Tracy J Doyle

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (8)54.6 Total impact

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    ABSTRACT: Objective: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a relatively common extra-articular manifestation of RA that contributes significantly to disease burden and excess mortality. Peripheral blood biomarkers of RA-ILD are therefore needed to facilitate earlier diagnosis and to provide insight regarding pathogenesis of this potentially devastating disease complication.Methods: Subjects with RA that were enrolled into a well characterized Chinese identification cohort and a US replication cohort were subclassified as RA-no ILD, RA-mild ILD, and RA-advanced ILD based on high resolution computed tomography scans of the chest. Multiplex ELISAs employing Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases, and acute-phase proteins in the identification cohort. Quantitative sandwich ELISAs for MMP7 and IP10/CXCL10 were then used to confirm results from both the identification and replication cohorts. Unadjusted and adjusted logistic regression models quantified the strength of association between RA-ILD and biomarkers of interest.Results: Multiplex ELISAs identified MMP-7 and IP10/CXCL10 as potential biomarkers of RA-ILD in 133 Chinese RA patients (n=50 RA-no ILD, n=41 RA-ILD, n=42 RA-indeterminate ILD). Standard solid phase sandwich ELISAs confirmed these findings in the Chinese identification cohort as well as an independent US cohort of patients with different stages of RA-ILD (n=22 RA-no ILD, n=49 RA-ILD, and n=13 RA-indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analysis.Conclusion: MMP-7 and IP10/CXCL10 are elevated in the serum of patients with different stages of RA-ILD, supporting their value as pathogenically relevant biomarkers contributing to non-invasive detection of this extra-articular disease complication. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 10/2014;
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    ABSTRACT: Previous work has demonstrated a correlation between serum anti-citrullinated HSP90 antibodies and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). To further investigate this potential pathogenic relationship, we used ELISA-based techniques to assess anti-citrullinated HSP90 antibody profiles in bronchoalveolar lavage fluid (BALF) of patients with different stages of RA-ILD. 9/21 RA-derived BALF specimens demonstrated IgG and/or IgA antibodies targeting citrullinated HSP90 proteins/peptides, highlighting disease specific responses (with a predilection for RA-ILD) that did not occur in IPF patients (0/5) or healthy control subjects (0/5). Comparison of antibody profiles between BALF and matching serum specimens revealed various recognition patterns favoring predominant production of anti-citrullinated HSP90 antibodies within the lung microenvironment-further supporting the connection between this antibody specificity and parenchymal lung disease. Equally important, qualitative as well as quantitative differences in anti-citrullinated HSP90 profiles between BALF and serum indicate that the lung plays a direct role in shaping the immune repertoire of RA/RA-ILD.
    Clinical Immunology 08/2014; · 3.99 Impact Factor
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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. · 7.13 Impact Factor
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    ABSTRACT: Approximately 10% of rheumatoid arthritis (RA) patients have interstitial lung disease (ILD) and one-third have subclinical ILD on chest CT. In this study, we aim to further characterize functional decrements in a spectrum of RA-ILD. All subjects were enrolled in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). The presence of interstitial lung abnormalities (ILA) on clinically indicated chest CT scans was determined using a previously validated sequential reading method. Univariate and multivariate analyses were used to assess the association between degree of ILA and physiologic, functional and demographic variables of interest. Ninety one (8%) from a total of 1145 BRASS subjects were included in this study; 12 had radiologically severe ILA, 34 had ILA, and 38 had no ILA on CT scan. Subjects with radiologically severe ILA were older (p=0.0037), had increased respiratory symptoms (cough p=0.027, dyspnea p=0.010), and more severe RA disease (rheumatoid factor p=0.018, total swollen joints p=0.046) compared to no ILA. Participants also had a trend toward being heavier smokers (p=0.16) and having lower FVC% (77% vs. 94%, p=0.097) and DLco% (52% vs. 77%, p=0.068). Similar, but attenuated, increases in respiratory symptoms, functional decrements, and RA disease severity were observed in subjects with ILA compared to no ILA. We have shown that RA patients have varying degrees of ILA that are associated with a spectrum of functional and physiologic decrements. Our findings suggest that improved risk-stratification and detection of ILA will provide a therapeutic window that could improve RA-ILD outcomes.
    Chest 12/2013; · 7.13 Impact Factor
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    ABSTRACT: Original Investigation SlidePRESENTED ON: Wednesday, October 30, 2013 at 02:45 PM - 03:45 PMPURPOSE: Cigarette smokers are at risk for developing IPF. Identifying at-risk individuals with subclinical interstitial lung disease could provide a better understanding of disease progression and earlier therapeutic interventions. As such, we hypothesized that a peripheral blood biomarker signature can identify patients with radiographic interstitial lung abnormalities (ILA).METHODS: CT scans and plasma samples were obtained from the Univ. of Pittsburgh Lung Screening Study (PluSS). CT scans were scored on a 0-3 scale (0=no evidence;1=indeterminate;2=ILA;3=fibrosis). We then examined plasma samples using multiplex technology for the expression of 126 proteins. Univariate analyses were performed to identify a specific signature in patients with ILA. In addition, the random forest method was used to assess the performance of classification based on overall patterns of all clinical parameters and bioanalytes. We chose the subset of smallest number of variables whose error rate was within the standard error of the minimum error rates of all forests. During each step, the least important variable would be deleted successively and stopped when the reduced and full models did not have similar performance. Out-of-bag error was reported.RESULTS: Of 415 patients, 148 had CT scores of 2 or 3 of which 80 were selected as cases. 150 controls with CT scores of 0 or 1 were matched for age, gender, race, and semi-quantitative assessment of CT emphysema. An analysis of the protein biomarker data with unadjusted ANCOVA identified 35 analytes that had significant differential expression in cases versus controls. After Bonferonni correction, 6 analytes remained significant: PARC, MIP-3α, SP-D, ICAM-1, E-selectin, CRP. The adjusted model for the above analytes yielded similar p values. Using random forest, a signature with 7 variables-age, emphysema score, MMP-7, PARC, SP-D, resistin, TNFRSF1A-is able to identify patients with ILA on CT with an 18.4% out-of-bag error. The performance of this model was similar to the model using all variables.CONCLUSIONS: Smokers with ILA on CT can be identified using a specific peripheral blood biomarker signature. Of significance, a number of proteins in the signature have also been shown to have increased expression and predict survival in patients with IPF.CLINICAL IMPLICATIONS: This biomarker signature, if validated, could serve as the basis for identifying subclinical pulmonary fibrosis in at-risk individuals. These individuals could then be monitored closely for development and progression of IPF.DISCLOSURE: The following authors have nothing to disclose: Avignat Patel, Tracy Doyle, Yushi Liu, Hiroto Hatabu, Mizuki Nishino Hatabu, Yuka Okajima, Cristobal Risquez, Yuanyuan Shi, Juan Osorio, Maria Golzarri, James Lederer, Souheil El-Chemaly, Victor Pinto-Plata, Bartolome Celli, Gary Hunninghake, George Washko, Frank Sciurba, Naftali Kaminski, Joseph Leader, Jill Siegfried, Joel Weissfeld, Ivan RosasNo Product/Research Disclosure Information.
    Chest 10/2013; 144(4_MeetingAbstracts):1029A. · 7.13 Impact Factor
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    ABSTRACT: Recent advances in the field of clinical biomarkers suggest that quantification of serum proteins could play an important role in the diagnosis, classification, prognosis, and treatment response of smoking-related parenchymal lung diseases. COPD and idiopathic pulmonary fibrosis (IPF), two common chronic progressive parenchymal lung diseases, share cigarette smoke exposure as a common dominant risk factor for their development. We have recently shown that COPD and interstitial lung disease may represent distinct outcomes of chronic tobacco use, whereas others have demonstrated that both diseases coexist in some individuals. In this perspective, we examine the potential role of peripheral blood biomarkers in predicting which individuals will develop COPD or IPF, as well as their usefulness in tracking disease progression and exacerbations. Additionally, given the current lack of sensitive and effective metrics to determine an individual's response to treatment, we evaluate the potential role of biomarkers as surrogate markers of clinical outcomes. Finally, we examine the possibility that changes in levels of select protein biomarkers can provide mechanistic insight into the common origins and unique individual susceptibilities that lead to the development of smoking-related parenchymal lung diseases. This discussion is framed by a consideration of the properties of ideal biomarkers for different clinical and research purposes and the best uses for those biomarkers that have already been proposed and investigated.From the Pulmonary and Critical Care Division (Drs Doyle, Pinto-Plata, Morse, Celli, and Rosas), Brigham and Women's Hospital, Harvard Medical School, Boston MA; and Lovelace Respiratory Research Institute (Dr Rosas), Albuquerque NM.Correspondence to: Ivan O. Rosas, MD, Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Thorn 9, Boston, MA 02115; e-mail: irosas@rics.bwh.harvard.eduFinancial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Pinto-Plata has received honoraria as a member of the speakers' bureau from GlaxoSmithKline plc. Dr Celli has received consulting fees from ALTANA, AstraZeneca, Boehringer Ingelheim GmbH, and GlaxoSmithKline plc; speaking fees from ALTANA, AstraZeneca, Boehringer Ingelheim GmbH, and GlaxoSmithKline plc; and grant support from Boehringer Ingelheim GmbH and GlaxoSmithKline plc. Dr Rosas has received consulting fees from Stromedix, Inc/Biogen Idec, Synovex Corporation, and sanofi-aventis U.S. LLC. Drs Doyle and Morse have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.Other contributions: This work was performed at Brigham and Women's Hospital.Funding/Support: This study was funded by the National Institutes of Health [Grant 5T32 HL007633-25 to Dr Doyle, Grant HL107165-01 to Dr Celli, and Grant K23 HL087030 to Dr Rosas] and by the National Heart, Lung and Blood Institutes [Grant R01 HL087122 to Dr Morse].Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
    Chest 10/2012; 142(4):1027-34. · 7.13 Impact Factor
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    ABSTRACT: The widespread use of high-resolution computed tomography in clinical and research settings has increased the detection of interstitial lung abnormalities (ILA) in asymptomatic and undiagnosed individuals. We reported that in smokers, ILA were present in about 1 of every 12 high-resolution computed tomographic scans; however, the long-term significance of these subclinical changes remains unclear. Studies in families affected with pulmonary fibrosis, smokers with chronic obstructive pulmonary disease, and patients with inflammatory lung disease have shown that asymptomatic and undiagnosed individuals with ILA have reductions in lung volume, functional limitations, increased pulmonary symptoms, histopathologic changes, and molecular profiles similar to those observed in patients with clinically significant interstitial lung disease (ILD). These findings suggest that, in select at-risk populations, ILA may represent early stages of pulmonary fibrosis or subclinical ILD. The growing interest surrounding this topic is motivated by our poor understanding of the inciting events and natural history of ILD, coupled with a lack of effective therapies. In this perspective, we outline past and current research focused on validating radiologic, physiological, and molecular methods to detect subclinical ILD. We discuss the limitations of the available cross-sectional studies and the need for future longitudinal studies to determine the prognostic and therapeutic implications of subclinical ILD in populations at risk of developing clinically significant ILD.
    American Journal of Respiratory and Critical Care Medicine 02/2012; 185(11):1147-53. · 11.04 Impact Factor
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    ABSTRACT: The relationship between interstitial lung abnormalities (ILA) and exercise capacity has not been comprehensively evaluated. To assess the validity of the 6-minute walk test in subjects with ILA, and to examine the association between ILA and 6-minute walk distance (6MWD). Spearman correlation coefficients were used to assess the strength of the relationships between 6MWD and relevant measures of dyspnea, health-related quality of life, and pulmonary function in a cohort of 2,416 people who smoke from the COPDGene study. Unadjusted and adjusted linear and logistic regression models were used to assess the strength of the association between ILA and 6MWD. In all subjects, and in those with ILA, 6MWD in COPDGene was associated with relevant clinical and physiologic measures. The mean 6MWD in COPDGene subjects with ILA was 386 m (SD, 128 m), and 82% and 19% of subjects with ILA had 6MWDs less than or equal to 500 and 250 m, respectively. ILA was associated with a reduced 6MWD in univariate (-30 m; 95% confidence interval, -50 to -10; P = 0.004) and multivariate models (-19 m; 95% confidence interval, -33 to -5; P = 0.008). Compared with subjects without ILA, subjects with ILA had an 80% and 77% increase in their odds to have a walk distance limited to less than or equal to 500 and 250 m, respectively. Although these findings were dependent on ILA subtype, they were not limited to those with COPD. Our study demonstrates that ILA is associated with measurable decrements in the 6MWD of people who smoke. Clinical trial registered with (NCT 00608764).
    American Journal of Respiratory and Critical Care Medicine 01/2012; 185(7):756-62. · 11.04 Impact Factor