title: An open-label trial of rituximab therapy in pulmonary alveolar proteinosis.
abstract: Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean ± sem 15 ± 2% to <0.05% (n = 10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5 ± 2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n = 8) but unchanged in sera (n = 9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.
authors.affiliation: Division of Pulmonary, East Carolina University, Brody School of Medicine, 3E-149 Brody Medical Sciences Building, Greenville, NC 27834, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Kavuru
authors.forename: A
authors.initials: A
authors.lastname: Malur
authors.forename: I
authors.initials: I
authors.lastname: Marshall
authors.forename: B P
authors.initials: BP
authors.lastname: Barna
authors.forename: M
authors.initials: M
authors.lastname: Meziane
authors.forename: I
authors.initials: I
authors.lastname: Huizar
authors.forename: H
authors.initials: H
authors.lastname: Dalrymple
authors.forename: R
authors.initials: R
authors.lastname: Karnekar
authors.forename: M J
authors.initials: MJ
authors.lastname: Thomassen
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000097:blood; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015331:Cohort Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007155:Immunologic Factors / Q000627:therapeutic use*; D008168:Lung / Q000000981:diagnostic imaging / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000097:blood; D011649:Pulmonary Alveolar Proteinosis / Q000188:drug therapy* / Q000276:immunology; D011859:Radiography; D000069283:Rituximab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D001323:Autoantibodies; D007074:Immunoglobulin G; D007155:Immunologic Factors; D000069283:Rituximab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010100:Oxygen