Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis
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{"title"=>"Autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis", "type"=>"journal", "authors"=>[{"first_name"=>"Michael", "last_name"=>"Donahoe", "scopus_author_id"=>"6701599925"}, {"first_name"=>"Vincent G.", "last_name"=>"Valentine", "scopus_author_id"=>"7003857529"}, {"first_name"=>"Nydia", "last_name"=>"Chien", "scopus_author_id"=>"56779775200"}, {"first_name"=>"Kevin F.", "last_name"=>"Gibson", "scopus_author_id"=>"7202666589"}, {"first_name"=>"Jay S.", "last_name"=>"Raval", "scopus_author_id"=>"36449699100"}, {"first_name"=>"Melissa", "last_name"=>"Saul", "scopus_author_id"=>"6604051800"}, {"first_name"=>"Jianmin", "last_name"=>"Xue", "scopus_author_id"=>"8519864400"}, {"first_name"=>"Yingze", "last_name"=>"Zhang", "scopus_author_id"=>"55739972400"}, {"first_name"=>"Steven R.", "last_name"=>"Duncan", "scopus_author_id"=>"56744127600"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84939140106", "isbn"=>"1932-6203", "scopus"=>"2-s2.0-84939140106", "pui"=>"605585509", "pmid"=>"26083430", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0127771"}, "id"=>"e5dd64c9-fad7-3f21-aeb8-b0e059a880c6", "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.\\n\\nMETHODS: 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.\\n\\nRESULTS: 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.\\n\\nCONCLUSION: 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.\\n\\nTRIAL REGISTRATION: ClinicalTrials.gov NCT01266317.", "link"=>"http://www.mendeley.com/research/autoantibodytargeted-treatments-acute-exacerbations-idiopathic-pulmonary-fibrosis", "reader_count"=>33, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>9, "Other"=>6, "Student > Bachelor"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>9, "Other"=>6, "Student > Bachelor"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>25, "Agricultural and Biological Sciences"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>25}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "group_count"=>3}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2119314"], "description"=>"<p>A.) Indirect Immuno-fluorescence Assays (IFA). a.) Pretreatment anti-HEp-2 autoantibodies were present at plasma titrations of 1:80 in Subject #6. b.) Autoantibodies were diminished immediately following his TPE treatment (image here at 1:20 titration). c.) Normal plasma control specimen (1:20 titration). B.) IFA Titers. Anti-HEp-2 autoantibody titers were determined in the first eight subjects. Titers were reduced following the initial TPE series in all except Subject #1 (dotted line, solid circles), who was also the only subject among these that did not have a beneficial clinical response.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451501, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g004", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_HEp_2_Autoantibodies_in_Trial_Patients_/1451501", "title"=>"Anti-HEp-2 Autoantibodies in Trial Patients.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119313"], "description"=>"<p>In addition to better lung function and gas exchange, experimental treatments frequently improved the chest radiographs (CXR) of these subjects. a) Pretreatment CXR of Subject #5 during relapse shows diffuse infiltrates; b.) Radiographic improvement (and extubation) of this subject to 2<sup>nd</sup> TPE series. c.) CXR of Subject #7 immediately prior to treatment and d.) after first three TPE. These (and other) radiographic and clinical improvements in the subject population were not attributable to changes in intravascular volume status or infection.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451500, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g003", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Radiographic_Changes_with_Experimental_Treatment_/1451500", "title"=>"Radiographic Changes with Experimental Treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119318"], "description"=>"<p>Pre and Post are relative to experimental treatment courses (Rx); O<sub>2</sub> requirements denoted as that necessary to maintain resting arterial oxygen saturations at ≥93%; MI = myocardial infarction; FM = face mask; NC = nasal cannula; NC<sub>oxi</sub> = nasal cannula with “oxymizer” reservoir; CMO = comfort measures only; MS gtts = morphine sulfate infusion; TPE = therapeutic plasma exchange; SNF = skilled nursing facility.</p><p>Individual Treatment Outcomes.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451505, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.t002", "stats"=>{"downloads"=>1, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Individual_Treatment_Outcomes_/1451505", "title"=>"Individual Treatment Outcomes.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119316"], "description"=>"<p>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).</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451503, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g006", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survival_Comparisons_/1451503", "title"=>"Survival Comparisons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119317"], "description"=>"<p>Age denoted in years. IPF Dx denotes when the original IPF diagnosis was established in these subjects, prior to their admission for acute exacerbations. AE = acute exacerbation; UIP = usual interstitial pneumonia.[<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127771#pone.0127771.ref001\" target=\"_blank\">1</a>] Subjects were not listed for lung transplantation due to advanced age (Subjects #1,2,4–6,8,11), irreparable coronary artery disease (#3), or being too acutely ill to undergo the extensive necessary pre-transplantation evaluations (#7,#9). The AE-IPF in all subjects was rapidly progressive, with daily or near daily increases of hypoxemia and dyspnea. None had infections, congestive heart failure, or other causes of pulmonary dysfunction aside from the AE-IPF (2).</p><p>Demographic Characteristics and Prior Histories of Trial Subjects.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451504, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.t001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Demographic_Characteristics_and_Prior_Histories_of_Trial_Subjects_/1451504", "title"=>"Demographic Characteristics and Prior Histories of Trial Subjects.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119315"], "description"=>"<p>Plasma MMP7 levels did not appear to consistently decrease with TPE, nor correlate with clinical responses. In particular, three subjects (#3,4,7, open circles, dotted lines) had increases or no changes of MMP7 levels from pretreatment values despite having prolonged clinical remissions.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451502, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g005", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Matrix_Metalloproteinase_7_MMP7_/1451502", "title"=>"Matrix Metalloproteinase 7 (MMP7).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119312"], "description"=>"<p>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 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127771#pone.0127771.t002\" target=\"_blank\">Table 2</a>). 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 <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127771#pone.0127771.t001\" target=\"_blank\">1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0127771#pone.0127771.t002\" target=\"_blank\">2</a>). 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).</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451499, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_Responses_to_Experimental_Therapy_/1451499", "title"=>"Clinical Responses to Experimental Therapy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119311"], "description"=>"<p>Original Regimen denotes the first series of subjects who were treated with the initial, relatively more conservative regimen (#1–7). Augmented Regimen denotes the most recent four subjects (#8–11) who received a more aggressive therapeutic course, based on interval results in the first cohort (see text for details). TPE = therapeutic plasma exchange; IVIG = intravenous immunoglobulin; * denotes oral consent of patients, under auspices of innovative clinical practice, that were given by these patients after being fully informed of potential risks and yet-unproven efficiencies of the novel treatments.</p>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451498, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0127771.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Flowchart_of_subject_recruitments_for_these_experimental_trials_/1451498", "title"=>"Flowchart of subject recruitments for these experimental trials.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-06-17 02:53:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/2119319", "https://ndownloader.figshare.com/files/2119320"], "description"=>"<div><p>Background</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusion</p><p>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.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href=\"http://clinicaltrials.gov/ct2/results?term=NCT01266317\" target=\"_blank\">NCT01266317</a></p></div>", "links"=>[], "tags"=>["ivig", "tpe", "medications.ConclusionThis pilot trial", "therapy", "plasma MMP 7 levels", "Idiopathic Pulmonary Fibrosis BackgroundSevere", "elisa", "trial subjects", "Autoantibodie", "IPF progression", "autoantibody reduction treatments", "ae", "nct"], "article_id"=>1451506, "categories"=>["Biological Sciences"], "users"=>["Michael Donahoe", "Vincent G. Valentine", "Nydia Chien", "Kevin F. Gibson", "Jay S. Raval", "Melissa Saul", "Jianmin Xue", "Yingze Zhang", "Steven R. Duncan"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0127771.s001", "https://dx.doi.org/10.1371/journal.pone.0127771.s002"], "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Autoantibody_Targeted_Treatments_for_Acute_Exacerbations_of_Idiopathic_Pulmonary_Fibrosis_/1451506", "title"=>"Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-06-17 02:53:47"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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