Millaisia keuhkomuutoksia eri sidekudossairauksien yhteydessä

Transcription

18/04/15 Sidonnaisuuteni kaupalliseen yritykseen
(ky) viimeisten 2 v aikana
Millaisia keuhkomuutoksia eri sidekudossairauksien yhteydessä esiintyy Rii:a Kaarteenaho Keuhkolääkäripäivät 19.3.2015 Kuopio Ky 1
Ky 2
Saanut ky:lta apurahan
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Ei
Omistan ky:n osakkeita
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Saanut ky:lta palkkaa/palkkion
(luentopalkkion)
GSK Eli Lilly Finland
Mundipharma
ResMed
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ky:lta palkkion
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Osallistunut kongressiin ky:n osittain tai
kokonaan maksamana
BoehringerIngelheim
Intermune
Osallistunut ky:n hallintoelinten toimintaan
Ei
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Olen työsuhteessa ky:een
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Vastaanottanut muuta tukea ky:lta
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Systeeminen sidekudossairaus ja keuhkot Esityksen sisältö •  Sidekudostauteihin lii:yvät keuhkomuutokset •  Sidekudostauteihin lii:yvät intersDDaaliset keuhkomuutokset –  Nimet, lyhenteet, yleisyys, ennuste •  Oireet ja diagnosDikka •  Kaikkiin sidekudossairauksiin voi lii:yä monenlaisia keuhkomuutoksia –  Suuret ja pienet ilmaDet, intersDDum, ilmaDlat, verisuonet, pleura •  Tietyt keuhkomuutokset assosioituvat De:yihin sidekudostauteihin •  SamanaikaisesD voi olla myös useita muutoksia –  Autoimmuunivasta-‐aineet •  IIM-‐ILD ja anDsyntetaasi-‐syndrooma •  UCTD-‐ILD •  Tosielämän poDlaita SidekudostauDen tavallisimmat keuhkomanifestaaDot CTD UIP NSIP OP Ilma.et Pleura Verisuo-‐ DAH net SSc ± +++ ± _ _ +++ _ RA ++ + + ++ ++ + ± SjS _ + ± ++ + + _ MCTD + ++ + + + ++ _ PM/DM (IIM) ± ++ +++ _ _ + _ SLE _ + + + +++ + ++ Maher TM, Semin Respir Crit Care Med 2014 Sidonnaisuuden laatu
IntersDDaalisten keuhkosairauksien ryhmi:elyä Kaarteenaho & Jar\, Duodecim 127:197-‐207, 2011 1 moking-related interith combined emphyl practice, respiratory
is increasingly diagsmokers on the basis
nd-glass opacities and
veolar lavage (smokphocytosis).
c pulmonary fibrosis
ogeneous with some
nged periods, others
ion, and still others
online supplement). A literature search was performed to identify new publications that pertained to these key questions,
assisted by two librarians experienced in literature searches for
pulmonary diseases. Literature retrieved from Medline searches
between 2000 and 2011 was used to produce this statement.
The committee was divided into subgroups assigned to specific sections of the document. These subgroups reviewed the relevant literature and produced the first draft of their respective
sections. These sections were compiled by the committee chair
and a complete first draft was edited by the writing subcommittee. This document was reviewed and edited by all committee
members before final review by the writing subcommittee.
The revised document was approved by all authors.
d and recognized to
and NSIP).
SUMMARY OF MAJOR REVISIONS OF THE
IIP CLASSIFICATION
lt to classify, often
njury.
In the revision of the IIP classification, the main entities are preserved (Table 1). However, there are several important changes.
First, cryptogenic fibrosing alveolitis is removed, leaving idiopathic
pulmonary
(IPF) as the sole clinical
•  Yleisiä fibrosis
perustaudin IIP term for this diagnosis.
Second,
idiopathic nonspecific interstitial
pneumonia (NSIP) is now
ekstra-‐arDkulaarisia •  UIP/IPF accepted
as a distinct clinical entity with removal of the term “promanifestaaDoita • 
NSIP visional”
(2).kThird,
major IIPs are distinguished from rare IIPs and
•  Suuria uolleisuuden •  DAD/AIP unclassifiable cases. Fourth, rare histologic
patterns of acute fibriaiheu:ajia nous and organizing pneumonia (AFOP)
and interstitial pneumo•  OP/COP •  with
Luokitellaan nykyisin distribution are recognized. Fifth, the
nias
a bronchiolocentric
•  LIP majorsamoin IIPs arekuin grouped into chronic fibrosing (IPF and NSIP; Fig•  DIP bronchiolitis–interstitial
ures 1idiopaa\set and 2), smoking-related (respiratory
•  RB-‐ILD interstitial pneumonia
lung intersDDaaliset disease [RB-ILD] and desquamative
pneumoniat (IIP) [DIP];
Figure 3), and
acute/subacute
IIPs (cryptogenic organizing
•  Luoki:elematon pneumonia [COP] and acute interstitial pneumonia [AIP]; Figure 4
and Table 2). Sixth, a clinical disease behavior classification is proposed. Last, molecular and genetic features are reviewed.
to provide a clinical
ng IIP cases. This is
psy is available and
hy is not diagnostic.
cognized as a specific
less well-defined hiscentric inflammation
ular markers holds
approaches. These
cting prognosis and
rporation of genetic
onize the approach
e IIPs.
the 2002 American
ety (ATS/ERS) class (IIPs) (1). Focus is
escribed clinical entiribing new histologic
and-alone document
ginal 2002 IIP classion (1) defined seven
ed terminology and
l “gold standard” of
amic integrated apMDD). The 2002 IIP
f all clinical publica2011. The new infored in this update.
n by the ATS Docuommittee in collabne supplement). An
sembled. The panel
eases (19 pulmonolts in evidence-based
eral meetings were
ltidisciplinary panel
t, which were vetted
committee believed
e APPENDIX 1 in the
18/04/15 Sidekudostauteihin lii:yvät intersDDaaliset keuhkosairaudet (ILD) IIP:n radiologis-‐histologiset ja kliiniset nimet Histologia, radiologia Kliininen nimi •  UIP (usual intersDDal pneumonia) •  NSIP (nonspecific intersDDal pneumonia) •  OP (organizing pneumonia) •  IPF (idiopathic pulmonary fibrosis) •  NSIP (nonspecific intersDDal pneumonia) •  COP (cryptogenic organizing pneumonia) •  AIP (acute intersDDal pneumonia) •  DAD (diffuse alveolar damage) GENERAL PROGRESS IN IIPS SINCE 2002
Multidisciplinary Approach
The process of achieving a multidisciplinary diagnosis in a patient
with IIP is dynamic, requiring close communication between clinician, radiologist, and when appropriate, pathologist (1). Clinical data (presentation, exposures, smoking status, associated
SidekudostauDen ja ILD-‐tauDen nimet IIP:n uusi luoki:elu (ATS/ERS 2013) TABLE 1. REVISED AMERICAN THORACIC SOCIETY/EUROPEAN
RESPIRATORY SOCIETY CLASSIFICATION OF IDIOPATHIC
INTERSTITIAL PNEUMONIAS: MULTIDISCIPLINARY DIAGNOSES
Major idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis
Idiopathic nonspecific interstitial pneumonia
Respiratory bronchiolitis–interstitial lung disease
Desquamative interstitial pneumonia
Cryptogenic organizing pneumonia
Acute interstitial pneumonia
Rare idiopathic interstitial pneumonias
Idiopathic lymphoid interstitial pneumonia
Idiopathic pleuroparenchymal fibroelastosis
Unclassifiable idiopathic interstitial pneumonias*
CTD ConnecDve Dssue disease CVD Collagen vascular disease RA Rheumatoid arthriDs MCTD Mixed connecDve Dssue disease SLE Systemic lupus erythematosus IIP vs CTD-‐ILD UIP NSIP OP DAD LIP RB-‐ILD/DIP Luoki:elematon IdiopaaBnen inters..aalinen pneumonia IPF NSIP COP AIP LIP RB-‐ILD/DIP Luoki:elematon RA-‐ILD RA-‐UIP RA-‐NSIP SSc Scleroderma * Causes of unclassifiable idiopathic interstitial pneumonia include (1) inadeTravis W et al, AJRCCM 2013 quate clinical, radiologic, or pathologic data and (2) major discordance between
clinical, radiologic, and pathologic findings that may occur in the following situations: (a) previous therapy resulting in substantial alteration of radiologic or histologic findings (e.g., biopsy of desquamative interstitial pneumonia after steroid
therapy, which shows only residual nonspecific interstitial pneumonia [153]);
(b) new entity, or unusual variant of recognized entity, not adequately characterized by the current American Thoracic Society/European Respiratory Society classification (e.g., variant of organizing pneumonia with supervening fibrosis) (79); and
(c) multiple high-resolution computed tomography and/or pathologic patterns that
may be encountered in patients with idiopathic interstitial pneumonia.
Histologinen ja/
tai radiologinen muutos CTD-‐ILD ConnecDve Dssue associated intersDDal lung disease Sidekudostau.in liiDyvä inters..aalinen muutos RA-‐UIP SSc-‐NSIP RA-‐OP SLE-‐DAD SjS-‐LIP (CTD-‐DIP) CTD-‐ILD REVIEWS
PM/DM (IIM) Poly/dermato-‐
myosiDs (Idiopathic inflammatory myopathy) SSc-‐ILD SSc-‐NSIP MCTD-‐ILD MCTD-‐UIP SjS Sjögren syndrome Eri CTD-‐ILD-‐tyyppien yleisyys Table 1 | The relative prevalence of histological patterns in IIP in CTDs
Lung pattern
IIP
Rheumatoid
arthritis
Systemic
sclerosis
SLE
Polymyositis–
dermatomyositis
Sjögren
syndrome
Usual interstitial pneumonia
+++
++
+
+
+
±
Nonspecific interstitial pneumonia
++
++
+++
++
++
++
Desquamative interstitial pneumonia and/or RB-ILD
+
±
±
±
±
±
Organizing pneumonia
++
+
±
±
++
±
Lymphocytic interstitial pneumonia
±
±
±
±
±
++
Pleuroparenchymal fibroelastosis
±
?
?
?
?
?
Diffuse alveolar damage
+
+
±
+
+
±
Abbreviations: ?, prevalence unknown; ±, rare; +, infrequent; ++, frequent, but not clearly in the majority of cases; +++, common, clearly in the majority of
cases; CTD, connective tissue disease; IIP, idiopathic interstitial pneumonia; RB-ILD, respiratory bronchiolitis-associated interstitial lung disease; SLE,
systemic lupus erythematosus.
likewise, primary vasculitis or sarcoidosis commonly
disease is more benign than in IPF, possibly linked to a
cause parenchymal lung disease, but further discussion
low profusion of fibroblastic foci at biopsy.48 A subset
of these matters is beyond the Wells scope of&this
Review. Nat Rev ofRpatients
with2RA-associated
UIP with a poor IPF Denton, heumatol 014 like outcome might be captured by high-resolution CT
Classification of CTD-ILD
(HRCT) appearances that are strongly indicative of UIP,
Lung complications in CTDs
with predominantly basal subpleural honeycomb change.
The only currently used classification of CTD-ILD is
In one study, patients with RA-associated ILD with this
the histological classification of idiopathic interstitial
feature on HRCT scan (n = 20; <25% of the cohort) had
39
pneumonia (IIP). All histological patterns seen in IIP
the same poor outcome as patients with IPF (n = 51),
are also reported to occur in CTD-ILD,40 apart from the
despite less severe pulmonary function impairment at
newly described pattern of pleuroparenchymal elastosis
presentation.33 However, the remaining patients in this
(which has yet to be completely clinically characterized).
study, undoubtedly including a large proportion with
However, the relative prevalence and prognostic imporunderlying UIP but no honeycomb appearance on HRCT,
tance of histological patterns differs greatly between
had a much better outcome.
idiopathic disease and CTD-ILD (Table 1). In idiopathic
Indirect evidence is available that UIP subsets exist
disease, UIP, corresponding to IPF, is the most prevalent
in RA (and possibly in other CTDs) with differences in
pattern.41 IPF has a worse prognosis than other interoutcome. In a study examining biopsy samples, patients
stitial lung disorders, including fibrotic NSIP, the other
with RA-associated UIP (n = 19) had an overall survival
predominantly fibrotic idiopathic disease.41 By contrast,
that was intermediate between CTD-associated NSIP
in CTD-ILD, NSIP is the most prevalent histological
(n = 57) and IPF (n = 203).49 Although difficult to interpattern in ILD associated with SSc, 42 polymyositis–
pret due to the small size of the RA-associated UIP subdermatomyositis43 and primary Sjögren syndrome,44 and
group, survival in this group was clearly bimodal with
is probably more prevalent than UIP in SLE, based on
most deaths occurring within 12 months and survival
our anecdotal clinical experience. Furthermore, in these
similar to CTD-associated NSIP after the first year. When
disorders, whether the histological distinction between
compared with IPF, patients with CTD-associated UIP
UIP and NSIP has prognostic importance is unclear. In
had lower scores for fibroblastic foci and higher scores
SSc-ILD, the most-studied disorder, a histological pattern
for germinal centres and bronchocentric inflammation,
of UIP was not associated with a worse outcome in the
with these differences having prognostic significance.47
42
largest histological series of 78 patients, although this
However, the range of scores was wide with substantial
conclusion has been questioned in one small series, in
overlap with IPF histological scores, suggesting that
which UIP was associated with a very poor outcome.45
inflammation might be pathogenic in some, but not all,
2 18/04/15 REVIEWS
Kuinka yleinen CTD-‐ILD on? Muiden keuhkomuutosten yleisyys Table 2 | The relative prevalence of pulmonary comorbidities, other than interstitial lung disease arising from CTD
Lung complication
Rheumatoid
arthritis
Systemic
sclerosis
SLE
Polymyositis–
dermatomyositis
Sjögren
syndrome
Pulmonary hypertension disproportionate to ILD
±
++
++
±
±
Bronchiectasis
++
±
+
±
+
Obliterative bronchiolitis
+
±
+
±
+
Diffuse alveolar haemorrhage
±
?
+
±
?
Pleural disease
++
±
++
±
±
Respiratory muscle impairment
?
?
±
+
?
Abbreviations: ?, prevalence unknown; ±, rare; +, infrequent; ++, frequent, but not clearly in the majority of cases; +++, common, clearly in the majority of cases;
CTD, connective tissue disease; ILD, interstitial lung disease; SLE, systemic lupus erythematosus.
by HRCT67 and yet in large historical series, chest radioCTD-ILD, a pulmonary function profile of preservation
graphic evidence of pulmonary fibrosis was present in
of lung volumes and a severe reduction in DLCO can also
only 2% of patients.68,69 In a series of >200 patients with
represent the coexistence of ILD and smoking-related
72,73
SSc-ILD, the extent of interstitial
Thus, a clear understanding of this
Wells abnormalities
& Denton, Nwas
at Rev emphysema.
Rheumatol 2014 minor or very mild (involving <10% of the lung) in >40%
frequent pulmonary function profile in the individual
of cases.70
patient with CTD-ILD requires the integration of HRCT
Thus, although HRCT is sensitive, it might be too senand echocardiographic data. The principle of multisitive to serve as a useful screening tool for CTD-ILD in
disciplinary evaluation applies equally to the delineation
unselected patients with CTD. It follows logically that
of symptom severity and pulmonary function impairHRCT should be used by protocol to confirm or exclude
ment when the wide range of other pulmonary comorbidCTD-ILD only in higher risk groups (for example,
ities in CTD-ILD is considered. In Table 2, the spectrum
patients with SSc who are positive for anti-topoisomerase
of chronic pulmonary comorbidities is shown with a
or anti-RNA polymerase III antibodies) or when there is
semiquantitative statement of relative prevalence in indireason to suspect the presence of CTD-ILD, according
vidual CTDs. So-called multicompartment lung disease
to symptoms, clinical examination, chest radiography or
with variable airway, interstitial, pleural and pulmonary
pulmonary function abnormalities. Optimal screening
vascular components is a frequent clinical problem in
protocols for CTD-ILD are currently being developed by
CTD-ILD. In Box 1, the frequently encountered clinical
a group of international experts.
scenarios of multicompartment disease are shown with
characteristic pulmonary function profiles.
Evaluation of disease severity
Given the sensitivity of HRCT, the identification of ILD
Monitoring of ILD
should be followed by a multidisciplinary evaluation
The accurate monitoring of CTD-ILD is centred on serial
of disease severity, with the integration of symptoms,
pulmonary function testing. The FVC is highly reprothe severity of pulmonary function impairment and the
ducible and in the absence of major extrapulmonary
morphological extent of disease on HRCT. Amongst
restriction due to pleural disease or muscle weakness,
these measures, pulmonary function tests provide the
changes in FVC are specific to ILD. Forced spirometric
most precise measurement of disease severity. However,
manoeuvres are occasionally contraindicated or difficult
pulmonary function variables should not be interpreted
to interpret due to glaucoma or clinically significant chest
in isolation due to the confounding effect of the normal
wall discomfort; for this reason, plethysmography is comrange, which is particularly misleading when there is mild
monly performed at presentation (to provide an alternapulmonary function impairment. A reduction in FVC
tive means of monitoring disease progression). Measures
to 70% at presentation, for example, can be indicative
of gas transfer are less reproducible than lung volumes
equally of a relatively minor decrease of 10% or a major
and are confounded by changes in pulmonary vascular
reduction of 50% from premorbid values of 80% and
limitation. On the basis of reproducibility data, serial
120%, respectively. In isolated ILD, typically, a restrictive
pulmonary function trends are compatible with disease
ventilatory defect exists, with reduced FVC and total lung
progression only when a decline in FVC exceeds 10%
capacity, an increased forced expiratory volume 1 to FVC
of the baseline value or a decline in DL CO exceeds
ratio of >0.8, and reduced carbon monoxide diffusing
15% of the baseline value (reflecting the greater varicapacity (DLCO) and lung compliance.
ability of DLCO estimation). Even when these thresholds
are exceeded, clinicians should consider alternative
The problem of pulmonary comorbidities
explanations for changes in pulmonary function tests,
Reductions in DLCO that are disproportionate to lung
including infection, pulmonary embolism, pulmonary
volumes might result from coexistent pulmonary vashypertension and cardiac disease. As with the evalucular limitation: an elevation in the FVC:DLCO ratio
ation of severity at presentation, combined clinical
was found to be predictive of underlying pulmonary
experience indicates that the evaluation of change is
hypertension in the SSc DETECT study.71 However, in
a multidisciplinary exercise requiring the integration
Ovatko CTD-‐ILD:t yleistyneet? •  Perussairauden ennuste parantunut –  Enemmän poDlaita, joilla myös keuhkomanifestaaDo –  Onko todellistakin lisääntymistä? •  Yksi:äisinä harvinaisia –  Vain suurissa keskuksissa runsaasD poDlaita •  Tutkimuksiin vaikeaa saada rii:ävää poDlasmäärää ilman monikeskustutkimuksia •  Viime vuosiin saakka luoki:elu puu:unut ja nimikkeistöä käyte:y kirjavasD 734 | DECEMBER 2014 | VOLUME 10
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© 2014 Macmillan Publishers Limited. All rights reserved
Moua et al. Respiratory Research 2014, 15:154
http://respiratory-research.com/content/15/1/154
RESEARCH
Open Access
Predictors of diagnosis and survival in idiopathic
pulmonary fibrosis and connective tissue
disease-related usual interstitial pneumonia
Teng Moua*, Ana C Zamora Martinez, Misbah Baqir, Robert Vassallo, Andrew H Limper and Jay H Ryu
Abstract
-‐ Biopsoidut UIP-‐fibroosit analysoiDin uudelleen -‐ 625 tapausta, joista 89 CTD-‐UIP -‐ Mayo Clinicissa tutkitut poDlaat 1995-‐2010 Results: Six hundred and twenty five patients were included in the study of which 89 had diagnosed CTD-UIP
representing
7 disease entities. Survival was better among those with
CTD-UIP except in UIP associated
with rheumatoid
-‐ Kliinis-‐radiologis-‐histologinen re-‐analyysi, elinaika arthritis, which had similar presenting features and survival to IPF. Predictors of underlying CTD included female gender,
Background: Although usual interstitial pneumonia (UIP) appears to portend better survival when associated with
connective tissue disease (CTD-UIP), little is known about the presenting clinical, radiologic, and pathologic features
that differentiate pathologically confirmed UIP with CTD from idiopathic pulmonary fibrosis (IPF). In patients with
atypical radiologic and clinical features, what specific findings predict underlying IPF vs. CTD-UIP diagnosis and their
respective long term survival?
Methods: A large retrospective cohort analysis was done of consecutive patients seen from 1995 through 2010
with biopsy confirmed UIP completed or reviewed at our institution. CTD-UIP was defined by independent rheumatology
consultation with exclusion of all other secondary causes of lung fibrosis. Primary clinical data was collected and
compared for IPF and CTD-UIP along with logistic regression performed for predictors of disease likelihood and Cox
proportional hazards analysis for predictors of survival.
younger age, positive autoimmune serology, and inconsistent presenting radiologic findings. Only age and forced vital
capacity corrected for a priori covariates were predictive of survival in CTD-UIP.
Conclusions: UIP pathology occurs frequently
Moya among
et al, Rpatients
espir with
Res atypically
2014 presenting clinical and radiologic features,
and may represent IPF or CTD-UIP with improved prognosis if underlying CTD is diagnosed. Presenting radiologic and
pathologic features alone are not predictive of underlying secondary cause or survival between the two groups.
Keywords: Idiopathic pulmonary fibrosis, Usual interstitial pneumonia, Connective-tissue disease interstitial lung disease
Introduction
Usual interstitial pneumonia (UIP) is characterized by
temporally heterogenous parenchymal fibrosis with architectural distortion, interstitial thickening, fibroblast foci,
and honeycombing [1]. Although a defining pathologic
finding in idiopathic pulmonary fibrosis (IPF), it has been
found in other chronic fibrotic lung disease such as the
connective tissue-disease associated interstitial lung disease (CTD-ILD) [2,3], chronic hypersensitivity pneumonitis (HP) [4], sarcoidosis [5], and advanced asbestosis [6].
* Correspondence: [email protected]
Division of Pulmonary and Critical Care Medicine, Mayo Clinic, 200 First St.
SW, Rochester, MN 55901, USA
Current classification of the idiopathic interstitial pneumonias (IIP) allows not only pathological distinction of fibrotic disease, but implied characteristic clinical and
prognostic significance [7]. For example, it is well known
that UIP has worse prognosis than non-specific interstitial
pneumonia (NSIP), the two most commonly presenting
pathologies [8,9]. Both again may be idiopathic or associated with known etiologies, which has clinical significance
in terms of survival and response to therapy [10]. Prior
studies have suggested secondary UIP such as that seen in
certain connective-tissue diseases (CTD-UIP) may have
better prognosis and survival than IPF [2,10]. Other studies have been conflicting regarding better survival in difficult to diagnose CTD or all CTD-ILD [11,12]. Specific
© 2014 Moua et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
•  Radiologisissa tutkimuksissa prevalenssi 33-‐57% –  RA-‐ILD 10%, SSc-‐ILD 20-‐25%, PM/DM 20-‐78% •  Muitakin syitä ILD:lle voi olla –  Lääkkeet –  InfekDot –  Muut ILD:n aiheu:ajat (allerginen alveolii\) –  MaligniteeDt Onko ILD:n tyypillä mitään merkitystä poDlaan hoidon kannalta? •  Osassa ei selkeää ennusteellista eroa olipa kyseessä NSIP tai UIP (esim. SSc) •  RA-‐UIP:n ennuste huonompi kuin RA-‐NSIP:n Moua et al. Respiratory Research 2014, 15:154
Page 6 of 9
Table 6 Subgroup analysis of clinical predictors of death in IPF
Univariable HR (95% CI)
P value
Multivariable, HR (95% CI)
P value
Age at biopsy
1.03 (1.02-1.04)
<0.0001
1.03 (1.01-1.04)
0.0002
Gender (male risk)
1.48 (1.15-1.93)
0.003
1.52 (1.15-2.02)
0.003
Smoking Hx
1.13 (0.88-1.46)
0.34
1.04 (0.77-1.37)
0.79
Duration of symptoms prior to biopsy
0.99 (0.99-1.00)
0.51
0.99 (0.99-1.00)
Autoimmune serology
0.89 (0.65-1.19)
0.43
0.95 (0.69-1.27)
0.72
GERD
1.05 (0.82-1.35)
0.66
1.02 (0.80-1.31)
0.87
–  Sekamuotojen esiintyminen vaikeu:aa usein diagnosDikkaa •  OP paranee yleensä steroidilla, joten tärkeää ero:aa muista 0.40
FEV1, % pred
0.98 (0.98-0.99)
0.0004
0.99 (0.97-1.02)
0.53
FVC, % pred
0.98 (0.98-0.99)
0.0001
0.99 (0.98-0.99)
0.03
DLCO, % pred
0.99 (0.98-0.99)
0.0001
0.99 (0.98-0.99)
0.02
TLC,
% et
pred
Moua
al. Respiratory Research 2014, 15:154 0.98 (0.98-0.99)
0.0012
1.00 (0.99-1.02)
Page0.65
7 of 9
Probable UIP
0.76 (0.56-1.04)
0.09
0.78 (0.57-1.08)
0.13
0.91 (0.65-1.27)
0.56
0.96 (0.69-1.35)
0.82
Initial HRCT pattern
Probable NSIP or inconsistent with UIP
0.98
(0.67-1.35)
0.82
with CTD-ILD
have 0.96
better
prognosis than IPF, confirmatory biopsy appears unnecessary to justify treatment as
response to therapy appears better among all pathologic
subclasses. Even so, most patients undergoing biopsy do
so as a result of clinical equipoise in defining early or
Our main findings support better survival in patients atypical radiologic findings increased the risk of underatypical lung fibrosis radiologically with possible or inwith CTD-UIP compared to IPF, despite the presence of lying CTD diagnosis. Finally, despite CTD-UIP overall
consistent IPF features and no clearly defined CTD or
similar initial radiologic and PFT findings. Frequency of having better survival, RA-UIP had similar survival to IPF
secondary cause. In our cohort, presenting radiologic
positive autoimmune serologies was higher in CTD than with worse survival compared to other CTD-UIP in our
and PFT findings were no different in those with susIPF, though still occurred in 29% of tested IPF patients. cohort.
pected IPF and eventual CTD. Prior studies support the
UIP represents a commonly found interstitial pneumoClinical predictors for survival in CTD-UIP were age
relatively high frequency of positive autoimmune seroland FVC, compared to IPF which included additionally nia pattern whose defining features belie a heterogenously
ogies in IPF further confounding diagnostic evaluation
gender and DLCO. Atypical or additional pathologic progressive fibrotic process characterized by fibroblast
in early disease [27,28]. Our study confirms that even
findings such as organizing pneumonia, lymphoid aggre- foci and honeycombing. Characteristic pathologic findings
among
patients with UIP, female gender, younger age,
Figureor
3 Survival
in RA-UIP
vs. all otherwere
CTD-UIP;
(P = frequently
0.0163
may be diagnosed variably among evaluating pathologists,
gates,
chronic
inflammation
more
atypical CT findings, and positive autoimmune serology
Log Rank).
seen in CTD-UIP, but did not predict survival ((HR 0.83 though little is known about the prognostic features of
were still predictive of subsequent CTD. On the other
findings such as organizing pneumonia or lymph(0.59-1.14), P =0.27)in either cohort. In patientsPage
with4 of atypical
Moua et al. Respiratory Research 2014, 15:154
9hand UIP
pathology with inconsistent UIP CT pattern
pathologically confirmed UIP, younger age, female gen- oid hyperplasia in the setting of histopathologic UIP pathttp://respiratory-research.com/content/15/1/154
have suggested increased lymphoid aggregates [22] or occurs relatively frequently in IPF with similar survival
der, presence of positive autoimmune serology, and tern other than their association with CTD. Prior studies
hyperplasia [23] associated with underlying CTD, along to radiologically consistent disease. A recent study prowith decreased number of fibroblast foci [23,24]. The spe- poses perhaps increased frequency of acute exacerbation
cific features of pathologic findings in UIP have also been in IPF compared to CTD-ILD as a reason for this differpredictive of survival in IPF, in particular the frequency of ence in survival, as deterioration of PFT findings over
Table 2 Specific connective-tissue disease distributions
Given
the current UIP cohort was predominantly
fibroblast foci [25]. The study by Park et al. compared time appeared similar between the two groups [29].
representative
of IPFamong
patients,
CTD subtype (N = 89)
N (%)
pathologic features
differingsubgroup
ILD groupsanalysis
and noted was In our pathologically defined cohort, UIP associated
performed
onsurvival
CTD-UIP
for clinicalwith RA appears to have similar clinical presentation
improved
amongand
thoseIPF
withseparately
CTD-UIP compared
RA
24 (27)
to IPF of
[2].survival
Others have
found
no difference
survival
predictors
(Tables
5 and
6). Whileinage,
gender,and survival to IPF. In particular, RA patients were older
SLE
2 (2)
those with
IPF and
CTD-ILD
[12] or
withpre-with more male predominance compared to other CTDFVC,among
and DLCO
adjusted
forgeneral
a priori
covariates
were
Scleroderma (systemic sclerosis)
13 (15)
autoimmune
dominant
lung
fibrosis
[26]
not
fitting
dictive of survival in IPF patients, only age and FVC CTD
adjustedILD, and did worse despite similar presenting PFT and
criteria. Little is known about the pathologic mechanisms CT patterns among all CTD patients. A recent study
MCTD
2 (2)
were that
predictive
in CTD-UIP. Initial univariable analysis suglead to a common final pathway of UIP pattern yet dif- suggested better survival in comparison to case-matched
DM/PM
13 (15)
gestedferent
smoking
andand
FVC
were An
predictive
rates ofhistory,
disease FEV1,
progression
survival.
under- inIPF controls who received treatment [30]. While an
CTD standing
but wereofno
after
correction
for age and gender.NSIP CT pattern and histology are most common in
Sjogren’s syndrome
5 (5)
thelonger
perhaps
presumptive
inflammatory-based
mechanisms
that lead being
to UIP predictive
in CTD-ILDof
compared
to the CTD-ILD, recent work suggests UIP CT features may
Despite
female
gender
CTD diagnosis,
Undifferentiated CTD
30 (34)
relatively
unknown
mechanisms
in
IPF
may
be
helpful
in occur more frequently than previously noted [31] and is
gender was not predictive of survivalPage
among
et al. Respiratory
Research
2014,
15:154
7 of 9 CTD patients
CTDMoua
= connective
tissue disease,
DM/PM
= dermatomyositis/polymyositis,
MCTD =
with
underlying
pathology
[20].
future IPF treatment approaches.
Figure consistent
2 Survival in IPF
stratified
by 5 yearUIP
periods
(1995–2010);
mixed
connective tissue disease, RA = rheumatoid arthritis, SLE = systemic
whiledeciphering
in IPF male
gender portended worse survival in bothhighly
radiologic
features of advanced disease appear preOur
study
highlights
several
insights
in
comparing
bi- Such
(P = 0.03
Log Rank).
Figure
1
Survival
in
IPF
vs.
CTD-UIP;
(P
=
0.0005
Log-rank).
lupus erythematosus.
univariable
and multivariable
opsy confirmed
UIP in IPFanalysis.
and CTD. As most patients dictive of survival similar to IPF, though in our cohort,
Figure 1 compares transplant-free survival from biopsy tosimilar presenting radiologic patterns were seen between
date of have
deathbetter
fromprognosis
any cause
mortality) betweenRA-UIP patients and other CTD-UIP (predominantly
with CTD-ILD
than(all-cause
IPF, confirmatory biopsy
appears
unnecessary
to justify
treatment
as was notablyatypical or probable UIP CT findings). As UIP pathology
organizing pneumonia were predominant atypical
IPF and
CTD-UIP.
Survival
among
CTD-UIP
response
to therapy
appears
among
all pathologic
pathologic findings seen in IPF. The majority of CTD
better
(median
79.4 better
vs. 47.7
months,
Log rank P = 0.0005). appears to bode worse survival, confirmatory biopsy in
this subset of CTD-ILD particularly with atypical CT
subclasses. Even so, most patients undergoing biopsy do
diagnoses associated with UIP were UCTD (34%) and
Figure 2 depicts survival in biopsy confirmed IPF pa-may not be unreasonable. Underlying mechanisms as to
so as a result of clinical equipoise in defining early or
RA (27%).
tients stratified by 5 year intervals (a) 1995–1999, b)why RA-UIP may do poorly is currently unknown and
atypical lung fibrosis radiologically with possible or inAmong patients with pathologically confirmed UIP,
2000–2004,
c) and
2005–2010).
appeared
greatest inthe subject of ongoing study.
consistent
IPF features
no clearly Survival
defined CTD
or
younger age, female gender, positive autoimmune serpatients
from presenting
2005–2010radiologic
(median 58.3 (42.3- Survival in IPF is known to be variable and may be afsecondary
cause. biopsied
In our cohort,
and PFT
findings
were and
no different
thosebiopsied
with sus-between 2000–fected by multiple factors including disease severity at
ology, and non-UIP consistent radiologic patterns un71.5)
months)
least in inthose
the time of presentation and access to tertiary or expert
pected 2004
IPF and
eventual43.7
CTD.
Prior studies
support
adjusted by logistic regression were predictive of CTD
(median
(34.2-48.9);
(Log
rank the
P = 0.03)).
care with earlier assessment [32]. Whether earlier diagrelatively As
high CTD-UIP
frequency ofrepresents
positive autoimmune
seroldiagnosis (Table 3). After adjusting for a priori covariates
a heterogenous
group ofnosis affects outcome remains tentative, as most patients
ogies in IPF further confounding diagnostic evaluation
(age, gender, smoking history, percent predicted FVC and
underlying
diseases,
and
there
have
been
recent
reports
with consistent UIP pattern on CT likely represent more
in early disease [27,28]. Our study confirms that even
DLCO), age, positive autoimmune serology, and inconsistadvanced disease with worse survival. We note survival
of
rheumatoid
related
lung
fibrosis
representing
more
agamong patients with UIP, female gender, younger age,
Figure 3 Survival in RA-UIP vs. all other CTD-UIP; (P = 0.0163
by 5 year intervals in our cohort suggest recently biopent Log
CTRank).
findings remained predictive of underlying CTD.atypicalgressive
disease
[20,21],
subgroup
analysis
CT findings,
positive
autoimmune
serology
Figure
4 and
Survival
in RA-UIP
vs.
IPF; (P =0.76
Log Rank). of survival
were still
predictive
of subsequent
CTD.
On the other
Table 4 represents univariable and multivariable adamong
RA-UIP
vs all other
CTD-UIP
and IPF was per-sied patients had better survival than those biopsied a
hand UIP
pathology
with inconsistent
UIP3CT
justed predictors of survival among all UIP patients. Iniformed
and depicted
in Figures
andpattern
4. RA-UIP appears
occurs to
relatively
frequently
in IPF
with similar
survival
suggested increased
[22] or (HR
tialhave
unadjusted
analysis lymphoid
suggestedaggregates
both smoking
have worse
survival
compared
to the
other CTDs (mehyperplasia [23] associated with underlying CTD, along to radiologically consistent disease. A recent study pro1.32 [1.04-1.69], P =0.023) and positive autoimmune ser- dian 38 vs. 103.9 months, Log rank P =0.0163) with simiwith decreased number of fibroblast foci [23,24]. The spe- poses perhaps increased frequency of acute exacerbation
ology
of findings
survivalin (HR
0.72,also[0.55-0.93],
lar survival
to IPF (Log
rank Pfor=0.76).
RA-UIP patients
to CTD-ILD
as a reason
this differcific were
featurespredictive
of pathologic
UIP have
been in IPF compared
P =predictive
0.02), though
were
noin longer
after
olderas and
predominantly
ence inwere
survival,
deterioration
of PFT male,
findingsthough
over with similar
of survival
in IPF,
particularpredictive
the frequency
of corbetween
two groups
[29].
fibroblast
The FVC,
study by
et al. compared time appeared
rection
for foci
age,[25].
gender,
andPark
DLCO.
baselinesimilar
CT and
PFTthefindings
compared
to other CTDIn our pathologically defined cohort, UIP associated
pathologic features among differing ILD groups and noted
improved survival among those with CTD-UIP compared with RA appears to have similar clinical presentation
to IPF [2]. Others have found no difference in survival and survival to IPF. In particular, RA patients were older
Table
3 Clinical
predictors
of IPF CTD-ILD
vs. CTD-UIP
among
those with
IPF and general
[12] diagnosis
or with with more male predominance compared to other CTDUnivariable
OR (95%
CI) and did Pworse
valuedespite similar
Multivariable
OR (95%
CI)
P value
ILD,
presenting
PFT and
autoimmune dominant lung fibrosis [26] not
fitting CTD
CT patterns among
patients.
A recent study
Little is known about the pathologic
Agecriteria.
at biopsy
1.06mechanisms
(1.03-1.09)
<0.0001all CTD 1.06
(1.02-1.08)
0.0012
that lead to a common final pathway of UIP pattern yet dif- suggested better survival in comparison to case-matched
Gender (male risk)
2.52 (1.44-4.49)
1.87 (0.95-3.7)
0.07
who received treatment
[30]. While an
ferent rates of disease progression and survival.
An under- IPF controls <0.0001
Atypical findings on biopsy
0.99 (0.70-1.39)
% pred = percent predicted.
Complete case analysis (list-wise deletion).
Multivariable adjusting for age, gender, smoking hx, FVC, and DLCO.
Moya et al, Respir Res 2014 Duration
of symptoms
prior topresumptive
biopsy
1.01 (0.99-1.02)
standing
of the perhaps
inflammatory-based
mechanisms
that lead
to UIP in CTD-ILD compared
to the
Positive
autoimmune
serology
0.08 (0.04-0.15)
relatively unknown mechanisms in IPF may be helpful in
FEVdeciphering
1.01 (0.99-1.03)
1, % pred
future IPF treatment approaches.
Our
study highlights several insights in1.00
comparing
FVC, %
pred
(0.98-1.02)biopsy% confirmed
UIP in IPF and CTD. As1.01
most
patients
DLCO,
pred
(0.99-1.03)
TLC, % pred
0.99 (0.98-1.02)
Initial HRCT pattern
Probable UIP
1.00 (0.42-2.27)
Probable NSIP or inconsistent with UIP
0.40 (0.17-0.86)
Atypical findings on biopsy
0.36 (0.19-0.69)
% pred = percent predicted.
Complete case analysis.
0.27 and histology
1.01are
(0.99-1.03)
NSIP CT pattern
most common in
CTD-ILD, recent
work suggests
CT features may
<0.0001
0.09UIP
(0.04-0.17)
occur more frequently than previously noted [31] and is
0.17with underlying
1.03 (0.97-1.10)
highly consistent
UIP pathology [20].
Such radiologic0.61
features of advanced
disease appear pre0.99 (0.92-1.07)
dictive of survival
in our cohort,
0.31 similar to IPF,
1.02though
(0.99-1.05)
similar presenting radiologic patterns were seen between
0.74and other CTD-UIP
0.98 (0.94-1.03)
RA-UIP patients
(predominantly
atypical or probable UIP CT findings). As UIP pathology
appears to bode worse survival, confirmatory biopsy in
0.98
0.79 (0.29-2.05)
this subset of CTD-ILD particularly with atypical CT
0.02
0.31 (0.11-0.76)
may not be unreasonable.
Underlying
mechanisms as to
why RA-UIP may
do poorly is0.56
currently
unknown and
0.003
(0.27-1.22)
the subject of ongoing study.
Survival in IPF is known to be variable and may be affected by multiple factors including disease severity at
the time of presentation and access to tertiary or expert
care with earlier assessment [32]. Whether earlier diagnosis affects outcome remains tentative, as most patients
with consistent UIP pattern on CT likely represent more
advanced disease with worse survival. We note survival
0.19
<0.0001
0.27
0.73
0.15
0.36
0.64
0.01
0.56
3 18/04/15 Downloaded from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com
Interstitial lung disease
Kliinis-‐radiologiset ennustetekijät Figure 4 Kaplan-Meier survival curve
for connective tissue disease related
fibrotic lung disease (CTD-FLD)
-‐ Suurinta osa CTD-‐ILD:stä ei biopsoida patients based upon radiological
presentation (n–168).
-‐ AnalysoiDin kliinis-‐radiologisia ennustetekijöitä -‐ 168 CTD-‐ILD (51 biopsoitua) -‐ HRCT-‐luoki:elu: UIP, NSIP, määri:ämätön -‐ HRCT:n Downloaded
trakDonbronkiektasiat ja hunajakennot sekä DLCO from http://thorax.bmj.com/ on February 21, 2015 - Published by group.bmj.com
assosioituvat korkeaan kuolleisuuteen Interstitial lung disease
Table 3 Observers’ HRCT scores for patients with CTD-FLD assigned a radiological diagnosis of fibrotic NSIP, UIP or indeterminate (n=168)
Radiological diagnosis=fibrotic
NSIP (n=144)
Radiological diagnosis=UIP (n=15) Radiological diagnosis=indeterminate (n=9) p Value
Total interstitial disease extent
Ground-glass
Reticulation
Honeycombing
Traction bronchiectasis
Consolidation
Honeycombing absent/present
Traction bronchiectasis absent/present
27.3±19.7
10.0±13.2
16.7±12.7
0.2±0.2
3.7±3.2
1.4±4.8
141/3
42/102
37.7±18.1
3.7±6.9
25.7±14.6
7.5±2.8
9.4±8.7
1.6±1.3
0/15
0/15
31.0±18.4
9.4±14.9
18.6±11.4
0.1±0.28
4.9±3.1
1.1±1.6
6/3
1/8
CTD-FLD, connective tissue disease related fibrotic lung disease; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia.
Walsh et al, Thorax 2013 bronchiectasis when compared with patients assigned a diagnosis of fibrotic NSIP or deemed to have an indeterminate HRCT
pattern of disease (table 3). Honeycombing was identified in
21 cases (RA=10, SScl=3, MCTD=4, PM=0, SLE=3,
Sjögren’s disease=1) and was the least frequent pattern identified overall. Traction bronchiectasis was identified in 125 cases
(RA=33, SScl=22, MCTD=27, PM=26, SLE=8, Sjögren’s
disease=9). All 15 cases assigned a radiological diagnosis of UIP
had honeycombing and traction bronchiectasis on HRCT.
On univariable analysis, ground glass opacification was the only
parenchymal pattern, which was not associated with increased
mortality (table 4). Radiological diagnosis was strongly associated
with mortality (table 4, figure 4). On multivariable analysis,
increasing severity of traction bronchiectasis, increasing extent of
honeycombing and reduction in DLco independently associated
with increased mortality (table 5). These results remained independently associated with increased mortality on subgroup analysis
in patients with a radiological diagnosis of NSIP (and those with a
radiological diagnosis of UIP (see online supplementary appendix,
table 1)). On the basis of these results, the continuous traction
bronchiectasis scores and honeycombing scores for each patient
were converted to a simple binary absence/presence score.
Interobserver agreement for the absence/presence of traction bronchiectasis was good (κw=0.69) and for the absence/presence of
honeycombing was moderate (κw=0.50). A multivariable analysis,
substituting the continuous traction bronchiectasis and honeycombing scores for these binary scores again demonstrated that
the binary scores and DLco were the only variables independently
associated with increased mortality (traction bronchiectasis absent/
present=HR 4.00, p=0.001, 95% CI 1.19 to 13.38,
Akuu\ HR
95% CI
Total interstitial disease extent
Ground-glass opacification
Fine reticulation
Coarse reticulation
Honeycombing
Traction bronchiectasis
Radiological diagnosis
FVC %predicted
FEV1%predicted
DLco %predicted
1.02
0.99
1.04
1.06
1.13
1.10
4.37
0.99
0.98
0.96
1.01
0.97
1.01
1.01
1.07
1.05
2.20
0.98
0.42
0.94
to
to
to
to
to
to
to
to
to
to
p Value
1.04
1.02
1.06
1.11
1.19
1.15
8.62
1.01
1.02
0.99
Krooninen progressiivinen sis’ score, are associated with increasing mortality.4
<0.001
0.753
0.001
0.014
<0.001
<0.001
<0.001
0.394
0.511
<0.001
CTD-FLD, connective tissue disease related fibrotic lung disease.
More
of traction bronchiectasis also predicts increased mortality in
Patients with biopsy proven UIP (n=25) had more severe
fibrotic IIP.3 5 Although it is generally accepted that the predomdisease in terms of extent of disease as well as extent of reticulahistopathological patterns seen in CTD-FLD are UIP and
tion, honeycombing and severity of traction inant
bronchiectasis
NSIP, for a number of reasons it is unclear if CT data
when compared with those with biopsy proven fibrotic
fibrotic NSIP
derived
from patients with idiopathic fibrotic lung disease can
(n=26) (table 6). Patients for whom a histopathological
diagnosis was available were divided into four categories be
based
upon a applied to CTD-FLD. First, CTD-FLD does not
directly
combination of the assigned radiological and established
histoexactly replicate idiopathic fibrotic lung disease on histopathopathological diagnoses; (1) radiological and histopathological
logical analysis. Fewer fibroblastic foci, prominent lymphoid gerdiagnosis of UIP (n=13—concordant UIP), (2) radiological diagminal centres, lymphoplasmacytic infiltrates and distinctive
ILD ilmenee kun CTD jatkunut jo pitkään myofibroblast morphology are distinguishing features of
Walsh et al, Thorax 2013 CTD-FLD.10 11 28 29 Second and most importantly, CTD-FLD
appears to have a more favourable prognosis than fibrotic
IIP.12 15 30 Despite these differences, our study has shown that
traction bronchiectasis and honeycombing are also important
predictors of mortality in CTD-FLD.
The prognostic strength of traction bronchiectasis in our
study is an important finding. Honeycombing is a cardinal
fibrotic pattern on CT and most studies have focused the prognostic impact of this pattern4 26 rather than traction bronchiectasis. However, the interobserver agreement for the
identification of honeycombing is surprisingly poor,31 32 best
highlighted by Lynch et al who reported observer agreement
levels for honeycombing among expert thoracic radiologists in a
cohort of 315 patients with IPF as scarcely acceptable for clinical practice (weight κ coefficient of agreement no greater than
0.31).4 More recently, Watadani et al specifically quantified
interobserver agreement for the presence of honeycombing
among a large group of thoracic and non-thoracic radiologists as
moderate (weighted κ coefficient of agreement=0.40–0.58).33
Disagreement was in most cases due to the presence of subpleural pathology mimicking honeycombing such as traction
bronchiolectasis, paraseptal emphysema and subpleural cysts.
These findings raise doubts as to whether honeycombing can
always be relied upon as a prognostic CT pattern in routine clinical practice. The results of our study support those of others
confined to IIPs3 5 9 and suggest that traction bronchiectasis
may be a superior alternative CT sign for prognostication purposes in the CTD-FLDs
Clinical applicability is an important consideration in a study
of this kind. The continuous traction bronchiectasis and honeycombing scores are not easily applied to clinical practice and
this led to the testing of a simplified binary absent/present score
of these two patterns. Our study shows that simply the presence
of traction bronchiectasis was a significantly more powerful
prognostic index than the presence of honeycombing.
Importantly, determining the absence or presence of traction
bronchiectasis had a higher level of observer agreement than
ILD CTD:n ensimmäisenä manifestaaDona 5 7 26
Subgroup analysis in patients with surgical lung biopsy
data
recently,
two studies have demonstrated that increasing severity
(n=51)
•  Kun tutkitaan IIP-‐poDlasta on syytä muistaa e:ä kyseessä voi olla myös CTD-‐ILD:n ensimmäinen manifestaaDo •  ErityisesD tämä kanna:aa muistaa NSIP ja OP-‐
poDlaiden kohdalla, mu:a myös UIP/IPF-‐
epäilyissä nosis of fibrotic NSIP or indeterminate, with histopathological
diagnosis of UIP (n=12—discordant UIP) (3) radiological diagnosis of UIP or indeterminate, with histopathological diagnosis
of NSIP (n=9, discordant NSIP) and (4) radiological and histopathological diagnosis of fibrotic NSIP (n=17, Table
concordant
5 Multivariable HRs for mortality according to HRCT and
NSIP) This radiological-histopathological distinction
wasindices in CTD-FLD (n=168)
pulmonary
strongly associated with increased mortality (HR 2.65,
Variable UIP
HR
95% CI
p Value
p<0.001, 95% CI 1.67 to 4.99). Patients with concordant
had the highest mortality, while concordant NSIP was associated
Honeycombing
1.08
1.04 to 1.17
0.022
with the lowest mortality. Discordant NSIP and discordant
UIP
Traction
bronchiectasis
1.10
1.02 to 1.13
0.001
were associated with lower mortality than those with
concord%predicted
0.96
0.94 to 0.98
0.001
ant UIP, but greater mortality than those with DLco
concordant
fibrotic NSIP (figure 5). Multivariable analysis demonstrated
CTD-FLD, connective tissue disease related fibrotic lung disease.
that severity of traction bronchiectasis (HR 1.07, p=0.001,
95% CI 1.01 to 1.13) and extent of honeycombing (HR 1.21,
p=0.031, 95% CI 1.08 to 1.35) were the only220
independent
variables independently associated with increased mortality in
patients who underwent lung biopsy.
Subkliininen Table 4 Crude HRs for mortality according to HRCT and
pulmonary indices in CTD-FLD (n=168)
Variable
important HRCT predictors of mortality and traction bronchiectasis is the more powerful of the two. Second, the clinical utility
thisCIfinding
honeycombing absent/present=HR 2.87, p=0.022,of
95%
1.53 is enhanced by the superior level of interobserver
to 5.43, DLco=HR 0.97, p=0.013. 95% CI 0.95 agreement
to 0.99). Theassociated with an absent/present determination for
traction
when compared with the same determinprognostic strength of these binary scores was preserved
on bronchiectasis
subgroup analysis of the entire cohort with each CTD
ationsubgroup
for honeycombing. Lastly, our results suggest that in
removed in turn, (see online supplementary appendix,
tables 2patients with a histopathological diagnosis of UIP, but
CTD-FLD,
and 3). Two further analyses were performed: first,
all analyses
discordant
radiological features, have a more favourable prognowere repeated after censoring of non-respiratory sis
deaths
(n=4).
when
compared with those with radiological and histopathoSecond, as vasculopathy with PAH may occur in patients with SScl
logical UIP.
(SScl-PAH) or SLE (SLE-PAH), which already confers a particuAlthough
larly poor prognosis, a second analysis of all variables was per-there is a paucity of data on HRCT patterns, which
prognosis in CTD-FLD, several studies have identified
formed, censoring patients with SScl-PAH (n=10)predict
or SLE-PAH
prognostic
(SLE-PAH=0). These analyses resulted in no appreciable
changesHRCT patterns in the fibrotic (non-CTD related)
26 27
in significance of predictors or magnitude of their impact
IIPs.4 5on7 surMany of these have demonstrated that increasing
vival time estimates.
reticulation, honeycombing or a combination of both as a ‘fibro-
CTD-‐ILD:n monet muodot ILD on CTD:n ensimmäinen manifestaaDo 0.032
0.681
<0.012
<0.001
<0.001
0.843
Fulminan\, henkeä uhkaava Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843
DISCUSSION
Our study has demonstrated three novel findings in patients with
CTD-FLD. First, honeycombing and traction bronchiectasis are
Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843
219
Respiratory Medicine (2009) 103, 1152e1158
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Mitä oireita ja löydöksiä pitäisi tarkistaa ILD-‐epäilyjen kohdalla? Ascertainment of collagen vascular disease in
patients presenting with interstitial lung disease
Shikha Mittoo a, Allan C. Gelber b, Lisa Christopher-Stine b,
Maureen R. Horton c, Noah Lechtzin c, Sonye K. Danoff c,*
Collagen vascular disease in ILD
a
Division of Rheumatology, University of Manitoba, Winnipeg Rheumatic
Unit,
RR149indicate
Rehabilitation
Hospital,
and an Disease
earlier
study
that
CVD-UIP
Table 5 Underlying
rheumatologic
diagnoses
of CVD-ILD
Health Sciences
Centre, 800 Sherbrook
Street,
Winnipeg, MB, R3A 1M4, Canada
27,28
b
survival5200
in comparison
of Rheumatology, Johns Hopkins University School of Medicine,
Eastern Avenue,with
MasonIPF-UIP.
F. Lord Center
subjects by ACRDivision
criteria.
Tower, Suite 4100, Baltimore, MD 21224, USA
1157
has improved
Our findings need be interpreted in light of the retro-
-‐ 114 peräkkäistä ILD:tä tutki\in -‐ Oliko myös CTD? c
Division ofdisease
Pulmonary and Established
Critical Care Medicine,
University School of Medicine, 1830 E. Monument St,
Diagnosis of rheumatic
New Johns Hopkins
spective
study design. First, the decision to obtain
5th Floor, Baltimore, MD 21205, USA
CVD-ILD,
CVD-ILD,
a particular serologic parameter and the manner in which
n Z 17a
n Z 17a
the history and examination were conducted may have
Received 3 October 2008; accepted 16 February 2009
been influenced by the individual patient’s symptoms and
Systemic lupusAvailable online 21 March 2009
3 (18)
3 (18)
the physician’s practice pattern. Future study in this area
erythematosus, n (%)
ought to incorporate a predetermined protocol for ascerIdiopathic inflammatory
5 (29)
10 (59)
tainment of exposures and outcomes applied uniformly to
Summary
myositis, n (%)KEYWORDS
Introduction: Previous studies of all
interstitial
lung disease
(ILD) suggest
thatwere
prognosis
therAntinuclear antibody;
patients.
Second,
there
39andpatients
among this
Sjogren’s syndrome,
n
(%)
1
(6)
0
(0)
apeutic response are influenced by the presence of underlying collagen vascular disease (CVD).
Pulmonary fibrosis;
cohort
ofis ILD
referrals
forsought
whom no autoantiSystemic sclerosis,
n (%) lung disease; 1 (6)Yet, what proportion
1 (6) of patients consecutive
presenting with ILD
have CVD
largely
unknown. We
Interstitial
frequency of a bodies
new CVD diagnosis
an ILD referral
population.of this quarter of the
were intested.
Exclusion
vascular
UndifferentiatedCollagen
connective
0 (0)to determine the
2 (12)
Materials/patients and methods:referent
We retrospectively
studied
114
consecutive
patients
evaludisease
population due to missing data likely overtissue disease, n (%)
ated at the Johns Hopkins Interstitial Lung Disease Clinic for the development of CVD.
estimated
the prevalence
ofwith
positive
and
Rheumatoid arthritis, n (%)
5 (29)
(0)
Results: In this0retrospective
cohort,
nearly one-third
of the 114 patients
confirmedautoantibodies
ILD
satisfied published
Seventeen
(15%) patients
were diagnosed
thediagnosis.
frequency
of new
CVD diagnosis
in with
the remaining 114
Overlap syndrome, n (%)
2 (12)
0 (0)criteria for a CVD
a new CVD as a direct consequence
of their ILD
evaluation.
Patients
with new
CVDour
diagnosis
patients
who
formed
the basis
for
analyses. However,
Wegener’s granulomatosis, n (%)
0 (0)were younger 1than
(6)those without
new CVD diagnosis: 51.4 years (95% CI 45e58 years) and
Tulokset -‐ Lähes kolmasosalla myös CTD -‐ 15 % :lla CTD tode\in ILD:n kanssa samaan aikaan -‐ ErityisesD myosii:eja tode\in ILD:n toteamisen kanssa samaan aikaan -‐ the
Vasta-‐aineista korkea tuma-‐va, demographic
profile
of! the
including
60 years (95%1CIpatient
57e63), respectively
(p Z 0.01). Moreover,
an ANA
1:640omitted
(p Z 0.03) patients,
and
Percentages do not add to 100% due to rounding;
elevated levels of creatine phosphokinase
or aldolase
(pa
<ssosioituvat 0.001)
were associated
revealed
no statistical
differences
age
CK and
ja (CPK)
arace,
ldolaasi Iwith
LD:hen from
the
had lupus/myositis overlap and 1 patient had
myositis, lupus,
a new CVD diagnosis.
a
and scleroderma overlap.
•  Perifeerinen verenkierto –  Raynaudin oire •  Iho –  Sklerodaktylia, sormihaavat ja –arvet, telangiektasia, iho:umat, mekaanikon kädet •  Nivelet –  Kipu, turvotus, aamujäykkyys •  Lihakset –  Kipu, heikkous •  Suu ja silmät –  Kuiva suu, kuivat silmät (sicca-‐oire) study population, suggesting that the treating physician’s
Conclusions: Unrecognized collagen vascular disease may be more common than previously
decision
toHigh
send
overtly affected by
appreciated among patients referred
with ILD.
titerautoantibodies
ANA and an elevated was
CPK ornot
aldolase
are associated with a CVD diagnosis
in this referral population.
demographic
characteristics. On the other hand, as CVD is
ª 2009 Elsevier Ltd. All rights reserved.
Mi:oo et acenter.
l, Respir often
Med 2a 009 process in evolution, we would predict that
to an ILD clinic at an academic tertiary
care
a number of individuals who did not meet criteria for CVD at
Notably, 17 (15%) patients in this cohort were diagnosed
the point of evaluation might subsequently do so. As one
with a new CVD which satisfied published criteria, as
such example, one of the non-CVD patients was seroposia direct consequence of their evaluation at the ILD clinic. In
tive for Scl-70, an autoantibody with specificity for scleroaddition, we found
that two-thirds (n Z 75) demonstrate at
* Corresponding author. Tel.: þ1 410 955 4176; fax: þ1 410 955 0036.
derma, but did not yet satisfy diagnostic criteria for that
least one positiveE-mail
autoantibody.
The most
common autoaddress: [email protected]
(S.K. Danoff).
disorder. Moreover, since the diagnostic criteria for a CVD
antibodies were ANA and rheumatoid factor in 54% (n Z 61)
0954-6111/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved.
are used for research purposes, we may have missed CVD
and 25% (n Z 28),
respectively.
A
number
of
clinical
and
doi:10.1016/j.rmed.2009.02.009
cases diagnosed on clinical grounds.
demographic parameters were further related to the
The accurate recognition of CVD has significant therapeutic
establishment of a new CVD diagnosis. This included
and prognostic implication We, therefore, sought to deteryounger mean age at presentation, elevated levels of the
mine what clinical characteristics and serologic assays used
muscle enzymes, CPK and aldolase, and high titers of
routinely in clinical practice might identify patients with an
antinuclear antibody.
underlying and heretofore unrecognized CVD. We found that
The overall frequency of CVD in our population,
while patients with a new CVD diagnosis were younger at
including both established and new cases, was 30%: twice
presentation, there were no other demographic features that
that reported in the New Mexico ILD registry, where 13% of
significantly associated with the presence of CVD.
patients with ILD had CVD.26 This higher prevalence may
One of the striking findings related to CVD status was the
reflect the referral pattern at our tertiary care ILD clinic.
frequency of high titer positive ANA: a high titer ANA was
The relatively higher representation of lupus and myositis
associated with a new CVD diagnosis. A homogeneous
among the new CVD diagnoses in our cohort may similarly
immunofluorescence ANA pattern was seemingly associated
reflect the composition of our referent population or
with established and new CVD diagnoses. In a separate
practice patterns. Nevertheless, our findings emphasize
study of 276 patients with systemic sclerosis, a homogethat a full range of CVD diagnoses may be observed in
neous ANA pattern was associated with pulmonary
patients referred to an ILD clinic. Our experience suggests
fibrosis.29 In the same report, a centromere ANA pattern
that myositis may be under-recognized in the ILD popwas negatively related to pulmonary fibrosis.29 Consistent
ulation, as the levels of CK and aldolase are often not
with these observations, in our study we found no patients
markedly elevated and amyopathic forms of myositis with
with a centromere pattern among the 61 patients with
isolated lung disease does exist. We also find that at least
a positive ANA and ILD. In contrast to a different recent
one quarter of those with myositis and ILD who demonstudy,30 we did not find that rheumatoid factor predicted
strate anti-synthetase antibodies do not express the Jo-1
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Julkunen H & Ekblom-‐Kullberg S, Duodecim 2004 Ê
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reported on prognostic CT patterns, which are applicable to this
1ÃiÃÃ>Ê>LÀ>ÌÀÃÃ>Ê-]Ê,
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Û>ÃÌ>>iìÊBBÀÌÞÃiiÊiÝÌÀ>VÌ>LiÊ
group as a whole, that is,
idiopathic pulmonary fibrosis (IPF)
and
ÕVi>ÀÊ>Ì}iÃ®°ÊÊ
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fibrotic NSIP.3 13 An advantage
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can be predicted without
the need to separate these two entities
,-/ÃÞ`À>Ê>ÃÃ]Ê,>Þ>Õ`½ÊÀiÞÌÞB]ÊÀÕ>ÌÀÛiÊÞ«ÌÌiiÌÌ]ÊÃiÀ`>ÌÞ>]ÊÌii>}iÌ>Ã>Ì®ÊÊ>ÀÛ>
on CT, which can often be
problematic.14
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Until now, there are no studies which have evaluated the
Ê
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Ê
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Ê
prognostic impact of CT patterns in a large group of patients
with CTD-FLD. As individual CTD subsets often overlap clinic15
16
ally and on CT and most frequently present as either UIP or
fibrotic NSIP on CT, the identification of prognostic patterns
applicable across a variety of CTDs would be clinically useful.
The purpose of this study was to investigate high resolution
iÀÊmay
ÃìÕ`ÃÌ>ÕÌÊ
Ã«Û>Ê ÌÞÞ« Û>Ê>>>°Ê-ÞÃÌiiÃÌiÊÃìÕ`ÃÌ>ÕÌiÊ
computed tomography ÕÃi>«>>Ê
(HRCT) patterns that
predict prognosis in a variety of connective tissue diseases characterised by
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pulmonary fibrosis.
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METHODS
SSc «À>ÃÃ>Ê À«iLiÀ}>LiÀ}Ê >Ê ÌÌiÊ
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ÓääÓ®°
RA Figure 1 Axial high resolution computed tomography image at the
level of thelung
carina disease
in a patient with systemicInterstitial
sclerosis relatedlung
fibrotic
disease
iÌ>°Ê->>>Ê«Ì>>>ÊÛÊ>ÊÞÃÊ>ÃÊiÀÊ
Pulmonary function tests
and HRCTs were clinically indicatedInterstitial
lung disease. There is subpleural fine reticulation. Consensed scores at
in all cases, and for theÃìÕ`ÃÌ>ÕÌ>Ê>ìÊÌ>Õ`ÊÀÌiiÀÌÊÌBÞÌÌÞ
purposes of retrospective examination
this level were: total disease extent=20%, reticulation=100%. Traction
of which
this data,
informed to
patient
reported on prognostic CT patterns,
are applicable
this consent was not required by the
bronchiectasis was grade=0.
Table 1 Demographic data for the connective tissue disease
ÛBÌ®]Ê
Ì>Êwho
ÃìÕ`ÃÌ>ÕÌÊ
iÃÌÞÞÊ
ÞìÃÃBÊ Ê ÃÀiÃÌ>Ê`>}Ã
institutional
Patients
did not have a HRCT
group as a whole, that is, idiopathic
pulmonary review
fibrosis board.
(IPF)
and
related fibrotic lung disease (CTD-FLD) cohort (n=168), HRCT and
lung function
performed within three months of each
fibrotic NSIP.3 13 An advantage of and
this approach
is thattests
prognosis
ÕÕÊ
ÀiÕ>>ÌÌÃiÊ Ì>Ê ìiÃ«iÃw
selected pulmonary indices at time of CT
were expressedÊÃiÊ
as a >Õ
percentage of the predicted values for the
can be predicted without the needother
to separate
these twoThe
entities
were excluded.
diagnosis of CTD-FLD was made fol14
Value
patient’s age, sex and height.24 -ÞÃÌiiÃÌiÊ ÃìÕ`ÃÌ>ÕÌiÊ iÃÀiiÌÊ >> Variable (n=168)
on CT, which can often be problematic.
ÌÕÕÌ>Õ`Ê>ÃÃ>ÊÀ>`ÊÞ°Ê£Ó]Ê
lowing
a clinical, radiological
and when biopsy material was
Until now, there are no studies
which pathological
have evaluated
the of the patient data using the releavailable,
review
Age at the time of the scan; years±SD
53.9±10.9
ÀÊÞ°Ê£È®°Ê>ÃÃÃÌ>ÊÃìÕ`ÃÌ>ÕÌ>ÊÃ>À>Ã
Û>ÌÊÕÃiÌiÊÛÕÃ>ÊiiÊÛ>ÀÃ>ÃiÊÌ>Õ`Ê
17–22
prognostic impact of CT patternsvant
in asociety’s
large group
of patients
The presence of pulmondiagnostic
criteria.
Gender; male/female
65/103
Statistical analysis
with CTD-FLD. As individual CTD
often
clinicarysubsets
fibrosis
wasoverlap
determined
on HRCT by two radiologists of 9
Ì>ÛiÊÕÃÌ>ÊÞÌÞÞÊ>>ÀÞB]ÊìÊÃÃBBÊ
ÌÌi>ÃÌ>°Ê-ÞÃÌiiÃiÃÃBÊÕ«ÕÃiÃÃ>Ê-®ÊÛÛiÊ Follow-up; months±SD,
64.3±31.8
15
16
Data
are
given
as
means
with
SDs,
medians
with
IQR,
or
as
ally and on CT and most frequently
present
as either
UIP or respectively.
years’ and
25 years’
experience,
Current smoker; n(%)
6 (3.5)
Ì>Õ`ÕÛ>ÊÊÃ>>>iÊÌ>Ê>ÊÌiÌÞÌÊ>ÕÌ
iÃÀiÃÌ>Ê
`>}ÃÊ
Ê
iÃBBÀÊ
>ÃÊ
number
of
patients
and
percentage
where
appropriate.
Statistical
fibrotic NSIP on CT, the identification
of
prognostic
patterns
A diagnosis of pulmonary arterial hypertension (PAH), if
Ex-smoker; n(%)
60 (35.7)
applicable across a variety of CTDs
would
be
clinically
useful.
analyses
were
performed
using
STATA
(V
.12,
StataCorp,
College
established by right heart
catheterisation was also recorded.
102 (60.7)
Û>ÃÌ>>iiÌÊÌÌÞÛBÌÊÌiÌÌÞÊÃÊÞ`
ÛÕÌÌ>Ê
iÀÛiÀ>Ê Þ°Ê £Î®]Ê >Ê «À>>ÀÃÃ>Ê - Never smoker; n(%)
The purpose of this study was to
investigate
high
Station, Texas). The single determination SD was used to evaluate
Survival
period
wasresolution
calculated starting from the date of the
PA on RHC*; n(%)
20 (11.9)
computed tomography (HRCT) patterns
may to
predict
progÃÊiÃ°ÊÞÃÌÌiÊ>>ÀÞBÌÊÌ>ÊvÃv«`
}ÀiÊÃÞ`À>ÃÃ>ÊÃiÊ>ÊÃÕÕÊÕÛÕÕÃÊÊ
interobserver agreement for continuous
variables (total interstitial
Total interstitial disease extent; mean±SD,
28.5±19.6
baselinethat
HRCT
the date
of death, or in the case of survivors,
nosis in a variety of connective tissue
characterised
disease extent, ground-glass opacification, fine and coarse reticulaglass opacification; mean±SD
9.4±12.7
to thediseases
last known
pointÛ>ÃÌ>>iiÌÊ>ÊÌÀLÃ®°
of by
contact. In cases where patients were
Û>Û>ÕÌÊ«Ì>ÃÌ>ÊiÃBBÀÊÇqÊÛÕÌÌ>]Êi Ground
pulmonary fibrosis.
tion, honeycombing, consolidation and emphysema).25 The
Reticulation; mean±SD
15.6±14.6
lost to follow-up, status at the end of the study period was conHoneycombing; mean±SD
2.1±2.2
weighted κ statistic (κw) was used
to evaluate interobserver agree/BÃÃBÊ>ÀÌiÃÃ>Ê«`Ì>>Ê>ÕÃ«Ì>ìÊ
iÊÕÊÀiiÊÞìÌBBÊi>ÊÃiÌÞÃÊ>Ì
firmed by contacting the respective
family practitioners.
Consolidation; mean±SD
1.3±4.8
ment for categorical variables (traction bronchiectasis) and was
METHODS
ÃÞÃÌiiÃÌiÊ
ÃìÕ`ÃÌ>ÕÌiÊ
`>}ÃÌ>>Ê
À«iÊ
ÓääÓ®°Ê
ÃÊ≤0.40),
,>Þ>Õ`½Ê
ÀiÞÌÞBÊ ÌÌÞÞÊ Traction bronchiectasis; mean±SD
Figure 1 Axial
high resolution computed
tomography
at the
4.5±4.5
Figurefair
3 (0.20<κ
Axial thin wsection
computed tomographic image in a patient
categorised
asimage
follows:
poor (0<κw≤0.20),
Study population and clinical evaluation
HRCT protocol and image evaluation
level of the carinaÌÌÞÛBÊ
in a patient with
systemic
sclerosis(0.40<κ
related
fibrotic
Radiological diagnosis; UIP/fibrotic NSIP/indeterminate)
15/144/9
with rheumatoid
arthritis
related fibrotic lung
disease. There
is diffuse
moderate
(0.60<κ
and
excellent
Pulmonary function tests and HRCTs were clinically indicated
>ÊtheÕÌÌiÕÕÊ
ÞÃÞÞÃB]Ê
ÃÊ
iÃ good
>>Û>>Ê
ÃìÕ`ÃÌ>ÕÌ]Ê
Û`>>Ê
«iÀÕÃÌ>ÕÌÊ
w≤0.60),
w≤0.80)
A detailed description of
HRCT
protocol,
scoring
method
lung disease.
There
is subpleural
fine reticulation. Consensed scores at
ground glass opacification containing areas of marked traction
58.8±12.3
FEV1; % predicted
in all cases, and for the purposes of retrospective examination
thiscan
levelbewere:
total
extent=20%,
reticulation=100%.
Traction
and definitions of HRCT
patterns
found
indisease
the online
bronchiectasis.
Subpleural
honeycombing is>ìÊ
also present. ÛÕìÊ
Consensed > FVC; % predicted
iÀÌ>«>ÕÃÌiÊ
Û>ÃÃ>°Ê
6>ÀÃ>ÃiÌÊ
ÀiÕ>>Ì
ÌìÌ>Ê
ÞiiÃBÊ
iÃBÃiÊ
72.6±22.7
of this data, informed patient consent was not required by the
scores at this level were: total disease extent=90%, ground glass
repository. Briefly, two thoracic bronchiectasis
radiologists was
of grade=0.
9 years’ and
DLco;
%
predicted
44.9±17.27
institutional review board. Patients who did not have a HRCT
ÌÃiÌÊHRCTs
ÛiÌÕi`ÕÃiÌÊ
>>°ÊÃÕÃÊÃìÕ`ÃÌ>ÕÌiÊiÃÀiiÌÊ>>Û>ÌÊ
opacification=80% and honeycombing=20%. Traction bronchiectasis
10 years’ experience scored
for each patient on>Ê
theÛ>ÃÕÌÌÊ ÌiÌ>>Ê
*PA on RHC=pulmonary arterial hypertension diagnosed at right heart
and lung function tests performed within three months of each
was grade=3 within the ground-glass opacification in the right middle
catheterisation. Total interstitial disease extent=sum of each of the individual HRCT
extent
of four was
interstitial
patterns
(ground
glassasopacification,
were
expressed
a percentage of the predicted values for the
other were excluded. The diagnosis
of CTD-FLD
made follobe and grade 2 in the honeycombing.
patterns, except traction bronchiectasis, which was scored based upon severity within
reticulation,
honeycombing
andand
emphysema,
patient’s age, sex
height.24
lowing a clinical, radiological and
when biopsy
material wasand consolidation)
each interstitial pattern and summated (see online supplementary appendix).
-ÞÃÌiiÃÌiÊÃìÕ`ÃÌ>ÕÌiÊÕÌÃÕÕÃ
at six
levels.
traction
score was also assigned.
£nÇÇ CTD-FLD, connective tissue disease related fibrotic lung disease; NSIP, non-specific
available, pathological review of the
patient
dataA using
the bronchiectasis
rele(0.80<κw≤1.00).25 Cox regression analysis was used to identify
interstitial pneumonia; UIP, usual interstitial pneumonia.
Honeycombing
defined as air-filled cystic spaces with
The presencewas
of pulmonvant society’s diagnostic criteria.17–22
associations between mortality and HRCT variables and pulmonirregular
wallsradiologists
deemed not
representing
traction
bronchiectasis,
Statistical
analysis
ary fibrosis was determined on HRCT
by two
of 9
ary function indices. One univariable model was built for total
and traction bronchiectasis was defined
irregular
bronchial
Data areasgiven
as means
with SDs, medians with IQR, or as
years’ and 25 years’ experience, respectively.
interstitial disease extent, traction bronchiectasis, each HRCT
lung function was 6 days (IQR=1.0). There were 20 patients
dilatation
caused by(PAH),
surrounding
retractile
number
of pulmonary
patients and fibrosis.
percentage where appropriate. Statistical
A diagnosis of pulmonary arterial
hypertension
if
pattern score, FVC, FEV1 and DLco and a single multivariable
with an established diagnosis of pulmonary arterial hypertension
analysesdiagnosis
were performed
Lastly, observers
provided
a radiological
for eachusing
case STATA (V.12, StataCorp, College
established by right heart catheterisation
was also
recorded.
model was built using a backward elimination procedure for terms
(RA-FLD=2, SScl=10, MCTD=5, PM=3, SLE=0, Sjögren’s
Station,
Texas). The This
singleradiodetermination SD was used to evaluate
selectingfrom
fromthe
UIPdate
, fibrotic
NSIP and
indeterminate.
Survival period was calculated starting
of the
found statistically significant (p<0.05) on univariable analysis.
disease=0). A summary of patient demographics, radiological
23
agreement
for continuous
variables (total interstitial
logical
was
based uponinterobserver
current clinical
guidelines.
baseline HRCT to the date of death,
or indiagnosis
the case of
survivors,
The assumptions of linearity and proportional hazards were
scores and pulmonary function tests are given in table 1.
disease
extent, ground-glass
opacification, fine and coarse reticulaimages
in figures
1–3.
to the last known point of contact.Example
In cases scores
where with
patients
wereare given
assessed by visual inspection of Martingale residuals and scaled
Observer agreement for each of the HRCT patterns and traction
25
tion,
honeycombing,
consolidation
and
emphysema).
The
lost to follow-up, status at the end of the study period was conSchoenfeld residuals.
bronchiectasis are shown in table 2. Interobserver agreement for
weighted κ statistic (κw) was used to evaluate interobserver agreefirmed by contacting the respectivePulmonary
family practitioners.
radiological diagnosis assignment was good (κw=0.74).
function tests
ment for categorical variables (traction bronchiectasis) and was
Assigned diagnoses were fibrotic NSIP (85.7%, 144/168), indeSpirometry ( Jaeger Master screen PFT, Carefusion, Warwick, UK),
RESULTS image 1cm below
categorised as follows: poor (0<κw≤0.20),
fair
(0.20<κ
≤0.40),computed tomography
wsection
Figure
2
Axial
thin
terminate (5.3%, 9/168) and UIP (8.9%, 15/168). Patients
HRCT protocol and image evaluation
plethysmographic lung volumes ( Jaeger Master screen Body,
total of
patients were identified. Of these, 47 patients
moderate (0.40<κw≤0.60), good (0.60<κ
w≤0.80)
the dome
of theand
rightexcellent
hemidiaphragm in aApatient
with205
mixed
assigned a radiological diagnosis of UIP had more extensive
A detailed description of the HRCT
protocol,
scoring
method
Carefusion, Warwick, UK) and diffusion capacity for carbon monwereThere
excluded
because:
connective tissue disease fibrotic lung disease.
is patchy
ground(1) on detailed evaluation of clinical
reticulation and honeycombing and more severe traction
and definitions of HRCT patternsoxide
can be
found( Jaeger
in the Master
online screen PFT, Carefusion, Warwick,
(DLco)
data, a multidisciplinary
glass opacification and subpleural honeycombing,
both containing diagnosis of CTD had not been secured
repository. Briefly, two thoracic UK)
radiologists
of to
9 measure
years’ and
were used
lung function according to established
and (2)
HRCT
areas of traction bronchiectasis. Consensed(n=25)
scores were
at this
level:not performed within 3 months of lung
10 years’ experience scored HRCTs
for each
onindices
the were recorded: FEV1, FVC, total
protocols.
The patient
following
function test (n=22). The remaining 168 patients made up the
total disease extent=85%, ground glass opacification=60%,
extent of four interstitial patternslung
(ground
glass
Table 2 Interobserver agreement for HRCT parenchymal patterns
capacity
andopacification,
single breath carbon dioxide diffusing capacity
study
honeycombing=40%. Traction bronchiectasis
waspopulation.
grade=2 in This
both group consisted of patients with a diagreticulation, honeycombing and consolidation)
emphysema,concentration (DLco). These values
expressed as the single determination SD for continuous variables
nosis of rheumatoid arthritis (RA, n=39), scleroderma (SScl,
corrected forand
haemoglobin
parenchymal patterns.
at six levels. A traction bronchiectasis score was also assigned.
and the weighted κ coefficient for categorical variables* (n=168)
n=32), mixed connective tissue disease (MCTD, n=33), polyHoneycombing was defined as Walsh
air-filled
cystic spaces with
myositis (PM, n=33), 217
systemic lupus erythematosus (SLE,
Interobserver
SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843
irregular walls deemed not representing traction bronchiectasis,
Pattern
variation
n=17) and Sjögren’s disease (n=14). Excluded patients did not
and traction bronchiectasis was defined as irregular bronchial
differ significantly in terms of functional impairment from the
Total disease extent
1.0%
dilatation caused by surrounding retractile pulmonary fibrosis.
final study population. Histopathological confirmation of the
Ground-glass opacification
6.2%
Lastly, observers provided a radiological diagnosis for each case
specific subtype of fibrosis (UIP/fibrotic NSIP) was available in
Fine reticulation
0.1%
selecting from UIP, fibrotic NSIP and indeterminate. This radio51 cases. During the study period, 48/168 patients died. Causes
Coarse reticulation
8.8%
logical diagnosis was based upon current clinical guidelines.23
of death were documented as progression of their interstitial
Honeycombing
1.2%
Example scores with images are given in figures 1–3.
lung disease (n=44) and sepsis (n=3) and lung cancer (n=1).
Study population and clinical evaluation
Fischer & Richeldi, Semin Respir Crit Care Med 2014 DiagnosDset stepit •  Varmennetaan systeeminen sidekudossairaus •  Arvioidaan sopiiko ILD kyseiseen CTD:hen –  HRCT •  Suljetaan pois infekDot, lääke-‐reakDot ja muut intersDDaaliset keuhkosairaudet MCTD –  BAL •  Päätetään otetaanko keuhkobiopsia –  Jos HRCT epätyypillinen kyseiselle CTD:lle tai jää epäspesifiseksi –  Kun epäillään malignoomaa tai infekDota Walsh et al, Thorax 2013 Pulmonary function tests
Spirometry ( Jaeger Master screen PFT, Carefusion, Warwick, UK),
plethysmographic lung volumes ( Jaeger Master screen Body,
Carefusion, Warwick, UK) and diffusion capacity for carbon monoxide (DLco) ( Jaeger Master screen PFT, Carefusion, Warwick,
UK) were used to measure lung function according to established
protocols. The following indices were recorded: FEV1, FVC, total
lung capacity and single breath carbon dioxide diffusing capacity
corrected for haemoglobin concentration (DLco). These values
Of the 120/168 remaining patients, 105 were confirmed as alive
at the end of the study period by reviewing the clinical records.
Fifteen patients were lost to follow-up but subsequently confirmed as alive at the end of the study period by contacting the
respective patients’ family practitioners.
Of the 168 patients enrolled in the study, 103 were female.
The mean age at the time of presentation was 55.9 years
(SD=10.9 years). Median follow-up time was 64 months
(IQR=38.4). The median interval between HRCT and baseline
Milloin ILD-‐poDlas on syytä lähe:ää reumatologille? Figure 2 Axial thin section computed tomography image 1cm below
the dome of the right hemidiaphragm in a patient with mixed
connective tissue disease fibrotic lung disease. There is patchy ground
glass opacification and subpleural honeycombing, both containing
areas of traction bronchiectasis. Consensed scores were at this level:
total disease extent=85%, ground glass opacification=60%,
honeycombing=40%. Traction bronchiectasis was grade=2 in both
parenchymal patterns.
•  Nainen, erityisesD alle 50 v. •  Oireet Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843
218
Consolidation
Emphysema
Traction bronchiectasis*
Traction bronchiectasis absent/present*
Honeycombing absent/present*
Radiological diagnosis* (UIP/Fibrotic NSIP/
Indeterminate)
3.5%
1.3%
0.61
0.69
0.50
0.74
Milloin ILD-‐poDlas on syytä lähe:ää reumatologille?...(jatkuu ed. sivu) *denotes the categorical variables.
NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia.
Walsh SLF, et al. Thorax 2014;69:216–222. doi:10.1136/thoraxjnl-2013-203843
217
–  Raynaud’n oire, ruokatorven hypomoDlitee\, ranteiden tai metakarpaali-‐falangeaalinivelten tulehduksellinen artrii\, sormien turvotus, oireinen keratokonjunDviDs sicca •  Histologia –  NSIP, LIP tai muu ILD + extensiivinen pleurii\, Divis perivaskulaarinen kollageeni, lymfafollikkelit ja itukeskukset, runsaasD plasmasoluja •  Serologiset löydökset –  ANA > 1:320, RF > 60 IU/ml –  AnD-‐Nucleolar-‐ANA (mikä tahansa Di:eri) –  AnD-‐CCP, anD-‐Scl-‐70, SS-‐A, SS-‐B, anD-‐dsDNA, Sm, anD-‐RNP, anD-‐tRNA syntetaasi Fischer & Richeldi, Semin Respir Crit Care Med 2014 Fischer & Richeldi, Semin Respir Crit Care Med 2014 5 18/04/15 IIM-‐ILD ja anDsyntetaasi-‐syndrooma AnDsyntetaasi-‐syndrooma •  Idiopaa\set inflammatoriset myopaDat (IIM) •  ARS-‐va + IIM + ILD = anDsyntetaasi-‐syndrooma –  PM, DM, inkluusiokappalemyosii\, amyopaa\nen DM –  IIM-‐ILD prevalenssi 20-‐78% –  ILD edeltää DM/PM-‐diagnoosia 13-‐37,5%:lla •  Myosii\-‐spesifiset vasta-‐aineet –  Ro52, MDA-‐5, 155/40, SRP, Mi-‐2, PM/Scl, ARS –  Lisäksi nonerosiivinen artrii\, kuume, mekaanikon kädet, Raynaudin ilmiö –  Eri ARS-‐vasta-‐aineet assosioituvat erilaisiin subfenotyyppeihin •  Mikä tahansa ARS-‐va assosioituu korkeaan (67-‐100%) ILD:n kehi:ymisen riskiin –  Jo-‐1 tavallisin: 15-‐30 % IIM-‐poDlaista –  PL-‐12-‐, KS-‐, OJ-‐posiDivisilla suurin ILD-‐riski •  AnDsyntetaasi-‐syndrooma vasta-‐aineet (ARS) –  Jo-‐1, EJ, PL-‐7, PL-‐12, KS, OJ, Zo, YRS CTD-‐ILD:n histologiset ilmentymät CTD-‐ILD:n histologia •  Kirurgisia keuhkobiopsioita otetaan harvoin –  Tulevaisuudessa enemmän kryobiopsioita? •  Histologia monimuotoisempaa kuin IIP:ssa –  Monien alueiden (eri-‐aikaiset) affiisiot ja monien muutoksien yhdistelmät tyypillisiä –  Parenkyymi (intersDDum), alveoli, ilmaDet, pleura, verisuonet voivat affisoitua –  ”Acute on chronic” RA SLE PM/DM SSc SjS DAD 6% Harvoin 3-‐27% Harvoin Harvoin OP 11-‐15% Harvoin 5-‐40% 1% < 22% C-‐NSIP 12-‐15% 9% 7-‐73% 19-‐68% 3-‐28% F-‐NSIP 29-‐33% 4% 11-‐54% 59-‐68% 28-‐58% UIP 13-‐56% Harvoin 5-‐33% 15-‐26% < 17% CB 6% ? ? ? 78% FB 6-‐65% ? ? ? 11% OB/CB + ? ? Harvoin Harvoin Pleurii\ > 10 % 18-‐40% ? 67% ? ValDmomuut. + + + + Kyllä Urisman & Jones, Semin Respir Crit Care Med 2014 DAD = diffuusi alveolivaurio •  Voi olla CTD-‐ILD:n ensimmäinen ilmentymä tai kroonisen taudin yhteydessä •  Voi ilmetä (harvoin) minkä tahansa CTD:n yhteydessä •  KliinisesD usein ARDS •  Perustaudin akuu\en pahenemisvaiheiden tai infekDoiden yhteydessä –  Akuu\en pahemisvaiheiden histologis-‐
radiologinen ilmentymä, myös IIP:ssa Organisoituva pneumonia (OP) ja bronkioliiDt (CB, FB, OB) •  COP-‐diagnoosi (=idiopaa\nen) on poissulkua –  OP voi olla infekDoiden, CTD:n, lääkereakDoiden, sädehoidon yhteydessä –  CTD-‐ILD:ssa OP voi olla muiden muutosten joukossa •  BronkioliiDt –  Follikulaarinen (FB), sellulaarinen (CB) ja obliteroiva eli konstrikDivinen (OB) bronkiolii\ –  Tavallisimpia RA:ssa ja SjS:ssa –  Voivat olla ILD:n kanssa samanaikaisesD 6 18/04/15 [
Original Research Diffuse Lung Disease
]
Pulmonary Function and Survival in Idiopathic
vs Secondary Usual Interstitial Pneumonia
KeuhkofunkDoiden käy:äytyminen IPF vs CTD-‐UIP Matthew J. Strand, PhD; David Sprunger, MD; Gregory P. Cosgrove, MD, FCCP;
Evans R. Fernandez-Perez, MD, MPH, FCCP; Stephen K. Frankel, MD, FCCP; Tristan J. Huie, MD, FCCP;
Amy L. Olson, MD, MSPH; Joshua Solomon, MD, FCCP; Kevin K. Brown, MD, FCCP; and Jeffrey J. Swigris, DO
The usual interstitial pneumonia (UIP) pattern of lung injury may occur in the
setting of connective tissue disease (CTD), but it is most commonly found in the absence of a
known cause, in the clinical context of idiopathic pulmonary fibrosis (IPF). Our objective was
to observe and compare longitudinal changes in pulmonary function and survival between
patients with biopsy-proven UIP found in the clinical context of either CTD or IPF.
BACKGROUND:
We used longitudinal data analytic models to compare groups (IPF [n 5 321] and
CTD-UIP [n 5 56]) on % predicted FVC (FVC %) or % predicted diffusing capacity of the lung
for carbon monoxide (Dlco %), and we used both unadjusted and multivariable techniques to
compare survival between these groups.
METHODS:
RESULTS: There were no significant differences between groups in longitudinal changes in
FVC % or Dlco % up to diagnosis, or from diagnosis to 10 years beyond (over which time,
the mean decrease in FVC % per year [95% CI] was 4.1 [3.4, 4.9] for IPF and 3.5 [1.8, 5.1] for
CTD-UIP, P 5 .49 for difference; and the mean decrease in Dlco % per year was 4.7 [4.0, 5.3]
for IPF and 4.3 [3.0, 5.6] for CTD-UIP, P 5 .60 for difference). Despite the lack of differences
in pulmonary function, subjects with IPF had worse survival in unadjusted (log-rank P 5 .003)
and certain multivariable analyses.
Figure 1 – A, B, Change in FVC% (A) or DLCO% (B) over time for sample stratified on clinical context of UIP. Points represent observed values, with
fitted (predicted) functions for groups (blue 5 IPF, red 5 CTD-UIP) superimposed; predicted means are solid, 95% confidence bands are dashed. Predicted values were obtained using mixed-model fits, using knots (ie, allowing change points) at 20.5, 0, 0.5, 1, and 2 y from diagnosis. A spatial power
covariance structure was included in the model to account for repeated measures within subjects; random effect terms for subjects were also included, as
described in e-Appendix 1. There were no significant differences between groups for segments between comparable time points. The plots demonstrate
sharper declines near time of diagnosis for both groups. CTD-UIP 5 connective tissue disease-related usual interstitial pneumonia; DLCO% 5 % predicted diffusing capacity of the lung for carbon monoxide; FVC% 5 % predicted FVC; IPF 5 idiopathic pulmonary fibrosis.
Despite no significant differences in changes in pulmonary function over time,
patients with CTD-UIP (at least those with certain classifiable CTDs) live longer than patients
with IPF—an observation that we suspect is due to an increased rate of mortal acute exacerbations in patients with IPF.
CHEST 2014; 146(3):775-785
CONCLUSIONS:
Strand MJ et al, Chest 2014 Strand MJ et al, Chest 2014 Manuscript received October 11, 2013; revision accepted March 3,
2014; originally
Online
First April only
3, 2014.
In a Coxpublished
model that
contained
the group variable
ABBREVIATIONS: AEx 5 acute exacerbation pulmonary fibrosis; CTD 5
(IPF vs each of the four individual CTD categories, with
connective tissue disease; CTD-UIP 5 connective tissue disease-related
IPF as thepneumonia;
reference D
category),
a signifi
cant of
orthe
strong
usual interstitial
lco 5 diffusing
capacity
lung
for carbon
monoxide;
5 hazard ratio;
interstitial
lungfor
disease;
trend
towardHR
a protective
effILD
ect 5
was
observed
three
IPF 5 idiopathic pulmonary fibrosis; NJH 5 National Jewish Health;
subgroups
RA
5 0.437,arthritis;
P 5 .046;
for
PFT 5CTD
pulmonary
function(HR
test; for
RA 5
rheumatoid
SScHR
5 systemic SSc
sclerosis;
UCTD
5 undiff
connective
tissue
disease;
5 0.175,
P5
.014; erentiated
HR for other
5 0.550,
P5
.10).
UIP 5 usual interstitial pneumonia
There was no significant difference in time to death for
AFFILIATIONS: From the Division of Biostatistics (Dr Strand) and
IPF vs UCTD
(e-Fig
4).Interstitial Lung Disease Program
Autoimmune
Lung Center
and
(Drs Sprunger, Cosgrove, Fernandez-Perez, Frankel, Huie, Olson,
Solomon,
Brown, and Swigris), National Jewish Health, Denver, CO.
Discussion
Drs Brown and Swigris are co-senior authors.
We identified Dr
a cohort
ofsupported
patientsinwho,
over
a 25-year
FUNDING/SUPPORT:
Swigris is
part by
a Career
Development
Awardwere
from diagnosed
the National at
Institutes
of Health
[K23
HL092227].
period,
our center
with
UIP
and met
CORRESPONDENCE TO: Jeffrey J. Swigris, DO, Autoimmune Lung
current diagnostic criteria for IPF or rheumatologistCenter and Interstitial Lung Disease Program, National Jewish Health,
nedSt,
CTD.
WeCO
examined
whether
pulmonary func1400defi
Jackson
Denver,
80206; e-mail:
[email protected]
© 2014
COLLEGE
OF CHEST
Reproduction
tionAMERICAN
over time
or survival
diffPHYSICIANS.
ered between
groups. of
this article
is prohibited
written permission
from
American
Interestingly
andwithout
surprisingly,
there were
nothesignifi
cant
College of Chest Physicians. See online for more details.
differences in change (decline) over time
DOI:between-group
10.1378/chest.13-2388
Elinaika IPF vs CTD-‐UIP Figure 2 shows spaghetti plots of raw data for withinsubject changes in FVC % and Dlco %: It is apparent that
some subjects who experienced sharp declines around
the time of diagnosis had shorter time of follow up. To
systematically assess for the impact of this within-group,
differential dropout, we stratified the groups on quartiles of time from diagnosis to last observed pulmonary
Lee et al.
function
test (PFT) and refit models (e-Fig 1); within
each quartile of time (, 0.42 years, 0.42-1.23 years,
1.24-3.33 years, ! 3.34 years), the proportions of subjects with IPF vs CTD-UIP, and the predicted mean
FVC % at time of diagnosis, between subjects with IPF
vs those with CTD-UIP were similar (see e-Appendix 1
for additional details). e-Figure 2 displays graphs of longitudinal changes in FVC % or Dlco % for subjects in
the upper quartile of (ie, longest) time from biopsy to
last PFT observation.
Vasta-‐aineiden prevalenssi IPF vs terve 775
journal.publications.chestnet.org
tiles of follow-up, but using data only from subjects with
early (, 100 weeks) or late (! 100 weeks) time from
diagnosis to last PFT observation, and including
analyses on the individual CTD subgroups (eg, RA, SSc,
UCTD, other), are displayed in Table 2 and Figure 3.
Within groups (or CTD subgroups), subjects with last
PFT observations , 100 weeks from biopsy generally
had greater declines in lung function than subjects with
late last PFT observations; however, significant betweengroups differences were not observed. In a logistic regression analysis, while controlling for age, sex, FVC %, and
Dlco %, there was no significant difference between
any individual CTD subgroup and IPF in the likelihood
of last PFT observation ! 100 Page
weeks
9 after biopsy (see
e-Table 1 for detailed results).
(P 5 .23 for difference). After diagnosis, the mean
decrease in FVC % per year was 4.1 [3.4, 4.9] for IPF
and 3.5 [1.8, 5.1] for CTD-UIP (P 5 .49 for difference);
the mean decrease in Dlco % per year was 4.7 [4.0, 5.3]
for IPF and 4.3 [3.0, 5.6] for CTD-UIP (P 5 .60 for difference). See e-Appendix 1 for more details.
Figure 3 – A-B, Estimated mean FVC% (A) and DLCO% (B) by diagnosis group (IPF 5 blue, CTD-UIP 5 red) and last time of follow-up (, 100 wk,
solid; ! 100 wk, dashed) based on linear mixed-model fits. Plots demonstrate that those with earlier last follow-up tended to have steeper declines in
lung function. See Figure 1 legend for expansion of abbreviations.
Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015
Survival
$watermark-text
Among subjects whose last PFT observation was within
100 weeks of diagnosis, there was no significant difference between groups in the proportion of subjects who
died (IPF, 74% of 184 vs CTD-UIP, 69% of 29, P 5 .63);
however, among those whose last observed PFT was
! 100 weeks after diagnosis, there was a difference
between groups (IPF, 68% of 132 vs CTD-UIP, 42% of
26, P 5 .01). In the unadjusted analysis, survival was
significantly longer in CTD-UIP than IPF (log-rank
P 5 .003) (Fig 4). Median survival was 7.1 years (95% CI,
4.6-11.3) for CTD-UIP and 4.4 years (95% CI, 4.1-5.2)
Nearly one-half of the subjects in each group (IPF or
CTD-UIP) had their last PFT obtained , 100 weeks
(1.92 years) after diagnosis. Results for additional
analyses similar to those previously described for quar-
[
778 Original Research
-‐ CTD-‐UIP:n elinaika pitempi kuin IPF:ssä vaikka keuhkofunkDoden kulku samanlainen journal.publications.chestnet.org
-‐ IPF:ssä enemmän akuu:eja pahenemisvaiheita? Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015
Strand MJ et al, Chest 2014 781
146#3 CHEST SEPTEMBER 2014
]
Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015
$watermark-text
Figure 4 – Kaplan-Meier survival curves for sample stratified on clinical context of usual interstitial pneumonia (IPF or CTD-UIP). See Figure 1 legend
for expansion of abbreviations.
Figure 1.
-‐  Autovasta-‐aineet eivät ole IPF:ssa merki:äväsD korkeampia kuin terveillä The frequency of circulating autoantibody positivity in healthy controls (white bars)
compared
idiopathic=pulmonary
(IPF, black
There were no significant
kontrolleilla (tomusta IPF, vfibrosis
alkoinen = tbars).
erve) differences in frequency of autoantibodies between healthy controls and IPF. “Other”
includes double stranded deoxyribonucleic acid (dsDNA), chromatin, ribosomal P, anti-Ro
(SS-A), anti-La (SS-B), centromere B, Smith (Sm), ribonucleoprotein (RNP), SmRNP,
Lee et al, Respir Med 2013 Scl-70, Jo-1, proteinase 3 (PR3), myeloperoxidase (MPO) and glomerular basement
membrane (GBM). Abbreviations: ANA – anti-nuclear antibody, RF – rheumatoid factor,
CCP – cyclic citrullinated peptide.
$watermark-text
Mitä uu:a lääkityksestä? Rituksimabi vaikean CTD-‐ILD:n hoidossa CONNECTIVE TISSUE LUNG DISEASE
TABLE 1
•  Pirfenidonista, nintedanibista tai NAC:sta ei ole julkaistuja tutkimuksia CTD-‐ILD:ssa –  Pirfenidoni faasi II SSc:ssa tehty, ei vielä julkaistu •  Rituksimabista lupaavia tuloksia 3 tutkimuksessa –  PM/DM-‐ILD, SSc-‐ILD –  Vaikea etenevä CTD-‐ILD huolima:a korkea-‐
annoksisesta steroidista ja muusta immunosupressiivisesta lääkityksestä –  Tutkimuksia meneillään G.J. KEIR ET AL.
Baseline characteristics of patients treated with rituximab, including immunosuppressive therapy in the previous 12
months
Patient
Age/sex
HRCT pattern
Year of ILD
Serum auto-antibody/CTD
Pre-rituximab
diagnosis
features
immunosuppression
2009
ENA, anti-Ro positive DM
2003
Anti-Jo 1, myositis
Respir Med. Author manuscript; available in PMC 2014 February 01.
Polymyositis/dermatomyositis
1
45/M
2
60/M
Organising
pneumonia/DAD
Fibrotic NSIP*
i.v. methylprednisolone
on muscle biopsy
MMF, prednisolone,
cyclosporine i.v. cyclophosphamide
3
60/F
Fibrotic NSIP
2000
Anti-Jo 1, myositis
MMF, prednisolone i.v.
rheumatoid factor
cyclophosphamide
4
29/F
Fibrotic NSIP
2009
Anti-Jo 1, myositis
anti-Ro
cyclophosphamide
5
51/M
Fibrotic NSIP
2005
Anti-Jo 1, myositis
49/M
Fibrotic NSIP
2006
ANA +++ (speckled)
i.v. cyclophosphamide
cyclophosphamide
Undifferentiated CTD
6
7
37/F
Organising
2009
pneumonia/DAD
Raynaud’s, GORD
prednisolone, MMF
Rheumatoid factor
i.v. methylprednisolone
anti-CCP, anti-Ro
Systemic sclerosis
8
63/M
Fibrotic NSIP
1999
ATA
MMF, prednisolone
HRCT: high-resolution computed tomography; ILD: interstitial lung disease; CTD: connective tissue disease; M: male; F: female; DAD: diffuse alveolar damage; ENA:
-‐ 7 poDlaalla ILD parani, yhdellä stabiloitui (keuhkofunkDot ja oireet) extractable nuclear antigen; DM: dermatomyositis; NSIP: non-specific interstitial pneumonia; MMF: mycophenolate mofetil; ANA: anti-nuclear antibody; GORD: gastrooesophageal reflux disease; CCP: cyclic citrullinated peptide; ATA: anti-topoisomerase antibody. *: fibrotic NSIP confirmed on surgical lung biopsy.
Sem M Rheumatology 2009, Daoussis D Clin Exp Rheumatol 2012, Daoussis D Rheumatology 2010, Keir M Eur Respir J 2012, ClinicalTrials.gov cell reconstitution begins 6–9 months later [10].
Keir Evidence
G, Eur forRthe
espir occurred
J 2012 in association with undifferentiated CTD, and in one
effectiveness of B cell depletion exists in a number of immunewith SSc. All patients had failed to respond to conventional
mediated conditions, including rheumatoid arthritis [11–13],
immunosuppressive therapy, with ongoing deterioration in
anti-neutrophil cytoplasmic antibody-associated vasculitis [14, 15],
pulmonary function tests (PFTs) and/or worsening respiratory
pulmonary alveolar proteinosis [16] and immune thrombocyfailure. At the time of referral, two patients were mechanically
topenic purpura [17]. A few case series have suggest rituventilated and transferred directly to the intensive care unit
ximab may also be effective in ILD occurring in the context of
(ICU) of our hospital. Table 1 lists demographic information
immunological over-activity, with favourable responses reported
and immunosuppressive therapy in the 9–12 months prior to
in anti-synthetase-associated ILD [18] and SSc-ILD [19]. Howrituximab therapy.
ever, patients in these series had interstitial lung involvement of
predominantly mild-to-moderate severity.
Statistical analysis
Evidence for the effectiveness of rituximab as ‘‘rescue’’ therapy
in patients with severe, life-threatening ILD is limited [20, 21].
We report the use of rituximab as rescue therapy in eight
patients with underlying features of CTD, and exceedingly
severe fibrotic lung disease, progressing in spite of vigorous
conventional immunosuppression.
METHODS
Patient groups
Review of our medical records and hospital pharmacy prescribing database identified all patients treated with rituximab
between December 2007 and December 2010. All consecutive
patients with severe, progressive CTD-ILD were included in our
analysis, with a total of eight patients. No patients with CTDILD were excluded due to poor outcome or early death. A
minimum of 9 months post treatment follow-up was available
for all patients. ILD occurred in association with polymyositis or dermatomyositis (PM/DM) in five patients, of whom
four had anti-synthetase Jo-1 antibody. In two patients, ILD
642
VOLUME 40 NUMBER 3
All patients had PFT follow up of at least 9 months following
rituximab. In the six patients with PFT data prior to rituximab
treatment, the significance of median DL,CO and forced vital
capacity (FVC) percentage change before and after treatment
was assessed by Wilcoxon signed rank test. To evaluate
statistical significance of response to treatment in all patients,
categorical variables of change (worse, stable, improved) were
generated by combining significant changes in pulmonary
function tests (defined as a change in FVC of o10% and/or a
change in DL,CO of o15%) and/or clinical status (for the two
patients requiring mechanical ventilation, the requirement for
mechanical ventilation was classified as a significant deterioration). Change was assessed 9–12 months before and after
rituximab, and analysed using the Wilcoxon signed-rank test.
A p-values of o0.05 was considered statistically significant.
Analysis of follow-up data at 9–12 months was chosen based
upon previously reported responses of CTD-ILD to rituximab
[18, 19], and the expected duration of B cell ablation following
rituximab [10, 15].
EUROPEAN RESPIRATORY JOURNAL
7 that a subset of this patient population may eventually meet the criteria for a well-defined CTD. These
findings demonstrate that identification of subtle CTD clinical features, when associated with presence of
auto-antibodies, do impact on the clinical and imaging presentation of ILD and are associated with distinct
attributes. In other words, subtle manifestations of CTD should be considered in a patient evaluated for
ILD, even if overt CTD criteria are not fulfilled.
In another study, CORTE et al. [6] elegantly demonstrated that the proportion of patients with idiopathic
interstitial pneumonia that fulfil UCTD criteria is dependent on the criteria used (table 3). Using ‘‘broad
criteria’’ [5], UCTD could be diagnosed in 36% of patients with IPF and in 71% of patients with NSIP,
whereas UCTD was considered to be present in only 13% and 21%, respectively, of the same patients groups
using the more stringent criteria of UCTD [40]. The presence of UCTD was associated with a higher
frequency of NSIP histopathology [6].
18/04/15 In a recent study, FISCHER et al. [17] suggested the terminology of lung-dominant CTD to account for the
subset of patients with interstitial pneumonia who have clinical features suggesting an associated CTD, but
the features fall short of a clear diagnosis of CTD under the current rheumatologic classification systems.
The proposed provisional criteria for this condition include four criteria: 1) a histological or radiological
pattern of NSIP, UIP, lymphocytic interstitial pneumonia, organising pneumonia or diffuse alveolar
damage; 2) insufficient extra-thoracic features of a definite CTD to allow a specific CTD designation; 3) no
identifiable alternative aetiology for interstitial pneumonia; 4) any one of a list of auto-antibodies or at least
two of four predefined histopathology features (lymphoid aggregates with germinal centres, extensive
pleuritis, prominent plasmacytic infiltration and dense perivascular collagen). Such provisional conceptual
classification carries the advantage of setting the stage for future studies of the prognostic, therapeutic and
pathobiological implications of CTD features in patients with ILD. However, the proposed criteria need
further refinement based on evidence, especially since they imply that patients may be classified as having
UCTD:n diagnosDset kriteerit Epäspesifinen sidekudostauD ja ILD TABLE 3 Diagnostic criteria for undifferentiated connective tissue disease (UCTD)
UCTD diagnostic criteria
Broader definition of UCTD
•  UndifferenDated connecDve Dssue disease A. Symptoms associated with CTD
At least one of: 1) Raynaud’s phenomenon;
At least one of: 1) Raynaud’s phenomenon;
associated ILD = UCTD-‐ILD 2) arthralgias/multiple joint swelling; 3) morning 2) arthralgias/multiple joint swelling; 3) photosensitivity;
stiffness; 4) dry mouth or dry eyes (Sicca
4) unintentional weight loss; 5) morning stiffness;
•  Autoimmune-‐featured intersDDal lung disease features); 5) proximal muscle weakness
6) dry mouth or dry eyes (Sicca features);
7) dysphagia; 8) recurrent unexplained fever;
9) gastro-oesophageal reflux; 10) skin changes (rash);
•  Parhaillaan tekeillään ATS/ERS suositus, jossa 11) oral ulceration; 12) nonandrogenic
alopecia; 13) proximal muscle weakness
nimeksi ehdotetaan B. Positive autoimmune serology
Positive finding of at least one of: 1) ANA
Positive finding of at least one of: 1) ANA; 2) RF;
(high titre); 2) RF (high titre); 3) positive ENA;
3) anti-Scl70 antibody; 4) SS-A or SS-B; 5) Jo-1
•  IntersDDal pneumoniDs with autoimmune-‐
4) anti-Scl70 antibody; 5) anti-RNP antibody;
antibody; 6) ESR (.2 times normal), CRP
6) anticentromere antibody; 7) SS-A or SS-B;
features 8) Jo-1 antibody
CTD: connective tissue disease; ANA: antinuclear antibody; RF: rheumatoid factor; ENA: extractable nuclear antigen; RNP: ribonucleoprotein;
•  Useita tutkimuksia v. 2007 alkaen SS-A: anti-Ro; SS-B: anti-La; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein. : a diagnosis of UCTD requires having one or more of
#
TABLE 2
] Comparison of the Baseline Features Between the UCTD-UIP and UCTD-NSIP Groups
Features
TABLE 2
] Comparison of the Baseline Features Between the UCTD-UIP and UCTD-NSIP Groups
Features
UIP
Patient number
44 (41.9)
Age, y
62.8 ! 8.0
Sex, male
15 (34.1)
6 (20.7)
Smoking (ever smoker)
16 (36.4)
6 (20.7)
BAL (UIP: No. 5 34; NSIP: No. 5 18)
WBC count, /mL
297.7 ! 304.1
287.7 ! 191.0
12.1 ! 17.2
5.9 ! 7.1
Neutrophil, %
Lymphocyte, %
17.5 ! 18.2
18.1 ! 16.9
71.4 ! 15.1
68.4 ! 16.2
Baseline PFT (UIP: No. 5 44; NSIP: No. 5 29)
FVC, %
FEV1, %
[
81.7 ! 16.4
DLCO, %
TLC, % Research Diffuse Lung Disease
Original
6MWT, distance
55.3 ! 16.0
55.0 ! 15.3
69.4 ! 14.2
437.5 ! 94.7
464.1 ! 90.3
DLCO, %
.424
TLC, %
.246
6MWT, distance
.930
Patient number
Treatment regimen
Steroid only
Steroid 1
immunosuppressant
None
Stable
Deterioration
Median follow-up, mo
Survival (%)
Treatment regimen
P Value
tissue disease (UCTD)
involves conditions char-‐ connective
788 IIP-‐poDlasta 2005-‐2012 acterized by both having symptoms of connective tissue disease (CTD) and autoantibodies but
-‐ AnalysoiDin uudestaan not fulfilling the criteria of a specifi
c CTD. The frequency
or prognosis of the usual interstitial
pneumonia (UIP) pattern in UCTD
is unknown, which may
be confused with idiopathic pul-‐ UCTD-‐kriteerit tarkiste\in monary fibrosis (IPF). This study aimed to investigate the frequency of the UIP pattern in
105 UCTD-‐ILD-‐poDlasta that of IPF and
interstitial pneumonia related-‐ to
UCTD
and compare its prognosis with
UCTD-nonspecific interstitial pneumonia
-‐ 4(UCTD-NSIP).
4 UIP, 29 NSIP, 9 OP Steroid only
.695
17 (38.6)
13 (44.8)
14 (31.8)
10 (34.5)
13 (29.5)
6 (20.7)
17 (38.6)
13 (44.8)
Steroid 1
immunosuppressant
14 (31.8)
10 (34.5)
None
13 (29.5)
6 (20.7)
5 (16.1)
3 (13.0)
6 (20.7)
.153
TABLE 5
19 (61.3)
17 (73.9)
7 (22.6)
3 (13.0)
Improvement
Stable
Deterioration
Th
medical records of 788 patients presumptively diagnosed with
idiopathic inter3 e(13.0)
Median2012
follow-up,
stitial
pneumonia
at Asan Medical Center from January 2005 to December
weremo
retro19 (61.3)
17 (73.9)
Survival (%)
spectively
7 (22.6) reviewed.
3 (13.0) UCTD was diagnosed according to the criteria by Corte and colleagues,
1y
and 21
the prognoses
were
44
… compared between UCTD-UIP and UCTD-NSIP and between
3y
UCTD-UIP and IPF. .021
METHODS:
5 (16.1)
] Comparison Between IPF and UCTD-UIP
Features
#
Patient number
IPF
287.7 ! 191.0
5.9 ! 7.1
Sex, male
.900
Co\n .173
V, Eur Respir Rev 2Smoking
013 (ever smoker)
17.5 ! 18.2
18.1 ! 16.9
.920
71.4 ! 15.1
68.4 ! 16.2
.424
81.7 ! 16.4
76.9 ! 18.4
.246
55.3 ! 16.0
55.0 ! 15.3
.930
71.5 ! 11.5
69.4 ! 14.2
.494
464.1 ! 90.3
Surgical lung biopsy
Comparison of the Survival Between
IPF and UCTD-UIP
UCTD-‐NSIP vs UCTD-‐UIP P Value
21
44
97.7
96.6
76.6
96.6
, .005
16 (36.4)
, .005
24 (54.5)
.080
204 (40.9)
WBC count, /mL
204.0 ! 343.1
297.7 ! 304.1
Neutrophil, %
.122
9.6 ! 16.3
277
12.1 ! 17.2
.384
9.8 ! 12.4
17.5 ! 18.2
.001
FVC
71.9 ! 19.7
71.4 ! 15.1
.890
FEV1
82.7 ! 20.2
81.7 ! 16.4
.745
DLCO
59.2 ! 21.5
55.3 ! 16.0
.242
Lymphocyte, %
TLC
71.5 ! 11.5
.811
410.4 ! 122.6
437.5 ! 94.7
.155
26
31
1y
82.3
97.7
3y
57.8
76.6
6MWT, distance
72.2 ! 17.3
Median follow-up, mo
Survival (%)
3y
97.7
RESULTS:
…
.042
Values are reported as mean ! SD or as frequency (%). IPF 5 idiopathic pulmonary fibrosis. See Table 1 and 2 legends for expansion of other
abbreviations.
total subjects. Vij et al7 reported that the prevalence of
autoimmune-featured ILD was 52% of presumable IIP;
however, their criteria included several nonspecific
features as mentioned previously.
UCTD-‐UIP vs IPF …
.695
…
.021
Figure 1 – Comparison of the survival curves of the patients with
UCTD-UIP and UCTD-NSIP. NSIP 5 nonspecific interstitial
15 (34.1)
355 (71.1)
Baseline PFT, frequency (%) (IPF: No. 5 481;
UCTD-UIP: No. 5 44)
Ennuste The baseline characteristics of the IPF and UCTD-UIP
groups were summarized in Table 5. Kaplan-Meier
survival analysis showed significantly better prognosis
of the UCTD-UIP group (n 5 44) than the IPF group
(P 5 .042) (Fig 2). The univariate Cox proportional
…
.069
390 (78.2)
Figure 2 – Kaplan-Meier survival curves of the patients with UCTD-UIP
and IPF. IPF 5 idiopathic pulmonary fibrosis. See Figure 1 legend for
Although the frequency of UCTD was three times
higher in the NSIP than in the UIP pattern, our current
study showed that in patients with ILD and UCTD, the
UIP pattern was as frequent as or more frequent than
the NSIP pattern, which was consistent with the findings
of Vij et al7 (25 UIP pattern vs two NSIP pattern among
63 patients with autoimmune-featured ILD). We also
confirmed that among the patients with UCTD, the
overall prognosis was better for patients with the
NSIP pattern than those with the UIP pattern, although
not significant on multivariate analysis. Furthermore,
Kaplan-Meier survival analysis showed a significant
difference between UCTD-UIP and IPF; the presence
of UCTD in the patients with the UIP pattern was a
significant independent prognostic factor on multivariate analysis. Previously, Corte et al4 reported that
UCTD was not associated with a survival benefit, which
may be due to smaller numbers (total 101 patients) of
the subject compared with ours. Recently, Strand et al21
also reported that there was no significant difference
in survival between UCTD-UIP and IPF. However,
the number of their subjects was small (UCTD-UIP:
19 patients). Furthermore, there was no mention about
the diagnostic criteria of UCTD, which may affect the
expansion of other abbreviations.
reported as frequency (%). See Table 1 legend for expansion
pneumonia; UCTD 5 undifferentiated connective tissue disease;
96.6
Among
105 patients with UCTD (13.3% of total subjects),Values
44 are
had
a UIP pattern
UIP 5 usual interstitial pneumonia.
of abbreviations.
96.6
1 – Comparison of CT
the survival
patients
with
(by surgical lung
biopsy: 24; byFigure
high-resolution
scan:curves
20), of29thehad
a nonspecifi
c interstitial
UCTD-UIP and UCTD-NSIP. NSIP 5 nonspecific interstitial
Values are reported as frequency (%).
See Table 1 legend
for expansion
UCTD 5 undiff
connective
tissue disease;pneumonia pattern
pneumonia
pattern
(by surgicalpneumonia;
lung biopsy),
and erentiated
nine had
an organizing
[ 1 4 7 # 1 C H E S T J A N UKim A RY 2H
0 1C 5 e
] t al, Chest 2015 UIP
usual
interstitial
of abbreviations.
HC eof5t the
al, UCTD-UIP
C
hest pneumonia.
2015 (by biopsy). The overallKim survival
group was shorter than that of the UCTDDownloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User
NSIP group (P 5 .021) but significantly better than that of the IPF
groupFrom:
(P 5http://journal.publications.chestnet.org/
.042).
Downloaded
by a University of Eastern Finland User on 03/02/2015
[ 147#1 CHEST JANUARY 2015 ]
CONCLUSIONS: A UIP pattern, which seems to be frequent in UCTD, showed a poorer prognosis than thatby
ofaUCTD-NSIP.
However,
the prognosis
Downloaded From: http://journal.publications.chestnet.org/
University of Eastern
Finland User
on 03/02/2015of UCTD-UIP was significantly better
than that of IPF, highlighting the importance of searching for underlying UCTD in suspected
IPF cases.
CHEST 2015; 147(1):165-172
1y
44
62.8 ! 8.0
BAL (IPF: No. 5 426; UCTD-UIP: No. 5 34)
.234
group (62.8 ! 8.0 years) (e-Table 1). And the survival of
these patients was also similar to that of the UCTD-UIP
group (e-Fig 1).
P Value
UCTD-UIP
499
.619
Treatment response
(UCTD-UIP: No. 5 31;
UCTD-NSIP: No. 5 23)
.619
16 (36.4)
437.5 ! 94.7
the pathologic pattern was not confirmed in
23 patients, the clinical features and survival curves of
these patients were compared separately. As shown in
group (62.8 ! 8.0 years) (e-Table 1). And the survival of
Table 2, there was no difference in the clinical features
these patients was also similar to that of the UCTD-UIP
between UCTD-UIP and UCTD-NSIP except age and
group (e-Fig 1).
the age of these 23 patients with uncertain pathologic
Comparison of the Survival Between pattern was 62.0 ! 11.1 years, similar to UCTD-UIP
44
29Undifferentiated
…
BACKGROUND:
Treatment response
(UCTD-UIP: No. 5 31;
UCTD-NSIP: No. 5 23)
Improvement
UCTD-NSIP
.216
.494
Values
are reported as mean ! SD or as frequency (%). 6MWT 5 6-min walk test; DLCO 5 diffusing capacity of the lung for carbon monoxide;
PFT 5
pulmonary function test; TLC 5 total lung capacity. See Table 1 legend for expansion of other abbreviations.
.234
Interstitial Pneumonia Related to Undifferentiated
Connective Tissue Disease
UCTD-UIP
6 (20.7)
12.1 ! 17.2
Because the pathologic pattern was not confirmed in
23 patients, the clinical features and survival curves of
these patients were compared separately. As shown in
Table 2, there was no difference in the clinical features
between UCTD-UIP and UCTD-NSIP except age and
IPF and UCTD-UIP
the age of these 23 patients with uncertain pathologic
The baseline characteristics of the IPF and UCTD-UIP
pattern was 62.0 ! 11.1 years, similar to UCTD-UIP
TABLE 3 ] Clinical Course of the Patients With
groups were summarized in Table 5. Kaplan-Meier
Ho-Cheol Kim, MD; Wonjun Ji, MD; Mi Young Kim, MD, PhD; Thomas V. Colby, MD, PhD; Se Jin Jang, UCTD-UIP
MD, PhD;and UCTD-NSIP
survival analysis showed significantly better prognosis
Characteristics
UCTD-UIP
UCTD-NSIP
Chang-Keun Lee, MD, PhD; Seung Bong Han, PhD; and Dong Soon Kim, MD, PhD
of the UCTD-UIP group (n 5 44) than the IPF group
TABLE 3 ] Clinical Course of the Patients With
Patient number
44
29
UCTD-UIP and UCTD-NSIP
(P 5 .042) (Fig 2). The univariate Cox proportional
Characteristics
…
, .005
15 (34.1)
297.7 ! 304.1
Values are reported as mean ! SD or as frequency (%). 6MWT 5 6-min walk test; DLCO 5 diffusing capacity of the lung for carbon monoxide;
Because
PFT 5 pulmonary function test; TLC 5 total lung capacity. See Table 1 legend for expansion of other abbreviations.
Pathologic Pattern and Prognosis
29 (27.6)
52.5 ! 9.3
Age, y
65.1 ! 7.9
one or more of the laboratory findings listed in B; ": criteria proposed by K
INDER et al. [5]. Reproduced from [6] with
Lymphocyte, %
.900
Baseline
.173 PFT (UIP: No. 5 44; NSIP: No. 5 29)
FVC, %
DOI: .920
10.1183/09059180.00003013
FEV1, %
76.9 ! 18.4
71.5 ! 11.5
]
62.8 ! 8.0
Smoking
(ever smoker)
,
.005
(UIP: No. 5 34; NSIP: No. 5 18)
theBAL
symptoms
outlined in A, and
.216
WBC count, /mL
.153
permission.
Neutrophil, %
P Value
NSIP
44 (41.9)
PAge,
Valuey
Sex,
… male
29 (27.6)
52.5 ! 9.3
UIP
Patient number
NSIP
#,"
76.6
Manuscript received February 2, 2014; revision accepted August 10,
2014; originally published Online First September 11, 2014.
ABBREVIATIONS: ANA 5 antinuclear antibody; CTD 5 connective tissue
disease; Dlco 5 diffusing capacity of the lung for carbon monoxide;
ENA 5 extractable nuclear antigen; HRCT 5 high-resolution CT; IIP 5
idiopathic interstitial pneumonia; ILD 5 interstitial lung disease; IPF 5
idiopathic pulmonary fibrosis; NSIP 5 nonspecific interstitial pneumonia; OP 5 organizing pneumonia; RF 5 rheumatoid factor; UCTD 5
undifferentiated connective tissue disease; UCTD-IP 5 interstitial pneumonia related to undifferentiated connective tissue disease; UIP 5 usual
interstitial pneumonia
AFFILIATIONS: From the Department of Pulmonary and Critical Care
Medicine (Drs H.-C. Kim, Ji, and D. S. Kim) and Department of Radiology
(Dr M. Y. Kim), Asan Medical Center, College of Medicine, University
of Ulsan, Seoul, South Korea; Department of Laboratory Medicine and
Pathology (Dr Colby), Mayo Clinic, Scottsdale, AZ; and the Department
of Pathology (Dr Jang), Division of Rheumatology, Department of
Internal Medicine (Dr Lee), and Department of Clinical Epidemiology
and Biostatistics (Dr Han), Asan Medical Center, College of Medicine,
University of Ulsan, Seoul, South Korea.
Drs H.-C. Kim and Ji contributed equally as the co-first authors.
FUNDING/SUPPORT: The authors have reported to CHEST that no
funding was received for this study.
CORRESPONDENCE TO: Dong Soon Kim, MD, PhD, Department of
Pulmonary and Critical Care Medicine, Asan Medical Center, College
of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu,
Seoul, South Korea 138-736; 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.14-0272
Haku •  7.11.2011 haku OYS –  Hoidonpää:ämisaineisto –  Poliklinikkarekisteri journal.publications.chestnet.org
•  Ajanjakso 1.11.2010-‐7.11.2011 •  Dg-‐nrot: J84.0, J84.1, J84.8, J84.9 •  Ensisijainen tavoite: kolmoislääkitystä käy:ävien poDlaiden selvi:äminen Downloaded From: http://journal.publications.chestnet.org/ by a University of Eastern Finland User on 03/02/2015
–  poDlaiden määrä /eri tauDtyypit 165
[
147#1 CHEST JANUARY 2015
on 03/02/2015
PoDlaat •  Haussa saaDin noin 200 poDlaasta •  Mukaan ote\in 188 poDlasta, loput poissulje\in –  Väärä dg-‐nro –  Muun sairaalan kuin OYS:n poDlas (esim biopsiano:oa varten OYS:ssa) –  1 obliteroiva bronkiolii\ –  Parantunut Dlanne (aluperin epäilty fibroosia mu:a ollutkin esim tulehdus) 8 ]
18/04/15 PoDlasryhmät • 
• 
• 
• 
• 
• 
• 
• 
IPF: 60 NSIP: 26 CTD-‐ILD: 33 UIP:n ja NSIP:n piirteitä, epäselvä fibroosi: 35 COP, OP: 16 Asbestoosi: 10 DIP, RBILD: 5 AIP, ARDS (H1N1), akuu\ keuhkovaurio: 3 RA-‐ILD (15) • 
• 
• 
• 
• 
• 
RA-‐UIP: 5 RA-‐NSIP: 5 Epäselvä ILD eli RA-‐ILD: 4 (joista yksi ehkä UIP) RA-‐OP-‐epäily (nivelreumatutkimukset kesken) 1 AEx, johon exitus 1 keuhkonsiirto tehty (RA-‐UIP) CTD-‐ILD (33) • 
• 
• 
• 
• 
• 
• 
RA-‐ILD: 15 SSc-‐ILD: 4 SLE-‐ILD: 3 SjS-‐ILD: 2 PM/DM-‐ILD: 5 Selkärankareuma: 2 Epäselvä sidekudostauD (UCTD?): 2 PM/DM-‐ILD, SjS, selkärankareuma ja epäselvä sidekudostauD •  4 PM-‐ILD, 1 DM-‐ILD –  3 NSIP –  2 luoki:elematonta •  SjS-‐ILD –  2 luoki:elematonta •  Selkärankareuma –  1, jossa hunajakennoa, biopsiassa aikanaan DIP –  1 OP •  Epäselvä sidekudostauD –  2 NSIP Johtopäätökset Kiitos! •  Eri:äin haastava tauDryhmä –  Yksi:äiset tauDyhdistelmät harvinaisia –  Ryhmänä kohtalainen yleinen esh:ssa –  Toisinaan sekä ILD e:ä CTD epäselviä •  MoniammaDllinen yhteistyö keuhkolääkärin, reumatologin, radiologin ja joskus myös patologin kanssa tärkeää •  Tarvitaanko kansallista yhteistyötä keuhkokeskusten välillä? 9

Millaisia keuhkomuutoksia eri sidekudossairauksien yhteydessä

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