deb_pone XXXXXXXXXX
Usual Interstitial Pneumonia Preceding Collagen
Vascular Disease: A Retrospective Case Control Study of
Patients Initially Diagnosed with Idiopathic Pulmonary
Fi
osis
Masato Kono1,2, Yutaro Nakamura1*, Noriyuki Enomoto1, Dai Hashimoto1, Tomoyuki Fujisawa1,
Naoki Inui1, Masato Maekawa2, Takafumi Suda1, Thomas V. Colby3, Kingo Chida1
1 Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan, 2Department of Laboratory Medicine, Hamamatsu
University School of Medicine, Hamamatsu, Japan, 3Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, United Sates of America
Abstract
Background: The aim of this study was to evaluate the cumulative incidence and the predictive factors for collagen vascula
disease (CVD) in patients initially diagnosed with idiopathic pulmonary fi
osis (IPF), and to examine the features of patients
who then developed CVD.
Methods: This was a retrospective review of 111 consecutive patients with IPF diagnosed at our institution. None of the
patients fulfilled any of the CVD criteria from the American College of Rheumatology (ACR) within 6 months or more afte
the diagnosis of IPF.
Results: Ten patients (9.0%) developed CVD during the follow-up period: four had rheumatoid arthritis (RA); four had
microscopic polyangiitis (MPA); one had systemic sclerosis (SSc); and one had SSc and Sjogren’s syndrome (SjS). The mean
time until CVD diagnosis was 3.9 years. The cumulative incidences of CVD at 1, 5, and 10 years were 0.91%, 9.85%, and
15.5%, respectively. Patients who developed CVD were significantly younger, more likely to be women and had a bette
prognosis than those with IPF. Cox proportional hazards regression analysis showed that female sex and the presence of
lymphoid aggregates with germinal centers were significantly associated with the occu
ence of CVD in patients initially
diagnosed with IPF.
Conclusions: CVD is an important underlying condition in IPF, and shows better prognosis. The possibility of the
development of CVD should remain a consideration in the follow-up of IPF.
Citation: Kono M, Nakamura Y, Enomoto N, Hashimoto D, Fujisawa T, et al XXXXXXXXXXUsual Interstitial Pneumonia Preceding Collagen Vascular Disease: A
Retrospective Case Control Study of Patients Initially Diagnosed with Idiopathic Pulmonary Fi
osis. PLoS ONE 9(4): e94775. doi:10.1371/journal.pone XXXXXXXXXX
Editor: Carol Feghali-Bostwick, Medical University of South Carolina, United States of America
Received October 29, 2013; Accepted March 19, 2014; Published April 15, 2014
Copyright: � 2014 Kono et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was partly supported by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labor and Welfare, Japan. The
funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: XXXXXXXXXX
Introduction
Interstitial pneumonia (IP) commonly complicates collagen
vascular disease (CVD) [1–5], and it is well known that IP may
e the first or only manifestation of CVD [6]. None of these
patients with IP fulfill the diagnostic criteria for defined CVDs,
and most may be diagnosed as idiopathic interstitial pneumonias
(IIPs) [7,8]. It has been reported that patients with IIPs cannot be
distinguished from those with IP associated with CVD (CVD-IP)
efore the systemic signs of CVD appear [6]. Although we
sometimes encounter patients who fulfill the criteria for a CVD in
the clinical course of IIP, the cumulative incidence and predictive
factors associated with the occu
ence of CVD remain unclear.
In patients with IIPs, non-specific interstitial pneumonia (NSIP)
has been reported to be associated with autoimmune diseases
including CVDs [9–11], and there are some reports of idiopathic
NSIP preceding the diagnosis of CVD [11–14]. However, there
are a few reports of patients who fulfill the criteria for a CVD afte
the diagnosis of idiopathic pulmonary fi
osis (IPF)/usual inter-
stitial pneumonia (UIP) [4,15]. Recently, some patients with
CVD-associated signs and symptoms who nonetheless failed to
fulfill the criteria defined CVDs have been diagnosed using new
criteria, such as those for undifferentiated connective tissue disease
(UCTD) [16], lung-dominant connective tissue disease (LD-CTD)
[17], and autoimmune-featured interstitial lung disease (AIF-ILD)
[18]. However, these criteria are not always fulfilled in patients
with IIPs preceding the diagnosis of CVD.
Here, we evaluated the cumulative incidence of CVD and the
clinical features of patients who fulfilled the criteria for any CVD
after an initial diagnosis of IPF. Furthermore, we examined the
predictive factors associated with the development of CVD in
patients initially diagnosed with IPF.
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Patients and Methods
Patients and Diagnostic Criteria
We studied 155 consecutive patients with IPF who were
diagnosed clinically or underwent surgical lung biopsy (SLB) at ou
institution from 1990 through 2007. The diagnosis of IPF was
ased on a history, physical examination, high-resolution com-
puted tomography (HRCT) findings and/or histologic examina-
tion, and the appropriateness of the IPF diagnosis in each case was
etrospectively reevaluated according to the cu
ent international
diagnostic criteria [19]. Within at least 6 months of the initial
diagnosis, none of the patients fulfilled the American College of
Rheumatology (ACR) criteria defining CVDs, including rheuma-
toid arthritis (RA) [20], polymyositis/dermatomyositis (PM/DM)
[21], systemic sclerosis (SSc) [22], systemic lupus erythematosus
(SLE) [23] and Sjogren’s syndrome (SjS) [24], or the Chapel Hill
Consensus Conference criteria defining systemic vasculitis, includ-
ing microscopic polyangiitis (MPA) [25]. The study protocol was
approved by the Ethical Committee of Hamamatsu University
School of Medicine. Patient approval and/or informed consent
were waived because the study involved a retrospective review of
patient records, images and pathologies. Our institutional review
oard determined that ethical approval was not necessary and did
not require the patient’s approval or informed consent.
Data Collection
Clinical data were obtained from patients’ medical records.
Laboratory findings, pulmonary function test results and
on-
choalveolar lavage (BAL) data obtained at the time of the initial
diagnosis were also recorded. For the patients who developed
CVD, additional clinical data were obtained at the time of the
CVD diagnosis. The duration of time until the CVD diagnosis and
the cumulative incidence of CVD among patients with IPF were
calculated.
High-resolution Computed Tomography (HRCT)
HRCT examinations of the lungs were performed on 1.0- o
1.5-mm-thick sections to evaluate radiographic abnormalities at
the time of initial diagnosis. The HRCT images were based on
previously published international criteria for IPF [19]. We
eviewed the presence and the distribution of each of the following
signs: consolidation, ground-glass opacity (GGO), reticulation,
centrilobular nodules, honeycombing, traction
onchiectasis,
lymph node enlargement, and cysts.
Pathological Review
Histological classification was based on the previously published
criteria for IIPs and IPF [7,19]. A diagnosis of UIP was originally
made histologically by a lung pathologist at our facility. Lung
iopsy specimens were also reviewed by a second lung pathologist
(T. V. C.) who was unaware of the clinical or physical findings.
The degree of each of the following pathologic findings was scored
semiquantitatively (absent, 0; mild, 1; moderate, 2; marked, 3):
alveolar inflammation, fi
osis, intra-alveolar macrophages, orga-
nizing pneumonia, fi
oblastic foci, and lymphoid aggregates with
germinal centers. For lymphoid aggregates, the case was scored as
1 when there was one germinal center and as 3 when there were
six or more in a low-power field (26). The presence or absence of
each of the following pathologic findings was also assessed:
honeycombing, extensive pleuritis, prominent plasmacytic infiltra-
tion, and dense perivascular collagen including the histopatholog-
ical features of the proposed provisional criteria for LD-CTD [17].
Statistical Methods
For two-group comparisons involving binary data, we used the
chi-square test. Comparisons involving continuous data were
made using the Mann-Whitney U-test. The cumulative survival
probabilities and the cumulative incidence of CVD were estimated
using the Kaplan-Meier method. The log-rank test was used to
compare survival among the groups of patients. Cox proportional
hazards regression analysis was used to identify significant
variables predicting the development of CVD. Statistical analyses
were performed using JMP Start Statistics (SAS Institute Inc., NC,
USA). A P value ,0.05 was considered significant.
Results
Patient Characteristics
Of the original 155 patients, 44 patients were excluded because
of inadequate clinical information. The remaining 111 patients
were included in this study. All of them were diagnosed with IPF
(definite, n = 104; probable, n = 2; possible, n = 5) according to
HRCT and/or the histopathological pattern [19] (Figure 1), and
the clinical characteristics of these patients are shown in Table 1.
During the observation periods XXXXXXXXXXyears), 10 patients (9%)
developed CVD (all patients were initially diagnosed with definite
IPF). We compared the clinical characteristics of patients who
developed CVD and those with IPF at the initial diagnosis
(Table 1). Compared to patients with IPF, those who developed
CVD were younger and more often female. There were no
statistically significant differences in smoking habits, observation
period, or the rate of SLB between groups. Between-group
comparisons revealed no significant difference in serum levels of
lactate dehydrogenase (LDH), creatine phosphokinase (CPK), C-
eactive protein (CRP), KL-6, surfactant protein-D (SP-D), PaO2
in room air, or pulmonary function. BAL was performed in 83
patients (74.8%): in nine of 10 who developed CVD and in 74 of
101 who did not. The patients who developed CVD exhibited a
educed percentage of lymphocytes (P=0.04) in comparison to
those with IPF, but no other BAL findings were significantly
different between the groups.
The clinical characteristics of the patients who developed CVD
at the time of CVD diagnosis are shown in Table 2. These 10
patients included four patients with RA (40%), four patients with
MPA (40%), one patient with SSc (10%), and one patient with
overlap syndrome (SSc/SjS) (10%). This group included five
women (50%). Age at the time of CVD diagnosis was XXXXXXXXXX
years. The average time from the initial diagnosis of IPF to the
CVD diagnosis was XXXXXXXXXXyears. None of the patients had
undergone treatment for IP with corticosteroids and/or immuno-
suppressive agents (ISA) prior to the development of CVD. Each
had been diagnosed with CVD based on their symptoms and othe
findings associated with CVD. All four patients who developed RA
showed polyarthralgia and positivity for rheumatoid factor (RF). In
the four patients who developed MPA, two patients (Cases 7, 8)
had alveolar hemo
hage, three patients (Cases 6, 7, 8) showed
enal dysfunction with hematuria, two patients (Cases 5, 8)
exhibited a purpuric rash with small-vessel vasculitis detected by
skin biopsy, and all four patients showed positivity for myeloper-
oxidase antineutrophil cytoplasmic antibody (MPO-ANCA). Both
patients who developed SSc showed Raynaud’s phenomenon and
scleroderma, and