Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis

Michael Donahoe, Vincent G. Valentine, Nydia Chien, Kevin F. Gibson, Jay S. Raval, Melissa Saul, Jianmin Xue, Yingze Zhang, Steven R. Duncan

Research output: Contribution to journalArticle

41 Citations (Scopus)

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. Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT01266317.

Original languageEnglish (US)
Article numbere0127771
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 17 2015

Fingerprint

Idiopathic Pulmonary Fibrosis
autoantibodies
fibrosis
Autoantibodies
lungs
therapeutics
Plasmas
Plasma Exchange
Matrix Metalloproteinase 7
matrilysin
Intravenous Immunoglobulins
Therapeutics
Glucocorticoids
glucocorticoids
immunoglobulins
drug therapy
Pulmonary diseases
pulmonary gas exchange
Refractory materials
autoimmune diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Donahoe, M., Valentine, V. G., Chien, N., Gibson, K. F., Raval, J. S., Saul, M., ... Duncan, S. R. (2015). Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One, 10(6), [e0127771]. https://doi.org/10.1371/journal.pone.0127771

Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. / Donahoe, Michael; Valentine, Vincent G.; Chien, Nydia; Gibson, Kevin F.; Raval, Jay S.; Saul, Melissa; Xue, Jianmin; Zhang, Yingze; Duncan, Steven R.

In: PLoS One, Vol. 10, No. 6, e0127771, 17.06.2015.

Research output: Contribution to journalArticle

Donahoe, M, Valentine, VG, Chien, N, Gibson, KF, Raval, JS, Saul, M, Xue, J, Zhang, Y & Duncan, SR 2015, 'Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis', PLoS One, vol. 10, no. 6, e0127771. https://doi.org/10.1371/journal.pone.0127771
Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M et al. Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One. 2015 Jun 17;10(6). e0127771. https://doi.org/10.1371/journal.pone.0127771
Donahoe, Michael ; Valentine, Vincent G. ; Chien, Nydia ; Gibson, Kevin F. ; Raval, Jay S. ; Saul, Melissa ; Xue, Jianmin ; Zhang, Yingze ; Duncan, Steven R. / Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. In: PLoS One. 2015 ; Vol. 10, No. 6.
@article{eb7170b6c9244bb7ae027b453399e458,
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. Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT01266317.",
author = "Michael Donahoe and Valentine, {Vincent G.} and Nydia Chien and Gibson, {Kevin F.} and Raval, {Jay S.} and Melissa Saul and Jianmin Xue and Yingze Zhang and Duncan, {Steven R.}",
year = "2015",
month = "6",
day = "17",
doi = "10.1371/journal.pone.0127771",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis

AU - Donahoe, Michael

AU - Valentine, Vincent G.

AU - Chien, Nydia

AU - Gibson, Kevin F.

AU - Raval, Jay S.

AU - Saul, Melissa

AU - Xue, Jianmin

AU - Zhang, Yingze

AU - Duncan, Steven R.

PY - 2015/6/17

Y1 - 2015/6/17

N2 - 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. Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT01266317.

AB - 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. Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT01266317.

UR - http://www.scopus.com/inward/record.url?scp=84939140106&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939140106&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0127771

DO - 10.1371/journal.pone.0127771

M3 - Article

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - e0127771

ER -