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Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, Xue J, Zhang Y, Duncan SR - PLoS ONE (2015)

Bottom Line: Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days.Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments.Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Survival Comparisons.A.) Survival in the aggregate trial subject population (n = 11) was greater than among historical control AE-IPF patients (n = 20). Cross hatches and numbers in parentheses denote censored observations. Lung transplantation censoring is denoted with “T”. B.) Clinical responses may be more durable and survival may be further enhanced among the later trial subjects (n = 4) treated with a more aggressive regimen of autoantibody-targeted modalities (9 initial TPE + rituximab + IVIG).
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pone.0127771.g006: Survival Comparisons.A.) Survival in the aggregate trial subject population (n = 11) was greater than among historical control AE-IPF patients (n = 20). Cross hatches and numbers in parentheses denote censored observations. Lung transplantation censoring is denoted with “T”. B.) Clinical responses may be more durable and survival may be further enhanced among the later trial subjects (n = 4) treated with a more aggressive regimen of autoantibody-targeted modalities (9 initial TPE + rituximab + IVIG).

Mentions: The aggregate experimental trial cohort had significantly better one-year survival than historical controls (Fig 6A). Results to date also suggest the later, more aggressive treatment protocol (nine TPE + rituximab + IVIG), may result in more durable responses (Fig 6B).


Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, Xue J, Zhang Y, Duncan SR - PLoS ONE (2015)

Survival Comparisons.A.) Survival in the aggregate trial subject population (n = 11) was greater than among historical control AE-IPF patients (n = 20). Cross hatches and numbers in parentheses denote censored observations. Lung transplantation censoring is denoted with “T”. B.) Clinical responses may be more durable and survival may be further enhanced among the later trial subjects (n = 4) treated with a more aggressive regimen of autoantibody-targeted modalities (9 initial TPE + rituximab + IVIG).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470587&req=5

pone.0127771.g006: Survival Comparisons.A.) Survival in the aggregate trial subject population (n = 11) was greater than among historical control AE-IPF patients (n = 20). Cross hatches and numbers in parentheses denote censored observations. Lung transplantation censoring is denoted with “T”. B.) Clinical responses may be more durable and survival may be further enhanced among the later trial subjects (n = 4) treated with a more aggressive regimen of autoantibody-targeted modalities (9 initial TPE + rituximab + IVIG).
Mentions: The aggregate experimental trial cohort had significantly better one-year survival than historical controls (Fig 6A). Results to date also suggest the later, more aggressive treatment protocol (nine TPE + rituximab + IVIG), may result in more durable responses (Fig 6B).

Bottom Line: Severe acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days.Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments.Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus