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Original Research: Diffuse Lung Disease |

Thyroid Disease Is Prevalent and Predicts Survival in Patients With Idiopathic Pulmonary FibrosisHypothyroidism in IPF FREE TO VIEW

Justin M. Oldham, MD; Disha Kumar, MD; Cathryn Lee, MD; Shruti B. Patel, MD; Stephenie Takahashi-Manns, MD; Carley Demchuk, BS; Mary E. Strek, MD, FCCP; Imre Noth, MD
Author and Funding Information

From the Section of Pulmonary and Critical Care Medicine (Drs Oldham, Strek, and Noth and Ms Demchuk), Section of Endocrinology, Diabetes, and Metabolism (Dr Kumar), and the Department of Medicine (Dr Lee), University of Chicago, Chicago, IL; the Division of Pulmonary and Critical Care Medicine (Dr Patel), Loyola University Medical Center, Chicago, IL; and the Department of Critical Care Medicine (Dr Takahashi-Manns), The Intensivist Group of Pennsylvania, Philadelphia, PA.

CORRESPONDENCE TO: Justin M. Oldham, MD, Section of Pulmonary and Critical Care Medicine, University of Chicago, 5841 S Maryland Avenue, MC 6076, Chicago, IL 60637; e-mail: justin.oldham@uchospitals.edu


FUNDING/SUPPORT: This investigation was supported by a National Institutes of Health T32 training grant [T32-HL007605].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):692-700. doi:10.1378/chest.14-2714
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BACKGROUND:  A significant minority of patients with idiopathic pulmonary fibrosis (IPF) display features of autoimmunity without meeting the criteria for overt connective tissue disease. A link between IPF and other immune-mediated processes, such as hypothyroidism (HT), has not been reported. In this investigation, we aimed to determine whether HT is associated with IPF and if outcomes differ between patients with IPF with and without HT.

METHODS:  A retrospective case-control analysis was conducted. Of 311 patients referred to the University of Chicago Interstitial Lung Disease Center with an initial diagnosis of IPF, 196 met the inclusion criteria and were included in the final analysis. Each case was matched 1:1 by age, sex, and race to a control subject with COPD.

RESULTS:  HT was identified in 16.8% of cases and 7.1% of control subjects (OR, 2.7; 95% CI, 1.31-5.54; P = .01). Among patients with IPF, HT was associated with reduced survival time (P < .001) and was found to be an independent predictor of mortality in multivariable Cox regression analysis (hazard ratio, 2.12; 95% CI, 1.31-3.43; P = .002). A secondary analysis of two IPF clinical trial datasets supports these findings.

CONCLUSIONS:  HT is common among patients with IPF, with a higher prevalence than in those with COPD and the general population. The presence of HT also predicts mortality in IPF, a finding that may improve future prognostication models. More research is needed to determine the biologic link between IPF and HT and how the presence of thyroid disease may influence disease progression.

Figures in this Article

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown cause. It has a median survival of 3 to 5 years and a heterogeneous natural history, and research has focused on identifying unique IPF subgroups.1,2 Individuals with IPF and other ILDs who exhibit the features of autoimmunity, but who fail to meet the established rheumatologic criteria for connective tissue disease (CTD) compose one such group.35 Those who have interstitial pneumonia with autoimmune features, referred to as undifferentiated connective tissue disease (UCTD) and autoimmune-featured ILD (AIF-ILD), account for a significant minority of patients with IPF and other idiopathic interstitial pneumonias.35

UCTD and AIF-ILD criteria focus on CTD-related physical signs and serologies but do not address non-CTD autoimmune disease processes, several of which are common in the general population. Chronic autoimmune thyroiditis, also known as Hashimoto thyroiditis, is one such process and is characterized by T-cell and autoantibody-mediated destruction of the thyroid gland, leading to hypothyroidism (HT).6 Although congenital and postpartum forms of HT exist, and HT may be caused by iodine deficiency and some medications, the overwhelming majority of HT cases in developed nations have an autoimmune cause, which is estimated to affect 5% to 9% of women and 1% to 2% of men.68

The prevalence of HT and other non-CTD autoimmune processes among patients with IPF and other ILDs is currently unknown. We hypothesized that (1) HT is more common in patients with IPF than in matched control subjects and (2) clinical characteristics, including outcomes, differ between patients with IPF with and without HT. To test these hypotheses, we conducted a case-control analysis and then analyzed datasets from two randomized clinical trials conducted by the Idiopathic Pulmonary Fibrosis Network (IPFnet) to determine whether our results could be replicated.911

Study Design

This retrospective investigation was conducted at the University of Chicago and was approved by our institutional review board (IRB protocol 13-1180). A case-control analysis was conducted using patients with IPF referred to the University of Chicago ILD center along with age-, sex-, and race-matched control subjects with COPD. Of 311 individuals evaluated at the University of Chicago from 2004 to 2012 with an initial diagnosis of IPF based on International Classification of Diseases, Ninth Revision code (Fig 1), 247 met the criteria for IPF according to the 2011 American Thoracic Society/European Respiratory Society criteria.

Figure Jump LinkFigure 1 –  Consort diagram outlining case-finding methodology. ATS = American Thoracic Society; ERS = European Respiratory Society; HRCT = high-resolution CT; ICD-9 = International Classification of Disease, Ninth Revision; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; SLB = surgical lung biopsy.Grahic Jump Location

Of those failing to meet the criteria for IPF, 30 had possible IPF but declined surgical lung biopsy (SLB) after high-resolution CT (HRCT) scanning failed to demonstrate usual interstitial pneumonia (UIP), 14 were missing the clinical information needed to confirm the diagnosis (HRCT scan or SLB), and 20 were given a diagnosis of an alternative ILD. Patients with a diagnosis of IPF who exhibited features of autoimmunity according to previously suggested criteria35 (n = 38) were excluded from the analysis, as were 13 patients who participated in the clinical trials used for our replication cohort, leaving 196 cases for the primary analysis. Of these 196 cases, 155 (79%) demonstrated UIP on HRCT scan, whereas the remainder demonstrated histopathologic UIP after SLB.

The control group was composed of individuals with COPD who had been referred to the University of Chicago general pulmonary clinic from 2006 to 2014. Patients with an International Classification of Diseases, Ninth Revision code for COPD were systematically identified by the University of Chicago Center for Research Informatics and were matched according to age, sex, and race/ethnicity in a sequential fashion starting at the top of the alphabet by last name.

All data were extracted retrospectively from the electronic medical record using the initial clinic visit. These data included demographic information (age, race/ethnicity, sex), patient-reported medical/surgical history (HT, gastroesophageal reflux [GER], diabetes mellitus [DM], coronary artery disease [CAD], tobacco use, hyperthyroidism, thyroid ablation, thyroidectomy), patient-reported medications (thyroid replacement, GER and statin therapy, lithium, amiodarone, systemic corticosteroids, azathioprine, N-acetylcysteine, radioactive iodine [RAI] history), physical examination findings (BMI, clubbing, crackles), laboratory studies (antinuclear antibody with staining pattern, rheumatoid factors, anticitrullinated protein antibody, myositis-specific antibodies, antineutrophil cytoplasmic antibody, anti-Ro/SSA antibody, anti-La/SSB antibody, anti-Scl-70 antibody, aldolase, thyroid-stimulating hormone [TSH], and free thyroxine), and diagnostic studies (HRCT scan, SLB, pulmonary function testing, including FVC, FEV1, and percent predicted diffusion capacity of the lung for carbon monoxide [Dlco]).

HT was recorded when a patient reported the use of thyroid replacement therapy and did not report a previous history of thyroidectomy or RAI ablation. No patients reported the use of medications known to alter thyroid function, including lithium, amiodarone, or interferon-γ. No patients were immediately postpartum or endorsed a history of congenital HT. No patients lived outside the United States.

We then analyzed datasets from two IPFnet randomized clinical trials, Anticoagulant Effective in Idiopathic Pulmonary Fibrosis (ACE-IPF)9 and Prednisone, Azathioprine and N-acetylcysteine for Pulmonary Fibrosis (PANTHER),10,11 to determine whether our findings could be replicated. HT was recorded when a patient reported the use of thyroid replacement therapy.

Statistical Analysis

Continuous variables are reported as means with SD and are compared using a two-tailed Student t test. Categorical variables are reported as counts and percentages and were compared using the χ2 test or Fisher exact test, as appropriate. Conditional logistic regression was performed to compare the proportion of HT between cases and control subjects. Survival analysis was performed using univariate and multivariable Cox regression together with the unadjusted log-rank test and was plotted using the Kaplan-Meier survival estimator. Survival time was defined as the time from diagnostic test (SLB or HRCT scan) to death, transplant, loss to follow-up, or end of study period. Patients undergoing lung transplant were censored at the time of transplant. All statistical analyses were performed using Stata 12 (StataCorp LP).

One hundred ninety-six patients with IPF were matched 1:1 by age, sex, and race/ethnicity to a control patient with a diagnosis of COPD. A comparison of baseline characteristics between case patients and control subjects is shown in Table 1. Case patients and control subjects were similar in terms of age (68.1 years vs 69 years, respectively), sex (74.5% male), and race/ethnicity (80.1% white, 8.2% black, 9.2% Hispanic, and 2.5% Asian), as specified by the study design. Compared with control subjects, case patients had a higher BMI (30.2 vs 28.5, P = .01) and fewer ever smokers (74% vs 91%, P < .001). No significant differences between case patients and control subjects were observed regarding GER (44.4% vs 43.4%, respectively), DM (20.9% vs 21.9%, respectively) or chronic systemic corticosteroid use (12.8% vs 15.8%, respectively).

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are presented as mean ± SD or No. (%). IPF = idiopathic pulmonary fibrosis.

a 

Exception for number of patients: BMI (n = 195).

When comparing the proportion of patients with HT between cases and control subjects (Table 2), HT was found to be significantly associated with IPF in univariate analysis (OR, 2.72; 95% CI, 1.37-5.44; P = .004). In multivariable analysis adjusting for variables previously associated with IPF, HT, or both, including BMI,12 smoking history,13,14 DM,15 and GER,16 along with chronic corticosteroid use, HT remained significantly associated with IPF (OR, 2.7; 95% CI, 1.31-5.54; P = .01). HT was identified in 13% of male case patients compared with 4.1% of male control subjects and 28% of female case patients compared with 16% of female control subjects.

Table Graphic Jump Location
TABLE 2 ]  Hypothyroidism and IPF Risk

Data are presented as No. (%). See Table 1 legend for expansion of abbreviation.

a 

Adjusted for BMI, smoking history, diabetes mellitus, gastroesophageal reflux, and corticosteroid use.

We then stratified patients with IPF based on HT status (Table 3). Significantly fewer men were observed among those with IPF/HT compared with IPF alone (57.6% vs 77.9%, P = .02). Those with IPF/HT were also found to have a significantly lower mean Dlco % predicted compared with those with IPF alone (43.3 vs 50.4, P = .05), but 8.7% (n = 17) of individuals in the overall cohort could not perform this maneuver. No significant differences were observed between groups with respect to the following: age; race/ethnicity; BMI; crackles; clubbing; smoking history; GER; DM; the use of corticosteroid monotherapy, azathioprine monotherapy, prednisone/azathioprine/N-acetylcysteine (PAN) triple therapy, or GER therapy (proton pump inhibitor or histamine-2 blocker); FVC % predicted; radiographic UIP; antinuclear antibody seropositivity; rheumatoid factor/anticitrullinated protein antibody seropositivity; > 1 autoantibody seropositivity; TSH; gender, age, physiology (GAP)17 stage; or lung transplant.

Table Graphic Jump Location
TABLE 3 ]  Characteristics of Patients With IPF Stratified by HT Status (N = 196)a

aCCP = anticitrullinated protein antibody; ANA = antinuclear antibody; Dlco = diffusion capacity of the lung for carbon monoxide; GAP = gender, age, physiology; GER = gastroesophageal reflux; HT = hypothyroidism; PAN = prednisone/azathioprine/N-acetylcysteine; RF = rheumatoid factor; TSH = thyroid-stimulating hormone; UIP = usual interstitial pneumonia. See Table 1 legend for expansion of other abbreviation.

a 

Exceptions for number of patients: crackles (n = 192); clubbing (n = 179); Dlco (n = 179); radiographic UIP (n = 191); ANA (n = 179); RF/aCCP (n = 178); any autoantibody (n = 180); TSH (n = 79).

b 

Titer > 1:320 or nucleolar pattern.

c 

Based on Ley et al.17

In unadjusted survival analysis, those with IPF/HT demonstrated significantly shorter survival compared with those with IPF alone (P < .001) (Fig 2). Substratifying by HT status and sex (Fig 3) shows that men and women with IPF/HT demonstrated significantly shorter survival compared with their counterparts with IPF alone (P = .001), with women without HT having the best overall survival. Univariate and multivariable Cox regression was performed (Table 4) to identify predictors of mortality in this cohort. In univariate analysis, HT was found to be a significant predictor of mortality (hazard ratio [HR], 2.1; 95% CI, 1.34-3.28; P = .001), as was each increase in GAP stage (HR, 2.06; 95% CI, 1.56-2.73; P < .001) and PAN triple therapy (HR, 2.60; 95% CI, 1.07-6.49; P = .04).

Figure Jump LinkFigure 2 –  Survival among patients with IPF stratified by HT status. Those with combined HT and IPF demonstrate significantly reduced survival time compared with those with IPF alone (P < .001). HT = hypothyroidism. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3 –  Survival among patients with IPF stratified by sex and HT status. Men and women with combined HT and IPF demonstrate significantly shorter survival time compared with their counterparts with IPF alone (P = .001). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location
Table Graphic Jump Location
TABLE 4 ]  Variables Predicting Survival in Patients With IPF

CAD = coronary artery disease; HR = hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Adjusted for race/ethnicity, BMI, and variables listed above.

Other variables that may influence survival in IPF, including corticosteroid monotherapy,11 azathioprine monotherapy,11 GER therapy,18 smoking history,19 and CAD,20 did not predict survival in univariate analysis. A multivariable model that included these variables, along with race/ethnicity and BMI, showed that HT remained a significant predictor of mortality (HR, 2.12; 95% CI, 1.31-3.43; P = .002), as did each increase in GAP stage (HR, 1.91; 95% CI, 1.42-2.58; P < .001). PAN triple therapy no longer predicted survival after multivariable adjustment. These conclusions held when transplant-free, transplant-excluded, and transplant-as-a-competing-event Cox regression models were constructed (e-Tables 1-3). The GAP stage was chosen rather than individual pulmonary function metrics to account for individuals unable to perform the Dlco maneuver. A multivariable model using age, sex, FVC % predicted, and Dlco % predicted rather than the GAP stage was also constructed with missing Dlco values imputed to 7 (equal to the lowest recorded value in the cohort), but did not significantly change the overall conclusions (e-Table 4).

Similar methods were used with the ACE-IPF and PANTHER clinical trial datasets. HT was present in 9.4% (n = 10) and 11.7% (n = 31) of men and 15.4% (n = 6) and 23.4% (n = 18) of women in ACE-IPF and PANTHER trials, respectively (Table 5). These cohorts were combined, and univariate and multivariable Cox regression was performed to determine predictors of transplant-censored survival (Table 6). In univariate analysis, each increase in GAP stage along with PAN triple therapy and warfarin therapy were found to be significant predictors of mortality. A multivariable model was constructed that adjusted for race, BMI, GER therapy, smoking history, the ACE-IPF and PANTHER treatment arms, concurrent prednisone and azathioprine use in the ACE-IPF trial, and concurrent warfarin use in the PANTHER trial. In this multivariable model, HT was found to be a significant predictor of mortality (HR, 3.36; 95% CI, 1.4-8.05; P = .007), as was each increase in GAP stage along with PAN and warfarin therapy.

Table Graphic Jump Location
TABLE 5 ]  Prevalence of HT by Study

Data are presented as %. ACE-IPF = Anticoagulant Effective in Idiopathic Pulmonary Fibrosis; PANTHER = Prednisone, Azathioprine and N-acetylcysteine for Pulmonary Fibrosis. See Table 3 legend for expansion of other abbreviation.

a 

Based on Garber et al,6 Sawin et al,7 and Vanderpump et al.8

Table Graphic Jump Location
TABLE 6 ]  Variables Predicting Survival in Patients Enrolled in ACE-IPF and PANTHER Trials

NAC = N-acetylcysteine. See Table 3-5 legends for expansion of other abbreviations.

a 

Adjusted for race, BMI, CAD history, azathioprine use (ACE-IPF cohort), prednisone use (ACE-IPF cohort), and warfarin use (PANTHER cohort).

In this investigation, we report, to our knowledge for the first time, an association between HT and IPF. HT was found in 16.8% of our IPF cohort, including 13% of men and 28% of women. The proportion of IPF cases with HT was significantly higher than that found among matched control subjects with COPD and was markedly higher than the estimated prevalence of HT in the general population. A similar conclusion was reached with two IPFnet clinical trial datasets, supporting the association between HT and IPF. Although few phenotypic differences exist between patients with IPF with and without HT, survival analysis shows that HT was an independent predictor of mortality in our University of Chicago cohort, as well as in a combined cohort of patients enrolled in the ACE-IPF and PANTHER clinical trials. This finding may help improve future prognostication models.

The mechanism by which HT may contribute to IPF pathogenesis and mortality is unclear. A case series of two patients suggested a link between severe untreated HT and radiographic ILD that improved upon return to a euthyroid state.21 However, induction of HT in mice appears to prevent the pulmonary fibrosis associated with systemic sclerosis22 and to accelerate the recovery of liver fibrosis,23 raising doubt that biochemical HT itself could contribute to IPF onset or progression. Among those with thyrotropin data in our cohort (n = 79), all but four patients were biochemically euthyroid at the time of presentation. Furthermore, TSH level itself did not predict survival (e-Table 5). Longitudinal changes in thyroid state were not assessed in this investigation; therefore, any alteration in thyroid function at the time of IPF progression could not be determined.

A possible link between HT and IPF mortality lies in thyroid transcription factor-1 (TTF-1) expression. This transcription factor binds to the promoter regions of genes encoding surfactant protein (SP)-A, SP-B, and SP-C and is integral to lung development.24 Increased levels of alveolar and serum SP-A have been reported in patients with IPF and may predict survival.2528 High levels of TTF-1 expression, as seen in some forms of lung cancer, may result in increased production of SP-A and other SPs and have been shown to cause pulmonary inflammation and fibrosis in mice.2932 Increased TTF-1 expression has been demonstrated in patients with chronic autoimmune thyroiditis,33 raising the question of whether increased TTF-1 related to HT may contribute to the increased SP production observed in some patients with IPF.

Immune dysregulation provides another possible link between HT and IPF. A gene expression analysis of peripheral blood mononuclear cells in patients with IPF using an RNA microarray platform identified several differentially expressed genes, including CTLA-4, ICOS, and CD28, within the T-cell biocarta pathway.34 Reduced expression of each of these genes was associated with an increased hazard of death in two IPF cohorts. Genes encoding CTLA-4, ICOS, and CD28 lie within 300kb on the long arm of chromosome 2, and polymorphisms at this locus have been linked previously to autoimmune thyroid disease.35,36 Polymorphisms in CTLA-4 have also been shown to correlate with thyroid autoantibody production and may explain the increased risk of death in some patients with IPF and HT.37,38

A substantially higher proportion of control subjects had HT compared with that reported in the general population. An immunologic contribution to COPD pathogenesis has been described,39 and Karadag et al40 showed that thyroid dysfunction may occur in COPD, but nonthyroidal illness syndrome predominates over overt HT. However, an earlier case series by Dimopoulou et al41 did not support this correlation. Although COPD may be linked to thyroid dysfunction, active smoking has been shown to be protective against HT in several large population studies.42,43 We explored this association among control subjects but found no difference in the proportion of HT among those with a smoking history and never smokers (data not shown).

There were several limitations in this study. First, because of its retrospective design, causality could not be assessed and our findings represent only an association between HT and IPF. Second, biochemical confirmation of autoimmune thyroiditis was not possible for the majority of patients, because most individuals had received a diagnosis of HT years to decades prior to referral to our institution. We, therefore, chose to refer to the more broad diagnosis of HT rather than chronic autoimmune thyroiditis. By excluding other possible causes of nonautoimmune thyroid disease through our protocol, we feel confident that the overwhelming majority of cases of HT identified were indeed of autoimmune origin, as is the case among the general population.6 We were unable to apply these strict criteria to the IPFnet clinical trial datasets, because a history of RAI or thyroidectomy was not possible to ascertain, so the true proportion of patients with HT with an autoimmune cause may be somewhat lower.

Another limitation was the use of patient-reported medical history and medications. A minority of patient charts contained objective data confirming diagnoses such as GER or CAD, and medication administration could not be verified. We also chose to exclude those patients meeting the proposed criteria for UCTD and AIF-ILD. Validation of the criteria for UCTD/AIF-ILD is lacking and needs further research to determine the validity of such criteria. As such, we also performed survival analysis on the patients with UCTD/AIF-ILD included in our transplant-censored univariate and multivariable Cox models (n = 36; two were excluded because of ACE-IPF enrollment), but this did not change our findings (e-Table 6).

In conclusion, we demonstrate that HT, a largely autoimmune process, is common among patients with IPF and may represent an additional feature of autoimmunity in this patient population. Despite the paradigm shift away from an immunologic or inflammatory driver to that of alveolar injury and aberrant cellular repair, mounting evidence suggests involvement of the immune system in IPF pathogenesis and progression. Further investigation is needed to determine whether common pathogenic pathways exist between autoimmune thyroid disease and IPF and why the presence of HT is associated with the increased mortality risk observed in these cohorts.

Author contributions: J. M. O. is the guarantor of this paper and takes responsibility for the integrity of the work as a whole, from inception to published article. J. M. O., S. B. P., S. T.-M., M. E. S., and I. N. contributed to the conception and design; J. M. O., D. K., C. L., S. B. P., S. T.-M., C. D., M. E. S., and I. N. contributed to the data collection and interpretation; J. M. O., M. E. S., and I. N. contributed to the data analysis and interpretation; J. M. O., M. E. S., and I. N. contributed to the drafting of the manuscript and review for important intellectual content; and J. M. O., D. K., C. L., S. B. P., S. T.-M., C. D., M. E. S., and I. N. contributed to the writing and/or revising of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Strek has received institutional grants from the National Institutes of Health (NIH); Bristol-Myers Squibb; Gilead Sciences, Inc; Intermune; and MedImmune for the conduct of clinical trials in IPF. She has received honoraria for serving on a Data Monitoring Committee for Boehringer-Ingelheim GmbH and an advisory board for Intermune. Dr Noth has received honoraria for advisory boards with Boehringer-Ingelheim GmbH; Intermune; and Anthera Pharmaceuticals, Inc within the last 12 months related to IPF. He has also received speaking honoraria from GlaxoSmithKline and receives consulting fees from Immuneworks. He also has study contracts with the NIH, Stromedix, Sanofi SA, and Boehringer-Ingelheim GmbH for the conduct of clinical trials in IPF. Drs Oldham, Kumar, Lee, Patel, and Takahashi-Manns and Ms Demchuk 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 National Institutes of Health provided financial support for this investigation but did not play a role in its conception or execution.

Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.

ACE-IPF

Anticoagulant Effective in Idiopathic Pulmonary Fibrosis

AIF-ILD

autoimmune-featured interstitial lung disease

CAD

coronary artery disease

CTD

connective tissue disease

Dlco

diffusion capacity of the lung for carbon monoxide

DM

diabetes mellitus

GAP

gender, age, physiology

GER

gastroesophageal reflux

HR

hazard ratio

HRCT

high-resolution CT

HT

hypothyroidism

ILD

interstitial lung disease

IPF

idiopathic pulmonary fibrosis

IPFnet

Idiopathic Pulmonary Fibrosis Network

PAN

prednisone/azathioprine/N-acetylcysteine

PANTHER

Prednisone, Azathioprine and N-acetylcysteine for Pulmonary Fibrosis

RAI

radioactive iodine

SLB

surgical lung biopsy

SP

surfactant protein

TSH

thyroid-stimulating hormone

TTF-1

thyroid transcription factor-1

UCTD

undifferentiated connective tissue disease

UIP

usual interstitial pneumonia

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George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V. Reversibility of fibrotic appearance of lungs with thyroxine replacement therapy in patients with severe hypothyroidism. Endocr Pract. 2009;15(7):720-724. [CrossRef] [PubMed]
 
Bagnato G, Bitto A, Irrera N, et al. Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis. Arthritis Res Ther. 2013;15(5):R120. [CrossRef] [PubMed]
 
Bruck R, Weiss S, Traister A, et al. Induced hypothyroidism accelerates the regression of liver fibrosis in rats. J Gastroenterol Hepatol. 2007;22(12):2189-2194. [CrossRef] [PubMed]
 
Whitsett JA, Glasser SW. Regulation of surfactant protein gene transcription. Biochim Biophys Acta. 1998;1408(2-3):303-311. [CrossRef] [PubMed]
 
Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):1557-1563. [CrossRef] [PubMed]
 
McCormack FX, King TE Jr, Bucher BL, Nielsen L, Mason RJ. Surfactant protein A predicts survival in idiopathic pulmonary fibrosis [published correction appearsAm J Respir Crit Care Med. 1995;152(4 pt 1):1425]. Am J Respir Crit Care Med. 1995;152(2):751-759. [CrossRef] [PubMed]
 
Phelps DS, Umstead TM, Mejia M, Carrillo G, Pardo A, Selman M. Increased surfactant protein-A levels in patients with newly diagnosed idiopathic pulmonary fibrosis. Chest. 2004;125(2):617-625. [CrossRef] [PubMed]
 
Kuroki Y, Tsutahara S, Shijubo N, et al. Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis. 1993;147(3):723-729. [CrossRef] [PubMed]
 
Kelly SE, Bachurski CJ, Burhans MS, Glasser SW. Transcription of the lung-specific surfactant protein C gene is mediated by thyroid transcription factor 1. J Biol Chem. 1996;271(12):6881-6888. [CrossRef] [PubMed]
 
Fujita J, Ohtsuki Y, Bandoh S, et al. Expression of thyroid transcription factor-1 in 16 human lung cancer cell lines. Lung Cancer. 2003;39(1):31-36. [CrossRef] [PubMed]
 
Yan C, Sever Z, Whitsett JA. Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. J Biol Chem. 1995;270(42):24852-24857. [CrossRef] [PubMed]
 
Wert SE, Dey CR, Blair PA, Kimura S, Whitsett JA. Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation. Dev Biol. 2002;242(2):75-87. [CrossRef] [PubMed]
 
Huang H, Li X, Lin L, et al. Upregulation of thyroid transcription factor-1 and human leukocyte antigen class I in Hashimoto’s disease providing a clinical evidence for possible triggering autoimmune reaction. Eur J Endocrinol. 2011;164(5):795-800. [CrossRef] [PubMed]
 
Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med. 2013;5(205):205ra136. [CrossRef] [PubMed]
 
Ikegami H, Awata T, Kawasaki E, et al. The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan. J Clin Endocrinol Metab. 2006;91(3):1087-1092. [CrossRef] [PubMed]
 
Nithiyananthan R, Heward JM, Allahabadia A, Franklyn JA, Gough SC. Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom. Thyroid. 2002;12(1):3-6. [CrossRef] [PubMed]
 
Zaletel K, Krhin B, Gaberscek S, Bicek A, Pajic T, Hojker S. Association of CT60 cytotoxic T lymphocyte antigen-4 gene polymorphism with thyroid autoantibody production in patients with Hashimoto’s and postpartum thyroiditis. Clin Exp Immunol. 2010;161(1):41-47. [PubMed]
 
Pastuszak-Lewandoska D, Domańska D, Rudzińska M, et al. CTLA-4 polymorphisms (+49 A/G and -318 C/T) are important genetic determinants of AITD susceptibility and predisposition to high levels of thyroid autoantibodies in Polish children - preliminary study. Acta Biochim Pol. 2013;60(4):641-646. [PubMed]
 
Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009;360(23):2445-2454. [CrossRef] [PubMed]
 
Karadag F, Ozcan H, Karul AB, Yilmaz M, Cildag O. Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med. 2007;101(7):1439-1446. [CrossRef] [PubMed]
 
Dimopoulou I, Ilias I, Mastorakos G, Mantzos E, Roussos C, Koutras DA. Effects of severity of chronic obstructive pulmonary disease on thyroid function. Metabolism. 2001;50(12):1397-1401. [CrossRef] [PubMed]
 
Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2004;89(12):6077-6086. [CrossRef] [PubMed]
 
Asvold BO, Bjøro T, Nilsen TI, Vatten LJ. Tobacco smoking and thyroid function: a population-based study. Arch Intern Med. 2007;167(13):1428-1432. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Consort diagram outlining case-finding methodology. ATS = American Thoracic Society; ERS = European Respiratory Society; HRCT = high-resolution CT; ICD-9 = International Classification of Disease, Ninth Revision; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; SLB = surgical lung biopsy.Grahic Jump Location
Figure Jump LinkFigure 2 –  Survival among patients with IPF stratified by HT status. Those with combined HT and IPF demonstrate significantly reduced survival time compared with those with IPF alone (P < .001). HT = hypothyroidism. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 3 –  Survival among patients with IPF stratified by sex and HT status. Men and women with combined HT and IPF demonstrate significantly shorter survival time compared with their counterparts with IPF alone (P = .001). See Figure 1 and 2 legends for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Baseline Characteristics

Data are presented as mean ± SD or No. (%). IPF = idiopathic pulmonary fibrosis.

a 

Exception for number of patients: BMI (n = 195).

Table Graphic Jump Location
TABLE 2 ]  Hypothyroidism and IPF Risk

Data are presented as No. (%). See Table 1 legend for expansion of abbreviation.

a 

Adjusted for BMI, smoking history, diabetes mellitus, gastroesophageal reflux, and corticosteroid use.

Table Graphic Jump Location
TABLE 3 ]  Characteristics of Patients With IPF Stratified by HT Status (N = 196)a

aCCP = anticitrullinated protein antibody; ANA = antinuclear antibody; Dlco = diffusion capacity of the lung for carbon monoxide; GAP = gender, age, physiology; GER = gastroesophageal reflux; HT = hypothyroidism; PAN = prednisone/azathioprine/N-acetylcysteine; RF = rheumatoid factor; TSH = thyroid-stimulating hormone; UIP = usual interstitial pneumonia. See Table 1 legend for expansion of other abbreviation.

a 

Exceptions for number of patients: crackles (n = 192); clubbing (n = 179); Dlco (n = 179); radiographic UIP (n = 191); ANA (n = 179); RF/aCCP (n = 178); any autoantibody (n = 180); TSH (n = 79).

b 

Titer > 1:320 or nucleolar pattern.

c 

Based on Ley et al.17

Table Graphic Jump Location
TABLE 4 ]  Variables Predicting Survival in Patients With IPF

CAD = coronary artery disease; HR = hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.

a 

Adjusted for race/ethnicity, BMI, and variables listed above.

Table Graphic Jump Location
TABLE 5 ]  Prevalence of HT by Study

Data are presented as %. ACE-IPF = Anticoagulant Effective in Idiopathic Pulmonary Fibrosis; PANTHER = Prednisone, Azathioprine and N-acetylcysteine for Pulmonary Fibrosis. See Table 3 legend for expansion of other abbreviation.

a 

Based on Garber et al,6 Sawin et al,7 and Vanderpump et al.8

Table Graphic Jump Location
TABLE 6 ]  Variables Predicting Survival in Patients Enrolled in ACE-IPF and PANTHER Trials

NAC = N-acetylcysteine. See Table 3-5 legends for expansion of other abbreviations.

a 

Adjusted for race, BMI, CAD history, azathioprine use (ACE-IPF cohort), prednisone use (ACE-IPF cohort), and warfarin use (PANTHER cohort).

References

Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998;157(1):199-203. [CrossRef] [PubMed]
 
Raghu G, Collard HR, Egan JJ, et al; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. [CrossRef] [PubMed]
 
Kinder BW, Collard HR, Koth L, et al. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med. 2007;176(7):691-697. [CrossRef] [PubMed]
 
Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140(5):1292-1299. [CrossRef] [PubMed]
 
Corte TJ, Copley SJ, Desai SR, et al. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur Respir J. 2012;39(3):661-668. [CrossRef] [PubMed]
 
Garber JR, Cobin RH, Gharib H, et al; American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028. [CrossRef] [PubMed]
 
Sawin CT, Castelli WP, Hershman JM, McNamara P, Bacharach P. The aging thyroid. Thyroid deficiency in the Framingham Study. Arch Intern Med. 1985;145(8):1386-1388. [CrossRef] [PubMed]
 
Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). 1995;43(1):55-68. [CrossRef] [PubMed]
 
Noth I, Anstrom KJ, Calvert SB, et al; Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet). A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2012;186(1):88-95. [CrossRef] [PubMed]
 
Martinez FJ, de Andrade JA, Anstrom KJ, King TE Jr, Raghu G; Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2093-2101. [CrossRef] [PubMed]
 
Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. [CrossRef] [PubMed]
 
Iacobellis G, Ribaudo MC, Zappaterreno A, Iannucci CV, Leonetti F. Relationship of thyroid function with body mass index, leptin, insulin sensitivity and adiponectin in euthyroid obese women. Clin Endocrinol (Oxf). 2005;62(4):487-491. [CrossRef] [PubMed]
 
Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA. Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1997;155(1):242-248. [CrossRef] [PubMed]
 
Nyström E, Bengtsson C, Lapidus L, Petersen K, Lindstedt G. Smoking—a risk factor for hypothyroidism. J Endocrinol Invest. 1993;16(2):129-131. [CrossRef] [PubMed]
 
Enomoto T, Usuki J, Azuma A, Nakagawa T, Kudoh S. Diabetes mellitus may increase risk for idiopathic pulmonary fibrosis. Chest. 2003;123(6):2007-2011. [CrossRef] [PubMed]
 
Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27(1):136-142. [CrossRef] [PubMed]
 
Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691. [CrossRef] [PubMed]
 
Lee JS, Ryu JH, Elicker BM, et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;184(12):1390-1394. [CrossRef] [PubMed]
 
King TE Jr, Schwarz MI, Brown K, et al. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med. 2001;164(6):1025-1032. [CrossRef] [PubMed]
 
Nathan SD, Basavaraj A, Reichner C, et al. Prevalence and impact of coronary artery disease in idiopathic pulmonary fibrosis. Respir Med. 2010;104(7):1035-1041. [CrossRef] [PubMed]
 
George JT, Thow JC, Rodger KA, Mannion R, Jayagopal V. Reversibility of fibrotic appearance of lungs with thyroxine replacement therapy in patients with severe hypothyroidism. Endocr Pract. 2009;15(7):720-724. [CrossRef] [PubMed]
 
Bagnato G, Bitto A, Irrera N, et al. Propylthiouracil prevents cutaneous and pulmonary fibrosis in the reactive oxygen species murine model of systemic sclerosis. Arthritis Res Ther. 2013;15(5):R120. [CrossRef] [PubMed]
 
Bruck R, Weiss S, Traister A, et al. Induced hypothyroidism accelerates the regression of liver fibrosis in rats. J Gastroenterol Hepatol. 2007;22(12):2189-2194. [CrossRef] [PubMed]
 
Whitsett JA, Glasser SW. Regulation of surfactant protein gene transcription. Biochim Biophys Acta. 1998;1408(2-3):303-311. [CrossRef] [PubMed]
 
Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):1557-1563. [CrossRef] [PubMed]
 
McCormack FX, King TE Jr, Bucher BL, Nielsen L, Mason RJ. Surfactant protein A predicts survival in idiopathic pulmonary fibrosis [published correction appearsAm J Respir Crit Care Med. 1995;152(4 pt 1):1425]. Am J Respir Crit Care Med. 1995;152(2):751-759. [CrossRef] [PubMed]
 
Phelps DS, Umstead TM, Mejia M, Carrillo G, Pardo A, Selman M. Increased surfactant protein-A levels in patients with newly diagnosed idiopathic pulmonary fibrosis. Chest. 2004;125(2):617-625. [CrossRef] [PubMed]
 
Kuroki Y, Tsutahara S, Shijubo N, et al. Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis. 1993;147(3):723-729. [CrossRef] [PubMed]
 
Kelly SE, Bachurski CJ, Burhans MS, Glasser SW. Transcription of the lung-specific surfactant protein C gene is mediated by thyroid transcription factor 1. J Biol Chem. 1996;271(12):6881-6888. [CrossRef] [PubMed]
 
Fujita J, Ohtsuki Y, Bandoh S, et al. Expression of thyroid transcription factor-1 in 16 human lung cancer cell lines. Lung Cancer. 2003;39(1):31-36. [CrossRef] [PubMed]
 
Yan C, Sever Z, Whitsett JA. Upstream enhancer activity in the human surfactant protein B gene is mediated by thyroid transcription factor 1. J Biol Chem. 1995;270(42):24852-24857. [CrossRef] [PubMed]
 
Wert SE, Dey CR, Blair PA, Kimura S, Whitsett JA. Increased expression of thyroid transcription factor-1 (TTF-1) in respiratory epithelial cells inhibits alveolarization and causes pulmonary inflammation. Dev Biol. 2002;242(2):75-87. [CrossRef] [PubMed]
 
Huang H, Li X, Lin L, et al. Upregulation of thyroid transcription factor-1 and human leukocyte antigen class I in Hashimoto’s disease providing a clinical evidence for possible triggering autoimmune reaction. Eur J Endocrinol. 2011;164(5):795-800. [CrossRef] [PubMed]
 
Herazo-Maya JD, Noth I, Duncan SR, et al. Peripheral blood mononuclear cell gene expression profiles predict poor outcome in idiopathic pulmonary fibrosis. Sci Transl Med. 2013;5(205):205ra136. [CrossRef] [PubMed]
 
Ikegami H, Awata T, Kawasaki E, et al. The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease: a multicenter collaborative study in Japan. J Clin Endocrinol Metab. 2006;91(3):1087-1092. [CrossRef] [PubMed]
 
Nithiyananthan R, Heward JM, Allahabadia A, Franklyn JA, Gough SC. Polymorphism of the CTLA-4 gene is associated with autoimmune hypothyroidism in the United Kingdom. Thyroid. 2002;12(1):3-6. [CrossRef] [PubMed]
 
Zaletel K, Krhin B, Gaberscek S, Bicek A, Pajic T, Hojker S. Association of CT60 cytotoxic T lymphocyte antigen-4 gene polymorphism with thyroid autoantibody production in patients with Hashimoto’s and postpartum thyroiditis. Clin Exp Immunol. 2010;161(1):41-47. [PubMed]
 
Pastuszak-Lewandoska D, Domańska D, Rudzińska M, et al. CTLA-4 polymorphisms (+49 A/G and -318 C/T) are important genetic determinants of AITD susceptibility and predisposition to high levels of thyroid autoantibodies in Polish children - preliminary study. Acta Biochim Pol. 2013;60(4):641-646. [PubMed]
 
Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009;360(23):2445-2454. [CrossRef] [PubMed]
 
Karadag F, Ozcan H, Karul AB, Yilmaz M, Cildag O. Correlates of non-thyroidal illness syndrome in chronic obstructive pulmonary disease. Respir Med. 2007;101(7):1439-1446. [CrossRef] [PubMed]
 
Dimopoulou I, Ilias I, Mastorakos G, Mantzos E, Roussos C, Koutras DA. Effects of severity of chronic obstructive pulmonary disease on thyroid function. Metabolism. 2001;50(12):1397-1401. [CrossRef] [PubMed]
 
Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2004;89(12):6077-6086. [CrossRef] [PubMed]
 
Asvold BO, Bjøro T, Nilsen TI, Vatten LJ. Tobacco smoking and thyroid function: a population-based study. Arch Intern Med. 2007;167(13):1428-1432. [CrossRef] [PubMed]
 
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