Elizabeth A. Tindall

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.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

Duodenal and Gastric Ulcer Prevention with Misoprostol in Arthritis Patients Taking NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) remain the agents of choice in the treatment of many rheumatic diseases because of their analgesic and anti-inflammatory properties. However, use of NSAIDs is also associated with an increased frequency of peptic ulcers and ulcer complications, such as major upper gastrointestinal bleeding and perforation [1-8]. It has been estimated that in the United States, NSAID-induced gastrointestinal complications account for at least 2600 deaths and 20 000 hospitalizations each year in rheumatoid arthritis patients alone [9]. The concern about NSAID-induced gastroduodenal damage is heightened because complications often occur without preceding symptoms of ulcer disease [10, 11]. The prevalence of endoscopically confirmed upper gastrointestinal ulcers in NSAID users has been reported to range between 15% and 31% [12-17]. Despite the predominance of gastric ulcers in chronic NSAID users, ulcer complications in NSAID users are often associated with duodenal ulcers [7, 11, 18-20]. Duodenal ulcers are more common than gastric ulcers in patients not taking NSAIDs, suggesting that many duodenal ulcers associated with NSAID use may reflect NSAID exacerbation of preexisting peptic ulcer disease [21, 22]. Misoprostol, a synthetic prostaglandin E1 analog, has been shown to be effective in decreasing the incidence of gastric ulcers in chronic NSAID users [17, 23] without interfering with the antirheumatic effects of the NSAID. The H2-receptor antagonist, ranitidine, and the topical agent, sucralfate, have not been effective in preventing gastric ulcers in long-term NSAID users [23-25]. Ranitidine-NSAID cotherapy decreased the frequency of duodenal ulcers in NSAID-treated patients, suggesting that duodenal ulcers in NSAID users may have a different pathogenesis than gastric ulcers [24, 25]. Our study was designed to investigate the efficacy of misoprostol for the prevention of NSAID-induced duodenal ulcers in arthritis patients receiving long-term NSAID therapy. Methods Patients were recruited from private practice offices, Veterans Affairs clinics, health maintenance organizations, and academic institutions. The study was done between June 1989 and February 1991. Patients were eligible to enter the study if they had rheumatoid arthritis, osteoarthritis, psoriatic arthritis, ankylosing spondylitis, or the Reiter syndrome. Upper gastrointestinal pain was not required for entry into the study, but patients were expected to require at least 3 additional months of daily NSAID therapy with either ibuprofen, piroxicam, naproxen, sulindac, tolmetin, indomethacin, or diclofenac. Women were required to be postmenopausal, surgically sterilized, or practicing adequate contraception. Other exclusion criteria were a history of peptic ulcer disease requiring treatment in the 30 days immediately before entry, upper gastrointestinal malignancy, pyloric obstruction, acute hepatitis, pancreatitis, bleeding diathesis, upper gastrointestinal surgery within 30 days, or severe renal impairment. In addition, patients taking antineoplastic drugs, anticoagulants, anti-ulcer drugs other than the study drug, or prednisone at dosages of more than 7.5 mg/d were excluded. Study Design The study was a randomized, double-blind, placebo-controlled, multicenter trial of misoprostol, 200 g given four times a day (with meals and at bedtime with food). Upper gastrointestinal symptoms were scored using a 0 to 3 grading scale; zero corresponded to no abdominal pain, 1 corresponded to mild pain, 2 corresponded to moderate pain, and 3 corresponded to severe abdominal pain. Patients with gastric or duodenal ulcers of any size as well as those with erosions 0.3 cm in diameter at baseline upper gastrointestinal endoscopy were excluded. Patients who were accepted were randomized (randomization was balanced within each center) and received misoprostol or placebo within 72 hours of the entry endoscopic examination. Patients continued to take NSAIDs at the same dosage administered before the study. Patients were allowed to take up to three aluminum hydroxide antacid tablets (Amphojel [600 mg], Wyeth-Ayerst Laboratories, Philadelphia, Pennsylvania) per day for the first 2 weeks of the study for relief of upper gastrointestinal pain. After 4 weeks ( 3 days), 8 weeks ( 5 days), and 12 weeks ( 5 days) of treatment with misoprostol or placebo, endoscopic examinations and upper gastrointestinal pain evaluations were repeated. Endoscopists remained blinded to the patients medication. Patients were instructed to take the study medication the night before the endoscopy and not to take the next dose until after the procedure was completed. Noncompliance was defined as failure to take at least 60% of prescribed medication during the study period, determined by pill count at 4, 8, and 12 weeks of therapy. The protocol was approved by an institutional review board, and each patient gave written, informed consent. Data Analysis Any patient who received at least one dose of study medication qualified for analysis of the frequency of adverse experiences. The primary analysis for efficacy was of the intention-to-treat group. In addition, any patient who took at least 60% of the doses of study medication during the time of study participation, who had not missed more than 3 consecutive days of study medication, who satisfied the inclusion or exclusion criteria, and who had an initial and final endoscopic examination was considered evaluable for efficacy. Figure 1. Percentage of evaluable and intent-to-treat patients with duodenal ulcers. P P The primary end point of the study was the development of a duodenal ulcer at follow-up endoscopic examination. An ulcer was defined as a circumscribed break in the duodenal or gastric mucosa of 0.5 cm in diameter (0.5 cm by 0.5 cm or larger) and with perceptible depth. The comparability of the misoprostol and placebo treatment groups with respect to demographic characteristics at admission was assessed for all patients enrolled in the study. These characteristics included age, sex, race, height, and weight. When expected cell sizes were adequate, nominal measures were compared using the Pearson chi-square test. Otherwise, the Fisher exact test was used. Height, weight, and age measures were compared in the two treatment groups using the Wilcoxon rank-sum test. Treatment group differences in the proportion of patients who completed the study and the proportion of evaluable patients were assessed using the Pearson chi-square test. Patients who discontinued study participation without an endoscopy at week 4, week 8, or week 12 were classified as unknown for each time period at which their endoscopy status was undetermined. A chi-square analysis of duodenal ulcer development during the 12-week period was then conducted. Secondary analyses using identical methods were done for gastric ulcer development and gastroduodenal ulcer development. The rates of developing ulcers presented above did not account for censoring (that is, patients who discontinued the study before endoscopic verification of outcome or before they finished the full 12 weeks of study participation). Therefore, rates of developing duodenal, gastric, and gastroduodenal ulcer were also compared in the two treatment groups using a life-table analysis, which provided actuarial method estimates of the rate of ulcer development. The grouping intervals used for the life-table were prestudy to week-4 endoscopy, week-4 to week-8 endoscopy, and week-8 to week-12 endoscopy. The actual number of days from the prestudy endoscopy to the week 4, week 8, and week 12 endoscopies was not used to construct the life-table intervals; consequently, they can only be considered nominal categories. The log-rank test was used to compare the survival distributions of the two treatment groups. Figure 2. Percentage of intention-to-treat patients developing ulcers during the 12-week study period. Additional analyses using a stepwise logistic regression model were done to assess the effect of selected demographic and medical history measures on ulceration. Age, sex, alcohol consumption, smoking, type of arthritis, baseline erosions, and treatment group were the independent variables for these models. A forward selection procedure was used, with step selection of variables based on the maximum likelihood ratio and resulting P values from the chi-square statistics. A variable entered the model if its P value for entry was less than 0.15 and was retained in the model if its P value for removal was 0.15. Treatment group was initially entered in each model before beginning the stepping process. For these analyses, type of arthritis was categorized as osteoarthritis versus rheumatoid arthritis; patients who had both osteoarthritis and ankylosing spondylitis, or both osteoarthritis and psoriatic arthritis, were categorized as having osteoarthritis. Patients who had the other types of arthritis (including both osteoarthritis and rheumatoid arthritis) were excluded from the logistic regression analyses. The qualitative investigator assessments (daytime and nighttime pain and upper gastrointestinal symptoms) were tabulated at each visit by treatment group for evaluable patients. The distributions of the investigators severity ratings for daytime and nighttime pain were each compared for the two treatment groups at 12 weeks using the Fisher exact test. For patients who reported daytime or nighttime pain at the prestudy visit, changes from prestudy to week 12 in daytime and nighttime pain were categorized as better, same, or worse and compared in the two treatment groups using the Pearson chi-square test or the Fisher exact test, depending on the distribution of responses. For patients who did not report daytime or nighttime pain at the prestudy visit, the proportion of patients who developed daytime or nighttime pain at week 12 was compared in the two treatment groups using the Pearson chi

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis: ACR RA Treatment Recommendations

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

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

Abetimus sodium for renal flare in systemic lupus erythematosus: Results of a randomized, controlled phase III trial†

OBJECTIVE To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare. METHODS We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients. Three hundred seventeen patients with a history of renal flare and anti-dsDNA levels >15 IU/ml were randomized to a treatment group (158 abetimus, 159 placebo); 298 (94%) were enrolled in the intent-to-treat (ITT) population (145 abetimus, 153 placebo), based on the presence of high-affinity antibodies for the oligonucleotide epitope of abetimus at baseline screening. RESULTS Abetimus did not significantly prolong time to renal flare, time to initiation of high-dose corticosteroid and/or cyclophosphamide treatment, or time to major SLE flare. However, there were 25% fewer renal flares in the abetimus group compared with the placebo group (17 of 145 abetimus-treated patients [12%] versus 24 of 153 placebo-treated patients [16%]). Abetimus treatment decreased anti-dsDNA antibody levels (P < 0.0001), and reductions in anti-dsDNA levels were associated with increases in C3 levels (P < 0.0001). More patients in the abetimus group experienced > or =50% reductions in proteinuria at 1 year, compared with the placebo group (nominal P = 0.047). Trends toward reduced rates of renal flare and major SLE flare were noted in patients treated with abetimus who had impaired renal function at baseline. Treatment with abetimus for up to 22 months was well tolerated. CONCLUSION Abetimus at 100 mg/week significantly reduced anti-dsDNA antibody levels but did not significantly prolong time to renal flare when compared with placebo. Multiple positive trends in renal end points were observed in the abetimus treatment group.

Equivalent responses to disease-modifying antirheumatic drugs initiated at any time during the first 15 months after symptom onset in patients with seropositive rheumatoid arthritis

Objective. To evaluate responses by time to initiation of nonbiologic disease-modifying antirheumatic drugs (DMARD) in a DMARD-naive cohort of patients with early seropositive rheumatoid arthritis (RA). Methods. Subjects were categorized by the time from symptom onset to the first DMARD use (median 5.7 months, range 0.6–15.9). Subjects who started their first DMARD within 5 months of symptom onset were compared to subjects who started after 5 months. Disease Activity Scores (DAS-44) and total Sharp Score (TSS) progression rates were analyzed using Wilcoxon rank-sum and chi-square tests; multiple linear regression analysis adjusted for potential covariates. The slope of the least-squares regression line was calculated to estimate the annualized TSS progression rates. Results. Of 233 RA patients, 76% were female and mean age was 50 (SD 13) years. At DMARD start, DAS-44 was similar in all subsets within the 0.6 to 15 months’ duration between symptom onset and DMARD initiation. Erosion scores tended to be higher in those who started DMARD later, but Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were higher in those who started DMARD earlier. During the 2 years after DMARD initiation, improvements in HAQ-DI and DAS-44 were similar in the various duration subsets, with about 25% ever achieving DAS remission (DAS < 1.6). Radiographic progression tended to be numerically but not statistically more rapid in the earlier subsets. Conclusion. Following initiation of nonbiologic DMARD therapy at various times within 15 months of symptom onset, improvements of DAS-44, HAQ-DI, remission rate, and radiographic progression rate were similar, although higher baseline erosion scores were present in those with later initiation of DMARD.