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.

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.

Gout, a rheurnatologic disorder, affects approximately 5.1 million people in the United States, and its prevalence seems to be increasing.(1-3) Most patients visit a primary care physician (PCP) for gout disease management; however, there are a number of challenges to diagnosing and treating gout in the PCP setting. Newer investigational agents for gout that are on the horizon have prompted rheumatologists to consider how they can share current information to improve gout management with PCP colleagues in a way that can be practically implemented in their clinical setting. To make this information practical, an understanding of some of the educational gaps and lingering misperceptions about gout need to be appreciated. Leading rheumatologists spent time talking with PCP colleagues at a series of educational meetings and collected survey data to validate educational needs. With this appreciation of PCP challenges, key information on best practices was developed.

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.

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.

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.

From the Department of Rheumatology, University of Nebraska Medical Center, Omaha, Nebraska. Arthur L. Weaver, MD, MS, FACP, MACR, has served as a consultant to and on advisory boards for Savient Pharmaceuticals, Inc. and TAP Pharmaceutical Products Inc. He has received honoraria for speaking at CME programs supported by unrestricted educational grants from TAP Pharmaceutical Products Inc. Reprints: Arthur L. Weaver, MD, MS, FACP, MACR, University of Nebraska Medical Center, Rheumatology, 9914 Weaver Point Road, Pequot Lakes, MN. E-mail: [email protected].

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. Am J Ther. 2008;15:S12-S16 .

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.

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.

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.

Patient MA, a 56-year-old postmenopausal white woman with sudden onset of acute pain in the right great toe, was seen by her primary care physician the following day. She walked with support from her husband because she was unable to walk or bear weight without assistance. The patient—a homemaker—reported that she had had 2 previous episodes of similar pain in the great toe and ankle lasting 4 to 5 days that were treated by emergency room physicians with analgesics.

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.

SummaryUntil recently, cyclo‐oxygenase‐2 inhibitors were one of the mainstays of therapy for patients with osteoarthritis and rheumatoid arthritis because of their improved gastrointestinal safety profile compared with traditional, non‐selective non‐steroidal anti‐inflammatory drugs.The withdrawal of both rofecoxib and valdecoxib from the market because of concerns about cardiovascular risk has prompted a re‐evaluation of treatment choices for arthritis patients who require treatment with non‐steroidal anti‐inflammatory drugs. Non‐steroidal anti‐inflammatory drugs, both prescription and over‐the‐counter, are widely used in the USA. Patients often take several agents concurrently which significantly increases their risk of gastrointestinal adverse events. In addition, many patients also take low‐dose aspirin because of its proven beneficial effects in the prevention of cardiovascular events. However, large clinical trials have shown that the concomitant use of aspirin negates the gastrointestinal‐sparing effects of selective cyclo‐oxygenase‐2 inhibitors.Clinicians need to consider a patient's cardiovascular and gastrointestinal risks when prescribing non‐steroidal anti‐inflammatory drugs, and in the case of non‐selective non‐steroidal anti‐inflammatory drugs, gastroprotection with an agent such as a proton‐pump inhibitor or misoprostol should be considered, particularly in aspirin users.

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.