Nonspecific interstitial pneumonia preceding diagnosis of collagen vascular disease

Respiratory Medicine 117 (2016) 40e47

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Nonspecific interstitial pneumonia preceding diagnosis of collagen vascular disease Masato Kono a, b, Yutaro Nakamura a, *, Katsuhiro Yoshimura a, Yasunori Enomoto a, Yoshiyuki Oyama a, Hironao Hozumi a, Noriyuki Enomoto a, Tomoyuki Fujisawa a, Naoki Inui a, Etsuko Hamada b, Thomas V. Colby c, Masato Maekawa b, Takafumi Suda a a b c

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 25 February 2016 Received in revised form 10 May 2016 Accepted 31 May 2016 Available online 1 June 2016

Background: The aim of this study was to evaluate the incidence and clinical features of patients who developed collagen vascular disease (CVD) after an initial diagnosis of idiopathic nonspecific interstitial pneumonia (NSIP). Methods: We conducted a retrospective review of 72 consecutive patients with NSIP who were diagnosed by surgical lung biopsy in our institution (idiopathic NSIP, n ¼ 35; CVD-NSIP, n ¼ 37 at initial diagnosis). No patients fulfilled the American College of Rheumatology criteria for a diagnosis with CVD within six months after the diagnosis of idiopathic NSIP. Results: Of 35 patients initially diagnosed with idiopathic NSIP, six patients (17.1%) developed CVD during the follow-up period (5.5 ± 5.0 years); three patients were diagnosed with dermatomyositis (DM), two patients with overlap syndrome (DM and Sjogren’s syndrome), and one patient with rheumatoid arthritis. The mean time until CVD diagnosis was 2.0 years (six months e 3.5 years), and the one-, twoand three-year incidences of CVD development were 3.6%, 15.2% and 20.0%, respectively. There was no significant difference in clinical characteristics and survival among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, or those with CVD-NSIP. In addition, at the time of initial diagnosis, there was no significant difference for the fulfillment of previous criteria such as interstitial pneumonia with autoimmune feature (IPAF) between patients with NSIP preceding CVD diagnosis and those with idiopathic NSIP. Conclusions: It is difficult to predict CVD occurrence and careful attention is needed to detect the development of CVD in patients with idiopathic NSIP. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Nonspecific interstitial pneumonia (NSIP) Collagen vascular disease (CVD) Connective tissue disease (CTD) Idiopathic interstitial pneumonias (IIPs) Interstitial pneumonia with autoimmune features (IPAF)

1. Introduction Nonspecific interstitial pneumonia (NSIP) was originally described as a pathologic pattern distinct from other defined interstitial pneumonias by Katzenstein and Fiorelli [1]. Later, the 2002 Joint Statement of American Thoracic Society (ATS) and European Respiratory Society (ERS) on the classification of idiopathic interstitial pneumonias (IIPs) identified idiopathic NSIP as a provisional diagnosis [2]. On the basis of case analyses and available

* Corresponding author. 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan. E-mail address: [email protected] (Y. Nakamura). http://dx.doi.org/10.1016/j.rmed.2016.05.030 0954-6111/© 2016 Elsevier Ltd. All rights reserved.

literature, the recent ATS project recommended that idiopathic NSIP be accepted as a distinct entity among the IIPs [3,4]. However, the NSIP pattern occurs not only as an idiopathic condition, but also with a number of other conditions including collagen vascular disease (CVD)/connective tissue disease (CTD). Many studies demonstrated that NSIP is the most common histologic pattern in interstitial pneumonia associated with CVD (CVD-IP) [5e7], and a relationship between NSIP and autoimmune diseases was suggested [8e10]. Interstitial pneumonia (IP) commonly complicates CVD. It has been reported that approximately 15e20% of patients with IP have an underlying CVD [11e15], and it may be the first or only manifestation of a CVD [10e21]. We previously reported that the rate of

M. Kono et al. / Respiratory Medicine 117 (2016) 40e47

Abbreviations ADM AIF-ILD ATS AZA BAL CPA CPK CRP CTD CVD CVD-IP

amyopathic dermatomyositis autoimmune-featured interstitial lung disease American Thoracic Society azathioprine bronchial alveolar lavage cyclophosphamide creatine phosphokinase C-reactive protein connective tissue disease collagen vascular disease interstitial pneumonia associated with collagen vascular disease CVD-NSIP nonspecific interstitial pneumonia associated with collagen vascular disease CyA cyclosporine A DM dermatomyositis ERS European Respiratory Society F female FEV1.0 forced expiratory volume in 1 s FVC forced vital capacity HRCT high-resolution computed tomography IP interstitial pneumonia IIPs idiopathic interstitial pneumonias

CVD development was 10 cases (9%) in 111 consecutive patients initially diagnosed with IPF, and patients with IPF who developed CVD had a significantly better prognosis than patients who did not [19]. Although there are some reports of patients who developed CVD after an initial diagnosis of idiopathic NSIP [3,10,16e18], the clinical features of those patients is still unclear. The present study was conducted to investigate the incidence of patients who developed CVD after an initial diagnosis of idiopathic NSIP, and to evaluate the clinical features of those patients in detail. Furthermore, we attempted to compare clinical characteristics, including the prognosis among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, or those with NSIP associated with CVD (CVD-NSIP).

2. Patients and methods 2.1. Patients and diagnostic criteria We studied 72 consecutive patients with NSIP (idiopathic NSIP, n ¼ 35; CVD-NSIP, n ¼ 37 at initial diagnosis) who were diagnosed by surgical lung biopsy (SLB) in our institution from 1990 to 2012. The diagnosis of NSIP was based on international consensus criteria [2,4]. Six months after the initial diagnosis, none of the patients fulfilled the American College of Rheumatology criteria defining CVDs, including rheumatoid arthritis (RA) [22], polymyositis/dermatomyositis (PM/DM) [23], systemic sclerosis (SSc) [24], systemic lupus erythematosus (SLE) [25], Sjogren’s syndrome (SjS) [26], or mixed connective tissue disease (MCTD), or the Chapel Hill Consensus Conference criteria defining systemic vasculitis, including microscopic polyangiitis (MPA) [27]. Four previously published criteria, such as undifferentiated connective tissue disease (UCTD) [28], lung dominant connective tissue disease (LDCTD) [29], autoimmune featured interstitial lung disease (AIF-ILD) [30] or interstitial pneumonia with autoimmune features (IPAF) [31], were applied to patients with initial diagnosis of idiopathic

41

IPAF interstitial pneumonia with autoimmune features IPF idiopathic pulmonary fibrosis LDH lactate dehydrogenase LD-CTD lung-dominant connective tissue disease M male MPO-ANCA myeloperoxidase antineutrophil cytoplasmic antibody mo months n.s. not significant NSIP nonspecific interstitial pneumonia PR3-ANCA proteinase 3-antineutrophil cytoplasmic antibody PSL prednisolone PM/DM polymyositis/dermatomyositis PM/DM-IP interstitial pneumonia associated with polymyositis/ dermatomyositis RA rheumatoid arthritis SD standard deviation SjS Sjogren’s syndrome SLB surgical lung biopsy SP-D surfactant protein-D SSc systemic sclerosis SLE systemic lupus erythematosus UCTD undifferentiated connective tissue disease UIP usual interstitial pneumonia yr years

NSIP (n ¼ 35) retrospectively to identify four separate cohorts. 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 and pathologies. Our institutional review board determined that ethical approval was not necessary and did not require the patient’s approval or informed consent. 2.2. Data collection Clinical data were obtained from patients’ medical records. Laboratory findings, pulmonary function test results and bronchoalveolar lavage (BAL) data obtained at the time of the initial diagnosis of idiopathic NSIP were recorded. For patients who developed CVD, additional clinical data were obtained at the time of CVD diagnosis. In addition, for the assessment of outcome, the observation period was defined as time to death or last visit to our institution, and the endpoint was used death in the statistical analysis. 2.3. High-resolution computed tomography (HRCT) HRCT examination of the lungs was performed on 1.0- or 1.5mm-thick sections to evaluate radiographic abnormalities. The HRCT images were reviewed by two pulmonologists (Y.N. and M.K.) for the distribution and presence of each of the following signs: ground-glass attenuation, consolidation, intralobular reticular opacity, traction bronchiectasis, and honeycombing. 2.4. Pathological review Lung biopsy specimens were originally made a histological diagnosis in all cases by a pathologist in our hospital. All biopsy specimens were also reviewed by a second pathologist (expert

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pulmonary pathologist; T.V.C.) who were unaware of the clinical or physiological findings. Histological classification was based on the previously published criteria for IIPs [2,4]. The degree of each of the following pathologic findings was scored semiquantitatively (absent, 0; mild, 1; moderate, 2; marked, 3): alveolar inflammation, fibrosis, intra-alveolar macrophages, organizing pneumonia, fibroblastic foci. The presence or absence of each of the following pathologic findings was also assessed: honeycombing, lymphoid aggregates with germinal centers, extensive pleuritis, prominent plasmacytic infiltration, and dense perivascular collagen. 2.5. 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. Cumulative incidence of CVD and survival probabilities was estimated using the Kaplan-Meier method. The log-rank test was used to compare survival rate among groups of patients. Statistical analyses were performed using JMP Start Statistics (SAS Institute Inc., NC, USA). A p-value of 0.05 or less was considered significant. 3. Results 3.1. Clinical characteristics of patients who developed CVD after an initial diagnosis of idiopathic NSIP Of 72 consecutive patients with an initial diagnosis of NSIP, 35 patients had idiopathic NSIP and 37 patients had CVD-NSIP (Fig. 1). In patients with CVD-NSIP at the initial diagnosis, there were 18 patients with PM/DM associated diseases [PM, n ¼ 5; DM, n ¼ 5; amyopathic dermatomyositis (ADM), n ¼ 8], 6 patients with RA, 6 patients with SjS, 5 patients with SSc and 2 patients with overlap syndrome (SSc and SjS, n ¼ 1; RA, SSc and SjS, n ¼ 1). Of 35 patients with idiopathic NSIP, six patients (17.1%) developed CVD after the initial diagnosis of idiopathic NSIP during the mean follow-up period (5.5 ± 5.0 years). The clinical characteristics of six patients with NSIP preceding CVD diagnosis are shown in Table 1. The mean age of these patients is 54 years old and five of the six patients are women (83.3%). There were three patients with DM, two patients with overlap syndrome (DM and SjS), and one patient with RA. The mean duration until CVD diagnosis after the initial diagnosis of NSIP was 2.0 ± 1.1 years. The cumulative incidence of CVD development at one, two and

Initial diagnosis

Idiopathic NSIP n=35

CVD-NSIP n=37

three year was 3.6%, 15.2% and 20.0%, respectively (Fig. 2). All six patients presented with CVD-associated symptoms, including Raynaud’s phenomenon, rash (Gottron’s sign and/or heliotrope rash), muscular pain/weakness with creatine phosphokinase (CPK) elevation and arthralgia at the time of CVD diagnosis (Table 1). Patients were diagnosed with CVD by a rheumatologist. Two patients with DM and SjS (case 4, 5) were diagnosed with myositis and salivary gland inflammation by biopsy. Although only one patient (case 1) had CVD-associated symptoms, including anterior chest rash and photosensitivity at the time of initial NSIP diagnosis, she did not meet the criteria of definite CVD. Three patients (case 1, 2 and 3) were treated by corticosteroids before CVD diagnosis, but all three patients revealed CVD after withdrawal or tapering corticosteroids. After the diagnosis of CVD, five of the six patients were treated with prednisolone (PSL) and/or cyclosporine A (CyA) and all were living. 3.2. Clinical features at the time of NSIP diagnosis among the three groups We compared clinical features at the time of NSIP diagnosis among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, and those with CVD-NSIP (Table 2). Patients with CVD-NSIP tended to have higher CPK and forced vital capacity (FVC) compared to the other two groups, but the difference was not significant. In addition, there were no significant differences in age, sex, smoking habits, observation period, laboratory data, pulmonary function tests, or BAL findings among the three groups. 3.3. HRCT and pathological findings at the time of NSIP diagnosis among the three groups As shown in Table 3, we compared the HRCT and pathological findings among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, and those with CVD-NSIP. HRCT findings revealed that most patients had a distribution of lower zone predominance and ground-glass attenuation. There was no statistical difference in the distribution of abnormalities or the presence of ground-glass attenuation, consolidation, intralobular reticular opacity, traction bronchiectasis, or honeycombing among the three groups. Pathological findings revealed that 62 of the 67 patients (92.5%) demonstrated a fibrotic NSIP pattern. There was no significant difference in the scores for alveolar inflammation, fibrosis, intra-alveolar macrophages, organizing pneumonia, or fibroblastic foci among groups. Moreover, there was also no statistical difference in the presence of honeycombing, extensive pleuritis, prominent plasmacytic infiltration, or dense perivascular collagen among the three groups. 3.4. Treatment for IP and outcome after NSIP diagnosis among the three groups

Final diagnosis

Idiopathic NSIP n=29

CVD-NSIP (NSIP preceding CVD diagnosis) n=6 PM/DM n=3 RA n=1 Overlap n=2

CVD-NSIP n=37 PM/DM RA SjS SSc Overlap

n=18 n=6 n=6 n=5 n=2

Fig. 1. The algorithm for the diagnosis of NSIP among enrolled patients. All 72 patients were initially diagnosed with idiopathic NSIP (n ¼ 35) or CVD-NSIP (n ¼ 37). Six patients (17.1%) initially diagnosed with NSIP developed CVD during the follow-up period.

Treatment for IP and outcome in patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, and those with CVDNSIP are shown in Table 4. Most patients in all groups were treated with corticosteroids alone or in combination with immune suppressive agent (ISA) therapy during the follow-up period; and there was no treatment-related statistical difference among the three groups. In addition, there was no statistical difference among the three groups in overall death rate or in deaths due to respiratory causes. A comparison of the survival curves from the time of initial NSIP diagnosis among the three groups was shown in Fig. 3. There was no statistical difference in survival rate among the three groups.

M. Kono et al. / Respiratory Medicine 117 (2016) 40e47

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Table 1 Clinical characteristics of 6 patients with NSIP preceding CVD diagnosis. Case Age, Sex, CVD yr F/M

Duration until CVD diagnosis

CVD-associated symptoms at the CVD-associated symptoms at the Treatment before CVD time of NSIP diagnosis time of CVD diagnosis diagnosis

Treatment after CVD diagnosis

Outcome

1

67

F

DM

3.5yr

Rash, photosensitivity

PSL þ CyA

Alive

2

42

F

DM

3yr

None

Raynaud’s phenomenon, rash, muscular pain rash, muscular pain

PSL þ CyA

Alive

3

57

F

ADM

6mo

None

rash

4

55

F

DM þ SjS 2yr

None

5 6

55 49

M F

DM þ SjS 1yr2mo RA 1yr7mo

None None

rash, muscular pain and weakness rash arthralgia

None (after withdrawal of corticosteroids) Tapering corticosteroids (PSL 7.5 mg) Tapering corticosteroids (PSL 7.5 mg) None

PSL þ CyA

Alive

PSL

Alive

None None

PSL None

Alive Alive

Cumulative incidence of CVD (%)

F, female; M, male; CVD, collagen vascular disease; CPK, creatine phosphokinase; DM, dermatomyositis; ADM, amyopathic dermatomyositis; SjS, sjogren’s syndrome; RA, rheumatoid arthritis; yr, years; mo, months; PSL, prednisolone; CyA, cyclosporine A.

3.5. CVD-associated symptoms and autoantibodies at the time of initial NSIP diagnosis

100 1-yr incidence rate = 3.6 % 2-yr incidence rate = 15.2 % 3-yr incidence rate = 20.0 %

80

60 40 20 0 0

6

12

18

24

30

36

42

48

54

60

Time (months) Fig. 2. Cumulative incidence of CVD in patients with an initial diagnosis of idiopathic NSIP. The cumulative incidence of CVD in patients with an initial diagnosis of idiopathic NSIP at one, two and three years were 3.6%, 15.2% and 20.0%, respectively.

We examined the difference of CVD-associated symptoms and autoantibodies between patients with NSIP preceding CVD diagnosis and those with idiopathic NSIP at the time of initial NSIP diagnosis to see if we could predict the occurrence of CVD after an initial diagnosis of idiopathic NSIP (Table 5). Of the patients who presented with one or more CVD-associated symptoms, one (16.7%) was in the group diagnosed with NSIP preceding CVD diagnosis, and 11 (37.9%) were in the idiopathic NSIP group. In addition, five patients (83.3%) with NSIP preceding CVD diagnosis had one or more positive autoantibodies, compared to sixteen (57.1%) with idiopathic NSIP. Although patients with NSIP preceding CVD diagnosis were observed to more frequently have positive autoantibodies than those with idiopathic NSIP, there was no statistical difference in CVD-associated symptoms or positive autoantibody results between the two groups.

Table 2 Clinical features at the time of NSIP diagnosis among the three groups. Characteristics

NSIP preceding CVD diagnosis

Idiopathic NSIP

CVD-NSIP

p-value

No. of cases Age, yr Sex, M/F Smoking habit, n current/former/never Observation period, yr Laboratory data LDH, IU/L CPK, IU/L CRP, mg/dL KL-6, U/mL SP-D, ng/mL PaO2 on room air, Torr Pulmonary function tests FVC, L FVC, % predicted FEV1.0, L FEV1.0, % predicted BAL Macrophages, % Lymphocytes, % Neutrophils, % Eosinophils, % CD4/CD8 ratio

6 54.2 ± 8.4 1/5 0/1/5 6.7 ± 3.5

29 60.5 ± 9.5 12/17 7/7/14 5.3 ± 5.4

37 57.5 ± 8.5 20/17 5/13/19 4.9 ± 5.0

0.23 0.17 0.27 0.41

244 ± 81 107 ± 118 0.69 ± 1.17 788 ± 268 184 ± 74 82.7 ± 8.1

301 ± 131 112 ± 124 0.47 ± 0.56 1678 ± 1634 215 ± 137 80.4 ± 9.1

306 ± 127 455 ± 1007 0.86 ± 1.2 1492 ± 1754 204 ± 110 82.7 ± 10.7

0.39 0.08 0.24 0.64 0.94 0.76

1.9 ± 0.4 68.6 ± 10.6 1.6 ± 0.3 74.4 ± 12.1

2.1 ± 0.7 71.9 ± 19.2 1.8 ± 0.6 85.1 ± 12.3

2.4 ± 0.6 75.6 ± 15.7 2.0 ± 0.6 79.8 ± 16.5

0.06 0.46 0.14 0.21

65.2 ± 35.4 24.8 ± 31.3 8.0 ± 11.6 2.9 ± 2.0 0.8 ± 0.6

83.7 ± 13.3 11.5 ± 12.6 2.4 ± 3.3 2.4 ± 3.5 1.5 ± 1.5

82.4 ± 13.1 12.0 ± 11.8 2.9 ± 4.3 2.5 ± 4.0 1.2 ± 2.0

0.79 0.91 0.69 0.95 0.47

NSIP, nonspecific interstitial pneumonia; CVD, collagen vascular disease; yr, years; F, female; M, male; LDH, lactate dehydrogenase; CPK, creatine phosphokinase; CRP, Creactive protein; SP-D, surfactant protein-D; FVC, forced vital capacity; FEV1.0, forced expiratory volume in 1 s; BAL, bronchial alveolar lavage; n.s., not significant.

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Table 3 HRCT and pathological findings at the time of NSIP diagnosis among the three groups. Characteristics HRCT findings No. of cases Lower distribution, % Ground-glass attenuation, % Consolidation, % Intralobular reticular opacity, % Traction bronchiectasis, % Honeycombing, % Pathological findings No. of cases Fibrotic/cellular NSIP, n Alveolar wall inflammationa Fibrosisa Intra alveolar macrophagea Organizing pneumoniaa Fibroblastic focia Honeycombing, % Lymphoid aggregates with germinal centers, % Extensive pleuritis, % Prominent plasmacytic infiltration, % Dense perivascular collagen, %

NSIP preceding CVD diagnosis

Idiopathic NSIP

CVD-NSIP

p-value

6 83.3 100 66.7 50.0 83.3 0

24 87.5 95.8 54.2 45.8 87.5 4.2

34 94.1 97.1 44.1 44.1 76.5 2.9

0.57 0.79 0.51 0.96 0.55 0.79

6 6/0 1.83 1.83 1.33 0.83 0.17 50.0 50.0 16.7 83.3 16.7

29 26/3 1.59 ± 1.79 ± 0.93 ± 0.82 ± 0.28 ± 20.7 44.8 3.5 55.2 13.8

37 35/2 1.89 ± 1.79 ± 1.21 ± 0.84 ± 0.35 ± 21.6 48.7 13.5 54.1 13.5

± ± ± ± ±

0.41 0.98 0.82 0.98 0.40

0.50 0.81 0.53 0.80 0.53

0.77 0.81 0.75 0.83 0.58

0.48 0.16 0.94 0.15 0.99 0.72 0.33 0.94 0.35 0.97 0.28

HRCT, high-resolution computed tomography; NSIP, nonspecific interstitial pneumonia; CVD, connective vascular disease; n. s., not significant. a Scoring of the severity: absent 0, mild 1, moderate 2, and marked 3. Data were shown as mean ± SD.

Table 4 Treatment for IP and outcome after NSIP diagnosis among the three groups. Characteristics

NSIP preceding CVD diagnosis

Idiopathic NSIP

CVD-NSIP

p-value

No. of cases Treatment for IP, n (%) Corticosteroids alone, n (%) Corticosteroids þ ISA, n (%) Death due to respiratory failure, n (%) Overall death, n (%)

6 5 (83.3) 2 (33.3) 3a (50.0) 0 0

29 19 (66.5) 11 (37.9) 8b (27.6) 3 (10.3) 4d (13.8)

37 30 (81.1) 14 (37.8) 16c (43.2) 1 (2.7) 5e (13.5)

0.32 0.97 0.34 0.30 0.43

NSIP, nonspecific interstitial pneumonia; CVD, collagen vascular disease; IP, interstitial pneumonia; ISA, immune suppressive agents; n. s., not significant. a Cyclosporine A (CyA), n ¼ 3. b CyA, n ¼ 5; cyclophosphamide (CPA), n ¼2, azathioprine (AZA), n ¼1. c CyA, n ¼ 9; CPA; n ¼ 5; FK506, n ¼ 2. d Acute exacerbation, n ¼ 2; bacterial pneumonia, n ¼ 1; sudden death, n ¼ 1. e Bacterial pneumonia, n ¼ 1; sepsis, n ¼ 1; acute heart failure, n ¼ 1; malignancy, n ¼ 1; sudden death, n ¼ 1.

100

Survival rate (%)

80 P=0.67

60 40

NSIP preceding CVD diagnosis Idiopathic NSIP CVD-NSIP

20

0 0

12

24

36

48

60

72

84

96

108

120

Time (months) Fig. 3. Survival curves among the three groups. No survival difference was found among patients with NSIP preceding CVD diagnosis (n ¼ 6), those with idiopathic NSIP (n ¼ 29), or those with CVD-NSIP (n ¼ 37).

3.6. Frequency of fulfillment of the criteria for UCTD, LD-CTD, AIFILD or IPAF at the time of initial NSIP diagnosis Finally, we examined whether patients with NSIP preceding CVD diagnosis fulfilled the criteria of UCTD [28], LD-CTD [29], AIFILD [30] or IPAF [31] at the time of initial NSIP diagnosis in

comparison to those with idiopathic NSIP. These criteria were previously proposed and suggest an autoimmune process, but do not meet established criteria for a CVD [28e31]. As shown in Table 6, there was no statistical difference in the rate of patients who met these criteria between two groups at the time of initial NSIP diagnosis. In IPAF criteria, there were 4 (66.7%) and 14 (50.0%) patients who fulfilled the definition in patients with NSIP preceding CVD diagnosis and idiopathic NSIP, respectively. All patients fulfilled the morphologic domain because of having a pathological NSIP diagnosis, and positive of clinical domain were 1 (16.7%) and 9 (31.0%), and positive of serologic domain were 3 (50.0%) and 8 (28.6%) in patients with NSIP preceding CVD diagnosis and idiopathic NSIP, respectively. 4. Discussion The present study demonstrated that the rate of CVD development was 17.1% in NSIP patients who initially diagnosed as idiopathic NSIP after a mean period of 2.0 years until CVD occurrence. The most frequently diagnosed CVD after initial diagnosis of idiopathic NSIP was PM/DM-associated disease although it was the predominant disease in our cohort for CVD-NSIP. We also found that the cumulative incidence of CVD in patients with an initial diagnosis of idiopathic NSIP at one, two and three years were 3.6%, 15.2% and 20.0%, respectively. In those patients, intriguingly, it was

M. Kono et al. / Respiratory Medicine 117 (2016) 40e47

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Table 5 CVD-associated symptoms and autoantibodies at the time of initial NSIP diagnosis. Characteristics

NSIP preceding CVD diagnosis

Idiopathic NSIP

p-value

CVD-associated symptoms, n (%) Raynaud’s phenomenon Arthralgia/joint swelling Photosensitivity Unintentional weight loss Morning stiffness Dry eye or dry mouth Dysphagia Recurrent unexpected fever Gastroesophageal reflex Skin change (rash) Oral ulceration Nonandrogenic alopecia Autoantibodies, n (%) Anti-nuclear antibody Rheumatoid factor Anti-SCL 70 antibody Anti-SSA antibody Anti-SSB antibody Anti-Jo1 antibody Anti-centromere antibody Anti-RNP antibody Anti-DNA antibody MPO-ANCA PR3-ANCA

1/6 0/6 0/6 1/6 0/6 0/6 1/6 0/6 0/6 0/6 1/6 0/6 0/6 5/6 3/6 2/6 0/5 2/5 0/5 0/4 0/4 0/4 0/5 0/5 0/5

11/29 4/29 1/29 0/29 2/29 3/29 2/29 1/29 1/29 1/29 2/29 0/29 0/29 16/28 12/28 7/27 0/17 3/21 0/21 1/16 0/13 0/13 0/24 0/15 1/15

0.29 0.20 0.54 0.06 0.38 0.27 0.38 0.54 0.54 0.54 0.47 e e 0.20 0.75 0.72 e 0.22 e 0.45 e e e e 0.44

(16.7) (0) (0) (16.7) (0) (0) (16.7) (0) (0) (0) (16.7) (0) (0) (83.3) (50.0) (33.3) (0) (40.0) (0) (0) (0) (0) (0) (0) (0)

(37.9) (13.7) (3.4) (0) (6.9) (10.3) (6.9) (3.4) (3.4) (3.4) (6.9) (0) (0) (57.1) (42.9) (25.9) (0) (14.3) (0) (6.3) (0) (0) (0) (0) (6.7)

CVD, collagen vascular disease; NSIP, nonspecific interstitial pneumonia; MPO-ANCA, myeloperoxidase antineutrophil cytoplasmic antibody; PR3-ANCA, proteinase 3antineutrophil cytoplasmic antibody; n. s., not significant.

Table 6 Frequency of fulfill of the criteria for UCTD, LD-CTD, AIF-ILD or IPAF at the time of initial NSIP diagnosis. Characteristics

NSIP preceding CVD diagnosis

Idiopathic NSIP

p-value

UCTD criteria, n (%) LD-CTD criteria, n (%) AIF-ILD criteria, n (%) IPAF criteria, n (%)

1/6 4/6 1/6 4/6

11/28 15/29 5/28 14/28

0.27 0.50 0.94 0.45

(16.7) (66.7) (16.7) (66.7)

(39.3) (51.7) (17.8) (50.0)

UCTD, Undifferentiated connective tissue disease; LD-CTD, lung-dominant connective tissue disease; AIF-ILD, autoimmune-featured interstitial lung disease; IPAF, interstitial pneumonia with autoimmune features; NSIP, nonspecific interstitial pneumonia; CVD, collagen vascular disease; n.s., not significant.

difficult to predict the latency of CVD by CVD-associated symptoms and/or the presence of autoantibodies at the time of initial NSIP diagnosis. Additionally, there was no statistical difference in clinical characteristics and survival among the three groups; patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP or those with CVD-NSIP. It has been estimated that up to 15e20% of patients with a chronic IP have occult CVD [11e15], and there have been some reports of NSIP preceding the diagnosis of CVD by several months or several years [3,10,16e18]. In these studies, the rate of CVD development was 3.0e11.0% in patients with initial NSIP diagnosis [3,10,16e18]. Our study revealed that of 35 patients who received an initial diagnosis of NSIP, six (17.1%) developed CVD after initial NSIP diagnosis; the rate of CVD occurrence was higher than has been observed in other studies. It may depend on the relatively longer follow-up period in the present study (mean 5.5 years). In addition, in comparison with our previous study, the cumulative incidence of CVD development in patients with an initial diagnosis of idiopathic NSIP was higher than those with initial IPF diagnosis [19]. In that study, the cumulative incidence of CVD in patients with initial IPF diagnosis at one, five, and ten years was 0.91%, 9.85%, and 15.5%, respectively [19]. We found that most patients with NSIP preceding CVD diagnosis revealed PM/DM-associated diseases during the follow-up period. Some previous reports also showed that PM/DM was the major CVD in patients with NSIP preceding CVD diagnosis [16,18]. Sato et al.

reported a small series of seven patients with histologically proven NSIP who later developed CVDs (PM/DM n ¼ 4, SSc n ¼ 1, RA n ¼ 1, MPA n ¼ 1) more than six months after the first presentation of NSIP [16]. In addition, Xu et al. showed that five patients (6.8%) were diagnosed with CVD at the end of the follow-up period (PM n ¼ 3, SSc n ¼ 1 and MPA n ¼ 1) out of 72 patients initially diagnosed with idiopathic NSIP [18]. Moreover, several reports have demonstrated that IP was often the sole manifestation in patients with IP associated with PM/DM (PM/DM-IP) [5,32]. Douglas et al. reported that in the series of 70 patients with PM/DM-IP, IP was the sole manifestation in 21patients (30%) [5]. Yang et al. also evaluated the onset of histologically confirmed IP associated with PM/DM and showed that IP was frequently (35 of 85 evaluable patients) the first onset [32]. On the other hand, we showed previously that patients with an initial diagnosis of IPF occurred RA, MPA, and SScassociated diseases during follow-up periods [19]. Occult CVD in patients with IIPs might be different depending on IP patterns such as usual interstitial pneumonia (UIP) or NSIP. Recent studies have demonstrated that NSIP is the most common histologic pattern in CVD-IP [5e7] and it has been reported that NSIP is associated with autoimmune diseases [8e10]. Fujita et al. demonstrated that NSIP is “an autoimmune interstitial pneumonia” because there is no significant difference clinically or radiologically between patients with idiopathic NSIP and those with NSIP associated with underlying autoimmune diseases [8]. In addition, Romagnoli et al. reported that more than 50% of the cases

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developed an autoimmune disease such as autoimmune thyroiditis (26%), UCTD (22%) and CVD (11%) in 27 patients with an initial diagnosis of idiopathic NSIP after a mean follow-up of 22 months [10]. The precise relationship between NSIP and CVD remains to be further clarified, but it is clearly a significant one. It has been reported that patients with IIPs can be difficult to predict the development of CVD clinically at the time of initial diagnosis [14,16,18], although clinical characteristics such as younger or more positive frequent of rheumatoid factor may suggest CVD development [17]. Consistent with these reports, we could not find the significant difference in clinical characteristics and the fulfillment of previous criteria such as UCTD [28], LD-ILD [29], AIF-ILD [30] and IPAF [31] suggestive of autoimmune disorder without fulfilling the criteria for defined CVDs between patients with NSIP preceding CVD diagnosis and those with idiopathic NSIP at the time of initial NSIP diagnosis. In addition, we found that all patients with NSIP preceding CVD diagnosis showed CVDassociated symptoms at the time of CVD diagnosis, although few patients had these symptoms at the time of initial NSIP diagnosis. Our previous study showed similar results in patients who developed CVD after an initial diagnosis with IPF [19]. These results suggest that patients with IIPs including NSIP could potentially develop CVD even if they had no symptoms and/or autoantibodies suggestive of CVD at the time of initial diagnosis. It has been reported that there is no prognostic difference between patients with idiopathic NSIP and those with CVD-NSIP [33,34]. Our data also suggest that those with NSIP preceding CVD diagnosis had a similar prognosis. In the series of Sato et al., seven patients with NSIP preceding CVD were all alive after treatment with corticosteroids and/or ISA [16]. In addition, Park et al. reported that eight patients (10%) with an initial diagnosis of NSIP developed CVDs with variable intervals (nine months to eight years) and showed that seven patients with fibrotic NSIP had no deteriorated progressively except one patient with cellular NSIP who died of tuberculous myositis secondary to steroid treatment [17]. These limited results suggested that patients with NSIP preceding CVD diagnosis had a good prognosis. Our study has several limitations. First, this was a retrospective study from a single institution and the sample size was too small. Second, not all patients were examined for all CVD-associated findings or for autoantibodies. Most patients could not be tested for recently developed autoantibody tests, such as the anti-cyclic citrullinated peptide (CCP) antibody and the anti-aminoacyl-tRNA synthetase (ARS) antibody. Thirdly, our ability to diagnose CVD may have been limited by several factors, including the use by some patients of immunomodulation drugs, short observation periods, and early death. In conclusion, some patients with idiopathic NSIP had occult CVDs: the most commonly diagnosed were PM/DM-associated diseases. It may be difficult to predict the occurrence of CVD at the time of initial NSIP diagnosis. Careful long-term follow-up is needed in patients with idiopathic NSIP. Financial disclosure The authors have nothing to disclose. Conflict of interest statement The authors declare no conflict of interest related to this work. Funding source None.

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