointestinal ( GI ) risk who were enrolled in the CONDOR (  Celecoxib vs Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis ) trial . Methods : CONDOR was a 6-month , prospect i ve , double-blind , triple-dummy , parallel-group , r and omized , multicenter trial comparing celecoxib 200 mg twice daily versus diclofenac slow release ( SR ) 75 mg twice daily plus omeprazole 20 mg daily . Patients were Helicobacter pylori negative , had osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) , were aged ≥60 years , were with or without a history of gastroduodenal ulceration , or were ≥18 years with previous gastroduodenal ulceration . Patients ’ Global Assessment of Arthritis was determined at each study visit . Results : A total of 4484 patients were r and omized to treatment ( 2238 celecoxib , 2246 diclofenac SR ) and included in the intention-to-treat analyses . Least squares mean ( LSM ) ( st and ard error [ SE ] ) for Patients ’ Global Assessment of Arthritis was 3.219 ( 0.017 ) and 3.221 ( 0.017 ) at baseline for celecoxib and diclofenac SR ( p=0.90 ) . Improvement in both groups was similar in months 2 , 4 , and 6 ; at month 1 the LSM ( SE ) was 2.647 ( 0.017 ) and 2.586 ( 0.017 ) for celecoxib and diclofenac ( p=0.0025 ) . LSM difference ( SE ) from baseline to final visit demonstrated an improvement of 0.75 ( 0.02 ) in celecoxib-treated patients and 0.77 ( 0.02 ) in diclofenac SR-treated patients ( p=0.42 ) . Conclusions : Celecoxib and diclofenac plus omeprazole were shown to have similar efficacy in patients with OA and /or RA at increased GI risk who were enrolled in the CONDOR trial . Trial Registry : Trial was registered under Clinical Trials.gov identifier NCT00141102 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 , r and omized 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 r and omly 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 prospect ively 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 clinical ly , was associated with a lower incidence of symptomatic ulcers and ulcer complications combined , as well as other clinical ly important toxic effects , compared with NSAIDs at st and ard dosages . The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly . JAMA . 2000;284:1247 - Conventional nonsteroidal anti-inflammatory drugs ( NSAIDs ) nonspecifically inhibit cyclooxygenase-1 ( COX-1 ) , an enzyme critical to normal platelet function , and COX-2 , which mediates inflammatory response mechanisms . Celecoxib , an antiarthritic agent that inhibits COX-2 but spares COX-1 at therapeutic doses , is expected to have minimal effects on platelet function . A double-blind , r and omized , placebo-controlled study of 10 days ' duration was conducted in 24 healthy adults to compare the effects on platelet function of a supratherapeutic dose of celecoxib ( 600 mg bid ) with a st and ard dose of naproxen ( 500 mg bid ) , a conventional NSAID . Ex vivo platelet aggregation in response to st and ard agonists ( collagen , arachidonate , or U46619 [ a thromboxane A2 receptor agonist ] ) , bleeding time , and serum thromboxane B2 ( TxB2 ) level were measured . Unlike celecoxib or placebo , naproxen produced statistically significant reductions in platelet aggregation and serum TxB2 levels and increased bleeding time . The results indicate that even at supratherapeutic doses , celecoxib will not interfere with normal mechanisms of platelet aggregation and hemostasis , supporting the premise that celecoxib is COX-1 sparing relative to conventional NSAIDs BACKGROUND Non-steroidal anti-inflammatory drugs ( NSAIDs ) inhibit cyclo-oxygenase ( COX ) , which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostagl and ins . Gastrointestinal injury is a common outcome . We compared the efficacy , safety , and tolerability of long-term therapy with celecoxib , a COX-1 sparing inhibitor of COX-2 , with diclofenac , a non-specific COX inhibitor . METHODS 655 patients with adult-onset rheumatoid arthritis of at least 6 months ' duration were r and omly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks . Anti-inflammatory and analgesic activity and tolerability were assessed at baseline , every 4 weeks , and at week 24 . We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available . Analysis was by intention-to-treat . FINDINGS 430 patients underwent endoscopy  ( celecoxib n=212 , diclofenac n=218 ) . The two drugs were similar in management of rheumatoid arthritis pain and inflammation . Gastroduodenal ulcers were detected endoscopically in 33 ( 15 % ) patients treated with diclofenac and in eight ( 4 % ) in the celecoxib group ( p<0.001 ) . The rate of withdrawal for any gastrointestinal-related adverse event , most commonly abdominal pain , diarrhoea , and dyspepsia , was nearly three times higher in the diclofenac-treated group than in the celecoxib group ( 16 vs 6 % ; p<0.001 ) . INTERPRETATION Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac , with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events , and tolerability was better BACKGROUND & AIMS Epidemiologic data indicate that the risk of nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal ( GI ) clinical events varies based on patients ' clinical characteristics . The authors determined risk factors for NSAID-related clinical upper GI events and the event rates , absolute risk reductions , and numbers needed to treat for individual risk factors for a nonselective NSAID and a selective cyclooxygenase 2 inhibitor in a double-blind outcomes trial . METHODS Eight thous and seventy-six rheumatoid arthritis patients aged > or=50 years ( or > or=40 on corticosteroid therapy ) were r and omly assigned to rofecoxib 50 mg daily or naproxen 500 mg twice daily for a median of 9 months . The development of clinical upper GI events ( bleeding , perforation , obstruction , and symptomatic ulcer identified on clinical ly indicated work-up ) was assessed . RESULTS Significant risk factors included prior upper GI events , age > or=65 , and severe rheumatoid arthritis ( RR , 2.3 - 3.9 ) . Patients administered naproxen who had prior upper GI complications or who were aged > or=75 years had 18.84 or 14.46 events per 100 patient-years , and the risk of events remained constant over time . The reduction in events with rofecoxib was similar in high- and low-risk subgroups ( RR , 0.31 - 0.68 ) . The number needed to treat with rofecoxib instead of naproxen to avert 1 GI event was 10 - 12 in highest risk patients ( prior event , age > or=75 years , or severe rheumatoid arthritis ) , 17 - 33 in patients with other risk factors , and 42 - 106 in low-risk patients . CONCLUSIONS NSAID-related GI events increase dramatically with risk factors such as prior events or older age . Ten to twelve high-risk patients need to be treated with a protective strategy such as the selective cyclooxygenase 2 inhibitor , rofecoxib , to avert a clinical GI event Objectives To determine whether non-steroidal anti-inflammatory drugs ( NSAIDs ) have a significant effect on ultrasonographic ( US ) grey scale ( GS ) and power Doppler ( PD ) assessment of synovitis in rheumatoid arthritis ( RA ) . Methods Patients with RA taking NSAIDs were r and omised to either stopping ( for a minimum of 5 drug half-lives ) or continuing the drug . All patients had a clinical assessment and US examination of both h and s and wrists before and after stopping/continuing the NSAID . Changes at follow-up were compared between groups using Mann – Whitney U tests . Results A total of 58 patients with RA were recruited . All the clinical assessment parameters ( including disease activity , pain , general state of health and physician global visual analogue score and tender and swollen joints count ) showed an increase in the group who stopped their NSAID treatment . The total GS and PD score showed median ( first to third quartiles ) increase of 9.5 ( 5.75 to 19.0 ) and 4.0 ( 2.0 to 6.0 ) per patient , respectively , in the patients who stopped their NSAID in comparison with 1.0 ( –1.0 to 2.25 ) and 0.0 ( –2.0 to 3.0 ) , respectively , in the patients who continued their NSAID ( p<0.001 ) . There was an increase in the number of joints scoring > 0 for GS and PD in the patients who stopped the NSAID . The inter- and intrareader agreement was good to excellent for the US examination . Conclusion NSAID usage may mask the GS and PD signal and result in lower scoring despite continuing disease activity . Consideration should be given to the NSAID effect in design ing clinical studies which use US to assess response to therapeutic OBJECTIVE To study the functional status and health-related quality of life ( HRQOL ) of patients with rheumatoid arthritis ( RA ) after treatment with celecoxib  , compared with placebo and naproxen . METHODS This was a prospect i ve , r and omized , double-blind , parallel group trial conducted at 79 sites in the United States and Canada over a 12-week treatment period . Patients were r and omly assigned to 5 groups : placebo , 100 mg twice a day of celecoxib , 200 mg twice a day of celecoxib , 400 mg twice a day of celecoxib , and 500 mg twice a day of naproxen . The Health Assessment Question naire ( HAQ ) disability index was used to measure functional status . The Medical Outcomes Study Short Form 36 ( SF-36 ) was used to measure general HRQOL . RESULTS Enrollees were 1,149 patients with diagnosed and active RA . At the end of the treatment period , patients in the 4 active treatment groups had significant improvement in both functional status and overall HRQOL in comparison with the placebo group . Patients in the twice-daily 100 mg celecoxib group significantly differed from placebo at weeks 2 and 6 on HAQ scores and at week 12 on 5 domains and both summary scores of the SF-36 . Patients treated with twice-daily 200 mg celecoxib had significantly better functional status than placebo at all times of testing with the HAQ , and also had significantly better function than those treated with naproxen after 2 and 12 weeks of treatment . Patients in the twice-daily 200 mg and 400 mg celecoxib groups showed similar improvement in HRQOL as determined by the 8 domain scores and 2 summary scores of the SF-36 . CONCLUSION Celecoxib was better than placebo and comparable with naproxen in improving functional status and overall HRQOL among RA patients 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 R and omized , 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 r and omized ; 688 ( 60 % ) of these completed the study . INTERVENTIONS Patients were r and omized 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 st and ard 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 evidence d by less frequent incidence of endoscopic ulcers compared with naproxen Rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) are frequently treated with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . Although NSAIDs are an effective therapy for the pain and inflammation of arthritis , they are associated with serious side effects , particularly ulceration , bleeding , and perforation of the gastrointestinal ( GI ) tract . In this study , 1826 OA or RA patients who either had been taking NSAIDS for > or = 6 months or had been unable to tolerate continuous NSAID use because of adverse GI symptoms or suspected NSAID-related gastroduodenal lesions were examined endoscopically for gastroduodenal lesions and ulcers . At the same time , the patients were asked to rate the severity of any GI symptoms they had been experiencing . Of the total number of patients studied , 817 ( 44.7 % ) were OA patients with a mean ( + /- SD ) age of 55.8+/-12.9 years , and 1009 ( 55.3 % ) were RA patients with a mean age of 53.1+/-13.1 years . Clinical ly significant gastroduodenal lesions were found in 37.1 % of patients ( n = 678 ) ; of these , 24.0 % ( n = 439 ) had ulcers . Gastric ulcers were more frequent than duodenal ulcers ( 14.8 % vs 10.2 % of patients ; P < 0.05 ) , and most gastric ulcers ( 72.0 % ) were found in the antrum of the stomach . The prevalence of gastroduodenal ulcers increased with age ( P < 0.001 ) , duration of OA ( P < 0.001 ) , and duration of current NSAID use ( P = 0.019 ) . The prevalence of gastroduodenal ulcers in patients taking NSAIDs for < 1 year was 13.8 % , compared with a nearly twofold higher prevalence ( 25.9 % ) in patients taking NSAIDs for periods of > or = 1 year and up to 15 years . The prevalence of gastric ulcers was 32.6 % in patients with a history of gastric ulcer but only 13.5 % in patients with no GI history ( previous gastric ulcer , duodenal ulcer , or upper GI hemorrhage ) . No relationship was found between the prevalence of gastroduodenal ulcers and sex ( men , 22.4 % ; women , 24.9 % ) or prevalence of gastroduodenal ulcers and type of arthritic disease ( RA , 23.6 % ; OA , 24.5 % ) . The prevalence of gastroduodenal ulcers increased with the severity of GI symptoms ( P = 0.007 ) . These results provide further endoscopic confirmation of the association between NSAID use and gastroduodenal lesions and ulcers and support the contention that safer treatment alternatives to conventional NSAIDs are required OBJECTIVE : Nonsteroidal anti-inflammatory drugs ( NSAIDs ) block prostagl and in production by inhibiting cyclooxygenase ( COX ) ; they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform . As compared to conventional NSAIDs , celecoxib , a COX-2 specific inhibitor , has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates . In response to concerns that such studies may under-represent ulceration rates , the present serial endoscopy study was design ed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen , a conventional NSAID . METHODS : In this double-blind , parallel-group , multicenter study , 537 patients with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) were r and omized to treatment with celecoxib 200 mg b.i.d . ( n = 270 ) or naproxen 500 mg b.i.d . ( n = 267 ) for 12 wk . Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4 , 8 , and 12 wk of therapy . Arthritis efficacy was evaluated with Patient 's and Physician 's Global Assessment s. RESULTS : Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4 % versus 19 % in the 0–4 wk interval ( p < 0.001 ) , 2 % versus 14 % in the 4–8 wk interval ( p < 0.001 ) , and 2 % versus 10 % in the 8–12 wk interval ( p < 0.001 ) , respectively . After 12 wk of treatment , the cumulative incidence of gastroduodenal ulcers was 9 % with celecoxib and 41 % with naproxen . In the celecoxib group , gastroduodenal ulcers were significantly associated with Helicobacter pylori status ( p < 0.05 ) , concurrent aspirin usage ( p = 0.001 ) , and a history of ulcer ( p = 0.010 ) , but not with disease type ( OA/RA ) , age , gender , other relevant medical histories , or concurrent corticosteroid or disease-modifying antirheumatic drugs usage ( p > 0.05 ) . Celecoxib produced a significantly lower incidence rate of both gastric ( p < 0.001 ) and duodenal ( p < 0.030 ) ulcers . The two agents produced similar improvements in Patient 's and Physician 's Global Assessment s of arthritis efficacy . The incidence of adverse events and withdrawal rates did not differ significantly between treatments . CONCLUSIONS : As compared to naproxen ( 500 mg b.i.d . ) , use of celecoxib ( 200 mg b.i.d . ) , a COX-2 specific agent , at the recommended RA dose and twice the most frequently prescribed OA dose , was associated with lower rates of gastric , duodenal , and gastroduodenal ulcers but had comparable efficacy , in patients with OA and RA To compare celecoxib ( 800 mg/day , n=1997 ) with diclofenac ( 150 mg/day , n=1996 ) on dyspepsia‐related tolerability Background : Lumiracoxib ( Prexige ; Novartis Pharma AG , Basel , Switzerl and ) is a cyclooxygenase‐2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti‐inflammatory drugs , in patients with osteoarthritis BACKGROUND Guidelines on pain management recommend that patients at risk of ulcers receive either a cyclo-oxygenase ( COX 2 ) inhibitor or a non-steroidal anti-inflammatory drug ( NSAID ) with a proton-pump inhibitor ( PPI ) . These two treatments have similar effectiveness , but they are insufficient for protection of patients at very high risk for ulcer bleeding . We aim ed to test the hypothesis that in patients with previous ulcer bleeding induced by non-selective NSAIDs , combined treatment with the COX 2 inhibitor celecoxib and the PPI esomeprazole would be better than celecoxib alone for prevention of recurrent ulcer bleeding . METHODS 441 consecutively presenting patients who were taking non-selective NSAIDs for arthritis were recruited to our single-centre , prospect i ve , r and omised , double-blind trial after admission to hospital with upper-gastrointestinal bleeding . Patients were enrolled after their ulcers had healed and a histological test for Helicobacter pylori was negative . All patients were given 200 mg celecoxib twice daily . 137 patients were r and omly assigned to receive 20 mg esomeprazole twice daily ( combined-treatment group ) , and 136 to receive a placebo ( control group ) for 12 months . The primary endpoint was recurrent ulcer bleeding during treatment or within 1 month of the end of treatment . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00365313 . FINDINGS Combination treatment was more effective than celecoxib alone for prevention of ulcer bleeding in patients at high risk . The 13-month cumulative incidence of the primary endpoint was 0 % in the combined-treatment group and 12 ( 8.9 % ) in the controls ( 95 % CI difference , 4.1 to 13.7 ; p=0.0004 ) . The median follow-up was 13 months ( range 0.4 - 13.0 ) . Discontinuation of treatment and the incidence of adverse events were similar in the two treatment groups . INTERPRETATION Patients at very high risk for recurrent ulcer bleeding who need anti-inflammatory analgesics should receive combination treatment with a COX 2 inhibitor and a PPI . Our findings should encourage guideline committees to review their recommendations for patients at very high risk of recurrent ulcer bleeding OBJECTIVE To investigate the efficacy and safety of SC-58635 ( celecoxib ) , an antiinflammatory and analgesic agent that acts by selective cyclooxygenase 2 ( COX-2 ) inhibition and is not expected to cause the typical gastrointestinal ( GI ) , renal , and platelet-related side effects associated with inhibition of the COX-1 enzyme . METHODS Four phase II trials were performed : a 2-week osteoarthritis efficacy trial , a 4-week rheumatoid arthritis efficacy trial , a 1-week endoscopic study of GI mucosal effects , and a 1-week study of effects on platelet function . RESULTS The 2 arthritis trials identified SC-58635 dosage levels that were consistently effective in treating the signs and symptoms of arthritis and were distinguished from placebo on st and ard arthritis scales . In the upper GI endoscopy study , 19 % of subjects receiving naproxen ( 6 of 32 ) developed gastric ulcers , whereas no ulcers occurred in subjects receiving SC-58635 or placebo . The study of platelet effects revealed no meaningful effect of SC-58635 on platelet aggregation or thromboxane B2 levels , whereas aspirin caused significant decreases in 2 of 3 platelet aggregation measures and thromboxane B2 levels . In all 4 trials , SC-58635 was well tolerated , with a safety profile similar to that of placebo . CONCLUSION SC-58635 achieves analgesic and antiinflammatory efficacy in arthritis through selective COX-2 inhibition , without showing any evidence of 2 of the toxic effects of COX-1 inhibition associated with nonsteroidal antiinflammatory drugs BACKGROUND & AIMS The gastric safety of cyclooxgenase-2 inhibitors and prophylactic antisecretory therapy in high-risk arthritis patients is unclear . We studied the ulcer incidence and factors predicting ulcer recurrence in a prospect i ve , double-blinded trial . METHODS We studied patients who presented with nonsteroidal anti-inflammatory drug-associated ulcer bleeding . After ulcer healing , patients who were negative for Helicobacter pylori were r and omly assigned to celecoxib 200 mg twice a day plus omeprazole placebo once daily or diclofenac 75 mg twice daily plus omeprazole 20 mg once daily for 6 months . Patients underwent endoscopy if they developed recurrent bleeding . Those without recurrent events underwent endoscopy at their last follow-up visit . RESULTS Two hundred eighty-seven patients were enrolled ; 24 had recurrent gastrointestinal complications . Among 259 patients without events , 222 underwent endoscopy ( 116 received celecoxib and 106 received diclofenac plus omeprazole ) . The probability of recurrent ulcers in 6 months was 18.7 % in the celecoxib group and 25.6 % in the diclofenac plus omeprazole group ( difference , -6.7 % ; 95 % CI : -17.8 % to 3.9 % ) ( P = 0.21 ) . Combining bleeding and endoscopic ulcers , 24.1 % in the celecoxib group and 32.3 % in the diclofenac plus omeprazole group had recurrent ulcers in 6 months ( difference , -8.2 % ; 95 % CI : -19.5 % to 2.9 % ) ( P = 0.15 ) . Treatment-induced significant dyspepsia ( hazard ratio , 5.3 ; 95 % CI : 2.6 - 10.8 ) , age > or = 75 ( hazard ratio , 2.0 ; 95 % CI : 1.1 - 3.5 ) , and comorbidity ( hazard ratio , 2.1 ; 95 % CI : 1.2 - 3.7 ) independently predicted ulcer recurrence . CONCLUSIONS Among patients with previous ulcer bleeding , neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence . Treatment-induced significant dyspepsia is an indication for endoscopic evaluation BACKGROUND Current guidelines recommend that patients at risk for ulcer disease who require treatment for arthritis receive nonsteroidal antiinflammatory drugs ( NSAIDs ) that are selective for cyclooxygenase-2 or the combination of a nonselective NSAID with a proton-pump inhibitor . We assessed whether celecoxib would be similar to diclofenac plus omeprazole in reducing the risk of recurrent ulcer bleeding in patients at high risk for bleeding . METHODS We studied patients who used NSAIDs for arthritis and who presented with ulcer bleeding . After their ulcers had healed , we r and omly assigned patients who were negative for Helicobacter pylori to receive either 200 mg of celecoxib twice daily plus daily placebo or 75 mg of diclofenac twice daily plus 20 mg of omeprazole daily for six months . The end point was recurrent ulcer bleeding . RESULTS In the intention-to-treat analysis , which included 287 patients ( 144 receiving celecoxib and 143 receiving diclofenac plus omeprazole )  , recurrent ulcer bleeding occurred in 7 patients receiving celecoxib and 9 receiving diclofenac plus omeprazole . The probability of recurrent bleeding during the six-month period was 4.9 percent ( 95 percent confidence interval , 3.1 to 6.7 ) for patients who received celecoxib and 6.4 percent ( 95 percent confidence interval , 4.3 to 8.4 ) for patients who received diclofenac plus omeprazole ( difference , -1.5 percentage points ; 95 percent confidence interval for the difference , -6.8 to 3.8 ) . Renal adverse events , including hypertension , peripheral edema , and renal failure , occurred in 24.3 percent of the patients receiving celecoxib and 30.8 percent of those receiving diclofenac plus omeprazole . CONCLUSIONS Among patients with a recent history of ulcer bleeding , treatment with celecoxib was as effective as treatment with diclofenac plus omeprazole , with respect to the prevention of recurrent bleeding . Renal toxic effects are common in high-risk patients receiving celecoxib or diclofenac plus omeprazole OBJECTIVE To determine the upper gastrointestinal ( GI ) tolerability of celecoxib , naproxen , and placebo in patients with rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) . METHODS An analysis of 5 , 12-week , r and omized , double blind , parallel group , placebo controlled clinical trials was conducted . In these trials , patients were r and omized to : naproxen 500 mg bid ( n = 1,099 ) , placebo ( n = 1,136 ) , celecoxib 50 mg bid ( n = 690 ) ( subtherapeutic dose ) , celecoxib 100 mg ( n = 1,131 ) or 200 mg bid ( n = 1,125 ) ( therapeutic dose ) , or celecoxib 400 mg bid ( n = 434 ) ( supratherapeutic dosage ) . The incidence and time until moderate to severe abdominal pain , dyspepsia , nausea , and any of the aforementioned 3 upper GI symptoms ( composite endpoint ) were determined using time-to-event analysis . RESULTS The cumulative incidences of moderate to severe abdominal pain , dyspepsia , or nausea ( composite endpoint ) were : naproxen 500 mg ( 12.0 % ; 95 % CI 9.9%-14.0 % ) , celecoxib 50 mg bid ( 7.1 % ; 95 % CI 5.0%-9.2 % ) , celecoxib 100 mg bid ( 7.8 % ; 95 % CI 6.0%-9.5 % ) , celecoxib 200 mg bid ( 8.1 % ; 95 % CI 6.4%-9.9 % ) , celecoxib 400 mg bid ( 6.0 % ; 95 % CI 3.6%-8.4 % ) , and placebo ( 8.5 % ; 95 % CI 6.5%-10.8 % ) . After controlling for independent predictors of the composite endpoint , relative risks ( RR ) for the various treatments relative to naproxen 500 mg bid were : celecoxib 50 mg ( RR 0.54 ; 95 % CI 0.37 - 0.77 ; p < 0.001 ) , celecoxib 100 mg ( RR 0.60 ; 95 % CI 0.45 - 0.80 ; p < 0.001 ) , celecoxib 200 mg bid ( RR 0.63 ; 95 % CI 0.47 - 0.83 ; p = 0.001 ) , celecoxib 400 mg bid ( RR 0.56 ; 95 % CI 0.35 - 0.89 ; p = 0.015 ) , and placebo ( RR 0.63 ; 95 % CI 0.47 - 0.85 ; p = 0.002 ) . After controlling for independent predictors of the composite endpoint , celecoxib treatment group patients did not differ from placebo patients when reporting the composite endpoint , with p values ranging from 0.40 to 0.96 . CONCLUSION The upper GI tolerability of celecoxib is superior to naproxen . A dose-response relationship between celecoxib and upper GI symptoms was not apparent Abstract Objective : To compare the safety and efficacy of celecoxib versus diclofenac slow release ( SR ) plus omeprazole in elderly arthritis patients . Research design and methods : Patients aged ≥65 years , with osteoarthritis and /or rheumatoid arthritis , at high gastrointestinal ( GI ) risk who participated in the CONDOR trial ( Celecoxib vs. Omeprazole and Diclofenac in Patients With Osteoarthritis and Rheumatoid Arthritis ) were included in this sub analysis . CONDOR was a 6-month prospect i ve , double-blind , r and omized , parallel-group , multicenter , international study comparing treatment with celecoxib 200 mg twice daily ( BID ) versus diclofenac SR 75 mg BID plus omeprazole 20 mg daily . Main outcome measures : The primary end point was a composite of Clinical ly Significant Upper and Lower GI Events adjudicated by an independent blinded expert committee . Efficacy was determined by the Patient ’s Global Assessment of Arthritis . Results : A total of 2446 patients aged ≥65 years were included in the intent-to-treat ( ITT ) population ( n = 1219 celecoxib ; n = 1227 diclofenac ) . Eight patients in the celecoxib group and 52 in the diclofenac group were adjudicated as having Clinical ly Significant Upper and Lower GI events ( adjusted odds ratio : 6.27 ; p < 0.0001 ) . Clinical ly significant reductions in hemoglobin ( ≥2 g/dL ) and /or hematocrit ( ≥10 % ) were observed in 23 patients in the celecoxib group and in 76 in the diclofenac group ( relative risk : 3.22 [ 95 % confidence interval : 2.04–5.07 ] ; p < 0.0001 ) . Incidence of moderate-to-severe abdominal symptoms and discontinuation of treatment due to GI adverse events ( AEs ) were lower in the celecoxib group . The Patient ’s Global Assessment of Arthritis score least squares mean change from baseline to final visit and percentage of patients rating treatment efficacy as good/very good at baseline and final visit were similar in both groups . Limitations : The dose of celecoxib used is consistent with the European label for the management of osteoarthritis and may not reflect what is commonly prescribed in current clinical practice in the United States . The data were obtained in a clinical trial setting where patients were enrolled based on specific inclusion and exclusion criteria ; as such , the patients may not be broadly representative of the patient population in a general practice setting . Conclusions : Efficacy was comparable in the two treatment groups . There were fewer endpoints as well as fewer GI AEs reported in patients treated with celecoxib compared with diclofenac . These data may help physicians in their treatment decisions for elderly patients with arthritis OBJECTIVE Selective inhibitors of cyclo-oxygenase-2 ( COX-2 ) appear to be safer than conventional NSAIDs on the gastrointestinal ( GI ) tract . Amtolmetin guacyl ( AMG ) , a NSAID that inhibits both COX-1 and COX-2 , has an anti-inflammatory effect comparable to that of traditional NSAIDs , with a better GI safety profile . The primary end-point of this study was to evaluate the gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients affected with rheumatoid arthritis . The assessment of efficacy was the secondary end-point . METHODS This study was a 24-week , r and omized , parallel group , double-blind , double dummy , multicentre trial ; 235 patients were enrolled and 180 patients ( 85 in the AMG group and 95 in the celecoxib group ) completed the study . Each patient received twice daily amtolmetin guacyl 600 mg or celecoxib 200 mg . Assessment of safety was performed by upper GI endoscopy , gastrointestinal symptoms evaluation , electrocardiography , blood and urine laboratory tests , adverse events recording . Assessment of efficacy was performed by using the American College of Rheumatology ( ACR-20 ) responder index . RESULTS Neither amtolmetin guacyl nor celecoxib determined a worsening of baseline gastro-duodenal endoscopy findings . The percentage of patients with normal findings did not significantly change after treatment with both drugs , being virtually identical with AMG ( i.e. 75.29 % ) and increasing from 75.79 % to 77.66 % with celecoxib . Moreover an evaluation of the other safety parameters did not reveal any difference between the two treatment groups . Therapeutic efficacy was equivalent in both groups , with no statistical difference between the two drugs at all time intervals . CONCLUSIONS In patients affected with rheumatoid arthritis , AMG and celecoxib proved to be equivalent , showing comparable gastrointestinal safety and therapeutic efficacy of treatment BACKGROUND Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) and non-selective NSAIDs plus a proton-pump inhibitor ( PPI ) have similar upper gastrointestinal outcomes , but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs . We aim ed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole . METHODS We undertook a 6-month , double-blind , r and omised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories . Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration . We used a computer-generated r and omisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day . Patients and investigators were masked to treatment allocation . The primary endpoint was a composite of clinical ly significant upper or lower gastrointestinal events adjudicated by an independent committee . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00141102 . FINDINGS 4484 patients were r and omly allocated to treatment ( 2238 celecoxib ; 2246 diclofenac plus omeprazole ) and were included in intention-to-treat analyses . 20 ( 0.9 % ) patients receiving celecoxib and 81 ( 3.8 % ) receiving diclofenac plus omeprazole met criteria for the primary endpoint ( hazard ratio 4.3 , 95 % CI 2.6 - 7.0 ; p<0.0001 ) . 114 ( 6 % ) patients taking celecoxib versus 167 ( 8 % ) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events ( p=0.0006 ) . INTERPRETATION Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI . These findings should encourage review of approaches to reduce risk of NSAID treatment . FUNDING Pfizer
BACKGROUND Rheumatoid arthritis is a systemic auto-immune disorder that causes widespread and persistent inflammation of the synovial lining of joints and tendon sheaths .
Presently , there is no cure for rheumatoid arthritis and treatment focuses on managing symptoms such as pain , stiffness and mobility , with the aim of achieving stable remission and improving mobility .
Celecoxib is a selective non-steroidal anti-inflammatory drug ( NSAID ) used for treatment of people with rheumatoid arthritis .
OBJECTIVES To assess the benefits and harms of celecoxib in people with rheumatoid arthritis .