Comparison of physician and patient global assessments over time in patients with rheumatoid arthritis: a retrospective analysis from the RADIUS cohort.

BACKGROUND: In rheumatoid arthritis (RA), there is discordance between patient and physician assessments of disease severity and treatment response. OBJECTIVE: This retrospective analysis of the RADIUS (RA Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) 1 cohort examined specific factors that influence differences in global assessments for therapeutic effectiveness of disease-modifying antirheumatic drugs made by physicians (physician global assessment [PhGA]) and patients (patient global assessment [PtGA]). METHODS: The RADIUS 1 cohort consisted of primarily community-based private practice patients with RA requiring either the addition of or a switch to a new biologic or nonbiologic disease-modifying antirheumatic drug and who were followed for up to 5 years by their rheumatologists. Periodic assessments included PhGA, PtGA, Health Assessment Questionnaire-Disability Index (HAQ-DI), 28-item tender/painful joint count (TJC28), swollen joint count (SJC28), pain Visual Analog Scale (VAS), and acute-phase reactants. RESULTS: Among 4359 patients (mean disease duration, 7.3 years), PhGA most highly correlated with TJC28 (0.6956; 95% confidence interval [CI], 0.6881-0.7030) and SJC28 (0.6757; 95% CI, 0.6678-0.6834). Moderate overall correlations were observed for PtGA with TJC28 (0.5000; 95% CI, 0.4890-0.5108) and less 50 with SJC28 (0.3754; 95% CI, 0.3628-0.3878). Patient global assessment most strongly correlated with pain VAS (0.8349; 95% CI, 0.8305-0.8392) and moderately correlated with HAQ-DI (0.5979; 95% CI, 0.5886-0.6071). Acute-phase reactants poorly correlated with PhGA and PtGA. CONCLUSIONS: Low correlations between PhGA and acute-phase reactants suggest that these measurements have a limited contribution compared with the physical examination when physicians make global assessments. These results also suggest that physicians should consider patients' assessments of their disease activity (HAQ, pain VAS, and PtGA) and put joint counts into proper context.

Rheumatoid arthritis disease activity and disability affect the risk of serious infection events in RADIUS 1.

OBJECTIVE: To determine whether disease activity and disability independently correlate with serious infection event (SIE) risk in a large rheumatoid arthritis (RA) cohort. METHODS: The associations between SIE and Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index (HAQ-DI) in the Rheumatoid Arthritis Disease-Modifying Antirheumatic Drug Intervention and Utilization Study (RADIUS 1) cohort were evaluated using the Andersen-Gill model (a proportional HR model allowing > 1 event per patient). RESULTS: Of 4084 patients with 347 SIE, 271 patients experienced ≥ 1 SIE. A 5-unit CDAI increase and 0.4-unit HAQ-DI increase corresponded to an increase in SIE risk with and without covariate adjustments. A 5-unit CDAI increase corresponded with a 7.7% increased SIE risk (adjusted HR 1.077, 95% CI 1.044-1.112, p < 0.0001) and a 0.4-unit HAQ-DI increase with a 30.1% increased risk (adjusted HR 1.301, 95% CI 1.225-1.381, p < 0.0001). Categorical analysis showed that more severe RA activity (even after controlling for disability) and disability were associated with an increased SIE risk. CONCLUSION: Increased RA disease activity and disability were each associated with a significantly increased SIE risk in the RADIUS 1 cohort, which could not be completely accounted for by disability.

Epidemiology of gout.

The incidence and prevalence of gout are rising, likely as a result of a changing pattern of risk factors. At-risk populations are growing, due to the fact that people are living longer. Longevity and current dietary and lifestyle choices have also contributed to increased rates of comorbidities associated with hyperuricemia and gout. The use of medications to treat such comorbidities also plays a role in some cases of gout. While dietary and lifestyle modification may be useful as adjunctive measures, such changes do not replace pharmacologic treatments for gout or associated comorbidities.

Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. 1989.

One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Unresolved issues in identifying and overcoming inadequate response in rheumatoid arthritis: weighing the evidence.

Rheumatoid arthritis (RA) is a chronic, multisystem, inflammatory disorder of the joints that affects about 1% of the world population. The ultimate goals of therapy include remission of disease and prevention of joint damage. Reaching these goals has become a realistic outcome for an increasing number of patients as treatment options have expanded over the past 3 decades. In addition to older therapies, such as methotrexate (MTX), other disease modifying drugs (DMARD), and tumor necrosis factor (TNF) inhibitors, newer biologic treatments have become available. For the substantial number of patients who experience an inadequate response to standard medications, biologic response modifiers (BRM) provide an important therapeutic alternative. The availability of multiple treatment options in the absence of clear definitions or criteria for remission and inadequate response, however, makes clinical decisions about measuring outcomes, predicting response to treatment, and prescribing pharmacologic therapies challenging. In this program, distinguished rheumatologists weigh the evolving body of clinical evidence to draw sound conclusions and resolve key issues in managing inadequate response to treatment and in achieving optimal outcomes in RA.

Current and emerging treatments for mild/moderate acute ambulatory pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs), the mainstay of therapy for acute musculoskeletal pain, are among the most widely used drugs in the world. The major limitation of traditional (nonselective) NSAIDs is gastrointestinal (GI) toxicity, which includes dyspepsia, mucosal injury, and serious events, such as ulcers, GI bleeding, and perforation. This article reviews the mechanism of action, safety, and efficacy of traditional and selective NSAIDs (coxibs); risk factors for GI complications; and strategies for reducing risk and preventing NSAID-related gastropathy and cardiovascular complications. The article also discusses the use of aspirin for cardioprotection in patients taking analgesic/anti-inflammatory agents for musculoskeletal pain and the need to balance competing GI and cardiovascular risks. Topical NSAIDs and other formulations that may prove to be safer than currently available agents also are addressed.

Rofecoxib 12.5 mg, rofecoxib 25 mg, and celecoxib 200 mg in the treatment of symptomatic osteoarthritis: results of two similarly designed studies.

OBJECTIVE: To compare the efficacy of rofecoxib and celecoxib for the treatment of knee or hip OA over 6 weeks. METHODS: Two similarly designed, multicenter, randomized, double-blind, placebo-controlled studies. Patients were randomly assigned 3:3:3:1 in Study 1 to once daily (QD) rofecoxib 12.5 mg (N = 456), rofecoxib 25 mg (N = 459), celecoxib 200 mg (N = 456), or placebo (N = 150) and 3:3:1 in Study 2 to QD rofecoxib 25 mg (N = 471), celecoxib 200 mg (N = 460), or placebo (N = 151). There was no rofecoxib 12.5 mg arm in Study 2. The primary outcome measure of both studies was pain at night over 6 weeks for rofecoxib 25 mg vs. celecoxib 200 mg. Efficacy comparisons with rofecoxib 12.5 mg in Study 1 were included as pre-specified study objectives but not as pre-specified study hypotheses. Secondary endpoints included Patient Global Assessment of Response to Therapy (PGART) over 6 weeks and over 1 week. Safety was evaluated through the assessment of spontaneously reported adverse experiences (AEs), evaluation of vital signs, and laboratory data reported by investigators and patients. RESULTS: For the primary endpoint, reduction in pain at night over 6 weeks in Study 1 was not significantly different between active treatments; in Study 2 rofecoxib 25 mg significantly (p = 0.023) reduced pain at night compared with celecoxib 200 mg over 6 weeks. For the secondary endpoints, in both studies, significantly (p < 0.05) more patients treated with rofecoxib 25 mg than celecoxib 200 mg had a good or excellent PGART over 6 weeks, and over the first week (p < 0.01). In both studies, there were no significant differences between active medications in the incidence of reported overall, serious, or drug-related AEs. The reported AE rates with the active treatments were generally similar to those with placebo in the two studies. CONCLUSIONS: Rofecoxib 25 mg was significantly better than celecoxib 200 mg in relieving night pain at 6 weeks in one study; this was not confirmed in the accompanying study.

Treatment of patients with osteoarthritis with rofecoxib compared with nabumetone.

BACKGROUND: Rofecoxib and nabumetone were developed to provide gastrointestinal benefits over traditional nonsteroidal antiinflammatory drugs (NSAIDs). However, there is limited comparative information relating to these 2 drugs. OBJECTIVE: The objective of this study was to compare rofecoxib and nabumetone, at their lower, recommended doses, in patients with osteoarthritis (OA). METHODS: Nine hundred seventy-eight patients with knee OA and a positive history of NSAID response were randomized to 12.5 mg rofecoxib per day (N=390), nabumetone 500 mg twice a day (N=392), or placebo (N=196) for 6 weeks. The primary efficacy end point was percent of patients with a "good" or "excellent" Patient Global Assessment of Response to Therapy (PGART) at week 6; PGART was also evaluated over days 1 to 6. Additional end points included investigator assessment of response, pain walking over 6 days and 6 weeks, joint tenderness, discontinuation as a result of lack of efficacy, and quality of life. Adverse experiences (AEs) were collected. RESULTS: Significantly more rofecoxib (50.4%) than nabumetone (43.3%, P=0.043) or placebo (29.5%, P<0.001) patients had a good or excellent PGART at week 6. Median time to a good or excellent PGART was significantly shorter with rofecoxib (52 hours) than nabumetone (100 hours, P=0.001) or placebo (>124 hours, P<0.001). Results for rofecoxib and nabumetone were similar in all additional end points except pain in walking over 6 days and 6 weeks, in both of which the rofecoxib treatment group demonstrated better results. There were significantly (P<0.050) more overall and serious AEs and discontinuations resulting from AEs with rofecoxib than nabumetone. Five rofecoxib and one nabumetone patients had confirmed thrombotic cardiovascular events (P=0.123). Information on thrombotic cardiovascular events from this study was included in a published, prespecified pooled analysis and is included here for completeness. CONCLUSIONS: At their recommended starting doses for OA, both agents were more effective than placebo. Rofecoxib at a dosage of 12.5 mg demonstrated significantly better efficacy in PGART than 1000 mg nabumetone in these patients known to be NSAID responders. Significantly more AEs occurred with rofecoxib than nabumetone. Considering these data and other recent safety information regarding cyclooxygenase-2 selective and nonselective NSAIDS, physicians must make risk/benefit assessments for each individual patient when considering the use of these agents, as recommended by the U.S. Food and Drug Administration.

Real-world utilization of DMARDs and biologics in rheumatoid arthritis: the RADIUS (Rheumatoid Arthritis Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) study.

OBJECTIVE: Rheumatoid Arthritis (RA) Disease-Modifying Anti-Rheumatic Drug (DMARD) Intervention and Utilization Study (RADIUS) is a unique, real-world, prospective, 5-year, observational study of over 10 000 patients with RA. RADIUS provides a snapshot of use patterns, effectiveness, and safety of DMARDs, biologics, and combination therapies used to manage RA in clinical practice. RESEARCH DESIGN AND METHODS: Patients with RA requiring a new DMARD or biologic (addition or switch) were eligible for the RADIUS study. Two separate patient cohorts were enrolled; RADIUS 1 patients initiated any new therapy at entry, and RADIUS 2 patients initiated etanercept at entry. Patient demographics and disease activity measures were collected at study entry, and baseline characteristics were summarized for various subgroups. Effectiveness, safety, and patterns of use will be tracked for therapies utilized during the 5-year study. RESULTS: RADIUS 1 enrolled 4959 patients, and RADIUS 2 enrolled 5102 patients, mostly at community private practices (88%). In RADIUS 1, most patients initiated methotrexate (MTX) monotherapy, followed by MTX in combination with a biologic (e.g. infliximab plus MTX) or other DMARD. In RADIUS 2, most patients initiated etanercept in combination with MTX, followed by etanercept monotherapy. When a new therapy was required, physicians tended to add another therapy versus switching therapies. Patients initiating a biologic had a longer duration of RA and more severe disease compared with patients initiating non-biologic therapy. CONCLUSIONS: These real-world data provide evidence of the prescribing practices of rheumatologists in 2001-2003. Future analyses will allow evidence-based comparisons of the long-term safety and effectiveness of DMARDs, biologics, and combination therapies to assist physicians in clinical decision-making.

Real-world effectiveness of select biologic and DMARD monotherapy and combination therapy in the treatment of rheumatoid arthritis: results from the RADIUS observational registry.

OBJECTIVE: To evaluate the effectiveness of select biologics, methotrexate (MTX), and other disease-modifying anti-rheumatic drugs (DMARDs) in the management of adult rheumatoid arthritis (RA) in routine clinical practice. RESEARCH DESIGN AND METHODS: RADIUS (Rheumatoid Arthritis DMARD Intervention and Utilization Study) comprises two prospective, 5-year, observational registries of over 10 000 patients. Over 4600 patients who initiated MTX or a biologic regimen (etanercept [ETN], infliximab [INF], ETN + MTX, and INF + MTX) and who had at least one on-regimen, follow-up evaluation, were included in this analysis. Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation. Other common DMARD regimens (N = 762) were also compared with MTX. Patients who initiated less commonly used regimens, such as anakinra or cyclosporine, and those who did not have at least one on-regimen, follow-up evaluation, were not eligible for this analysis. Because ESR/CRP measurements were often not available, a modified ACR20 response (mACR20), defined as three out of four response criteria excluding ESR/CRP, was used to assess response at 12 months. Logistic regression analysis was performed to control for baseline covariates that may affect outcomes. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry. RESULTS: After adjusting for baseline covariates, patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone (odds ratio [OR] 1.29, 95% confidence interval [CI] 1.09-1.52; p < 0.01 and OR 1.23, 95% CI 1.02-1.47; p < 0.05, respectively). Conversely, patients treated with MTX + leflunomide (LEF) were less likely to achieve a mACR20 response than those receiving MTX alone (OR 0.68, 95% CI 0.48-0.96; p < 0.05). Significant differences were not observed between patients receiving MTX alone and either INF + MTX, MTX + hydroxychloroquine, MTX + hydroxychloroquine + sulfasalazine, INF monotherapy, or LEF monotherapy. CONCLUSION: These data from routine rheumatology clinical practice settings highlight the effectiveness of common biologic and DMARD therapies, and provide additional data beyond those of randomized, controlled trials.

Current state of therapy for pain and inflammation.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclo-oxygenase (COX)-2 inhibitors, are among the most widely used medications in the USA. Traditional NSAIDs, although effective at relieving pain and inflammation, are associated with a significant increase in the risk for gastrointestinal adverse events. Throughout the 1990s these events were estimated to result in approximately 100,000 hospitalizations and 16,500 deaths each year nationally. Recent studies have indicated that the risk for serious NSAID gastropathy has declined substantially during the past decade as a result of a number of factors, including lower doses of NSAIDs, the use of gastroprotective agents such as proton pump inhibitors and misoprostol, and the introduction of the selective COX-2 inhibitors. One therapeutic approach that may reduce the risk for gastrointestinal side effects associated with traditional NSAIDs while retaining their efficacy is the inclusion of co-therapy with a proton pump inhibitor; these agents inhibit acid secretion and have been demonstrated to promote ulcer healing in patients with NSAID-related gastric ulcers. Alternatively, COX-2 selective agents have been used to treat patients at high risk for such events. Both nonselective and selective COX-2 inhibitors have now been shown to be associated with an increased risk for cardiovascular events. These studies, together with the outcomes of the recent US Food and Drug Administration decision to require 'black box' warnings regarding potential cardiovascular risks associated with NSAIDs, suggest that the use of COX-2 inhibitors as the sole strategy for gastroprotection in patients with arthritis and other pain syndromes must be reconsidered, particularly among those at risk for cardiovascular events.

Efficacy of rofecoxib, celecoxib, and acetaminophen in patients with osteoarthritis of the knee. A combined analysis of the VACT studies.

OBJECTIVE: To compare efficacy among 1578 patients with osteoarthritis randomized to take acetaminophen 4000 mg (n=269), celecoxib 200 mg (n=523), rofecoxib 12.5 mg (n=259), or rofecoxib 25 mg (n=527) in a double blind trial [Vioxx, Acetaminophen, Celecoxib Trial (VACT2)]. Results were also pooled with the similarly designed VACT1 trial. METHODS: Patients evaluated over Days 1 to 6 and 6 weeks with Patient Global Assessment of Response to Therapy (PGART) and Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. RESULTS: For VACT2, median time to good or excellent PGART response was 6, 5, 4, and 3 days for acetaminophen, celecoxib, rofecoxib 12.5 mg, and rofecoxib 25 mg (COX-2 inhibitors vs acetaminophen, p

Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of etoricoxib, a cyclooxygenase 2 (COX-2) selective inhibitor, administered continuously over 52 weeks for the treatment of ankylosing spondylitis (AS). METHODS: This 2-part, multicenter, double-blind, parallel-group, 52-week study evaluated 2 doses of etoricoxib (90 and 120 mg) compared with naproxen at 1,000 mg. A 6-week, active-comparator- and placebo-controlled period (part I) was followed by a 46-week active-comparator-controlled period (part II). The primary outcome measures (on 100-mm visual analog scales) were patient's assessment of spine pain, patient's global assessment of disease activity, and the Bath Ankylosing Spondylitis Functional Index. RESULTS: Of the 387 patients randomized to receive treatment, 301 (77.8%) completed part I and 284 (75.9%) completed part II. Compared with placebo over 6 weeks, those receiving 90 mg etoricoxib, 120 mg etoricoxib, and naproxen demonstrated significantly (P < 0.001) greater improvement in all primary end points; treatment effects (expressed as the difference in least squares mean change versus placebo) were 21-29 mm for spine pain, 18-25 mm for disease activity, and 11-15 mm for function. Compared with patients receiving naproxen, significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks, in each individual etoricoxib treatment group over 6 weeks, and in the combined etoricoxib group over 1 year (all P < 0.05); results for secondary and exploratory end points were generally consistent with those from the primary analysis. Among all groups, there were no significant differences in the incidence of overall clinical, drug-related, or serious adverse experiences (AEs) and discontinuations due to AEs. Safety observations during part II were generally consistent with those in part I. CONCLUSION: Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks, and compared with naproxen over 1 year. These study results demonstrate that etoricoxib is generally safe, well-tolerated, and efficacious for the treatment of AS.

A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and safety of a selective inhibitor of secretory phospholipase (sPLA2), LY333013, in the treatment of rheumatoid arthritis (RA). METHODS: Two hundred and fifty-one patients with active RA despite treatment with one or more disease modifying antirheumatic drugs (DMARD) received oral doses of LY333013 (50, 250, and 1000 mg) or placebo once daily for 12 weeks. Concomitant low-dose glucocorticoids (< or = 10 mg/day prednisone equivalent) were allowed. Clinical improvement was assessed using the response criteria of the American College of Rheumatology (ACR20), and safety was evaluated with respect to adverse events and laboratory test abnormalities. RESULTS: The demographic characteristics of the treatment groups were similar. Dose-response relationships were found for ACR20 responses (p = 0.058) and reductions in C-reactive protein (p = 0.058) at week 1. The proportions of patients with an ACR20 response subsequently increased in all study groups including the placebo group at weeks 4 and 8, and the initial treatment benefit was lost. Adverse events were generally mild in severity and not associated with treatment. CONCLUSION: Treatment with LY333013 for 12 weeks was well tolerated but ineffective as an adjunct to DMARD treatment of active RA.