Showing papers by "Yoshikazu Inoue published in 2010"

Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis.

Abstract: Rationale: Inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a PaO2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar–arterial oxygen difference [A–aDO2] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 μg Days 1–8, none Days 9–14; × six cycles; 12 wk); low-dose therapy (125 μg Days 1–4, none Days 5–14; × six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A–aDO2 of 12.3 mm Hg (95% confidence interval, 8.4–16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A–aDO2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

The International LAM Registry: A Component of an Innovative Web-Based Clinician, Researcher, and Patient-Driven Rare Disease Research Platform

Abstract: Background: A relative inability to capture a sufficiently large patient population in any one geographic location has traditionally limited research into rare diseases. Methods and Results: Clinicians interested in the rare disease lymphangioleiomyomatosis (LAM) have worked with the LAM Treatment Alliance, the MIT Media Lab, and Clozure Associates to cooperate in the design of a state-of-the-art data coordination platform that can be used for clinical trials and other research focused on the global LAM patient population. This platform is a component of a set of web-based resources, including a patient self-report data portal, aimed at accelerating research in rare diseases in a rigorous fashion. Conclusions: Collaboration between clinicians, researchers, advocacy groups, and patients can create essential community resource infrastructure to accelerate rare disease research. The International LAM Registry is an example of such an effort.82

Autoimmune Pulmonary Alveolar Proteinosis

Abstract: Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant lipids and proteins in pulmonary alveoli that can result in progressive impairment in gas exchange and respiratory insufficiency. The serendipitous discovery of PAP in GM-CSF-deficient mice and subsequent identification that neutralizing GM-CSF autoantibodies are strongly associated with PAP in humans led to our current concepts of the pathogenesis of PAP and the central role GM-CSF and alveolar macrophages play in surfactant homeostasis in health and disease. PAP comprises part of a spectrum of disorders of surfactant homeostasis that includes disorders of surfactant clearance and disorders of surfactant production. The former are caused by disruption of GM-CSF signaling (primary PAP) or by an underlying disease that impairs alveolar macrophage functions including surfactant catabolism (secondary PAP). Disorders of surfactant production are caused by inborn errors of surfactant metabolism (surfactant metabolic dysfunction disorders), e.g., mutations in the SFTPB, SFTPC, or ABCA3 genes. Important differences in clinical presentation, natural history, pathogenesis, and surfactant function suggest that these latter diseases should be considered separately from PAP rather than as a form of the same syndrome. The overall prevalence of PAP is approximately 6–8 per million. Ninety percent of cases are specifically associated with high levels of GM-CSF autoantibodies, which has diagnostic importance and has led to common use of the term autoimmune PAP to replace other terms including idiopathic PAP. Autoimmune PAP typically presents as dyspnea of insidious onset; however, up to one third of individuals may be asymptomatic. Whole lung lavage remains the most effective therapy but GM-CSF inhalation therapy is a promising alternative currently in clinical evaluation. Progress in understanding PAP pathogenesis and the role of GM-CSF in surfactant homeostasis and in inflammatory and autoimmune diseases are important benefits derived from integration of basic science, clinical medicine, and translational research. Future studies will focus on pathogenesis, development of improved therapies for PAP and the role of GM-CSF in health and disease.