Idiopathic interstitial lung disease with anti-SSA antibody

Prévia do material em texto

Original article
Idiopathic interstitial lung disease with anti-SSA
antibody
Jean-François Boitiaux1,2, Marie-Pierre Debray3, Pascale Nicaise-Roland4,
Homa Adle-Biassette5, Claire Danel2,5, Christine Clérici2,6,7, Michel Aubier1,2,8,
Xavier Mariette9,10, Jacques Cadranel11,12 and Bruno Crestani1,2,8
Abstract
Objectives. Consensus is lacking on the immunological tests to perform for diagnosis of interstitial lung
diseases (ILDs). In particular, the value of detecting anti-SSA antibody in this context is unknown.
We aimed to determine whether the detection of anti-SSA antibody in patients with ILD can identify a
subgroup of patients with CTD.
Methods. We compared the characteristics of patients with newly diagnosed apparently idiopathic ILD
with anti-SSA antibody [anti-SSA(+) group] and without anti-SSA antibody (control group).
Results. Anti-SSA(+) patients (n = 15) more often had extra-respiratory signs (xerostomia and ocular
dryness), auto-immune features, a CT scan pattern of non-specific interstitial pneumonia and more
severe lung function alteration than controls (n = 30). Of patients who were anti-SSA(+), 2 met the criteria
for SS and 13 (86%) of 15 met the criteria for the diagnosis of undifferentiated CTD.
Conclusions. Our results suggest that identification of anti-SSA antibody in patients with early ILD can
reveal a specific subgroup of patients with more ground glass opacity and more severe lung function
impairment than those without anti-SSA antibody.
Key words: Autoimmune conditions, Other idiopathic inflammatory disorders, Sjögren’s syndrome, Computed
tomography scanning.
Introduction
Interstitial lung diseases (ILDs) encompass a heteroge-
neous group of diffuse parenchymal lung diseases that
can be divided into primary or idiopathic disorders [e.g.
idiopathic pulmonary fibrosis (IPF)] and secondary dis-
orders such as those associated with CTDs. ILD is a
well-known complication of various CTDs, particularly
SSc, RA, SS and DM/PM. ILD may be the first manifest-
ation of a CTD and can precede other signs of the disease
by many years [1,2]. In an estimated 15% of patients who
present with ILD, CTD is present or will develop, with the
initial clinical features of the lung disease being essentially
indistinguishable from those of idiopathic ILD.
Recognition of CTD is particularly challenging when ILD
is the first or sole manifestation or when extrathoracic fea-
tures of CTD are subtle. Attempts to identify underlying
CTD include a thorough history, physical examination and
biologic assessment for the presence of autoantibodies.
Consensus is lacking on the serological assessment to
perform when an ILD is identified. However, RF, ANAs,
anti-ENAs and ANCAs are usually assessed. The identifi-
cation of an autoantibody in recent ILD has been the sub-
ject of a limited number of studies. Fischer et al. [3]
showed that the detection of ANA with anti-Th/To speci-
ficity could help to distinguish patients with scleroderma
sine scleroderma from those with idiopathic lung fibrosis.
Our group previously showed that patients with ANCA and
lung fibrosis could be at increased risk of vasculitis [4].
1Pneumology A Department, Regional Competence Center for Rare
Pulmonary Diseases, APHP, Bichat-Claude Bernard Hospital,
2Université Paris 7 � Denis Diderot, 3Radiology Department,
4Immunology Department, 5Pathology Department, APHP,
Bichat-Claude Bernard Hospital, 6INSERM, Unit 773, 7Service de
Physiologie et Explorations Fonctionnelles Multidisciplinaires, APHP,
Bichat-Claude Bernard Hospital, Paris, 8INSERM, Unit 700,
9Rheumatology Department, APHP, Bicetre Hospital, Le Kremlin
Bicêtre, 10Université Paris-Sud 11, 11Pneumology and Intensive Care
Unit, APHP, Tenon Hospital and 12Université Pierre et Marie Curie �
Paris 6, Paris, France.
Correspondence to: Bruno Crestani, Pneumology A Department,
APHP, Bichat-Claude Bernard Hospital, 46 rue Henri Huchard,
75018 Paris, France. E-mail: bruno.crestani@bch.aphp.fr
Submitted 9 November 2010; revised version accepted 27 June 2011.
! The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
RHEUMATOLOGY
Rheumatology 2011;50:2245�2250
doi:10.1093/rheumatology/ker267
Advance Access publication 8 October 2011
C
L
IN
IC
A
L
S
C
IE
N
C
E
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628 by guest on 12 July 2019
Anti-Ro/SSA and anti-La/SSB autoantibodies are mem-
bers of the anti-ENA family. Anti-Ro/SSA antibodies are
detected mainly in SS and SLE. Anti-Ro/SSA and anti-La/
SSB autoantibodies recognize different epitopes on poly-
peptides associated with small RNAs, in particular human
cytoplasmic RNA or hY-RNA. Anti-SSA antibody detected
in patients with ILD could be associated with the severity
of the ILD, particularly when it is associated with anti-
synthetase antibodies [5].
We wondered whether the detection of anti-SSA anti-
body in patients with idiopathic ILD could reveal a subset
of patients with CTD, particularly SS. We performed a
retrospective case�control study to compare patients
with newly detected idiopathic ILD with anti-SSA antibody
[anti-SSA(+) group] and without anti-SSA antibody (con-
trol group).
Methods
Selection of patients
This study was conducted in two university pneumology
departments in Paris with an extensive expertise in CTD-
associated lung involvement. A systematic search for a
CTD, including salivary gland biopsy and testing for
anti-SSA antibody, is standard for the diagnosis of ILD
in both departments. The criteria for inclusion in the
anti-SSA(+) group were the presence of a recently identi-
fied ILD on a high-resolution CT scan, absence of an iden-
tified cause of ILD and detection of anti-SSA antibody.
Patients with a known CTD were excluded from the
study. We reviewed records for patients included with a
diagnosis obtained between 1997 and 2007.
For each patient included in the anti-SSA(+) group, we
included two control patients randomly chosen from pa-
tients files in each department, evaluated in the same year
and in the same department, with the same criteria
but without anti-SSA antibody. This study was
approved as an observational study by the Institutional
Review Board of the Société de Pneumologie de Langue
Française (number 2010-009). All patients gave their in-
formed consent.
Data collection
One physician (J.-F.B.) used a standard form to record the
data for patients from medical files. The data collected
included epidemiological characteristics, ILD characteris-
tics, extrapulmonary manifestations and outcome data
evaluating the progression of ILD and extrarespiratory
manifestations on follow-up and survival. The results of
Schirmer’s tests, performed by an ophthalmologist, were
recorded [6]. When available, salivary gland biopsy results
were reviewed and the focal lymphocyte infiltrate intensity
was graded according to Chisholm [7]. For every patient,
we assessed whether they fulfilled the criteria for the diag-
nosis of primary SS [6] or UCTD (as suggested by Kinder
et al. [8]).
We recorded the results of analysis of pulmonary func-
tion tests (PFTs), arterial blood gas and bronchoalveolar
lavage (BAL) fluid analysis obtained at the time of the
diagnosis of ILD.
All available high-resolution CT images obtained at
diagnosis were reviewed by one experienced thoracic
radiologist (M.-P.D.), who was blinded to clinical informa-
tion and final diagnosis. The radiologist collected data on
elementary signs, quantitavely assessed the presence
of ground glass opacities and fibrosis according to
Kazerooni et al. [9] and gave an opinion on the predom-
inant radiographic pattern according to the American
Thoracic Society (ATS)/European Respiratory Society
(ERS) classification [10].
Anti-SSA antibody detection
Detectionof ANA and anti-SSA was performed in the
same laboratory for all samples and, respectively,
involved the use of HEp-2 cells and an Ouchterlony ID
method followed by an ELISA.
Statistical analysis
Statistical analysis involved use of GraphPad Prism 5�
software. Data are presented as mean (S.D.) or median.
Data with normal distribution were compared by unpaired
two-tailed Student’s t-test and data with non-normal dis-
tribution were compared by two-tailed Mann�Whitney
test. Qualitative data were compared using a Fisher’s
exact test or chi-squared test as appropriate. P< 0.05
was considered statistically significant.
Results
Clinical characteristics
Fifteen patients were included in the anti-SSA(+) group
and 30 in the control group. The clinical data of patients
and controls are presented in Table 1. Anti-SSA(+) pa-
tients (n = 15) included nine men and six women with a
mean (S.D.) age of 65 (11) years at diagnosis. Six patients
were active smokers or ex-smokers at the time of diag-
nosis. Mean cumulative tobacco exposure was 37 pack-
years for smokers.
Controls (n = 30) included 16 men and 14 women with a
mean (S.D.) age of 68 (12) years. Sixteen patients were
active smokers or ex-smokers at the time of diagnosis.
Mean cumulative tobacco exposure was 40 pack-years
for smokers. Anti-SSA(+) patients and controls did not
differ in these characteristics. All patients presented with
dyspnoea or cough. Crackles were present in most pa-
tients. Digital clubbing was present in 13% of patients and
23% of controls.
Extra-respiratory signs
In total, 57% of anti-SSA(+) patients but only 17% of con-
trols (P = 0.006) presented with a subjective sensation of
ocular dryness [data were available for 14 anti-SSA(+) pa-
tients and 30 controls] (Table 1). The Schirmer’s test per-
formed in 9 (60%) anti-SSA(+) patients and 12 (40%)
controls revealed abnormal results for 7 in each group
(P = 0.64). In total, 40% of anti-SSA(+) patients and 33%
of controls presented with a subjective sensation of oral
2246 www.rheumatology.oxfordjournals.org
Jean-François Boitiaux et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628 by guest on 12 July 2019
dryness. One patient in the anti-SSA(+) group reported
episodes of parotid gland swelling. Other extra-respiratory
signs (loss of weight, fever >38�C, RP, arthralgias, myal-
gias, gastroesophageal reflux) were very rare in both
groups. A minor salivary gland biopsy was performed in
11 (73%) of 15 anti-SSA(+) patients and 15 (50%) of 30
controls (P = 0.20). Four subjects in each group exhibited
salivary gland lymphocyte infiltration with a Chisholm
score 53 (P = 0.68).
Biological results
The biological results are presented in Table 2. The two
groups did not differ in complete blood count, electrolyte
test results or hepatic profile (data not shown).
Gammaglobulin concentration was higher, but not signifi-
cantly, in the anti-SSA(+) group [17.0 (4.5) g/l] than in the
control group [12.0 (5.3) g/l, P = 0.06].
Ten (67%) anti-SSA(+) patients (median titre = 1/320)
and 3 (10%) controls (median titre = 1/200) were positive
for ANA (P = 0.0002). Therefore 5 (33%) of 15 patients in
the anti-SSA(+) group were negative for ANA. By defin-
ition, anti-SSA antibodies were detected in all patients in
the anti-SSA(+) group; 4 (26%) of 15 patients in this group
also tested positive for anti-SSB antibodies. RF was pre-
sent in 7 of 14 anti-SSA(+) patients, but only 1 control
(P = 0.0006) (subjects were not systematically tested for
anti-CCP antibody, but this was present in one control
patient positive for RF). All patients were negative for
anti-synthetase antibodies (anti-Jo1, anti-PL7 and
anti-PL12). ANCA positivity was detected in one patient
in the anti-SSA(+) group (without identified specificity)
and in four patients in the control group (anti-
myeloperoxydase in one patient, anti-lactoferrin in one
patient, without specificity in two patients).
Lung function tests
The results of the lung function tests were available
for 14 of 15 anti-SSA(+) patients and for 28 of 30 controls
(Table 3). Lung function abnormalities were more severe
for anti-SSA(+) patients. Indeed, mean vital capacity and
forced expiratory volume in 1 s (FEV1) were lower for
anti-SSA(+) patients than controls. Vital capacity was
<80% in 8 (57%) of 14 anti-SSA(+) patients vs 1 (3%) of
28 controls (P = 0.003). The diffusing capacity for carbon
monoxide (DLCO), carbon monoxide transfer coefficient
(KCO) and resting arterial blood gas level did not differ
between the two groups.
BAL
Results of BAL fluid analysis were available for 14 of 15
anti-SSA(+) patients and 27 of 30 controls (Table 4).
Anti-SSA(+) patients showed a 2-fold increase in BAL
total cell count and increased lymphocytes and neutrophil
percentages, although not significant, as compared with
controls.
High-resolution computed tomography (HRCT)
analysis
Ground-glass opacities were more frequent in anti-SSA(+)
patients, whereas honeycomb opacities and subpleural
reticulations were more frequent in the control group
(Table 5). The CT patterns also differed between the
groups. Anti-SSA(+) patients (seven cases) more fre-
quently showed a non-specific interstitial pneumonia
(NSIP) pattern, followed by an organizing pneumonia pat-
tern (three cases) and an usual interstitial pneumonia (UIP)
pattern (two cases). In three patients, the CT pattern could
not be adequately classified. The UIP pattern was the
most frequent in the control group (21 cases), followed
by a NSIP pattern (6 cases). In three patients, the CT pat-
tern could not be adequately classified.
TABLE 1 Clinical characteristics of the patients
Clinical characteristics Anti-SSA(+) (n = 15) Controls (n = 30) P-value
Men, % 60 54 0.76
Age at diagnosis, mean (S.D.), years 65 (11) 68 (12) 0.39
Crackles, % 73 96 0.03
Weight loss, % 20 20 1
RP, % 13 3.3 0.18
Arthralgias, % 20 27 0.54
Subjective ocular dryness, % 57 17 0.006
Available Schirmer’s test, n 9 12 0.23
Positive Schirmer’s test result, n 7/9 7/12 0.64
Subjective oral dryness, % 40 33 0.75
Minor salivary gland biopsy Chisholm score 53 4/11 4/15 0.68
TABLE 2 Biological characteristics of the patients
Autoantibodies
Anti-SSA(+)
(n = 15)
Controls
(n = 30) P�value
ANA positive, % 67 17 0.02
Anti-SSA positive, % 15 0 �
ANCA positive, % 9.1 14.8 0.64
RF positive, % 53 3.3 0.0006
www.rheumatology.oxfordjournals.org 2247
Anti-SSA in ILD
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628 by guest on 12 July 2019
SS criteria and UCTD criteria
Among the anti-SSA(+) patients, 2 (13%) of 15 met the
criteria for SS [6] as compared with none in the control
group, and 13 (86%) of 15 met the criteria for the diagno-
sis of UCTD [8], a ratio considerably higher than that
observed in the control group [4 (13%) of 30, P< 0.0001].
Evolution
Mean (S.D.) follow-up was 30 (9) months in the anti-SSA(+)
group and 42 (8) months in the control group (P = 0.28).
Treatment modalities were similar in both groups. Only
four anti-SSA(+) patients and six controls did not receive
any treatment. Among those who were treated, CSs were
the most frequently used treatment [8 of 15 anti-SSA(+)
and 18 of 30 controls]. About one-half of all subjects
received immunosuppressants, mainly AZA
[5 anti-SSA(+) patients and 13 controls] and CYC
[3 anti-SSA(+) patients and 6 controls]. No subject de-
veloped a definite CTD.
During follow-up, 3 (20%) of 15 anti-SSA(+) patients and
10 (33%) of 30 controls died (P = 0.49). The two groups did
not differ in probability of survival (P = 0.44). Death was
related to lung disease in three anti-SSA(+) patients and
in 8 of 10 controls.
Discussion
In this study we evaluated the diagnostic value of
anti-SSA in patients with newly identified apparently idio-
pathic ILD. With detection of anti-SSA antibody we could
identifya group of patients with a high prevalence of
ocular dryness and autoimmunity, increased cellularity in
BAL with prominent lymphocytosis, marked restrictive
ventilatory disorder and predominantly ground-glass opa-
cities and minimal honeycombing on lung CT, which was
reminiscent of NSIP. Most of these patients met the cri-
teria for UCTD.
Our study has several limitations. The number of sub-
jects was low because it is rare to have positive anti-SSA
TABLE 3 Lung function test and blood gas analysis
Test/analysis
Anti-SSA(+)
(n = 14),
mean (S.D.)
Controls
(n = 28),
mean (S.D.) P-value
Lung function tests
VC (per cent predicted) 63 (22) 87 (23) 0.006
TLC (per cent predicted) 71 (20) 74 (18) 0.62
FEV1 (per cent predicted) 66 (20) 87 (26) 0.01
FEV1/FVC, % 82 (4) 86 (3) 0.40
DLCO (per cent predicted) 63 (24) 55 (16) 0.21
KCO/VA (per cent predicted) 76 (16) 73 (23) 0.74
Arterial blood gas
PaO2 (kPa) 9.6 (1.7) 10.3 (2.0) 0.32
PaCO2 (kPa) 5.2 (0.4) 5.5 (0.9) 0.53
VC: vital capacity; TLC: total lung capacity; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; DLCO: diffusing
capacity for carbon monoxide; KCO/VA: carbon monoxide transfer coefficient/alveolar volume ratio.
TABLE 4 Bronchoalveolar lavage fluid analysis
BAL cytology
Anti-SSA(+)
(n = 13), mean (S.D.)
Controls
(n = 27), mean (S.D.) P�value
Cellularity (�106/l) 330 (235) 165 (155) 0.02
Macrophages, % 51 (18) 72 (14) 0.001
Lymphocytes, % 19 (12) 13 (12) 0.07
Neutrophils, % 21 (22) 10 (7) 0.23
Eosinophils, % 3.5 (8) 4 (4) 0.99
TABLE 5 HRCT analysis
HRCT feature
Anti-SSA(+)
(n = 15)
Controls
(n = 30) P-value
Elementary signs, %
Honeycomb opacities 27 71 0.02
Reticulations 33 21 0.03
Ground-glass opacities 87 67 0.001
Predominant pattern, %
NSIP 47
9>>=
>>;
20
0.003
UIP 13 70
Organizing pneumonia 20 0
Unclassified pattern 20 10
2248 www.rheumatology.oxfordjournals.org
Jean-François Boitiaux et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628 by guest on 12 July 2019
antibody in the context of ILD, even if the test is system-
atically performed, as in our groups. Moreover, this was a
retrospective study, which implies the typical limitations of
this type of study. However, to limit bias related to the
collection of the data, we defined a precise list of data
to be collected before the beginning of the study, control
patients were matched to anti-SSA(+) patients on the
basis of date of diagnosis to avoid differences due to
the modification of clinical and biological practices, and
an experienced radiologist read CT images in a random
order, without knowledge of the underlying diagnosis,
thus limiting the risks of bias in interpretation.
Furthermore, the study was conducted in two centres
with long-standing expertise in the field of CTD-
associated lung diseases, where the clinical approach to
the diagnosis of ILD is very similar.
Despite these limitations, our results show that the de-
tection of an anti-SSA antibody in patients with apparently
idiopathic ILD can reveal a unique group of patients with a
rather homogeneous clinical presentation. Due to the lim-
ited number of lung biopsies performed in both groups,
we could not precisely characterize the underlying abnor-
mality, although the increased lymphocytosis in BAL and
predominant ground-glass opacities and minimal honey-
combing on lung CT were consistent, among other fea-
tures, with NSIP.
Interestingly, we found 33% of anti-SSA(+) patients
negative for ANA, a feature already described in the litera-
ture [11]. The use of HEp-2000 cells as a substrate for the
routine detection of ANA can reduce the false-negative
rate because this cell substrate expresses the SSA
60-kD protein [12].
We were surprised to find a limited diversity in extra-
respiratory signs in our patients. Indeed, anti-SSA(+)
patients exclusively demonstrated elements of sicca syn-
drome (xerostomia and xerophthalmia). However, only
two anti-SSA(+) patients fulfilled the European�American
criteria for the diagnosis of SS [6]. Since we did not evalu-
ate objective salivary secretion, we may have missed an
objective criterion, which limited our ability to use these
criteria. However, these criteria have been shown to have
better specificity, but lower sensitivity than the various
criteria used previously [13]. These are classification cri-
teria and probably not adapted to diagnosis in patients
with some specific systemic manifestations. Finally, our
patients showed hypergammaglobulinaemia and 55% of
them were positive for RF, the same frequency reported
for classical primary SS [14].
Most of our patients [13 (88%) of 15] presented with the
criteria for a UCTD used by Kinder et al. [8]. It has been
proposed that UCTD is a distinct clinical entity character-
ized by the presence of signs and symptoms suggestive
of a CTD, positive serological results and disease duration
of at least 1 year [15]. In one series, almost 90% of pa-
tients who were characterized as having idiopathic NSIP
with surgical lung biopsies met the criteria for UCTD [8].
Recent data suggest that patients with UCTD-ILD have
a more favourable clinical course than do patients
with IPF [16].
Despite the increased severity of lung involvement at
diagnosis in anti-SSA(+) patients, as assessed by a
more severe restrictive syndrome, patients and controls
did not differ in survival. CTD-associated ILD is con-
sidered to have a better prognosis than idiopathic ILD,
whatever the underlying pathology (NSIP or UIP) [17].
However, a recent Asian study suggested that the prog-
nosis for idiopathic NSIP and CTD-associated NSIP was
similar [18].
Whether the detection of an anti-SSA(+) antibody in a
patient with undefined ILD could affect the management
of ILD is unknown. Recently Fischer et al. described a
cohort of patients with ILD of unknown cause who were
confirmed to have primary SS on the basis of a compre-
hensive evaluation that included minor salivary gland
biopsy [19]. Even though the confirmation of primary SS
allowed for more precise classification of patients, the au-
thors concluded that this classification did not affect the
management of these patients [19]. In conclusion, identi-
fication of anti-SSA antibody in patients with ILD allows for
classifying such patients in a homogeneous group with
more ground-glass opacity and more severely impaired
lung function impairment than patients with ILD, but with-
out anti-SSA antibody.
Rheumatology key message
. Idiopathic ILD with anti-SSA are characterized by
an NSIP pattern and poorer lung function.
Disclosure statement: The authors have declared no
conflicts of interest.
References
1 Cottin V, Thivolet-Bejui F, Reynaud-Gaubert M et al.
Interstitial lung disease in amyopathic dermatomyositis,
dermatomyositis and polymyositis. Eur Respir J 2003;22:
245�50.
2 Poormoghim H, Lucas M, Fertig N, Medsger TA Jr.
Systemic sclerosis sine scleroderma: demographic,
clinical, and serologic features and survival in forty-eight
patients. Arthritis Rheum 2000;43:444�51.
3 Fischer A, Pfalzgraf FJ, Feghali-Bostwick CA et al.
Anti-Th/To-positivity in a cohort of patients with idiopathic
pulmonary fibrosis. J Rheumatol 2006;33:1600�5.
4 Foulon G, Delaval P, Valeyre D et al. ANCA-associated
lung fibrosis: analysis of 17 patients. Respir Med 2008;
102:1392�8.
5 La Corte R, Lo Mo Naco A, Locaputo A et al. In patients
with antisynthetase syndrome the occurrence of anti-Ro/
SSA antibodies causes a more severe interstitial lung
disease. Autoimmunity 2006;39:249�53.
6 Vitali C, Bombardieri S, Jonsson R et al. Classification
criteria for Sjogren’s syndrome: a revised version
of the European criteria proposed by the
American-European Consensus Group. Ann Rheum Dis
2002;61:554�8.
www.rheumatology.oxfordjournals.org 2249
Anti-SSA in ILD
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628by guest on 12 July 2019
7 Chisholm DM, Mason DK. Labial salivary gland biopsy
in Sjogren’s disease. J Clin Pathol 1968;21:656�60.
8 Kinder BW, Collard HR, Koth L et al. Idiopathic nonspecific
interstitial pneumonia: lung manifestation of undifferenti-
ated connective tissue disease? Am J Respir Crit Care
Med 2007;176:691�7.
9 Kazerooni EA, Martinez FJ, Flint A et al.
Thin-section CT obtained at 10-mm increments
versus limited three-level thin-section CT for idiopathic
pulmonary fibrosis: correlation with pathologic scoring.
AJR Am J Roentgenol 1997;169:977�83.
10 American Thoracic Society/European Respiratory Society
International Multidisciplinary Consensus Classification of
the Idiopathic Interstitial Pneumonias. This joint statement
of the American Thoracic Society (ATS), and the European
Respiratory Society (ERS) was adopted by the ATS board
of directors, June 2001 and by the ERS Executive
Committee, June 2001. Am J Respir Crit Care Med 2002;
165:277�304.
11 Locht H, Pelck R, Manthorpe R. Clinical manifestations
correlated to the prevalence of autoantibodies in a large
(n=321) cohort of patients with primary Sjögren’s
syndrome: a comparison of patients initially diagnosed
according to the Copenhagen classification criteria with
the American-European consensus criteria. Autoimmun
Rev 2005;4:276�81.
12 Fritzler MJ, Miller BJ. Detection of autoantibodies to SSA/
Ro by indirect immunofluorescence using a transfected
and overexpressed human 60 kD autoantigen in Hep-2
cells. J Clin Lab Anal 1995;9:218�24.
13 Novljan MP, Rozman B, Jerse M et al. Comparison of the
different classification criteria sets for primary Sjogren’s
syndrome. Scand J Rheumatol 2006;35:463�7.
14 Lazarus MN, Isenberg DA. Development of additional
autoimmune diseases in a population of patients with
primary Sjögren’s syndrome. Ann Rheum Dis 2005;64:
1062�4.
15 Mosca M, Tani C, Neri C et al. Undifferentiated
connective tissue diseases (UCTD). Autoimmun Rev 2006;
6:1�4.
16 Kinder BW, Shariat S, Collard HR et al.
Undifferenciated connective tissue disease-associated
interstitial lung disease: changes in lung function.
Lung 2010;188:143�9.
17 Bouros D, Wells AU, Nicholson AG et al. Histopathologic
subsets of fibrosing alveolitis in patients with systemic
sclerosis and their relationship to outcome. Am J Respir
Crit Care Med 2002;165:1581�6.
18 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;175:705�11.
19 Fischer A, Swigris JJ, du Bois RM et al. Minor salivary
gland biopsy to detect primary Sjogren syndrome in
patients with interstitial lung disease. Chest 2009;136:
1072�8.
2250 www.rheumatology.oxfordjournals.org
Jean-François Boitiaux et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/rheum
atology/article-abstract/50/12/2245/1789628 by guest on 12 July 2019