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2.  Lung disease with anti-CCP antibodies but not rheumatoid arthritis or connective tissue disease 
Respiratory medicine  2012;106(7):1040-1047.
We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD).
The study sample included 74 subjects with respiratory symptoms, evaluated January 2008–January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation.
The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days.
We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.
PMCID: PMC3753791  PMID: 22503074
Anti-cyclic citrullinated peptide; Rheumatoid arthritis; Interstitial lung disease; Lung diseases
3.  Heart rate recovery after six-minute walk test predicts pulmonary hypertension in patients with idiopathic pulmonary fibrosis 
Respirology (Carlton, Vic.)  2011;16(3):439-445.
Background and objective
In patients with IPF, we sought to validate that abnormal heart rate recovery at 1 min (HRR1) after six-minute walk test (6MWT) predicts mortality and to explore the relationship between abnormal HRR1 and pulmonary hypertension (PH).
We identified IPF patients who performed a 6MWT as part of their clinical evaluation between 2006 and 2009 and were followed to lung transplantation or death. Right heart catheterization (RHC) data were collated and analysed for the subgroup who had this procedure.
There were 160 subjects who qualified for the survival analysis, and those with an abnormal HRR1 had worse survival than subjects with normal HRR1 (log-rank P = 0.01). Eighty-two subjects had a right heart catheter (RHC); among them, abnormal HRR1 was associated with RHC-confirmed PH (χ2 = 4.83, P = 0.03) and had a sensitivity, specificity, positive predictive value and negative predictive value of 52%, 74%, 41% and 82%, respectively, for PH. In bivariate and multivariable analyses, abnormal HRR1 appeared to be the strongest predictor of RHC-confirmed PH (odds ratio (OR) = 4.0, 95% CI: 1.17–13.69, P = 0.02 in the multivariable analysis).
This study adds to data that support the validity of abnormal HRR1 as a predictor of mortality and of RHC-confirmed PH in IPF. Research is needed to further investigate the link between abnormal HRR1 and PH and to elucidate heart–lung interactions at work during exercise and recovery in patients with IPF.
PMCID: PMC3753822  PMID: 20946337
heart rate recovery; idiopathic pulmonary fibrosis; interstitial lung disease; pulmonary hypertension
4.  Obstructive sleep apnea does not promote esophageal reflux in fibrosing interstitial lung disease 
Respiratory Medicine  2012;106(7):1033-1039.
In patients with fibrosing interstitial lung disease (fILD), gastroesophageal reflux (GER) is highly prevalent, perhaps because of the effects of lung fibrosis on altering intrathoracic pressure, diaphragm morphology and lower esophageal sphincter (LES) function. For unclear reasons, obstructive sleep apnea (OSA) is also highly prevalent among patients with fILD. We conducted this study to test our hypothesis that, in patients with fILD, OSA would exacerbate diaphragm/LES dysfunction and increase the propensity for—and severity of—GER.
We identified patients with fILD who underwent screening polysomnogram and pH or pH/impedence probe at our center during the same week. We examined the association between OSA and GER and used logistic regression to determine independent predictors of OSA or GER.
In 54 included subjects, neither OSA (dichotomous) nor apnea hypopnea index (continuous) predicted the presence of GER. Regardless of body position (upright, recumbent), GER was no more frequent or severe among subjects with OSA vs. those without OSA. Subjects with idiopathic pulmonary fibrosis (IPF) had an odds of GER nearly seven-fold greater than subjects with other forms of fILD (odds ratio=6.84, 95% confidence interval 1.36–34.43, p=0.02). For the entire cohort and the subgroup with IPF, there was no correlation between pulmonary physiology and GER.
In fILD, OSA does not appear to promote GER. Research is needed to determine if compensatory mechanisms emanating from the crural diaphragm prevent GER in fILD patients with OSA and to sort out whether GER has a role in the pathogenesis of certain forms of fILD.
PMCID: PMC3362045  PMID: 22521226
5.  FEV1 over time in patients with connective tissue disease-related bronchiolitis 
Respiratory medicine  2013;107(6):883-889.
Fibrosis or inflammation of the bronchioles is a well-known manifestation of connective tissue disease (CTD). However, the natural history of CTD-related bronchiolitis is largely unknown.
We analyzed consecutive patients evaluated at National Jewish Health (Denver, CO) from 1998 to 2008 with CTD and surgical lung biopsy-confirmed bronchiolitis. Linear mixed effects models were used to estimate the longitudinal postbronchodilator FEV1 %predicted (%pred) course and differences between subjects with or without constrictive bronchiolitis (CB).
Of 28 subjects with a mean age of 53 ± 9 years, fourteen (50%) had CB. The most common CTD diagnosis was rheumatoid arthritis (n = 14; 50%). There were no significant differences in demographics, smoking status, underlying CTD diagnoses, 6-min walk distance, dyspnea score or drug therapy between subjects with CB and those with cellular bronchiolitis. Three subjects with CB (11%) and four with cellular bronchiolitis (14%) died. Compared with subjects with CB, those with cellular bronchiolitis had higher mean FEV1 %pred at all times. There were no significant differences in FEV1 %pred slope within- or between-groups (CB vs. cellular bronchiolitis) preceding surgical lung biopsy or afterward.
Subjects with CTD-related CB had lower FEV1 %pred values than those with CTD-related cellular bronchiolitis at all time points, but FEV1 %pred remained stable over time in both groups regardless of therapy received.
PMCID: PMC3697096  PMID: 23582575
Pulmonary function testing; Autoimmune disease; Obliterative bronchiolitis
6.  Mycophenolate Mofetil Improves Lung Function in Connective Tissue Disease-associated Interstitial Lung Disease 
The Journal of rheumatology  2013;40(5):640-646.
Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF.
We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF.
We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%.
In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD.
PMCID: PMC3676865  PMID: 23457378
7.  Ethnic and racial differences in the presence of idiopathic pulmonary fibrosis at death 
Respiratory Medicine  2012;106(4):588-593.
In studies of idiopathic pulmonary fibrosis (IPF), whites make up the vast majority of subjects. Whether ethnic/racial differences in idiopathic pulmonary fibrosis occur in the general population is unknown.
To compare the presence of IPF between ethnic/racial groups of U.S. decedents from 1989-2007 by using the National Center for Health Statistics database.
There were 251,058 U.S. decedents with IPF; 87.2% were non-Hispanic whites (White), 5.1% were non-Hispanic African-American (Black), 5.4% were Hispanic, and 2.2% were from other ethnic/racial groups (Other). Whites coded with IPF died older than those in the other groups (77.9 years vs. 72.1 years for Blacks, 75.3 years for Hispanics, and 75.6 years for Others; p<0.0001 for all pairwise comparisons). When controlling for age and for sex, compared with Whites, both Hispanics and Others were more likely to be coded with IPF (OR=1.47, 95% CI 1.44-1.49, p<0.0001 and OR=1.29, 95% CI 1.26-1.36, p<0.0001 respectively), while Blacks were significantly less likely to be coded with IPF (OR=0.48, 95% CI 0.47-0.49, p<0.0001). Among decedents with IPF, Hispanics were more likely, and Blacks were less likely, than Whites to die from IPF (OR=1.24, 95% CI 1.20-1.29, p<0.0001 and OR=0.91, 95% CI 0.87-0.94, p<0.0001).
From 1989-2007, Black decedents were less—and Hispanics were more— likely than Whites to die of/with IPF. Research is needed to determine if genetic differences between ethnic/racial groups explain these findings.
PMCID: PMC3294009  PMID: 22296740
Idiopathic pulmonary fibrosis; mortality; race; epidemiology
8.  Sarcoidosis-related Mortality in the United States from 1988 to 2007 
Rationale: It has been nearly 20 years since sarcoidosis mortality was examined at the population level in the United States.
Objectives: To examine mortality rates and underlying causes of death among United States decedents with sarcoidosis from 1988–2007.
Methods: We used data from the National Center for Health Statistics to (1) calculate age-adjusted sarcoidosis-associated mortality rates; (2) examine how those rates differ by age, sex, and race and ethnicity; and (3) determine underlying causes of death among sarcoidosis decedents.
Measurements and Main Results: From 1988–2007, there were 46,450,489 deaths in the United States and 23,679 decedents with sarcoidosis mentioned on their death certificates. Over this time, the age-adjusted, sarcoidosis-related mortality rate increased 50.5% in women and 30.1% in men. The greatest absolute increase in death rates was among non-Hispanic black females. Regardless of sex or race, mortality rates climbed most in decedents 55 years or older. The most common cause of death was sarcoidosis itself. Younger sarcoidosis decedents with pulmonary fibrosis were more likely to be black than white, and younger sarcoidosis decedents were more likely than similarly aged decedents in the general population to have a cardiac cause contribute to death.
Conclusions: From 1988–2007, sarcoidosis-related mortality rates increased significantly, particularly in non-Hispanic black females aged 55 years or older. The underlying cause of death in most patients with sarcoidosis was the disease itself. Among young sarcoidosis decedents, those with pulmonary fibrosis or a cardiac cause contributing to death were more likely to be black than white.
PMCID: PMC3137141  PMID: 21330454
sarcoidosis; mortality; epidemiology

Results 1-8 (8)