Early efficacy trial of anakinra in corticosteroid-resistant autoimmune inner ear disease

BACKGROUND. Autoimmune inner ear disease (AIED) is a rare disease that results in progressive sensorineural hearing loss. Patients with AIED initially respond to corticosteroids; however, many patients become unresponsive to this treatment over time, and there is no effective alternative therapy for these individuals. METHODS. We performed a phase I/II open-label, single-arm clinical trial of the IL-1 receptor antagonist anakinra in corticosteroid-resistant AIED patients. Given that the etiology of corticosteroid resistance is likely heterogeneous, we used a Simon 2-stage design to distinguish between an unacceptable (= 30%) response rate to anakinra therapy. Subjects received 100 mg anakinra by subcutaneous injection for 84 days, followed by a 180-day observational period. RESULTS. Based on patient responses, the Simon 2-stage rule permitted premature termination of the trial after 10 subjects completed the 84-day drug period, as the target efficacy for the entire trial had been achieved. Of these 10 patients, 7 demonstrated audiometric improvement, as assessed by pure tone average (PTA) and word recognition score (WRS). In these 7 responders, reduced IL-1 beta plasma levels correlated with clinical response. Upon discontinuation of treatment, 3 subjects relapsed, which correlated with increased IL-1 beta plasma levels. CONCLUSION. We demonstrated that IL-1 beta inhibition in corticosteroid-resistant AIED patients was effective in a small cohort of patients and that IL-1 beta plasma levels associated with both clinical hearing response and disease relapse. These results suggest that a larger phase II randomized clinical trial of IL-1 beta inhibition is warranted

Influenza Immunization in a Managed Care Organization

OBJECTIVE: To compare the effects of different types of computer-generated, mailed reminders on the rate of influenza immunization and to analyze the relative cost-effectiveness of the reminders. DESIGN: Randomized controlled trial. SETTING: Multispeciality group practice. PATIENTS: We studied 24,743 high-risk adult patients aligned with a primary care physician. INTERVENTION: Patients were randomized to one of four interventions: (1) no reminder, which served as control; (2) a generic postcard; (3) a personalized postcard from their physician; and (4) a personalized letter from their physician, tailored to their health risk. MEASUREMENTS: The immunization rate was measured using billing data. A telephone survey was conducted in a subgroup of patients to measure reactions to the mailed reminders. To evaluate the cost-effectiveness, a model was constructed that integrated the observed effect of the interventions with published data on the effect of immunization on future inpatient health care costs. MAIN RESULTS: All three of the reminders studied increased the influenza vaccination rate when compared with the control group. The vaccination rate was 40.6% in the control group, 43.5% in the generic postcard group, 44.7% in the personalized postcard group, and 45.2% in the tailored letter group. The rates of immunization increased as the intensity of the intervention increased (p < .0001). Seventy-eight percent of patients in the letter group deemed the intervention useful, and 86% reported that they would like to get reminders in the future. The cost-effectiveness analysis estimated that in a nonepidemic year, the net savings per 100 reminders sent would be $659 for the personalized postcard intervention and$735 for the tailored letter intervention. When these net cost-savings rates were each applied to the entire high-risk cohort of 24,743 patients, the estimated total net savings was $162,940 for the postcard and$181,858 for the tailored letter. CONCLUSIONS: Although the absolute increase in immunization rates with the use of reminders appeared small, the increases translated into substantial cost savings when applied to a large high-risk population. Personalized reminders were somewhat more effective in increasing immunization, and personalized letters tailored to the patients' condition were deemed useful and important by the individuals who received them and had a beneficial indirect effect on patient satisfaction

Constitutive Overexpression of the Oncogene Rac1 in the Airway of Recurrent Respiratory Papillomatosis Patients Is a Targetable Host-Susceptibility Factor

Recurrent respiratory papillomatosis (RRP) is caused by human papillomaviruses (HPVs), primarily types 6 and 11. The disease is characterized by multiple recurrences of airway papillomas, resulting in high levels of morbidity and significant mortality. The prevalence of latent HPV in the larynx of the general population is much greater than the prevalence of RRP, suggesting a host-susceptibility factor for disease. We report that the oncogene Rac1 and its downstream product cyclooxygenase-2 (COX-2) are both constitutively expressed at high levels throughout the airway of these patients, independent of active HPV infection. Use of the COX-2 inhibitor celecoxib in primary papilloma cell culture resulted in the downregulation of HPV transcription. Furthermore, a proof-of-principle study treating three patients with severe RRP with celecoxib resulted in remission of disease in all cases. Therefore, we have identified the first pharmacologically targetable host-susceptibility pathway that contributes to RRP recurrence