[
Original Research Diffuse Lung Disease
]
Lung-Dominant Connective Tissue Disease Clinical, Radiologic, and Histologic Features Norihito Omote, MD; Hiroyuki Taniguchi, MD, PhD; Yasuhiro Kondoh, MD, PhD; Naohiro Watanabe, MD; Koji Sakamoto, MD, PhD; Tomoki Kimura, MD, PhD; Kensuke Kataoka, MD, PhD; Takeshi Johkoh, MD, PhD; Kiminori Fujimoto, MD, PhD; Junya Fukuoka, MD, PhD; Kyoko Otani, MD; Osamu Nishiyama, MD, PhD; and Yoshinori Hasegawa, MD, PhD, FCCP
Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. This study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD.
BACKGROUND:
METHODS: We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Patients were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed.
The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan. After multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P 5 .002), who also had better survival than those with h-UIP (P 5 .031). In contrast, survival was not associated with HRCT scan pattern (P 5 .79).
RESULTS:
The major histologic patterns in LD-CTD were UIP followed by NSIP. Twothirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP. CHEST 2015; 148(6):1438-1446
CONCLUSIONS:
Manuscript received December 18, 2014; revision accepted April 2, 2015; originally published Online First May 7, 2015. ABBREVIATIONS: ANA 5 antinuclear antibody; anti-Jo1 5 anti-tRNA synthetase; CS 5 corticosteroid; CTD 5 connective tissue disease; h-NSIP 5 histologic nonspecific interstitial pneumonia; HRCT 5 highresolution CT; h-UIP 5 histologic usual interstitial pneumonia; IIP 5 idiopathic interstitial pneumonia; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fibrosis; LD-CTD 5 lung-dominant connective tissue disease; MDD 5 multidisciplinary discussion; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; %FVC 5 percent predicted FVC; PFT 5 pulmonary function test; SLB 5 surgical lung biopsy; UIP 5 usual interstitial pneumonia AFFILIATIONS: From the Department of Respiratory Medicine and Allergy (Drs Omote, Taniguchi, Kondoh, Kimura, and Kataoka), Tosei General Hospital, Seto, Aichi; the Department of Respiratory Medicine
1438 Original Research
(Drs Omote, Watanabe, Sakamoto, and Hasegawa), Nagoya University Graduate School of Medicine, Nagoya, Aichi; the Department of Radiology (Dr Johkoh), Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Hyogo; the Department of Radiology (Dr Fujimoto), Kurume University School of Medicine, Kurume, Fukuoka; the Department of Laboratory of Pathology (Dr Fukuoka), Nagasaki University Hospital, Nagasaki, Nagasaki; the Department of Diagnostic Pathology (Dr Otani), Kobe University Hospital, Kobe, Hyogo; and the Department of Respiratory Medicine and Allergology (Dr Nishiyama), Kinki University Faculty of Medicine, Osaka-sayama, Osaka, Japan. FUNDING/SUPPORT: This study was partially supported by a grant to the Diffuse Lung Disease Research Group from the Japanese Ministry of Health, Labor, and Welfare and the NPO Respiratory Disease Conference.
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Current guidelines for the diagnosis and management of idiopathic interstitial pneumonias (IIPs) recommend an evaluation for underlying connective tissue disease (CTD), including serologic and other markers.1,2 There are some patients with IIPs who have specific autoantibodies even in the absence of extrathoracic features of a definite CTD, and Fischer et al1 proposed a new term for those patients: lung-dominant CTD (LD-CTD). It is important to know whether LD-CTD has a similar natural history to classifiable forms of CTD-interstitial lung disease (ILD) and whether the approach to the management of LD-CTD should be similar to that of CTD-ILD or to that of IIPs. However, little is known about its clinical features and high-resolution CT (HRCT) scan and histologic findings.
Among the histologic findings of LD-CTD, the frequency of major histologic patterns, such as usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), is unknown. Also unknown is how disease behavior and survival are affected by histologic pattern and
Materials and Methods
information. Major histologic patterns were classified according to the current IIPs classification 2013.2 Consensus diagnoses were made by these pathologists in cases of initial disagreement. In addition, characteristic histologic features for LD-CTD, including lymphoid aggregates with germinal centers, extensive pleuritis, prominent plasmacytic infiltration, and dense perivascular collagen, were evaluated in all biopsy specimens1 (Figs 1A-C).
Study Subjects Two hundred six consecutive patients who underwent SLB for diagnosis of ILD between January 2007 and December 2011 in Tosei General Hospital were retrospectively reviewed. Serologically defined LD-CTD was diagnosed when the following criteria were satisfied: (1) presence of any one of the following autoantibodies at initial evaluation: antinuclear antibody (ANA) . 1:320, nucleolar-ANA, rheumatoid factor (. 60 IU/mL), cyclic anticitrullinated peptide, anti-Sclero 70, anti-Ro/SSA, antiLa/SSB, anti-double-stranded DNA, anti-Smith, anti-ribonucleoprotein, anti-tRNA synthetase (anti-Jo1), and anti-centromere antibodies; (2) absence of a definite diagnosis of CTD (CTD was diagnosed when patients fulfilled American College of Rheumatology criteria3-8) or other known causes of ILD, including hypersensitivity pneumonitis and sarcoidosis. Sixty-three patients were excluded from this study. They included patients with CTD-IP (n 5 27), hypersensitivity pneumonitis (n 5 23), sarcoidosis (n 5 1), and others (n 5 12). Among the remaining 143 patients, 44 patients were classified as serologically defined LD-CTD and included in this study. This study was approved by Tosei General Hospital institutional review board (IRB No. 263).
FOR EDITORIAL COMMENT SEE PAGE 1367
characteristic histologic features known to be associated with CTD, such as lymphoid aggregates with germinal centers and prominent plasmacytic infiltration. The aim of this study was to elucidate the clinical features, HRCT scan patterns, histologic patterns, multidisciplinary diagnosis, and clinical courses of serologically defined LD-CTD in patients who underwent surgical lung biopsy (SLB).
Radiologic Assessment HRCT scans within 1 month before SLB were randomized and reviewed by two expert thoracic radiologists (K. F. and T. J.) who were blinded to clinical information and histologic diagnosis. The probability of UIP was evaluated and categorized by the criteria of the American Thoracic Society/European Respiratory Society/Japanese Thoracic Society/Latin American Thoracic Association guideline for idiopathic pulmonary fibrosis (IPF) (eg, UIP pattern, possible UIP pattern, and inconsistent UIP pattern).12 Disagreements on the diagnosis were resolved by consensus. HRCT scan was performed with 1.0-mm-thick sections.
Data Collection Clinical data were obtained retrospectively from patient records. We evaluated patient characteristics, pulmonary function tests (PFTs), Pao2, BAL, and serologic test results. These tests were conducted in all patients who participated in this study within 1 month before biopsy. Spirometry (CHESTAC-55V; Chest M.I., Inc) and the diffusing capacity of the lung for carbon monoxide (CHESTAC-55V; Chest M.I., Inc) were measured according to the American Thoracic Society/European Respiratory Society recommendation as physiologic assessments and examined within 1 month before biopsy.9,10 Abnormal cell counts in BAL fluid were defined by neutrophils . 3%, lymphocytes . 15%, and eosinophils . 1%.11 Histologic Assessment The biopsy slides were all reviewed by two experienced pulmonary pathologists (J. F. and K. O.) who were blinded to clinical and radiologic CORRESPONDENCE TO: Hiroyuki Taniguchi, MD, PhD, Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwakecho, Seto, Aichi 489-8642, Japan; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-3174
journal.publications.chestnet.org
Figure 1 – A-C, Characteristic histologic features for lung-dominant connective tissue disease (hematoxylin-eosin, original magnifications: A, 31; B, 340; C, 3200). Representative patient photomicrographs of histologic usual interstitial pneumonia pattern (A) with lymphoid aggregates with germinal centers (arrows) (B) and prominent plasmacytic infiltration (C). 1439
Multidisciplinary Diagnosis After close communication between the clinician, radiologist, and pathologist, a multidisciplinary diagnosis of IPF, idiopathic NSIP, unclassifiable IIP, or other was made according to the current IIPs classification 2013.2 Patients were considered to have unclassifiable IIP if a review of clinical, radiologic, and histologic data did not reveal a specific diagnosis. Patients with IPF were required to fulfill established clinical criteria to receive a confident diagnosis of IPF.12 These diagnoses were performed in August 2014. Treatments and Outcomes Follow-up assessments of percent predicted FVC (%FVC) were available at 3- to 6-month intervals following biopsy. Annual change in pul-
Results Histologic Findings and Patient Characteristics
Of the 44 patients with LD-CTD, the major histologic pattern was UIP in 25 patients, NSIP in 13 patients, and another diagnosis in six patients (Table 1). Characteristic histologic features of LD-CTD are summarized in Table 2. The most frequent finding was prominent plasmacytic infiltration (n 5 32, 73%). Two or more specific histologic features for LD-CTD were observed in 30 patients with LD-CTD (68%), comprising 15 histologic UIP (h-UIP), 11 histologic NSIP (h-NSIP), and four other patterns. Clinical characteristics of h-UIP, h-NSIP, and other patterns are shown in Table 3. There were no significant differences in age, sex, smoking history, baseline Pao2 or PFTs between patients with h-UIP and h-NSIP patterns. The proportion of patients with eosinophil percentages . 1% in BAL fluid was significantly higher in patients with h-NSIP than in patients with h-UIP (P 5 .001). As for autoantibody profiles, ANA, TABLE 1
] Major Histologic Pattern From the SLB
Specimens in 44 Patients With LD-CTD
Histologic Diagnosis
Subjects, No. (%)
UIP
25 (57)
NSIP
13 (30)
Other
6 (14)
OP
1
DAD
1
Eosinophilic pneumonia
1
Airway-centered interstitial fibrosis
1
Mixed pattern
2
a
Data are presented as No. (%). DAD 5 diffuse alveolar damage; LD-CTD 5 lung-dominant connective tissue disease; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; SLB 5 surgical lung biopsy; UIP 5 usual interstitial pneumonia. aMixed pattern included UIP 1 DAD and NSIP 1 OP.
1440 Original Research
monary function and prognosis in the groups based on the histologic and multidisciplinary diagnosis was assessed, and treatment regimens were recorded over 1 year from initial evaluation. Statistical Analysis All values were described as the mean ⫾ SD or median (range). The x2 test or Fisher exact test were used for categorical data, and the MannWhitney U test was used for continuous data. Interobserver variation of radiologic diagnosis was analyzed using the k statistic. Differences in the values for PFTs from baseline to 1 year were evaluated using paired Student t test. x2 statistics or Fisher exact test were used for comparison of proportions. Survival curves were compared by the log-rank test, and Kaplan-Meier survival curves were plotted. All data were analyzed using a statistical software package (SPSS, version 19.0; IBM Corporation).
rheumatoid factor, and nucleolar-ANA were the most frequently positive autoantibodies, observed in 12 patients each. Four patients developed manifestations of rheumatoid arthritis during follow-up: one patient with an h-UIP pattern, one patient with an h-NSIP pattern, one patient with a histologic organizing pneumonia (OP) pattern, and one patient with eosinophilic pneumonia. Two patients with an h-NSIP pattern and positive for anti-Jo1 developed the manifestations of dermatomyositis. Radiologic Findings
Radiologic findings are shown in Table 4. Interobserver agreement between the two radiologists was good (k 5 0.76). Among patients with h-UIP, HRCT scan showed a UIP pattern in five (20%), a possible UIP pattern in five (20%), and an inconsistent UIP pattern in 15 (60%). Among patients with h-NSIP, HRCT scan showed a possible UIP pattern in two (15%) and an inconsistent UIP pattern in 11 (85%). The total number of radiologically inconsistent UIP patterns was 31 (70%), among which 15 showed an h-UIP pattern. All patients with radiologic UIP showed an h-UIP pattern. Multidisciplinary Diagnosis
After multidisciplinary discussion (MDD), 25 patients with an h-UIP were labeled as having unclassifiable IIP (n 5 18) or IPF (n 5 7). Twelve patients with h-NSIP were classified as having idiopathic NSIP and one patient as having unclassifiable IIP. Unclassifiable IIP (n 5 2), cryptogenic OP (n 5 1), acute interstitial pneumonia (n 5 1), eosinophilic pneumonia (n 5 1), and acute exacerbation of IPF (n 5 1) were diagnosed in the other six patients. Treatments and Outcomes
As shown in Table 5, corticosteroid (CS) (10 mg/d) and cyclosporine A (3 mg/kg/d) were introduced in 13 patients (52%) and 11 patients (44%), respectively,
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TABLE 2
] Characteristic Histologic Features of LD-CTD Total (N 5 44)
Histologic UIP (n 5 25)
Histologic NSIP (n 5 13)
Histologic Other (n 5 6)
Lymphoid aggregates with germinal centers
21 (48)
12 (48)
8 (62)
1 (17)
Extensive pleuritis
19 (43)
11 (44)
5 (38)
3 (50)
Prominent plasmacytic infiltration
32 (73)
18 (72)
11 (85)
3 (50)
Dense perivascular collagen
20 (45)
11 (44)
6 (46)
3 (50)
Two or more histologic features of LD-CTD
30 (68)
15 (60)
11 (85)
4 (67)
Histologic Features
Data are presented as No. (%). See Table 1 legend for expansion of abbreviations.
among those with an h-UIP pattern. In patients with an h-NSIP pattern, CS and cyclosporine A were introduced in nine (69%) and eight (62%) patients, respectively. Treatment with pirfenidone was introduced in five patients with an h-UIP pattern. Ten patients with an h-UIP pattern and one patient with an h-NSIP pattern died during the median follow-up duration of 3.6 years. Among patients with an h-UIP pattern, three died of acute exacerbation of interstitial pneumonia and three died of chronic respiratory failure, whereas the other four died of nonrespiratory causes. Among patients with an h-NSIP pattern, one patient died of a nonrespiratory cause. Patients with an h-NSIP pattern showed a significant improvement in %FVC from baseline to 1 year (baseline: 74.7%; 1 year: 91.1%; P 5 .002), whereas patients with an h-UIP pattern did not (baseline: 80.6%; 1 year: 78.4%; P 5 .48) (Fig 2). Patients with h-UIP had worse survival than those with h-NSIP (P 5 .031) (Fig 3A). Among patients with h-UIP and h-NSIP patterns, no significant difference in survival was seen depending on HRCT scan pattern (inconsistent UIP pattern vs possible UIP pattern and UIP pattern; P 5 .79). Among diagnoses based on MDD, patients in whom idiopathic NSIP was diagnosed showed better survival than patients in whom IPF was diagnosed (P 5 .014) (Fig 3B). Survival tended to differ, although not significantly, between patients with idiopathic NSIP and those with unclassifiable IIP (P 5 .078).
Discussion To our knowledge, this is the first report on the clinical, radiologic, and histologic features of patients with serologically defined LD-CTD who underwent SLB. The major histologic patterns of LD-CTD in this study were UIP followed by NSIP, and about two-thirds of these patients had characteristic histologic features for LD-CTD. Patients with LD-CTD were likely to show an inconsistent UIP pattern on HRCT scan.
journal.publications.chestnet.org
Therefore, most patients with h-UIP were believed not to have IPF but had unclassifiable IIPs diagnosed based on MDD. The result that patients with h-UIP had worse survival than those with h-NSIP suggests the prognostic value of histologic subclassification in LD-CTD. In the study, a UIP was the major histologic pattern in LD-CTD, whereas prior studies have shown that an NSIP pattern was the predominant histologic pattern in CTD-IP, except for rheumatoid arthritis-related IP.13-15 A majority of cases with an h-UIP pattern with LD-CTD were labeled as unclassifiable IIP after MDD because of characteristic histologic features such as prominent plasmacytic infiltration and lymphoid aggregates with germinal centers. Therefore, we believe that in these cases not only major histologic pattern but also these characteristic histologic features should be assessed. In our study, about one-half of patients with LD-CTD with an h-UIP pattern showed inconsistent UIP pattern on HRCT scan. In previous reports, one-third of patients with biopsy-proven IPF/UIP had atypical features for IPF on HRCT scan, which was less frequent than in our cases.16,17 Another study reported that CTD-UIP was more likely to show an inconsistent UIP pattern than IPF/UIP.18 In patients with LD-CTD, the frequency of an inconsistent UIP pattern with an h-UIP pattern seemed to be similar to that of patients with CTD-UIP. Song et al19 reported that IPF/UIP with positive autoantibodies had characteristic histologic features, such as germinal centers and plasma cells, and inconsistent UIP pattern on HRCT scan more frequently than did IPF/UIP without autoantibodies. These reports were consistent with our result that patients with LD-CTD with an h-UIP pattern showed an inconsistent UIP pattern on HRCT scan. In our study, a majority of patients with h-UIP with LD-CTD had multiple histologic patterns (eg, histologic
1441
16 (64)
24 (55)
25
Former/current smokers
80.0 (50.9-104)
PaO2 at rest, mm Hg
1 7 0 2 1
Anti-La/SSB
Anti-dsDNA
Anti-Smith
11
Anti-CCP
148#6 CHEST DECEMBER 2015
Anti-Ro/SSA
12
Nucleolar-ANA
[
Anti-Scl-70
12
Rheumatoid factor (. 60 IU/mL)
12
13
Eosinophils . 1.0%
Autoantibody
13
Neutrophils . 3.0%
Lymphocytes . 15.0%
7
54.5 (14.8-99.0)
DLCO
BAL fluid, %
75.9 (46.5-138)
FVC
Pulmonary function, % predicted
0.1 (0-3.6)
0.2 (0-19.3) 1,200 (200-5,600)
CRP, g/dL
KL-6, U/mL
1
2
0
3
0
5
8
6
9
2
3
2
76.1 (60.3-104)
53.5 (28.1-75.9)
82,5 (46.5-138)
1,200 (200-5,400)
7.1 (3.8-13.4)
14
11
7.2 (3.8-21.4)
WBC count, 103/mm3
Laboratory
19
Never smokers
Smoking
Male sex
Age, y
25 65 (39-74)
44 64 (36-74)
Patients
Histologic UIP
Total
] Baseline Characteristics of Each Histologic Subset of LD-CTD
Characteristic
TABLE 3
ANA (. 1:320)
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]
0
0
0
3
1
3
2
3
2
8
5
3
80.8 (58.4-91.6)
44.9 (14.8-99.0)
71.9 (48.3-112)
1,200 (300-4,400)
0.3 (0-6.9)
7.4 (5.1-15.5)
6
7
5 (38)
61 (36-71)
13
Histologic NSIP
0
0
0
1
0
3
2
3
1
3
5
2
71.1 (50.9-85.4)
58.5 (26.2-80.6)
75.7 (53.5-83.4)
800 (200-5,600)
2.3 (0-19.3)
9.7 (4.1-21.4)
5
1
3 (50)
63 (53-72)
6
Histologic Other
(Continued)
…
…
…
…
…
…
…
…
…
.001
.09
.32
.65
.99
.31
.96
.12
.28
…
.73
.18
.15
…
P Value (UIP vs NSIP)
… 0 1 1 Anti-centromere
Some patients had multiple positive serologic tests. Data are presented as No., No. (%), or median (range) unless otherwise noted. ANA 5 antinuclear antibody; anti-CCP 5 cyclic anticitrullinated peptide; anti-dsDNA 5 anti-double-stranded DNA; anti-Jo1 5 anti-tRNA synthetase; anti-Scl-70 5 anti-Sclero 70; CRP 5 C-reactive protein; DLCO 5 diffusing capacity of the lung for carbon monoxide. See Table 1 legend for expansion of other abbreviations.
… 0
0
… 0
0
3
2
3 Anti-Jo1
Anti-RNP
3
1
P Value (UIP vs NSIP) Histologic Other Histologic NSIP Histologic UIP Total Characteristic
] (continued) TABLE 3
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UIP pattern with prominent plasmacytic infiltration and lymphoid aggregates with germinal centers). According to the 2011 IPF guideline, the histologic classification of these patients was believed to be “not UIP pattern” and was diagnosed as unclassifiable IIPs. The current IIPs classification of 2013 noted that cases of “unclassifiable IIPs” in terms of overlap of histologic patterns often prove to be related to CTD.2 In fact, previous studies regarding histologic findings of CTD-IP reported that similar histologic features were frequently seen even in patients with histologic diagnosis of UIP.19,20 Overall, a majority of serologic LD-CTD cases in this study had histologic features compatible with CTD. In this study, patients with serologic LD-CTD who fulfilled the diagnostic criteria for the 2011 IPF guideline (h-UIP with possible UIP pattern or UIP pattern on HRCT scan) still had IPF diagnosed. Whether such cases should be diagnosed as IPF or should not be considered IIPs and instead diagnosed as LD-CTD still needs to be determined. Whether h-UIP with characteristic histologic features is associated with more favorable prognosis than IPF is a clinically important issue. In our study, there was no significant difference in prognosis between IPF and unclassifiable IIP. A previous study reported that patients with h-UIP who were initially diagnosed as IPF but subsequently developed CTD had more lymphoid aggregates with germinal centers and favorable prognosis than patients with IPF.21 These data suggest that h-UIP with characteristic histologic features may have a better prognosis than IPF in LD-CTD. However, further studies are needed to evaluate the impact of characteristic histologic features with UIP pattern on prognosis. In the clinical course of LD-CTD, patients with h-NSIP had better survival and greater improvement in %FVC than those with h-UIP, even though the treatment strategy was various (h-UIP: untreated in 11, pirfenidone in five, CS and/or cyclosporine A in 13; h-NSIP: untreated in four, CS and/or cyclosporine A in nine). For patients with IIPs, several previous studies reported that h-NSIP pattern was associated with better survival and physiologic improvement than h-UIP pattern.22-25 On the other hand, for patients with CTD-IP, the effect on survival of having h-UIP pattern rather than h-NSIP pattern is less certain.26,27 Further large studies are needed to confirm the prognostic value of histologic subclassification in LD-CTD. 1443
TABLE 4
] Radiologic Probability of UIP Pattern Segregated by Histologic Pattern HRCT Scan Diagnosis Total
UIP Pattern
Possible UIP Pattern
Histologic UIP
Histologic Diagnosis
25
5 (20)
5 (20)
15 (60)
Histologic NSIP
13
0 (0)
2 (15)
11 (85)
Histologic other
6
0 (0)
1 (17)
5 (83)
5 (11)
8 (18)
31 (70)
Total
44
Inconsistent UIP Pattern
Data are presented as No. (%). HRCT 5 high-resolution CT. See Table 1 legend for expansion of other abbreviations.
In this study, about one-half of patients with h-UIP with LD-CTD received CSs and immunosuppressants, and one-fifth of those patients received pirfenidone. Patients with h-UIP who have serologic features of LD-CTD were classified into two distinct groups, IPF and unclassifiable IIPs, according to the current IIPs classification. For patients with IPF, previous studies reported that antifibrotic agents such as pirfenidone and nintedanib showed favorable effects on disease progression.28-30 Conversely, treatment including CSs and immunosuppressants was reported to be harmful for patients with IPF.31 For CTD-UIP, CSs and immunosuppressants are regarded as the mainstay of therapy.27,32,33 We could not evaluate the impact of these treatments on disease progression and prognosis in patients with unclassifiable IIPs because of the small sample size. Further studies TABLE 5
] Summary of Treatment and Outcome of LD-CTD
Histologic UIP
Histologic NSIP
25
13
Corticosteroid
13 (52)
9 (69)
Cyclosporin A
11 (44)
8 (62)
Variables Patients, No.
are needed to clarify which therapeutic strategy, pirfenidone or CSs and/or immunosuppressants, is better for patients with LD-CTD with unclassifiable IIPs. The limitations of this study are as follows. First, there might be a selection bias because this was a retrospective study in a single center, and the study subjects were restricted to patients who underwent SLB. Second, some patients with typical findings of UIP on HRCT scan did not undergo SLB, which might affect the probability of inconsistent UIP pattern on HRCT scan in our cohort. In summary, we have shown the clinical, radiologic, and histologic features of patients with serologically defined LD-CTD who underwent SLB. The major histologic patterns in LD-CTD were UIP followed by NSIP pattern with characteristic histologic features for LD-CTD. The majority of patients with h-UIP were excluded from a diagnosis of IPF and believed to represent unclassifiable IIP after MDD. Patients with
Treatment
Pirfenidone No treatment Follow-up duration, y
5 (20)
0
11 (44)
4 (31)
3.0 (0.5-6.2)
4.0 (1.9-7.0)
Survival
15
12
Death
10
1
Acute exacerbation
3
0
Chronic respiratory failure
3
0
Nonrespiratory cause
4
Outcome
Cause of death
1
Data are presented as No., No. (%), or median (range). See Table 1 legend for expansion of abbreviations.
1444 Original Research
Figure 2 – Changes in %FVC between baseline and 1 y after follow-up of patients with h-UIP and h-NSIP patterns. Data are presented as mean ⫾ SD. Follow-up pulmonary function test data of two patients with h-UIP were not available. h-NSIP 5 histologic nonspecific interstitial pneumonia; h-UIP 5 histologic usual interstitial pneumonia; %FVC 5 percent predicted FVC.
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Figure 3 – A, B, Kaplan-Meier survival curves for (A) patients with h-NSIP (n 5 13, dashed line) and h-UIP (n 5 25, solid line) and (B) patients with a multidisciplinary diagnosis of iNSIP (n 5 12, dashed line) and unclassifiable IIP (n 5 19, dotted line) and IPF (n 5 7, solid line). IIP 5 idiopathic interstitial pneumonia; iNSIP 5 idiopathic nonspecific interstitial pneumonia; IPF 5 idiopathic pulmonary fibrosis. See Figure 2 legend for expansion of other abbreviations.
h-UIP had worse survival than those with h-NSIP. Therefore, SLB is useful in cases of LD-CTD and provides valuable information about the clinical courses.
Acknowledgments Author contributions: N. O. had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. H. T. contributed to the data conception and design, data analysis and interpretation, and final approval of the manuscript; Y. K. contributed to design of this project, data analysis, review, writing, and submission of this manuscript; N. W. contributed to data collection, preparation, review, writing, and submission of this manuscript; K. S. contributed to preparation, review, writing, and submission of this manuscript; T. K. contributed to data collection, organization, preparation, review, and submission of this manuscript; K. K., T. J., K. F., and K. O. contributed to data collection, organization, analysis, preparation, review, and submission of this manuscript; J. F. contributed to envisioning the initial concept and design of this project, data collection, organization, analysis, preparation, review, and submission of this manuscript; O. N. contributed to organization, preparation, review, and submission of this manuscript; and Y. H. contributed to envisioning the initial concept and design of this project, and submission of this manuscript.
Further investigations with a larger cohort are needed to guide the development of diagnostic and therapeutic strategies for LD-CTD.
analysis of the data, or the preparation of the manuscript. Other contributions: We thank K. Ono, PhD, Department of Pathology, Tosei General Hospital, Seto, Japan, for editorial assistance.
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Conflict of interest: None declared.
4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271-1277.
Role of sponsors: The sponsors had no role in the design of the study, the collection and
5. Preliminary criteria for the classification of systemic sclerosis (scleroderma).
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Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980;23(5):581-590. 6. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med. 1975;292(7):344-347. 7. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Preliminary criteria for the classification of Sjögren’s syndrome. Results of a prospective concerted action supported by the European Community. Arthritis Rheum. 1993; 36(3):340-347. 8. Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum. 1998;41(5):768-777. 9. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2): 319-338. 10. Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720-735. 11. Meyer KC, Raghu G, Baughman RP, et al; American Thoracic Society Committee on BAL in Interstitial Lung Disease. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung
1445
disease. Am J Respir Crit Care Med. 2012;185(9):1004-1014. 12. 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: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824. 13. Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1994;149(6):1583-1590. 14. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositisassociated interstitial lung disease. Am J Respir Crit Care Med. 2001;164(7): 1182-1185. 15. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest. 2005;127(6):2019-2027. 16. Sumikawa H, Johkoh T, Colby TV, et al. Computed tomography findings in pathological usual interstitial pneumonia: relationship to survival. Am J Respir Crit Care Med. 2008;177(4):433-439. 17. Sumikawa H, Johkoh T, Fujimoto K, et al. Pathologically proved nonspecific interstitial pneumonia: CT pattern analysis as compared with usual interstitial pneumonia CT pattern. Radiology. 2014;272(2):549-556. 18. Flaherty KR, Colby TV, Travis WD, et al. Fibroblastic foci in usual interstitial pneumonia: idiopathic versus collagen vascular disease. Am J Respir Crit Care Med. 2003;167(10):1410-1415. 19. Song JW, Do KH, Kim MY, Jang SJ, Colby TV, Kim DS. Pathologic and
1446 Original Research
radiologic differences between idiopathic and collagen vascular disease-related usual interstitial pneumonia. Chest. 2009;136(1):23-30.
interstitial pneumonia. Eur Respir J. 2005;25(3):528-533. 26. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-711.
20. Moua T, Zamora Martinez A, Baqir M, Vassallo R, Limper AH, Ryu JH. Predictors of diagnosis and survival in idiopathic pulmonary fibrosis and connective tissue disease-related usual interstitial pneumonia. Respir Res. 2014;15(1): 154.
27. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet. 2012;380(9842):689-698. 28. King TE Jr, Bradford WZ, CastroBernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092.
21. Kono M, Nakamura Y, Enomoto N, et al. Usual interstitial pneumonia preceding collagen vascular disease: a retrospective case control study of patients initially diagnosed with idiopathic pulmonary fibrosis. PLoS ONE. 2014;9(4): e94775.
29. Taniguchi H, Ebina M, Kondoh Y, et al; Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-829.
22. Riha RL, Duhig EE, Clarke BE, Steele RH, Slaughter RE, Zimmerman PV. Survival of patients with biopsy-proven usual interstitial pneumonia and nonspecific interstitial pneumonia. Eur Respir J. 2002;19(6):1114-1118.
30. Watanabe N, Sakamoto K, Taniguchi H, et al. Efficacy of combined therapy with cyclosporin and low-dose prednisolone in interstitial pneumonia associated with connective tissue disease. Respiration. 2014;87(6):469-477.
23. Nicholson AG, Colby TV, du Bois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 2000;162(6): 2213-2217.
31. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue diseaseassociated interstitial lung disease. J Rheumatol. 2013;40(5):640-646. 32. 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.
24. Daniil ZD, Gilchrist FC, Nicholson AG, et al. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med. 1999;160(3): 899-905.
33. Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
25. Kondoh Y, Taniguchi H, Yokoi T, et al. Cyclophosphamide and low-dose prednisolone in idiopathic pulmonary fibrosis and fibrosing nonspecific
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Original Research Diffuse Lung Disease
]
Lung-Dominant Connective Tissue Disease Clinical, Radiologic, and Histologic Features Norihito Omote, MD; Hiroyuki Taniguchi, MD, PhD; Yasuhiro Kondoh, MD, PhD; Naohiro Watanabe, MD; Koji Sakamoto, MD, PhD; Tomoki Kimura, MD, PhD; Kensuke Kataoka, MD, PhD; Takeshi Johkoh, MD, PhD; Kiminori Fujimoto, MD, PhD; Junya Fukuoka, MD, PhD; Kyoko Otani, MD; Osamu Nishiyama, MD, PhD; and Yoshinori Hasegawa, MD, PhD, FCCP
Lung-dominant connective tissue disease (LD-CTD) is a disease concept for interstitial pneumonia; however, it has not been robustly validated. This study was conducted to elucidate the clinical, radiologic, and histologic features of LD-CTD.
BACKGROUND:
METHODS: We retrospectively reviewed 44 consecutive patients with serologically defined LD-CTD who underwent surgical lung biopsy. Patients were identified as having LD-CTD if they had specific autoantibodies but did not meet the criteria for connective tissue disease. We conducted a multidisciplinary diagnosis and evaluated major histologic patterns according to the current idiopathic interstitial pneumonias (IIPs) classification of 2013. Characteristic histologic features for LD-CTD (eg, prominent plasmacytic infiltration, lymphoid aggregates with germinal centers), high-resolution CT (HRCT) scan patterns, and prognosis were also assessed.
The major histologic patterns were usual interstitial pneumonia (UIP) in 25 patients and nonspecific interstitial pneumonia (NSIP) in 13 patients. Two or more characteristic histologic features for LD-CTD were observed in 15 patients with histologic UIP (h-UIP) and 11 patients with histologic NSIP (h-NSIP). Fifteen patients with h-UIP (60%) showed an inconsistent UIP pattern on HRCT scan. After multidisciplinary discussion (MDD), 18 patients with h-UIP were labeled as having unclassifiable IIP. The annual change in percent predicted FVC improved significantly in patients with h-NSIP (P 5 .002), who also had better survival than those with h-UIP (P 5 .031). In contrast, survival was not associated with HRCT scan pattern (P 5 .79).
RESULTS:
The major histologic patterns in LD-CTD were UIP followed by NSIP. Twothirds of patients had characteristic histologic features for LD-CTD. A majority of patients with h-UIP were considered to have unclassifiable IIP based on MDD. Patients with h-UIP had worse survival than those with h-NSIP. CHEST 2015; 148(6):1438-1446
CONCLUSIONS:
Manuscript received December 18, 2014; revision accepted April 2, 2015; originally published Online First May 7, 2015. ABBREVIATIONS: ANA 5 antinuclear antibody; anti-Jo1 5 anti-tRNA synthetase; CS 5 corticosteroid; CTD 5 connective tissue disease; h-NSIP 5 histologic nonspecific interstitial pneumonia; HRCT 5 highresolution CT; h-UIP 5 histologic usual interstitial pneumonia; IIP 5 idiopathic interstitial pneumonia; ILD 5 interstitial lung disease; IPF 5 idiopathic pulmonary fibrosis; LD-CTD 5 lung-dominant connective tissue disease; MDD 5 multidisciplinary discussion; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; %FVC 5 percent predicted FVC; PFT 5 pulmonary function test; SLB 5 surgical lung biopsy; UIP 5 usual interstitial pneumonia AFFILIATIONS: From the Department of Respiratory Medicine and Allergy (Drs Omote, Taniguchi, Kondoh, Kimura, and Kataoka), Tosei General Hospital, Seto, Aichi; the Department of Respiratory Medicine
1438 Original Research
(Drs Omote, Watanabe, Sakamoto, and Hasegawa), Nagoya University Graduate School of Medicine, Nagoya, Aichi; the Department of Radiology (Dr Johkoh), Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Hyogo; the Department of Radiology (Dr Fujimoto), Kurume University School of Medicine, Kurume, Fukuoka; the Department of Laboratory of Pathology (Dr Fukuoka), Nagasaki University Hospital, Nagasaki, Nagasaki; the Department of Diagnostic Pathology (Dr Otani), Kobe University Hospital, Kobe, Hyogo; and the Department of Respiratory Medicine and Allergology (Dr Nishiyama), Kinki University Faculty of Medicine, Osaka-sayama, Osaka, Japan. FUNDING/SUPPORT: This study was partially supported by a grant to the Diffuse Lung Disease Research Group from the Japanese Ministry of Health, Labor, and Welfare and the NPO Respiratory Disease Conference.
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Current guidelines for the diagnosis and management of idiopathic interstitial pneumonias (IIPs) recommend an evaluation for underlying connective tissue disease (CTD), including serologic and other markers.1,2 There are some patients with IIPs who have specific autoantibodies even in the absence of extrathoracic features of a definite CTD, and Fischer et al1 proposed a new term for those patients: lung-dominant CTD (LD-CTD). It is important to know whether LD-CTD has a similar natural history to classifiable forms of CTD-interstitial lung disease (ILD) and whether the approach to the management of LD-CTD should be similar to that of CTD-ILD or to that of IIPs. However, little is known about its clinical features and high-resolution CT (HRCT) scan and histologic findings.
Among the histologic findings of LD-CTD, the frequency of major histologic patterns, such as usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), is unknown. Also unknown is how disease behavior and survival are affected by histologic pattern and
Materials and Methods
information. Major histologic patterns were classified according to the current IIPs classification 2013.2 Consensus diagnoses were made by these pathologists in cases of initial disagreement. In addition, characteristic histologic features for LD-CTD, including lymphoid aggregates with germinal centers, extensive pleuritis, prominent plasmacytic infiltration, and dense perivascular collagen, were evaluated in all biopsy specimens1 (Figs 1A-C).
Study Subjects Two hundred six consecutive patients who underwent SLB for diagnosis of ILD between January 2007 and December 2011 in Tosei General Hospital were retrospectively reviewed. Serologically defined LD-CTD was diagnosed when the following criteria were satisfied: (1) presence of any one of the following autoantibodies at initial evaluation: antinuclear antibody (ANA) . 1:320, nucleolar-ANA, rheumatoid factor (. 60 IU/mL), cyclic anticitrullinated peptide, anti-Sclero 70, anti-Ro/SSA, antiLa/SSB, anti-double-stranded DNA, anti-Smith, anti-ribonucleoprotein, anti-tRNA synthetase (anti-Jo1), and anti-centromere antibodies; (2) absence of a definite diagnosis of CTD (CTD was diagnosed when patients fulfilled American College of Rheumatology criteria3-8) or other known causes of ILD, including hypersensitivity pneumonitis and sarcoidosis. Sixty-three patients were excluded from this study. They included patients with CTD-IP (n 5 27), hypersensitivity pneumonitis (n 5 23), sarcoidosis (n 5 1), and others (n 5 12). Among the remaining 143 patients, 44 patients were classified as serologically defined LD-CTD and included in this study. This study was approved by Tosei General Hospital institutional review board (IRB No. 263).
FOR EDITORIAL COMMENT SEE PAGE 1367
characteristic histologic features known to be associated with CTD, such as lymphoid aggregates with germinal centers and prominent plasmacytic infiltration. The aim of this study was to elucidate the clinical features, HRCT scan patterns, histologic patterns, multidisciplinary diagnosis, and clinical courses of serologically defined LD-CTD in patients who underwent surgical lung biopsy (SLB).
Radiologic Assessment HRCT scans within 1 month before SLB were randomized and reviewed by two expert thoracic radiologists (K. F. and T. J.) who were blinded to clinical information and histologic diagnosis. The probability of UIP was evaluated and categorized by the criteria of the American Thoracic Society/European Respiratory Society/Japanese Thoracic Society/Latin American Thoracic Association guideline for idiopathic pulmonary fibrosis (IPF) (eg, UIP pattern, possible UIP pattern, and inconsistent UIP pattern).12 Disagreements on the diagnosis were resolved by consensus. HRCT scan was performed with 1.0-mm-thick sections.
Data Collection Clinical data were obtained retrospectively from patient records. We evaluated patient characteristics, pulmonary function tests (PFTs), Pao2, BAL, and serologic test results. These tests were conducted in all patients who participated in this study within 1 month before biopsy. Spirometry (CHESTAC-55V; Chest M.I., Inc) and the diffusing capacity of the lung for carbon monoxide (CHESTAC-55V; Chest M.I., Inc) were measured according to the American Thoracic Society/European Respiratory Society recommendation as physiologic assessments and examined within 1 month before biopsy.9,10 Abnormal cell counts in BAL fluid were defined by neutrophils . 3%, lymphocytes . 15%, and eosinophils . 1%.11 Histologic Assessment The biopsy slides were all reviewed by two experienced pulmonary pathologists (J. F. and K. O.) who were blinded to clinical and radiologic CORRESPONDENCE TO: Hiroyuki Taniguchi, MD, PhD, Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwakecho, Seto, Aichi 489-8642, Japan; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-3174
journal.publications.chestnet.org
Figure 1 – A-C, Characteristic histologic features for lung-dominant connective tissue disease (hematoxylin-eosin, original magnifications: A, 31; B, 340; C, 3200). Representative patient photomicrographs of histologic usual interstitial pneumonia pattern (A) with lymphoid aggregates with germinal centers (arrows) (B) and prominent plasmacytic infiltration (C). 1439
Multidisciplinary Diagnosis After close communication between the clinician, radiologist, and pathologist, a multidisciplinary diagnosis of IPF, idiopathic NSIP, unclassifiable IIP, or other was made according to the current IIPs classification 2013.2 Patients were considered to have unclassifiable IIP if a review of clinical, radiologic, and histologic data did not reveal a specific diagnosis. Patients with IPF were required to fulfill established clinical criteria to receive a confident diagnosis of IPF.12 These diagnoses were performed in August 2014. Treatments and Outcomes Follow-up assessments of percent predicted FVC (%FVC) were available at 3- to 6-month intervals following biopsy. Annual change in pul-
Results Histologic Findings and Patient Characteristics
Of the 44 patients with LD-CTD, the major histologic pattern was UIP in 25 patients, NSIP in 13 patients, and another diagnosis in six patients (Table 1). Characteristic histologic features of LD-CTD are summarized in Table 2. The most frequent finding was prominent plasmacytic infiltration (n 5 32, 73%). Two or more specific histologic features for LD-CTD were observed in 30 patients with LD-CTD (68%), comprising 15 histologic UIP (h-UIP), 11 histologic NSIP (h-NSIP), and four other patterns. Clinical characteristics of h-UIP, h-NSIP, and other patterns are shown in Table 3. There were no significant differences in age, sex, smoking history, baseline Pao2 or PFTs between patients with h-UIP and h-NSIP patterns. The proportion of patients with eosinophil percentages . 1% in BAL fluid was significantly higher in patients with h-NSIP than in patients with h-UIP (P 5 .001). As for autoantibody profiles, ANA, TABLE 1
] Major Histologic Pattern From the SLB
Specimens in 44 Patients With LD-CTD
Histologic Diagnosis
Subjects, No. (%)
UIP
25 (57)
NSIP
13 (30)
Other
6 (14)
OP
1
DAD
1
Eosinophilic pneumonia
1
Airway-centered interstitial fibrosis
1
Mixed pattern
2
a
Data are presented as No. (%). DAD 5 diffuse alveolar damage; LD-CTD 5 lung-dominant connective tissue disease; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; SLB 5 surgical lung biopsy; UIP 5 usual interstitial pneumonia. aMixed pattern included UIP 1 DAD and NSIP 1 OP.
1440 Original Research
monary function and prognosis in the groups based on the histologic and multidisciplinary diagnosis was assessed, and treatment regimens were recorded over 1 year from initial evaluation. Statistical Analysis All values were described as the mean ⫾ SD or median (range). The x2 test or Fisher exact test were used for categorical data, and the MannWhitney U test was used for continuous data. Interobserver variation of radiologic diagnosis was analyzed using the k statistic. Differences in the values for PFTs from baseline to 1 year were evaluated using paired Student t test. x2 statistics or Fisher exact test were used for comparison of proportions. Survival curves were compared by the log-rank test, and Kaplan-Meier survival curves were plotted. All data were analyzed using a statistical software package (SPSS, version 19.0; IBM Corporation).
rheumatoid factor, and nucleolar-ANA were the most frequently positive autoantibodies, observed in 12 patients each. Four patients developed manifestations of rheumatoid arthritis during follow-up: one patient with an h-UIP pattern, one patient with an h-NSIP pattern, one patient with a histologic organizing pneumonia (OP) pattern, and one patient with eosinophilic pneumonia. Two patients with an h-NSIP pattern and positive for anti-Jo1 developed the manifestations of dermatomyositis. Radiologic Findings
Radiologic findings are shown in Table 4. Interobserver agreement between the two radiologists was good (k 5 0.76). Among patients with h-UIP, HRCT scan showed a UIP pattern in five (20%), a possible UIP pattern in five (20%), and an inconsistent UIP pattern in 15 (60%). Among patients with h-NSIP, HRCT scan showed a possible UIP pattern in two (15%) and an inconsistent UIP pattern in 11 (85%). The total number of radiologically inconsistent UIP patterns was 31 (70%), among which 15 showed an h-UIP pattern. All patients with radiologic UIP showed an h-UIP pattern. Multidisciplinary Diagnosis
After multidisciplinary discussion (MDD), 25 patients with an h-UIP were labeled as having unclassifiable IIP (n 5 18) or IPF (n 5 7). Twelve patients with h-NSIP were classified as having idiopathic NSIP and one patient as having unclassifiable IIP. Unclassifiable IIP (n 5 2), cryptogenic OP (n 5 1), acute interstitial pneumonia (n 5 1), eosinophilic pneumonia (n 5 1), and acute exacerbation of IPF (n 5 1) were diagnosed in the other six patients. Treatments and Outcomes
As shown in Table 5, corticosteroid (CS) (10 mg/d) and cyclosporine A (3 mg/kg/d) were introduced in 13 patients (52%) and 11 patients (44%), respectively,
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TABLE 2
] Characteristic Histologic Features of LD-CTD Total (N 5 44)
Histologic UIP (n 5 25)
Histologic NSIP (n 5 13)
Histologic Other (n 5 6)
Lymphoid aggregates with germinal centers
21 (48)
12 (48)
8 (62)
1 (17)
Extensive pleuritis
19 (43)
11 (44)
5 (38)
3 (50)
Prominent plasmacytic infiltration
32 (73)
18 (72)
11 (85)
3 (50)
Dense perivascular collagen
20 (45)
11 (44)
6 (46)
3 (50)
Two or more histologic features of LD-CTD
30 (68)
15 (60)
11 (85)
4 (67)
Histologic Features
Data are presented as No. (%). See Table 1 legend for expansion of abbreviations.
among those with an h-UIP pattern. In patients with an h-NSIP pattern, CS and cyclosporine A were introduced in nine (69%) and eight (62%) patients, respectively. Treatment with pirfenidone was introduced in five patients with an h-UIP pattern. Ten patients with an h-UIP pattern and one patient with an h-NSIP pattern died during the median follow-up duration of 3.6 years. Among patients with an h-UIP pattern, three died of acute exacerbation of interstitial pneumonia and three died of chronic respiratory failure, whereas the other four died of nonrespiratory causes. Among patients with an h-NSIP pattern, one patient died of a nonrespiratory cause. Patients with an h-NSIP pattern showed a significant improvement in %FVC from baseline to 1 year (baseline: 74.7%; 1 year: 91.1%; P 5 .002), whereas patients with an h-UIP pattern did not (baseline: 80.6%; 1 year: 78.4%; P 5 .48) (Fig 2). Patients with h-UIP had worse survival than those with h-NSIP (P 5 .031) (Fig 3A). Among patients with h-UIP and h-NSIP patterns, no significant difference in survival was seen depending on HRCT scan pattern (inconsistent UIP pattern vs possible UIP pattern and UIP pattern; P 5 .79). Among diagnoses based on MDD, patients in whom idiopathic NSIP was diagnosed showed better survival than patients in whom IPF was diagnosed (P 5 .014) (Fig 3B). Survival tended to differ, although not significantly, between patients with idiopathic NSIP and those with unclassifiable IIP (P 5 .078).
Discussion To our knowledge, this is the first report on the clinical, radiologic, and histologic features of patients with serologically defined LD-CTD who underwent SLB. The major histologic patterns of LD-CTD in this study were UIP followed by NSIP, and about two-thirds of these patients had characteristic histologic features for LD-CTD. Patients with LD-CTD were likely to show an inconsistent UIP pattern on HRCT scan.
journal.publications.chestnet.org
Therefore, most patients with h-UIP were believed not to have IPF but had unclassifiable IIPs diagnosed based on MDD. The result that patients with h-UIP had worse survival than those with h-NSIP suggests the prognostic value of histologic subclassification in LD-CTD. In the study, a UIP was the major histologic pattern in LD-CTD, whereas prior studies have shown that an NSIP pattern was the predominant histologic pattern in CTD-IP, except for rheumatoid arthritis-related IP.13-15 A majority of cases with an h-UIP pattern with LD-CTD were labeled as unclassifiable IIP after MDD because of characteristic histologic features such as prominent plasmacytic infiltration and lymphoid aggregates with germinal centers. Therefore, we believe that in these cases not only major histologic pattern but also these characteristic histologic features should be assessed. In our study, about one-half of patients with LD-CTD with an h-UIP pattern showed inconsistent UIP pattern on HRCT scan. In previous reports, one-third of patients with biopsy-proven IPF/UIP had atypical features for IPF on HRCT scan, which was less frequent than in our cases.16,17 Another study reported that CTD-UIP was more likely to show an inconsistent UIP pattern than IPF/UIP.18 In patients with LD-CTD, the frequency of an inconsistent UIP pattern with an h-UIP pattern seemed to be similar to that of patients with CTD-UIP. Song et al19 reported that IPF/UIP with positive autoantibodies had characteristic histologic features, such as germinal centers and plasma cells, and inconsistent UIP pattern on HRCT scan more frequently than did IPF/UIP without autoantibodies. These reports were consistent with our result that patients with LD-CTD with an h-UIP pattern showed an inconsistent UIP pattern on HRCT scan. In our study, a majority of patients with h-UIP with LD-CTD had multiple histologic patterns (eg, histologic
1441
16 (64)
24 (55)
25
Former/current smokers
80.0 (50.9-104)
PaO2 at rest, mm Hg
1 7 0 2 1
Anti-La/SSB
Anti-dsDNA
Anti-Smith
11
Anti-CCP
148#6 CHEST DECEMBER 2015
Anti-Ro/SSA
12
Nucleolar-ANA
[
Anti-Scl-70
12
Rheumatoid factor (. 60 IU/mL)
12
13
Eosinophils . 1.0%
Autoantibody
13
Neutrophils . 3.0%
Lymphocytes . 15.0%
7
54.5 (14.8-99.0)
DLCO
BAL fluid, %
75.9 (46.5-138)
FVC
Pulmonary function, % predicted
0.1 (0-3.6)
0.2 (0-19.3) 1,200 (200-5,600)
CRP, g/dL
KL-6, U/mL
1
2
0
3
0
5
8
6
9
2
3
2
76.1 (60.3-104)
53.5 (28.1-75.9)
82,5 (46.5-138)
1,200 (200-5,400)
7.1 (3.8-13.4)
14
11
7.2 (3.8-21.4)
WBC count, 103/mm3
Laboratory
19
Never smokers
Smoking
Male sex
Age, y
25 65 (39-74)
44 64 (36-74)
Patients
Histologic UIP
Total
] Baseline Characteristics of Each Histologic Subset of LD-CTD
Characteristic
TABLE 3
ANA (. 1:320)
1442 Original Research
]
0
0
0
3
1
3
2
3
2
8
5
3
80.8 (58.4-91.6)
44.9 (14.8-99.0)
71.9 (48.3-112)
1,200 (300-4,400)
0.3 (0-6.9)
7.4 (5.1-15.5)
6
7
5 (38)
61 (36-71)
13
Histologic NSIP
0
0
0
1
0
3
2
3
1
3
5
2
71.1 (50.9-85.4)
58.5 (26.2-80.6)
75.7 (53.5-83.4)
800 (200-5,600)
2.3 (0-19.3)
9.7 (4.1-21.4)
5
1
3 (50)
63 (53-72)
6
Histologic Other
(Continued)
…
…
…
…
…
…
…
…
…
.001
.09
.32
.65
.99
.31
.96
.12
.28
…
.73
.18
.15
…
P Value (UIP vs NSIP)
… 0 1 1 Anti-centromere
Some patients had multiple positive serologic tests. Data are presented as No., No. (%), or median (range) unless otherwise noted. ANA 5 antinuclear antibody; anti-CCP 5 cyclic anticitrullinated peptide; anti-dsDNA 5 anti-double-stranded DNA; anti-Jo1 5 anti-tRNA synthetase; anti-Scl-70 5 anti-Sclero 70; CRP 5 C-reactive protein; DLCO 5 diffusing capacity of the lung for carbon monoxide. See Table 1 legend for expansion of other abbreviations.
… 0
0
… 0
0
3
2
3 Anti-Jo1
Anti-RNP
3
1
P Value (UIP vs NSIP) Histologic Other Histologic NSIP Histologic UIP Total Characteristic
] (continued) TABLE 3
journal.publications.chestnet.org
UIP pattern with prominent plasmacytic infiltration and lymphoid aggregates with germinal centers). According to the 2011 IPF guideline, the histologic classification of these patients was believed to be “not UIP pattern” and was diagnosed as unclassifiable IIPs. The current IIPs classification of 2013 noted that cases of “unclassifiable IIPs” in terms of overlap of histologic patterns often prove to be related to CTD.2 In fact, previous studies regarding histologic findings of CTD-IP reported that similar histologic features were frequently seen even in patients with histologic diagnosis of UIP.19,20 Overall, a majority of serologic LD-CTD cases in this study had histologic features compatible with CTD. In this study, patients with serologic LD-CTD who fulfilled the diagnostic criteria for the 2011 IPF guideline (h-UIP with possible UIP pattern or UIP pattern on HRCT scan) still had IPF diagnosed. Whether such cases should be diagnosed as IPF or should not be considered IIPs and instead diagnosed as LD-CTD still needs to be determined. Whether h-UIP with characteristic histologic features is associated with more favorable prognosis than IPF is a clinically important issue. In our study, there was no significant difference in prognosis between IPF and unclassifiable IIP. A previous study reported that patients with h-UIP who were initially diagnosed as IPF but subsequently developed CTD had more lymphoid aggregates with germinal centers and favorable prognosis than patients with IPF.21 These data suggest that h-UIP with characteristic histologic features may have a better prognosis than IPF in LD-CTD. However, further studies are needed to evaluate the impact of characteristic histologic features with UIP pattern on prognosis. In the clinical course of LD-CTD, patients with h-NSIP had better survival and greater improvement in %FVC than those with h-UIP, even though the treatment strategy was various (h-UIP: untreated in 11, pirfenidone in five, CS and/or cyclosporine A in 13; h-NSIP: untreated in four, CS and/or cyclosporine A in nine). For patients with IIPs, several previous studies reported that h-NSIP pattern was associated with better survival and physiologic improvement than h-UIP pattern.22-25 On the other hand, for patients with CTD-IP, the effect on survival of having h-UIP pattern rather than h-NSIP pattern is less certain.26,27 Further large studies are needed to confirm the prognostic value of histologic subclassification in LD-CTD. 1443
TABLE 4
] Radiologic Probability of UIP Pattern Segregated by Histologic Pattern HRCT Scan Diagnosis Total
UIP Pattern
Possible UIP Pattern
Histologic UIP
Histologic Diagnosis
25
5 (20)
5 (20)
15 (60)
Histologic NSIP
13
0 (0)
2 (15)
11 (85)
Histologic other
6
0 (0)
1 (17)
5 (83)
5 (11)
8 (18)
31 (70)
Total
44
Inconsistent UIP Pattern
Data are presented as No. (%). HRCT 5 high-resolution CT. See Table 1 legend for expansion of other abbreviations.
In this study, about one-half of patients with h-UIP with LD-CTD received CSs and immunosuppressants, and one-fifth of those patients received pirfenidone. Patients with h-UIP who have serologic features of LD-CTD were classified into two distinct groups, IPF and unclassifiable IIPs, according to the current IIPs classification. For patients with IPF, previous studies reported that antifibrotic agents such as pirfenidone and nintedanib showed favorable effects on disease progression.28-30 Conversely, treatment including CSs and immunosuppressants was reported to be harmful for patients with IPF.31 For CTD-UIP, CSs and immunosuppressants are regarded as the mainstay of therapy.27,32,33 We could not evaluate the impact of these treatments on disease progression and prognosis in patients with unclassifiable IIPs because of the small sample size. Further studies TABLE 5
] Summary of Treatment and Outcome of LD-CTD
Histologic UIP
Histologic NSIP
25
13
Corticosteroid
13 (52)
9 (69)
Cyclosporin A
11 (44)
8 (62)
Variables Patients, No.
are needed to clarify which therapeutic strategy, pirfenidone or CSs and/or immunosuppressants, is better for patients with LD-CTD with unclassifiable IIPs. The limitations of this study are as follows. First, there might be a selection bias because this was a retrospective study in a single center, and the study subjects were restricted to patients who underwent SLB. Second, some patients with typical findings of UIP on HRCT scan did not undergo SLB, which might affect the probability of inconsistent UIP pattern on HRCT scan in our cohort. In summary, we have shown the clinical, radiologic, and histologic features of patients with serologically defined LD-CTD who underwent SLB. The major histologic patterns in LD-CTD were UIP followed by NSIP pattern with characteristic histologic features for LD-CTD. The majority of patients with h-UIP were excluded from a diagnosis of IPF and believed to represent unclassifiable IIP after MDD. Patients with
Treatment
Pirfenidone No treatment Follow-up duration, y
5 (20)
0
11 (44)
4 (31)
3.0 (0.5-6.2)
4.0 (1.9-7.0)
Survival
15
12
Death
10
1
Acute exacerbation
3
0
Chronic respiratory failure
3
0
Nonrespiratory cause
4
Outcome
Cause of death
1
Data are presented as No., No. (%), or median (range). See Table 1 legend for expansion of abbreviations.
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Figure 2 – Changes in %FVC between baseline and 1 y after follow-up of patients with h-UIP and h-NSIP patterns. Data are presented as mean ⫾ SD. Follow-up pulmonary function test data of two patients with h-UIP were not available. h-NSIP 5 histologic nonspecific interstitial pneumonia; h-UIP 5 histologic usual interstitial pneumonia; %FVC 5 percent predicted FVC.
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Figure 3 – A, B, Kaplan-Meier survival curves for (A) patients with h-NSIP (n 5 13, dashed line) and h-UIP (n 5 25, solid line) and (B) patients with a multidisciplinary diagnosis of iNSIP (n 5 12, dashed line) and unclassifiable IIP (n 5 19, dotted line) and IPF (n 5 7, solid line). IIP 5 idiopathic interstitial pneumonia; iNSIP 5 idiopathic nonspecific interstitial pneumonia; IPF 5 idiopathic pulmonary fibrosis. See Figure 2 legend for expansion of other abbreviations.
h-UIP had worse survival than those with h-NSIP. Therefore, SLB is useful in cases of LD-CTD and provides valuable information about the clinical courses.
Acknowledgments Author contributions: N. O. had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. H. T. contributed to the data conception and design, data analysis and interpretation, and final approval of the manuscript; Y. K. contributed to design of this project, data analysis, review, writing, and submission of this manuscript; N. W. contributed to data collection, preparation, review, writing, and submission of this manuscript; K. S. contributed to preparation, review, writing, and submission of this manuscript; T. K. contributed to data collection, organization, preparation, review, and submission of this manuscript; K. K., T. J., K. F., and K. O. contributed to data collection, organization, analysis, preparation, review, and submission of this manuscript; J. F. contributed to envisioning the initial concept and design of this project, data collection, organization, analysis, preparation, review, and submission of this manuscript; O. N. contributed to organization, preparation, review, and submission of this manuscript; and Y. H. contributed to envisioning the initial concept and design of this project, and submission of this manuscript.
Further investigations with a larger cohort are needed to guide the development of diagnostic and therapeutic strategies for LD-CTD.
analysis of the data, or the preparation of the manuscript. Other contributions: We thank K. Ono, PhD, Department of Pathology, Tosei General Hospital, Seto, Japan, for editorial assistance.
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