Harold R Collard

University of California, San Francisco, San Francisco, California, United States

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Publications (151)1096.72 Total impact

  • Brett Ley, Kevin K Brown, Harold R Collard
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    ABSTRACT: Molecular biomarkers are highly desired in idiopathic pulmonary fibrosis (IPF) where they hold the potential to elucidate underlying disease mechanisms, accelerated drug development, and advance clinical management. Currently, there are no molecular biomarkers in widespread clinical use for IPF, and the search for potential markers remains in its infancy. Proposed core mechanisms in the pathogenesis of IPF for which candidate markers have been offered include alveolar epithelial cell dysfunction, immune dysregulation, and fibrogenesis. Useful markers reflect important pathologic pathways, are practically and accurately measured, have undergone extensive validation, and are an improvement upon the current approach for their intended use. The successful development of useful molecular biomarkers is a central challenge for the future of translational research in IPF and will require collaborative efforts among those parties invested in advancing the care of patients with IPF.
    AJP Lung Cellular and Molecular Physiology 09/2014; 307(9). DOI:10.1152/ajplung.00014.2014 · 4.04 Impact Factor
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    ABSTRACT: There is microscopic spatial and temporal heterogeneity of pathological changes in idiopathic pulmonary fibrosis (IPF) lung tissue, which may relate to heterogeneity in pathophysiological mediators of disease and clinical progression. We assessed relationships between gene expression patterns, pathological features, and systemic biomarkers to identify biomarkers that reflect the aggregate disease burden in patients with IPF.
    Thorax 09/2014; DOI:10.1136/thoraxjnl-2013-204596 · 8.56 Impact Factor
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    ABSTRACT: While widespread use of animal modeling has transformed pulmonary research, the overarching goal of biomedical research is to enhance our understanding of human physiology and pathology. Thus, we believe that future gains in understanding human lung disease will be enhanced when studying patient-derived samples becomes an integral part of the investigational process. For idiopathic pulmonary fibrosis (IPF), investigators need quality human specimens, collected in a standardized fashion, along with carefully annotated, long-term clinical and outcomes data to address current knowledge gaps. Access to human lung tissues through commercial entities or the Lung Tissue Resource Consortium, an NHLBI-funded consortium, has demonstrated the feasibility of this approach. However, these samples are not always well-annotated or collected uniformly, and are limited in their breadth to address future IPF research needs. Therefore, we propose leveraging ongoing and future studies in IPF to establish a biorepository which will meet current and future needs of IPF investigations. Specifically, we propose that blood, cell, and lung samples, linked to robust longitudinal clinical phenotyping generated from future industry, federally-sponsored, and investigator-initiated clinical studies be prospectively and uniformly collected and stored in a biorepository and linked registry. Here we outline standardized methodologies that would allow specimens and clinical data collected from different studies to be integrated and accessible to the IPF research community for investigations which will inform future basic and translational research in IPF. Such a biorepository needs the combined efforts of all stakeholders, to be driven by projected future scientific needs and to be available to all qualified researchers. We believe this infrastructure is crucial, is feasible, and would accelerate research in IPF.
    08/2014; DOI:10.1513/AnnalsATS.201406-289OI
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    ABSTRACT: Background:The feasibility of an interventional clinical trial in idiopathic pulmonary fibrosis (IPF) using death and hospitalization as primary endpoints is an area of uncertainty. This manuscript aims to illustrate the impact of cohort enrichment and study duration on sample size requirements for IPF clinical trials in which death alone or death plus hospitalization serve as the primary endpoint, using data from a large well-characterized clinical trial population. Methods:Event rate estimates for death and hospitalization were determined from patients enrolled into the NIH-sponsored idiopathic pulmonary fibrosis clinical research network clinical trials. Standard sample size formulae were applied to estimate the total sample size required for varying gender, age, and pulmonary function (GAP) stage-based cohorts. Results:Risk estimates for death and hospitalization in the clinical trial cohort were substantially lower than published. An IPF trial with death as its primary endpoint, enrolling GAP stage 1 and 2 subjects over one year with a minimum follow-up of 1 year, would require an estimated 7986 subjects to achieve 90% power for a hazard ratio of 0.70. Alternatively, an IPF trial with death plus hospitalization as its primary endpoint, enrolling GAP stage 2 and 3 subjects over two years with a minimum follow-up of 1 year, would require an estimated 794 subjects for the same power and hazard ratio. Conclusion:Study design decisions, in particular cohort enrichment strategies, have a substantial impact on sample size requirements for IPF clinical trials using time to event primary endpoints such as death and death plus hospitalization.
    Chest 08/2014; DOI:10.1378/chest.14-0492 · 7.13 Impact Factor
  • European Respiratory Journal 08/2014; 44(2):273-6. DOI:10.1183/09031936.00051914 · 7.13 Impact Factor
  • Christopher J Ryerson, Harold R Collard
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    ABSTRACT: The purpose of this review is to provide an update on acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF), with a specific focus on new data regarding the cause, clinical features, management and prognosis of AE-IPF. In addition, the limitations of the current definition of AE-IPF are discussed and a novel classification schema is proposed.
    Current opinion in pulmonary medicine 07/2014; DOI:10.1097/MCP.0000000000000073 · 2.96 Impact Factor
  • Christopher J Ryerson, Harold R Collard
    Thorax 07/2014; 69(9). DOI:10.1136/thoraxjnl-2014-205892 · 8.56 Impact Factor
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    ABSTRACT: Background Nintedanib is in clinical development as a treatment for idiopathic pulmonary fibrosis (IPF). Data from the Phase II TOMORROW study suggested that nintedanib 150 mg twice daily had clinical benefits with an acceptable safety profile. Methods The INPULSISTM trials are replicate Phase III, randomized, double-blind, studies comparing the efficacy and safety of nintedanib 150 mg twice daily with placebo in patients with IPF. Eligible patients were aged ≥40 years with a diagnosis of IPF within 5 years before randomization who had undergone a chest high-resolution computed tomography (HRCT) scan within 1 year before screening, and who had a forced vital capacity (FVC) of ≥50% predicted and a diffusing capacity for carbon monoxide of 30–79% predicted. Participants were randomized 3:2 to receive nintedanib or placebo for 52 weeks. The primary endpoint is the annual rate of decline in FVC. The key secondary endpoints are change from baseline in the total score on the St. George’s Respiratory Questionnaire (a measure of health-related quality of life) over 52 weeks and time to first acute exacerbation. Results Enrolment of 1066 patients in 24 countries was completed in September 2012. Results will be reported in the first half of 2014. Conclusion The INPULSIS™ trials will determine the efficacy of nintedanib in patients with IPF, including its impact on disease progression as defined by decline in FVC, acute exacerbations and health-related quality of life. In addition, they will characterise the adverse event profile of nintedanib in this patient population. Trial registration: Registered at ClinicalTrials.gov (identifiers: NCT01335464 and NCT01335477).
    Respiratory Medicine 07/2014; 108(7). DOI:10.1016/j.rmed.2014.04.011 · 2.92 Impact Factor
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    ABSTRACT: Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.
    The Lancet Respiratory Medicine 06/2014; DOI:10.1016/S2213-2600(14)70124-9
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    ABSTRACT: Purpose To investigate the prognostic value of quantitative computed tomographic (CT) scoring for the extent of fibrosis or emphysema in the context of a clinical model that includes the gender, age, and physiology (GAP model) of the patient. Materials and Methods Study cohorts were approved by local institutional review boards, and all patients provided written consent. This was a retrospective cohort study that included 348 patients (246 men, 102 women; mean age, 69 years ± 9) with idiopathic pulmonary fibrosis from two institutions. Fibrosis and emphysema visual scores were independently determined by two radiologists. Models were based on competing risks regression for death and were evaluated by using the C index and reclassification improvement. Results The CT-GAP model (a modification of the original GAP model that replaces diffusion capacity of carbon monoxide with CT fibrosis score) had accuracy comparable to that of the original GAP model, with a C index of 70.3 (95% confidence interval: 66.4, 74.0); difference in C index compared with the GAP model of -0.4 (95% confidence interval: -2.2, 3.4). The performance of the original GAP model did not change significantly with the simple addition of fibrosis score, with a change in C index of 0.0 (95% confidence interval: -1.8, 0.5) or of emphysema score, with a change in C index of 0.0 [95% confidence interval: -1.3, 0.4]). Conclusion CT fibrosis score can replace diffusion capacity of carbon monoxide test results in a modified GAP model (the CT-GAP model) with comparable performance. This may be a useful alternative model in situations where CT scoring is more reliable and available than diffusion capacity of carbon monoxide. © RSNA, 2014 Online supplemental material is available for this article .
    Radiology 06/2014; DOI:10.1148/radiol.14130216 · 6.21 Impact Factor
  • Martin Kolb, Harold R Collard
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is traditionally staged with terms such as "mild", "severe", "early" and "advanced" based on pulmonary function tests. This approach allows physicians to monitor disease progression and advise patients and their families. However, it is not known if the stages of this model reflect distinct biological or clinical phenotypes and the therapeutic and prognostic value of this system is limited. Novel methods of IPF staging have recently been developed. The GAP model includes four baseline variables that were found to be predictive of outcome, as identified by logistic regression. These factors are: gender (G), age (A) and two lung physiology variables (P) (forced vital capacity and diffusing capacity of the lung for carbon monoxide). The clinical utility and accuracy of staging models may be further improved in the future by the integration of dynamic parameters that can be measured over time, as well as biological data from biomarkers which may be able to directly measure disease activity. The development of an evidence-based, multidimensional IPF staging model that builds on the current staging approaches to IPF is an important objective for improving the management of IPF.
    European Respiratory Review 06/2014; 23(132):220-224. DOI:10.1183/09059180.00002114
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    ABSTRACT: IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas IL-13Rα1/IL-4Rα engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Rα2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Rα1/IL-4Rα complex but does not interact with IL-13Rα2. Idiopathic pulmonary fibrosis is a progressive and generally fatal parenchymal lung disease of unknown etiology with no current pharmacologic treatment options that substantially prolong survival. Preclinical models of fibrotic diseases have implicated IL-13 activity on multiple cell types, including macrophages and fibroblasts, in initiating and perpetuating pathological fibrosis. In this study, we show that IL-13, IL-4, IL-13Rα2, and IL-13-inducible target genes are expressed at significantly elevated levels in lung tissue from patients with idiopathic pulmonary fibrosis compared with control lung tissue. IL-4 and IL-13 induce virtually identical transcriptional responses in human monocytes, macrophages, and lung fibroblasts. IL-13Rα2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-α via a STAT6-independent mechanism. Endogenously expressed IL-13Rα2 decreases, but does not abolish, sensitivity of lung fibroblasts to IL-13 and does not affect sensitivity to IL-4. Genome-wide transcriptional analyses of lung fibroblasts stimulated with IL-13 in the presence of Abs that selectively block interactions of IL-13 with IL-13Rα1/IL-4Rα or IL-13Rα2 show that endogenously expressed IL-13Rα2 does not activate any unique IL-13-mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.
    The Journal of Immunology 05/2014; 193(1). DOI:10.4049/jimmunol.1301761 · 5.36 Impact Factor
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    ABSTRACT: BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
    New England Journal of Medicine 05/2014; 370(22):2071-82. · 54.42 Impact Factor
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    ABSTRACT: Published data for the epidemiology of idiopathic pulmonary fibrosis in the USA are scarce. We sought to estimate the incidence, prevalence, and mortality risk of idiopathic pulmonary fibrosis among US Medicare beneficiaries.
    The Lancet Respiratory Medicine 05/2014; DOI:10.1016/S2213-2600(14)70101-8
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    ABSTRACT: BACKGROUND: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. METHODS: We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George's Respiratory Questionnaire, both assessed over a 52-week period. RESULTS: A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was -114.7 ml with nintedanib versus -239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and -113.6 ml with nintedanib versus -207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P=0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P=0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. CONCLUSIONS: In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.
    New England Journal of Medicine 05/2014; 370(22):2071-82. DOI:10.1056/NEJMoa1402584 · 54.42 Impact Factor
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    ABSTRACT: Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
    Thorax 05/2014; 69(5):428-436. DOI:10.1136/thoraxjnl-2013-204202 · 8.56 Impact Factor
  • The Lancet Respiratory Medicine 05/2014; 2(5):e5. DOI:10.1016/S2213-2600(14)70075-X
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    ABSTRACT: Rheumatoid arthritis (RA) is a systemic inflammatory disorder affecting approximately 1.3 million adults in the United States. Approximately 10% of these individuals with RA have clinically evident interstitial lung disease (RA-ILD), and an additional one-third demonstrate subclinical ILD on chest CT scan. The risk of death for individuals with RA-ILD is three times higher than for patients with RA without ILD, with a median survival after ILD diagnosis of only 2.6 years. Despite the high prevalence and mortality of RA-ILD, little is known about its molecular features and its natural history. At present, we lack a standard validated approach to the definition, diagnosis, risk stratification, and management of RA-ILD. In this perspective, we discuss the importance of clinical and translational research and how ongoing research efforts can address important gaps in our knowledge over the next few years. Furthermore, recommendations are made to design multicenter collaborative studies that will expedite the development of clinical trials designed to decrease the significant morbidity and mortality associated with RA-ILD.
    Chest 03/2014; 145(3):454-63. DOI:10.1378/chest.13-2408 · 7.13 Impact Factor
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    ABSTRACT: Interstitial lung disease (ILD) is the leading cause of morbidity and mortality in patients with systemic sclerosis (SSc), however prognostication of SSc-ILD remains challenging. We conducted a systematic review to identify variables that predict mortality and ILD progression in SSc-ILD. Three databases were searched to identify all studies relating to predictors of mortality or ILD progression in SSc-ILD. Eligible studies were published in English and included 10 or more adults with SSc-ILD. Two authors independently reviewed and extracted data from acceptable studies. The initial search identified 3145 unique citations. Twenty-seven studies met inclusion criteria, including 6 abstracts. A total of 1616 patients with SSc-ILD were included. Patient-specific, ILD-specific and SSc-specific variables predicted mortality and progression, however most predictors were identified in only one study. Most studies did not fully account for potential confounders and none of the studies included a validation cohort. Older age, lower forced vital capacity and lower diffusing capacity of carbon monoxide predicted mortality in more than one study. Male sex, extent of disease on high-resolution computed tomography (HRCT), presence of honeycombing, elevated KL-6 and increased alveolar epithelial permeability were identified as predictors of both mortality and ILD progression on unadjusted analysis. Extent of disease on HRCT was the only variable that independently predicted both mortality and ILD progression. Mortality and ILD progression were predicted by several patient-specific, ILD-specific and SSc-specific factors. Additional prospective studies are required to validate these preliminary findings and identify combinations of variables that accurately predict prognosis of SSc-ILD.
    Chest 02/2014; 146(2). DOI:10.1378/chest.13-2626 · 7.13 Impact Factor
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    ABSTRACT: Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.
    The Journal of Rheumatology 02/2014; 41(4). DOI:10.3899/jrheum.131251 · 3.17 Impact Factor

Publication Stats

5k Citations
1,096.72 Total Impact Points

Institutions

  • 2001–2015
    • University of California, San Francisco
      • • Department of Medicine
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2013
    • CSU Mentor
      Long Beach, California, United States
  • 2007
    • Duke University
      Durham, North Carolina, United States
  • 2006
    • University of Ulsan
      • Asan Medical Center
      Ulsan, Ulsan, South Korea
  • 2005
    • University of Wisconsin, Madison
      • Department of Medicine
      Madison, MS, United States