title: Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.
abstract: BACKGROUND
  Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.
  
  
  METHODS
  Eleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.
  
  
  RESULTS
  Nine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.
  
  
  CONCLUSIONS
  This pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01266317.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Donahoe
authors.affiliation: Department of Medicine, University of Texas Medical Branch, Galveston, Texas, 77555, United States of America.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: Valentine
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Nydia
authors.initials: N
authors.lastname: Chien
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Gibson
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, 27599, United States of America.
authors.forename: Jay S
authors.initials: JS
authors.lastname: Raval
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Saul
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Duncan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood* / Q000737:chemistry; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D007155:Immunologic Factors / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010951:Plasma Exchange; D000069283:Rituximab / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D005938:Glucocorticoids; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D000069283:Rituximab