Arthur L. Weaver

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)–Fc Fusion Protein

BACKGROUND Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc). METHODS In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria. RESULTS Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples. CONCLUSIONS In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.

Two‐year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate

OBJECTIVE Three 6-12-month, double-blind, randomized, controlled trials have shown leflunomide (LEF; 20 mg/day, loading dose 100 mg x 3 days) to be effective and safe for the treatment of rheumatoid arthritis (RA). This analysis of the North American trial assessed whether the clinical benefit evident at month 12 was sustained over 24 months of treatment with LEF as compared with the efficacy and safety of methotrexate (MTX), an equivalent disease-modifying antirheumatic drug, at 24 months. METHODS The year-2 cohort, comprising patients continuing into the second year of treatment with > or = 1 dose of study medication and > or = 1 followup visit after week 52, consisted of 235 patients (LEF n = 98; placebo n = 36; MTX n = 101). The mean (+/- SD) maintenance dose of LEF was 19.6 +/- 1.99 mg/day in year 2 and that of MTX was 12.6 +/- 4.69 mg/week. Statistical analyses used an intent-to-treat (ITT) approach. Statistical comparisons of the active treatments only were prospectively defined in the protocol. RESULTS In total, 85% and 79% of LEF and MTX patients, respectively, who entered year 2 completed 24 months of treatment. From month 12 to month 24, the American College of Rheumatology improvement response rates of > or = 20% (LEF 79% versus MTX 67%; P = 0.049), > or = 50% (LEF 56% versus MTX 43%; P = 0.053), and > or = 70% (LEF 26% versus MTX 20%; P = 0.361) were sustained in both of the active treatment groups. The mean change in total Sharp radiologic damage scores at year 2 compared with year 1 and baseline (LEF 1.6 versus MTX 1.2) showed statistically equivalent sustained retardation of radiographic progression in the active treatment groups. Maximal improvements evident at 6 months in the Health Assessment Questionnaire (HAQ) disability index (HAQ DI) and the physical component score of the Medical Outcomes Survey 36-item short form were sustained over 12 months and 24 months; improvement in the HAQ DI with LEF4(-0.60) was statistically significantly superior to that with MTX (-0.37) at 24 months (P = 0.005). Over 24 months in the ITT cohort, serious treatment-related adverse events were reported in 1.6% of the LEF-treated patients and 3.7% of the MTX-treated patients. Frequently reported adverse events included upper respiratory tract infections, diarrhea, nausea and vomiting, rash, reversible alopecia, and transient liver enzyme elevations. CONCLUSION The safety and efficacy of LEF and MTX were maintained over the second year of this 2-year trial. Both active treatments retarded radiographic progression over 24 months. LEF was statistically significantly superior to MTX in improving physical function as measured by the HAQ DI over 24 months of treatment. Results indicate that LEF is a safe and effective initial treatment for active RA, with clinical benefit sustained over 2 years of treatment without evidence of new or increased toxicity.

Misoprostol Dosage in the Prevention of Nonsteroidal Anti-inflammatory Drug-Induced Gastric and Duodenal Ulcers: A Comparison of Three Regimens

Worldwide, nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed more frequently than any other group of medications [1]. Unfortunately, NSAID use is almost invariably accompanied by some degree of injury to the gastroduodenal mucosa, manifested by fecal blood loss or discovered by upper gastrointestinal endoscopy [2-10]. Gastroduodenal mucosal damage induced by NSAIDs may lead to the development of gastric or duodenal ulcers, or both, with the attendant possibility of hemorrhage and perforation in some patients. Several studies [4, 5, 8, 11-16] have shown that misoprostol, a synthetic analog of prostaglandin E1, affords significant protection against NSAID-induced gastric and duodenal ulcers; the drug has also been shown to reduce the incidence of ulcer complications [17]. However, the use of misoprostol at the currently recommended dosage of 200 g four times daily is associated with frequent side effects, which primarily affect the gastrointestinal tract. These side effects are generally mild but may lead to poor patient compliance. A lower dosage of misoprostol, such as 200 g twice or three times daily, might result in a lower incidence of adverse events (and, hence, better compliance) without adversely affecting efficacy. We sought to determine the effectiveness and tolerability of three different misoprostol regimens. Methods The study was a 12-week, randomized, parallel, placebo-controlled, double-blind comparison of three regimens of misoprostol (Cytotec, G.D. Searle & Co., Chicago, Illinois) and was done at 135 centers. A single study protocol was approved by the institutional review boards for all study sites. Informed consent was obtained from all patients. Patients qualifying for study entry had a clinical diagnosis of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or the Reiter syndrome and were receiving NSAID therapy that was expected to continue uninterrupted for at least 3 additional months at a fixed dose. The following minimum daily NSAID dosages were required: ibuprofen, 1200 mg; piroxicam, 20 mg; naproxen, 750 mg; sulindac, 200 mg; tolmetin, 1200 mg; indomethacin, 75 mg; flurbiprofen, 200 mg; ketoprofen, 150 mg; or diclofenac, 150 mg. Qualifying patients had to be having upper gastrointestinal symptoms, such as pain, cramps, bloating, or heartburn. Before study entry, patients supplied a medical history and had a physical examination, upper gastrointestinal symptom assessment, routine laboratory tests, and upper gastrointestinal endoscopy. Patients with a gastric or duodenal mucosal defect 0.3 cm or less in diameter, a mucosal defect of any size with perceptible depth, or any esophageal erosions or ulcers were excluded from the study. Also excluded were patients who had had upper gastrointestinal surgery within 30 days of anticipated entry into the study and patients with upper gastrointestinal malignancy, pyloric obstruction, acute hepatitis, pancreatitis, inflammatory bowel disease, or a bleeding diathesis. Patients were assigned to their regimens according to a centralized, computer-generated randomization schedule. Each center was assigned with one or more randomization blocks of seven in sealed envelopes. Patients were assigned sequentially to receive one of four regimens: placebo four times daily; 200 g of misoprostol twice daily plus placebo twice daily; 200 g of misoprostol three times daily plus placebo once daily; or 200 g of misoprostol four times daily. One patient was assigned to the group receiving misoprostol four times daily for every two patients assigned to the other groups. These assignment ratios were chosen in light of the known therapeutic effectiveness of four-times-daily dosing. They were calculated to demonstrate a reduction in the rate of gastric ulcer development from 13% in the placebo group to 4% in each of the active treatment arms (twice daily, three times daily, and four times daily), and to show a similar reduction in duodenal ulcer development from 6.3% to 1%, with an overall error rate of 0.05% and a power of 80%. Blister cards of scored tablets were supplied by the sponsor and contained tablets of misoprostol, 200 g, or identical tablets composed of inert excipient. Labels on the blister packs indicated the breakfast, lunch, dinner, and bedtime doses. For the first 3 days of the study, patients were instructed to take one half of one tablet four times daily and to discard the other halves of the tablets. Subsequently, full tablets were taken. Patients who missed a dose were instructed to skip that dose. Each patient was provided with antacid tablets, 84 600 mg aluminum hydroxide (Amphogel, Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania), and instructed to take as many as four tablets per day as required for relief of upper abdominal symptoms during the first 3 weeks of the study. Study medication dispensed at one visit was collected and inventoried at the next visit to ensure at least 60% compliance in the dosing of misoprostol. Patients had endoscopic and upper gastrointestinal symptom evaluations after 4, 8, and 12 weeks of therapy. Endoscopic examinations included assessment of the gastric and duodenal mucosa. Patient Groups Analyzed Of the 1623 patients enrolled in the study, 1259 finished the trial. Of these, 1197 met major accession, study drug compliance, and endoscopic evaluation criteria and composed the evaluable group of patients. Primary analyses were done on this evaluable group. Confirmatory analyses were also done on the intention-to-treat group, which comprised patients who had received at least one dose of study medication. End Points A patient who developed an endoscopically confirmed gastric or duodenal ulcer ( 0.3 cm in diameter and with perceptible depth) during the study was considered a prophylaxis failure. Statistical Analysis The baseline demographic characteristics of the study treatment groups were compared using either the Pearson chi-square test (sex and race) or the Kruskal-Wallis test (age). To evaluate the efficacy of misoprostol therapy in the prevention of NSAID-induced gastric and duodenal ulcers, the following three pairwise comparisons were made: misoprostol twice daily compared with placebo, misoprostol three times daily compared with placebo, and misoprostol four times daily compared with placebo. In addition, comparisons of the incidence of NSAID-induced ulcers in the groups receiving misoprostol twice and three times daily with that in the group receiving misoprostol four times daily were done to determine evidence of similar effectiveness in the prevention of ulcers. Treatment-by-investigator interactions were assessed qualitatively. The dosage-response effect of misoprostol was determined by using a logistic regression analysis with ulcer occurrence as the dependent variable and dosage as the independent variable. The placebo group was not included for these analyses. Incidence rates for adverse events were calculated for body system, type of event, severity (mild, moderate, and severe), and relation to study drug (none, uncertain, and probable). Interregimen incidence rate comparisons were made using the unadjusted, two-tailed chi-square test. If chi-square assessment of incidence rates for the four regimens for an individual adverse event showed a statistically significant difference, incidence rates for the particular adverse event were further tested without the placebo group to distinguish differences among the three active treatment groups. Adverse events causing withdrawal from the study were compared across treatment groups using the Pearson chi-square test or the Fisher exact test. Dosage-response effect on adverse events was determined by using a logistic regression analysis with adverse event as the dependent variable and dosage as the independent variable. The statistical analysis was done by G.D. Searle & Co. Results Study Population The disposition and randomization of patients entered into the study (n = 1623) is presented in Table 1. Five patients received no medication and were excluded from the intention-to-treat group. A total of 421 patients was excluded from the intention-to-treat group (359 were withdrawn before reaching an end point and 62 were excluded for other reasons), leaving 1197 patients in the evaluable group. Table 1. Disposition of Patients Entered into the Study Demographic Characteristics Demographic data for the intention-to-treat group are shown in Table 2. Neither the intention-to-treat group nor the evaluable groups differed significantly with respect to age, sex, race, NSAID use, type of arthritis, prevalence of smoking, or alcohol use. Table 2. Demographic Characteristics of the Intention-to-Treat Group Gastric Ulcers Gastric ulcers (evaluable for the gastric ulcer group) were noted in 51 of 325 patients (15.7%) receiving placebo, in 29 of 358 patients (8.1%) receiving misoprostol twice daily, in 13 of 336 patients (3.9%) receiving misoprostol three times daily, and in 6 of 152 patients (4.0%) receiving misoprostol four times daily (Table 3). The incidence of gastric ulcers was significantly lower in groups receiving misoprostol twice daily (difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) than in the group receiving placebo. Pairwise comparison showed no statistical difference between the group receiving misoprostol four times daily and the groups receiving it three times or twice daily. However, a significant difference (difference, 4.2% [CI, 0.7% to 7.7%]; P = 0.02) was noted between the group receiving misoprostol twice daily and the group receiving it three times daily. A significant dose-response effect across treatment groups was noted (P = 0.02). Table 3. Pairwise Comparison of Rates of Gastric Ulcer in the Evaluable-for-Gastric-Ulcer Group Duodenal Ulcers Duodenal ulcer

Treatment of early seropositive rheumatoid arthritis with minocycline: Four‐year followup of a double‐blind, placebo‐controlled trial

OBJECTIVE Rheumatoid arthritis (RA) causes substantial morbidity and mortality, and current treatments are suboptimal. Recent studies have demonstrated the short-term efficacy of minocycline in the treatment of patients with early RA. This study was undertaken to compare patients treated with conventional therapy in the early phase of their RA and those treated with minocycline, after 4 years of followup. METHODS Forty-six patients with seropositive RA of <1 years duration had been enrolled in a double-blind study of minocycline (100 mg twice daily) versus placebo. After the blinded portion of the study (3-6 months, depending upon response), all patients were treated with conventional therapy. This report compares those patients randomized to receive placebo for 3 months and then conventional therapy for the duration of 4 years versus those originally randomized to receive minocycline. RESULTS Twenty of the 23 original minocycline-treated patients and 18 of the 23 original placebo-treated patients were available for followup (mean 4 years). At followup, RA was in remission (American College of Rheumatology criteria) without disease-modifying antirheumatic drug (DMARD) or steroid therapy in 8 of the patients originally treated with minocycline compared with 1 patient in the placebo group (P = 0.02). Ten patients in the minocycline group versus 16 in the original placebo group currently require DMARD therapy (P = 0.02). CONCLUSION Among patients with seropositive RA, remissions are more frequent and the need for DMARD therapy is less in those treated early in the disease course with minocycline compared with those treated with conventional therapy delayed by an average of only 3 months. Minocycline appears to be an effective therapy for early RA; further investigation into its mechanism of action is needed.

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

ABSTRACT 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.

COX-2 specific inhibitors in the management of osteoarthritis of the knee: a placebo-controlled, randomized, double-blind study.

COX-2 specific inhibitors have demonstrated significant safety advantages and comparable efficacy in osteoarthritis (OA) compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs), but no direct comparative trials between COX-2 specific inhibitors have been published. In this double-blind, placebo-controlled, parallel group, multicenter study, 182 patients (≥40 years old) with OA of the knee were randomly assigned to treatment with celecoxib 200 mg q.d. (n = 63), rofecoxib 25 mg q.d. (n = 59), or placebo (n = 60) for 6 weeks. Arthritis assessments were performed at baseline and Weeks 3 and 6, or at early termination. At Week 6, celecoxib and rofecoxib treatment resulted in similar mean changes from baseline (p > 0.55) in arthritis pain visual analogue scale, patients global assessment, and total score for WOMAC; all changes were superior to placebo (p < 0.05). In the patients global assessment of arthritis pain at Week 6, 79% of celecoxib-treated and 78% of rofecoxib-treated patients improved by ≥1 grade, compared with 50% of placebo patients (celecoxib, p = 0.025; rofecoxib, p = 0.020). Adverse event incidences were similar among the active comparators; however, celecoxib-treated patients had significantly fewer adverse gastrointestinal symptoms compared with rofecoxib-treated patients, which suggests that celecoxib may have a better gastrointestinal tolerability profile than rofecoxib at these doses. Adverse events that prompted withdrawal occurred in fewer than 7% of patients, and the overall incidences were similar between the active agents. Once-daily doses of celecoxib 200 mg and rofecoxib 25 mg offer comparable efficacy and are an effective alternative to conventional NSAIDs in the management of OA.

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

ABSTRACT 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.

Comparison of the upper gastrointestinal safety of arthrotec® 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers

A 6-week, multicenter, double-masked, placebo-controlled, parallel-group study compared the upper gastrointestinal (UGI) safety of Arthrotec 75 (diclofenac sodium 75 mg-misoprostol 200 microg; G.D. Searle & Co., Skokie, Illinois) administered twice daily with that of nabumetone 1500 mg administered once daily in 1203 patients with symptomatic osteoarthritis (OA) of the hip or knee. All patients had a documented clinical history of endoscopically confirmed gastric, pyloric-channel, or duodenal ulcer or > or = 10 erosions in the stomach or duodenum. UGI endoscopy was performed at baseline and again at week 6 or early withdrawal. Treatment with Arthrotec 75 resulted in a significantly lower combined incidence of endoscopically confirmed gastric and duodenal ulcers compared with nabumetone (4% vs 11%), and its rate of endoscopically confirmed ulceration was equivalent to that of placebo. The incidence of gastric ulcers alone was also significantly lower with Arthrotec 75 than with nabumetone (1% vs 9%). The incidence of duodenal ulcer with Arthrotec 75 was not significantly different from that with nabumetone (4% vs 3%). Types of adverse events were similar for all treatment groups, with GI adverse events predominating. Arthrotec 75 was well tolerated by the majority of patients. The results of this study demonstrate that Arthrotec 75 has a superior UGI safety profile, causing significantly fewer UGI ulcers, in comparison with nabumetone in patients with symptomatic OA and a documented history of ulcers or > or = 10 erosions.

Serum selenium concentrations in rheumatoid arthritis.

Selenium is a trace element and an essential part of the enzyme glutathione peroxidase, which protects cells from oxidative damage. Selenium has been shown to have antiproliferative, anti-inflammatory, antiviral, and immune altering effects. Serum selenium concentrations in 101 patients with seropositive rheumatoid arthritis were found to be significantly lower than those in 29 normal, healthy controls (mean (SD) 148 (42) v 160 (25) micrograms/l) and also lower than those in eight patients with fibrositis (148 (42) v 166 (25) micrograms/l). It is speculated that serum selenium concentrations may modulate the effect of viral or other infections in subjects with the appropriate genetic background and in this way enhance the development or progression of rheumatoid arthritis.