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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.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.

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

Clinical Responses to Experimental Therapy.A.) Decreases in Supplemental Oxygen Requirements. Oxygen requirements decreased in only one of the historical control subjects during their hospitalizations, whereas pulmonary gas exchange improved with experimental treatments among most of the trial cohort (see also Table 2). B.) Changes in Abilities to Ambulate. Trial subjects who responded to experimental therapy reported improved exercise tolerance, but maximal walk distances were added as a formal outcome assessment in latest subjects, identified here by subject number (see Tables 1 and 2). With the exception of Subject #10 who showed no response to the experimental treatment, the walk distances of these later patients increased substantially. (Note: The post-treatment >2 mile distance of Subject #9 was limited by boredom rather than exercise capacity).
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pone.0127771.g002: Clinical Responses to Experimental Therapy.A.) Decreases in Supplemental Oxygen Requirements. Oxygen requirements decreased in only one of the historical control subjects during their hospitalizations, whereas pulmonary gas exchange improved with experimental treatments among most of the trial cohort (see also Table 2). B.) Changes in Abilities to Ambulate. Trial subjects who responded to experimental therapy reported improved exercise tolerance, but maximal walk distances were added as a formal outcome assessment in latest subjects, identified here by subject number (see Tables 1 and 2). With the exception of Subject #10 who showed no response to the experimental treatment, the walk distances of these later patients increased substantially. (Note: The post-treatment >2 mile distance of Subject #9 was limited by boredom rather than exercise capacity).

Mentions: A priori intentions to measure gas exchange as arterial oxygen partial pressures (PaO2) while subjects breathed 100% oxygen (FIO2 = 1.0) were precluded by the inabilities of many air-hungry patients to tolerate the requisite tight-fitting face masks, and dependence of an early subject on noninvasive (face mask) bi-level ventilator support (which confounds interpretations of PaO2/FIO2). Nonetheless, all but two of the experimental trial subjects (#1 and #10) had obvious improvements of gas exchange after TPE treatments (Table 2), in distinction to effects of conventional steroid therapy among historical controls (Fig 2A). Treatments among all the spontaneously breathing subjects except #10 resulted in subjective reports of less dyspnea and greater exertional tolerance. Maximal walk distances pre- and post-treatment were measured in Subjects #7–11 (Fig 2B). Total lung capacity of Subject #8 increased from 41% of predicted to 52% after therapy; respective measures of diffusing capacity also improved from 20% to 33% of predicted. Clinical responses were also accompanied by radiographic improvements (Fig 3).


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)

Clinical Responses to Experimental Therapy.A.) Decreases in Supplemental Oxygen Requirements. Oxygen requirements decreased in only one of the historical control subjects during their hospitalizations, whereas pulmonary gas exchange improved with experimental treatments among most of the trial cohort (see also Table 2). B.) Changes in Abilities to Ambulate. Trial subjects who responded to experimental therapy reported improved exercise tolerance, but maximal walk distances were added as a formal outcome assessment in latest subjects, identified here by subject number (see Tables 1 and 2). With the exception of Subject #10 who showed no response to the experimental treatment, the walk distances of these later patients increased substantially. (Note: The post-treatment >2 mile distance of Subject #9 was limited by boredom rather than exercise capacity).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127771.g002: Clinical Responses to Experimental Therapy.A.) Decreases in Supplemental Oxygen Requirements. Oxygen requirements decreased in only one of the historical control subjects during their hospitalizations, whereas pulmonary gas exchange improved with experimental treatments among most of the trial cohort (see also Table 2). B.) Changes in Abilities to Ambulate. Trial subjects who responded to experimental therapy reported improved exercise tolerance, but maximal walk distances were added as a formal outcome assessment in latest subjects, identified here by subject number (see Tables 1 and 2). With the exception of Subject #10 who showed no response to the experimental treatment, the walk distances of these later patients increased substantially. (Note: The post-treatment >2 mile distance of Subject #9 was limited by boredom rather than exercise capacity).
Mentions: A priori intentions to measure gas exchange as arterial oxygen partial pressures (PaO2) while subjects breathed 100% oxygen (FIO2 = 1.0) were precluded by the inabilities of many air-hungry patients to tolerate the requisite tight-fitting face masks, and dependence of an early subject on noninvasive (face mask) bi-level ventilator support (which confounds interpretations of PaO2/FIO2). Nonetheless, all but two of the experimental trial subjects (#1 and #10) had obvious improvements of gas exchange after TPE treatments (Table 2), in distinction to effects of conventional steroid therapy among historical controls (Fig 2A). Treatments among all the spontaneously breathing subjects except #10 resulted in subjective reports of less dyspnea and greater exertional tolerance. Maximal walk distances pre- and post-treatment were measured in Subjects #7–11 (Fig 2B). Total lung capacity of Subject #8 increased from 41% of predicted to 52% after therapy; respective measures of diffusing capacity also improved from 20% to 33% of predicted. Clinical responses were also accompanied by radiographic improvements (Fig 3).

Bottom Line: 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.

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