Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Long-term safety and efficacy of etanercept in patients with rheumatoid arthritis.

OBJECTIVE: Patients with rheumatoid arthritis (RA) treated with etanercept (Enbrel) in controlled studies of 3 to 6 months' duration had rapid and sustained improvement of their disease, with minimal safety issues. In this study, we examine safety and clinical benefit after longer term treatment with etanercept. METHODS: All adult patients with RA with a previously inadequate response to one or more disease modifying antirheumatic drugs, and who received at least one dose of etanercept as monotherapy in controlled or open label clinical trials were evaluated for safety and clinical benefit. Adverse event rates were compared as was evidence of continued benefit over time. RESULTS: Etanercept continued to be safe and well tolerated in 628 adult patients treated for a median of 25 mo (maximum 43 mo; 1109 patient-years). Nine percent of patients withdrew due to lack of efficacy and 7% due to adverse events. Most adverse events were mild, and no statistically significant increases in frequency of events were seen when patients received etanercept over longer periods of time. Clinical benefit was maintained with longterm therapy. A 100% improvement in individual disease activity measures was achieved by 17% to 28% of the patients. Fifty-five percent of patients who were taking corticosteroids (mean dose at baseline 6.6 mg/day) decreased or discontinued corticosteroid therapy while maintaining control of their arthritis symptoms. CONCLUSION: Etanercept continued to be safe and well tolerated, and its clinical benefit was sustained for a median of 25 mo and for as long as 43 mo in patients with RA.

Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial.

BACKGROUND: Etanercept, a tumour-necrosis-factor inhibitor, has shown efficacy in the treatment of rheumatoid arthritis. Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor, a proinflammatory cytokine, is present in increased concentrations in joints and in the skin. Therefore, psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept. METHODS: This randomised, double-blind, placebo-controlled, 12 week study assessed the efficacy and safety of etanercept (25 mg twice-weekly subcutaneous injections) or placebo in 60 patients with psoriatic arthritis and psoriasis. Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and who met the American College of Rheumatology preliminary criteria for improvement (ACR20). Psoriasis endpoints included improvement in the psoriasis area and severity index (PASI) and improvement in prospectively-identified individual target lesions. FINDINGS: In this 12 week study, 26 (87%) of etanercept-treated patients met the PsARC, compared with seven (23%) of placebo-controlled patients. The ARC20 was achieved by 22 (73%) of etanercept-treated patients compared with four (13%) of placebo-treated patients. Of the 19 patients in each treatment group who could be assessed for psoriasis (> or = 3% body surface area), five (26%) of etanercept-treated patients achieved a 75% improvement in the PASI, compared with none of the placebo-treated patients (p=0.015). The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients; similarly, median target lesion improvements were 50% and 0, respectively. Etanercept was well tolerated. INTERPRETATION: Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.

BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.

BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate. METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks. RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept. CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.

Acute rheumatic fever.

During the first half of this century rheumatic fever was a common disease with significant morbidity and mortality in the United States. In the 1980s, when many clinicians were hoping this disease was a disease of the past, anxieties were renewed when outbreaks were reported in several areas around the country. Although the etiology still eludes us, insight has been gained. Environmental and genetic factors are believed to play a role in the epidemiology of this disease. Additionally, the implicated organism, the group A streptococcus, has many strains, and differences in its many proteins may determine their potential for rheumatic fever. The mechanisms leading to disease are not clear, but the streptococcus has been implicated as a source of antigens with cross-reactivity with human tissues and has been shown to modify immune mechanisms. Clinical aspects are briefly reviewed and physicians are reminded to consider rheumatic fever as a diagnostic possibility in the appropriate settings.