Eur Respir Rev 2013; 22: 127, 2632

DOI: 10.1183/09059180.00006812
CopyrightERS 2013

CLINICAL YEAR IN REVIEW

Interstitial lung disease

Vincent Cottin*,#

ABSTRACT: This article reviews the most important articles published in interstitial lung disease, AFFILIATIONS
*Hospices Civils de Lyon, Hopital
as reviewed during the Clinical Year in Review session at the 2012 annual European Respiratory
Louis Pradel, Service de
Society Congress in Vienna, Austria. pneumologie Centre de reference
Since the recent international guidelines for the management of idiopathic pulmonary fibrosis national des maladies pulmonaires
(IPF), important new evidence is available. The anti-fibrotic drug pirfenidone has been recently rares et Centre de competences de
approved in Europe. Other pharmacological agents, especially nintedanib, are still being tested. lhypertension arterielle pulmonaire,
and
The so-called triple combination therapy, anticoagulation therapy and endothelin receptor #
Universite de Lyon, Universite
antagonists, especially ambrisentan, are either harmful or ineffective in IPF and are not Claude Bernard Lyon 1, INRA,
recommended as treatment. Although the clinical course of IPF is highly variable, novel tools UMR754 INRA-Vetagrosup EPHE IFR
have been developed for individual prediction of prognosis. Acute exacerbations of IPF are 128, Lyon, France.

associated with increased mortality and may occur with higher frequency in IPF patients with CORRESPONDENCE
associated pulmonary hypertension. V. Cottin
Interstitial lung disease associated with connective tissue disease has been definitely Hopital Louis Pradel
Service de Pneumologie
established to have a better long-term survival than IPF. A subset of patients present with
28 Avenue Doyen Lepine
symptoms and/or biological autoimmune features, but do not fulfil diagnostic criteria for a given 69677 Lyon Cedex
autoimmune disease; this condition is associated with a higher prevalence of nonspecific France
interstitial pneumonia pattern, female sex and younger age, although survival relevance is E-mail: [email protected]
unclear.
Received:
Nov 20 2012
KEYWORDS: Clinical trial, connective tissue disease, exacerbation, idiopathic pulmonary fibrosis, Accepted after revision:
prognosis, sarcoidosis Nov 27 2012

PROVENANCE
Submitted article, peer reviewed.
his article reports relevant progress in the publications could not be included into this article

T field of interstitial lung disease (ILD)

(table 1), as reviewed during the Clinical
Year in Review session that was held during the
because of space constraints.

TREATMENT OF IDIOPATHIC PULMONARY

2012 annual Congress of the European Respiratory FIBROSIS
Society (ERS) in Vienna, Austria. This session was Treatment of idiopathic pulmonary fibrosis (IPF)
jointly organised by the scientific Assemblies of is definitely a challenge, and numerous clinical
the ERS, especially the Clinical Assembly with trials have been conducted during the past decade
regard to ILD. [1], following progress in pathophysiology [24],
All relevant articles were identified via PubMed better definition and diagnosis of the disease [5, 6],
dedication of physicians in the field, and massive
using the keywords interstitial lung disease,
investment by pharmaceutical companies.
pulmonary fibrosis, connective tissue dis-
ease, collagen vascular disease, and pulmon- The potential efficacy of the triple tyrosine kinase
ary sarcoidosis. Articles that were published in inhibitor BIBF1120 (nintedanib) was evaluated in a
print before the 2011 ERS Congress in Amsterdam, 12-month, phase II, double-blind, placebo-controlled
the Netherlands, were excluded. Articles that randomised trial (ClinicalTrials.gov NCT00514683)
were published after the 2012 ERS Congress in [7]. Nintedanib, also developed in oncology, is an
Vienna were also excluded. Articles were then oral potent intracellular inhibitor of tyrosine kinases
selected on the basis of clinical relevance for chest targeting platelet-derived growth factor-a and -b,
physicians, and likelihood of impacting clinical vascular endothelial growth factor receptors 1, 2, and
practice. Although special attention was given to 3, and fibroblast growth factor receptors 1, 2, and 3. European Respiratory Review
the selection of articles, such a review cannot be These signalling pathways are involved in the patho- Print ISSN 0905-9180
exhaustive, and I apologise to authors whose genesis of lung fibrosis in humans and animal models. Online ISSN 1600-0617

26 VOLUME 22 NUMBER 127 EUROPEAN RESPIRATORY REVIEW

V. COTTIN CLINICAL YEAR IN REVIEW: ILD

TABLE 1 Twelve key messages

1. Significant new evidence has been made available in IPF since the recent international guidelines published in 2011
2. In a 12-month, phase II, double-blind, placebo-controlled randomised trial of patients with IPF, the triple tyrosine kinase inhibitor BIBF1120 (nintedanib) 150 mg
twice daily was associated with a 68.4% reduction in the rate of decline in FVC (p50.06)
3. The triple therapy combining prednisone, azathioprine and N-acetylcysteine was associated with an increased rate of all-cause mortality and hospitalisation
compared to placebo, providing compelling evidence against the initiation of this combination in patients with IPF
4. Results of clinical trials in IPF indicated that anticoagulation therapy and endothelin receptor antagonists are either harmful (especially ambrisentan) or ineffective
and are not recommended as treatment for IPF
5. Delayed access to a tertiary care centre is associated with a higher risk of death in patients with IPF independent of disease severity
6. Concomitant emphysema, DLCO ,47% of predicted value, and pulmonary hypertension are independent predictors of acute exacerbation of IPF
7. Standardised oxygen requirements, pulmonary hypertension at baseline and acute exacerbations of IPF predict mortality in patients with IPF
8. A simple-to-use staging system (GAP score) based on sex, age, FVC (% predicted), and DLCO (% predicted), predicts the individual risk of 1-, 2- and 3-yr
mortality, and may be helpful for management decisions in patients with IPF
9. In a population of systemic sclerosis patients, the alveolar nitric oxide concentration accurately identifies patients with a high risk of developing lung function
deterioration or death.
10. Patients with connective tissue disease and interstitial lung disease have a better long-term prognosis than patients with IPF
11. In the setting of interstitial lung disease, undifferentiated connective tissue disease (also referred to as autoimmune-featured interstitial lung disease or
lung-dominant connective tissue disease), defined by symptoms and/or biological autoimmune features without diagnostic criteria for a given autoimmune
disease, is associated with a higher frequency of nonspecific interstitial pneumonia pattern, female sex, age ,50 yrs, and Raynauds phenomenon compared to
idiopathic counterparts
12. Patients with sarcoidosis diagnosed after the age of 65 yrs are more frequently female, more frequently have asthenia, uveitis, specific skin lesions and
corticosteroid-related adverse events, and less frequently have erythema nodosum than younger patients

IPF: idiopathic pulmonary fibrosis; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide.

The trial included 432 patients who were randomised into five three-drug regimen combining prednisone, azathioprine and
groups to receive placebo or one of four doses of nintedanib N-acetylcysteine (PANTHER-IPF) [8]. This regimen has been
(50 mg once a day, 50 mg twice a day, 100 mg twice a day or widely used after a previous trial demonstrated better
150 mg twice a day). The primary end-point was the annual rate of preservation of FVC and diffusing capacity of the lung for
decline in forced vital capacity (FVC), and secondary end-points carbon monoxide (DLCO) in patients receiving the triple
included acute exacerbations, quality of life measured by the St therapy compared to those who received a combination of
Georges respiratory questionnaire and total lung capacity. The prednisone and azathioprine [9]. In this trial, sponsored by the
diagnosis of IPF was consistent with international criteria [5], National Heart Lung and Blood Institute (ClinicalTrials.gov
considered definite in 33% of patients and probable in 62% of NCT00650091), patients with IPF and mild-to-moderate lung
patients, with a surgical lung biopsy performed in 28% of cases. A function impairment were assigned in a 1:1:1 ratio to receive
total of 85% of the patients completed the study. FVC declined by a one of three groups of treatment for 60 weeks: combination
mean of 0.06 L per yr in the group receiving 150 mg of nintedanib therapy (prednisone, azathioprine and N-acetylcysteine), N-
twice daily, as compared to 0.19 L per yr in the group receiving acetylcysteine alone, or placebo. The primary end-point was
placebo, representing a 68.4% reduction in the rate of decline in the change in longitudinal measurements of FVC. After
FVC (p50.06 with the closed testing procedure for multiplicity approximately 50% of the data had been collected (77 patients
correction; p50.01 with the hierarchical testing procedure) [7]. receiving combination therapy and 78 receiving placebo), a
Encouraging results were also observed for secondary end-points, planned interim analysis revealed an increased rate of all-
especially a lower incidence of acute exacerbations of IPF (2.4 cause mortality (eight deaths versus one death, p50.01) and
versus 15.7 per 100 patient-yrs, p50.02) and a significant difference hospitalisation (23% versus 7%, p,0.001) in the group receiving
in the St Georges questionnaire score between groups, a lesser the triple combination therapy as compared to the placebo
decline in total lung capacity, and fewer patients whose FVC group, prompting the independent data safety and monitoring
decreased by o10% in the treated group. The main adverse events board to recommend termination of the study [8]. Patients (78
that were considered to be related to the study drug were in the combination therapy group and 77 in the placebo group)
gastrointestinal symptoms (diarrhoea, nausea and gastro-intestinal
had been followed for a mean of 32 weeks. No evidence was
pain) and increase in levels of liver aminotransferases, most with
observed for a clinical or physiological benefit, especially FVC,
mild or moderate intensity. Given the positive signal for a slower
in patients receiving the triple therapy. Of note, although
rate of decline in FVC and consistent secondary end-points, two
increased mortality was observed in patients receiving triple
large pivotal phase III trials are currently ongoing worldwide
therapy, no functional worsening was found in this group. 28%
(ClinicalTrials.gov NCT01335464 and NCT01335477, INPULSIS 1
of patients receiving the combination therapy discontinued all
and 2, respectively), testing 150 mg of nintedanib twice daily. The
three medications, compared to 4% in the placebo group
enrolment of 1,066 patients was completed on September 17, 2012,
(p,0.05). Thus, this study provides compelling evidence
and results are expected by the first quarter of 2014.
against the initiation of the triple therapy in patients with
Another randomised, placebo-controlled trial conducted by the
US IPFnet consortium evaluated the safety and efficacy of a
IPF [8]. In patients already receiving the triple combination
therapy, the decision of whether to continue or stop therapy c
EUROPEAN RESPIRATORY REVIEW VOLUME 22 NUMBER 127 27
CLINICAL YEAR IN REVIEW: ILD V. COTTIN

may be based on a number of factors, including: patient worldwide standard of care for the treatment of IPF although
preferences, duration of therapy, tolerance and prior evolution with low-quality evidence, is no longer recommended [10, 19].
in lung function [10]. Of note, this does not apply to patients Anticoagulation as a treatment of IPF is strongly discouraged.
presenting with non-IPF ILDs, especially idiopathic nonspe- One further study (ASCEND, ClinicalTrials.gov NCT01366209)
cific interstitial pneumonia or ILD in the setting of connective is being conducted with pirfenidone in the USA. The
tissue disease (CTD), who may in some circumstances benefit endothelin receptor antagonist bosentan, macitentan and
from corticosteroids and/or immunosuppressive therapy. The ambrisentan [1921] have not proven efficacious in patients
comparison of the N-acetylcysteine alone group and the with IPF. Further study is needed to evaluate the long-term
placebo group in IPF patients is ongoing, and shall decipher benefit:safety ratio of sildenafil [22]. Current international
whether this drug is beneficial in patients with IPF. guidelines already need to be updated to account for new
evidence [19, 23]. The choice of appropriate end-points in IPF
Results from two phase III randomised, double-blind, placebo- trials is controversial [2429], and priority is now given to
controlled, multinational trials evaluating pirfenidone in clinically relevant end-points in a realistic and ethical setting.
patients with mild-to-moderate IPF (as defined by FVC o50% Indeed, participation of patients in clinical trials is, more than
predicted and DLCO o35% pred) were published earlier the ever before, a priority to test other pharmacological agents.
same year [11]. Although only one of these studies reached the
primary end-point of change in FVC at week 72 (p,0.001), the
pooled analysis from both studies showed a significant PROGNOSIS OF IPF
reduction in the decline in FVC compared to placebo One study has evaluated the delay in accessing specialised care
(p,0.005), with further beneficial effects of pirfenidone with among patients with IPF, defined as the estimated time from
regard to several secondary end-points [1]. The most common the onset of dyspnoea to the initial visit at a tertiary care centre
adverse events were gastrointestinal (nausea, dyspepsia, vomit- [30], e.g. a centre specialised in ILD or a transplant centre.
ing and anorexia), skin rash and photosensitivity, and dizziness, Survival time and time to transplantation were evaluated, with
consistent with the known safety profile of the drug and covariates accounting for most variables that could affect
generally of mild-to-moderate severity [11]. A meta-analysis of prognosis, including age, sex, FVC, lead time, potential
these studies [12, 13] and another study conducted in Japan [14] barriers to accessing healthcare, comorbidities and treatment.
further demonstrated a beneficial effect regarding progression- The mean delay from onset of dyspnoea to access to a
free survival time (HR 0.70, 95% CI 0.560.88, p50.002). specialised centre was 2.2 yrs (interquartile range 1.03.8 yrs)
[30]. Delayed access to a tertiary care centre was associated
In the ACE-IPF trial (ClinicalTrials.gov NCT00957242) [15], with a higher risk of death in patients with IPF independent of
investigators from the IPFnet consortium tested the hypothesis disease severity [30]. A longer delay was not associated with a
that targeting the coagulation cascade at therapeutic doses lower likelihood of undergoing lung transplantation. This
would reduce the rates of mortality, hospitalisation, and decline important finding is not self-intuitive, as many clinicians used
in FVC. Rationale for this hypothesis was based on compelling to argue that referral of ILD patients had little implication due
evidence from both animal and human studies that have to limited therapeutic options in IPF. In fact, once referred,
demonstrated an increased risk of thrombosis in patients with patients may benefit from a correct diagnosis and early
IPF [16], enhanced pro-coagulant activity in alveoli of patients appropriate management. This indicates that early referral to
with IPF, stimulation of fibrosis by activated coagulation an ILD centre should be considered for those with suspected or
cascade [17], and a previous unblinded clinical trial suggesting known ILD. It is anticipated that patients may ultimately
increased survival in patients receiving anticoagulation [18]. In benefit from early detection of the disease (so-called subclinical
this 48-week, double blind, placebo-controlled trial, patients ILD) [31, 32], which may be triggered by velcro crackles at lung
were randomised to receive warfarin versus placebo targeting an auscultation [33], investigation by primary care providers and
international normalised ratio (INR) of 23 using an encrypted pulmonologists of patients with mild exercise dyspnoea or
INR home monitoring system. The primary end-point was time chronic cough, systematic screening in individuals with history
to death, hospitalisation (non-elective, non-bleeding), or a of familial ILD, innovative biomarkers or imaging methods in
decline of o10% in FVC. Termination of the study was the future [32, 33].
recommended by the independent data safety and monitoring
board after 145 of the planned 256 subjects had been randomised The clinical course of IPF is highly variable, with inter-
due to a low probability of benefit and an excess in mortality individual variability that impairs our ability to predict
[15]. The cause of the excess mortality was unknown, with prognosis and evaluate the appropriate timing for lung
deaths being related to respiratory worsening and not to severe transplantation. In order to optimise the individual prediction
bleeding complications, especially diffuse alveolar haemor- of outcome, MURA et al. [34] evaluated the survival and
rhage. The results of this trial, although disappointing, have incidence of acute exacerbations in a prospective cohort of 70
practical consequences. The use of anticoagulant therapy as a patients newly diagnosed with IPF. In this first prospective
treatment for IPF is strongly discouraged, as opposed to cohort of IPF patients diagnosed according to current guide-
international IPF guidelines which listed anticoagulation ther- lines, survival predictors were then tested in an independent,
apy as a possible choice in a minority of patients [5]. retrospective cohort of 68 IPF patients from another centre. The
median survival was 3021 months, and the 3-yr mortality
Altogether, results made available during the past year have was 46%, comparable with prior studies. Using multivariate
provided new evidence since the recent international evidence- analysis, a Medical Research Council dyspnoea score .3, a 6-
based guidelines for the management of IPF [5]. The triple min walk distance f72% pred and a composite physiologic
combination therapy, which has often been considered the index [35] were independent predictors of 3-yr survival, and a

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V. COTTIN CLINICAL YEAR IN REVIEW: ILD

risk stratification score was derived. Furthermore, the 3-yr Furthermore, IPF patients with pulmonary hypertension at
incidence of acute exacerbations was 18.6%, with concomitant the time of assessment for transplantation had a greater risk of
emphysema and DLCO f47% pred being independent acute exacerbation of IPF [39]. Neovascularisation evaluated as
predictors for acute exacerbations [34]. However, the use of microvessel density at histopathology was increased in cellular
this scoring system is limited by the use of the patients fibrosis and decreased in honeycombing, and inversely
perception of dyspnoea, which by essence is subjective. correlated with the mean pulmonary arterial pressure.
Pulmonary hypertension has not been evaluated as a potential
To improve prognostication, a multidisciplinary staging
predictor of acute exacerbations in previous studies [40], and
system was developed for IPF using commonly measured
this result needs confirmation by further studies. The
clinical and physiologic variables. LEY et al. [36] evaluated
mechanisms of the observed association between pulmonary
transplant-free survival in a derivation longitudinal cohort of
hypertension and acute exacerbation of IPF are not well
228 patients with IPF and, using competitive risk regression,
understood, however, the link may be related to endothelial
modelled an individual risk calculator which was then
dysfunction. Whether corticosteroid therapy and/or immuno-
validated in an independent cohort of 330 IPF patients. Four
suppressive therapy are beneficial in acute exacerbations of IPF
variables were included in the final model: sex (G), age (A),
requires further study [41].
and FVC and DLCO as physiology variables (P). The 3-yr
prognosis could be estimated by using either a formula (GAP To address the pathophysiology of acute exacerbations of IPF,
calculator) or a scoring system (GAP index), further identifying LEE et al. [42] measured the levels of pepsin, a marker of gastric
three stages of disease. The 1-yr mortality was 5.6%, 16.2% and aspiration, in bronchoalveolar lavage samples from 24 well-
39.2% in stages I, II, and III, respectively, and the 3-yr mortality characterised patients with acute exacerbation of IPF and 30
was 16.3%, 42.1% and 76.8%, respectively [36]. One drawback stable IPF controls. Acute exacerbations were diagnosed using
of this staging system is that the change in lung function (e.g. standard criteria [43], and bronchoalveolar lavage was per-
decline in FVC or DLCO) was not included; however, this formed using a standardised technique. Pepsin levels were
information may be taken into account using an alternative higher, on average, in patients with acute exacerbations as
mortality risk scoring system [37]. Incorporating the imaging compared with stable controls (a difference driven by a
data in the scoring system does not improve its predictive subgroup of eight patients with highly elevated pepsin levels)
value. This validated and simple-to-use staging system may be [42], suggesting that occult aspiration may play a role in some
helpful to inform IPF patients of their prognosis, to help cases of acute exacerbations of IPF. Gastro-oesophageal reflux,
management decisions, especially lung transplantation, and which is highly prevalent in patients with IPF [44, 45], may
might facilitate research by identifying patient populations at play a role in the induction or progression of the disease and
high risk of death and by providing an evidence-based setting may represent a relevant target for future IPF clinical trials
to investigate stage-specific management options. [45], as suggested by retrospective studies [46].
HOOK et al. [38] assessed whether oxygen requirement could be
used as a tool for prognostication in patients with IPF. Oxygen ILD ASSOCIATED WITH CTD
requirements were standardised, and titrated oxygen require- As ILD is a major and unpredictable cause of morbidity and
ment was defined as the lowest oxygen flow rate required to the first cause of death in patients with systemic sclerosis,
maintain an oxyhaemoglobin saturation of 96% while stand- biomarkers at the time of presentation that may predict the risk
ing, immediately prior to 6-min walk testing. Results were of subsequent lung function deterioration leading to respira-
derived from a prospective cohort of 104 patients with IPF and tory failure or death would be highly valuable. Previous
validated in a distinct retrospective cohort of 151 IPF patients. studies have shown that increased alveolar nitric oxide
The titrated oxygen requirement and 6-min walk test distance concentrations are correlated to the severity of ILD in patients
were independent predictors of survival. A higher titrated with systemic sclerosis [47, 48]. Measurement of alveolar nitric
oxygen requirement was associated with a greater mortality oxide concentrations requires partitioning to split fractional
rate independent of FVC and 6-min walk test results in IPF exhaled nitric oxide, reflecting both bronchial and alveolar
(adjusted HR 1.16, 95% CI 1.061.27 L?min-1) [38]. The inflammation, from alveolar nitric oxide reflecting alveolar
supplemental oxygen flow rate had a prognostic significance inflammation. To evaluate the value of partitioned measure-
comparable to that of DLCO, oxyhaemoglobin saturation at the ment of exhaled nitric oxide to predict subsequent lung
end of 6-min walk test and heart rate recovery. This simple function deterioration or death in systemic sclerosis, pulmon-
measure of gas exchange impairment might be used to help in ary function was evaluated in a cohort of 105 patients with
the referral of patients for lung transplantation. systemic sclerosis (including 49% with ILD and 6% with
pulmonary hypertension) followed longitudinally over a 3-yr
ACUTE EXACERBATION OF IPF period. The results were validated in a distinct prospective
Several studies significantly improved our understanding of cohort of 45 patients with systemic sclerosis (48% with ILD and
acute exacerbations of IPF. JUDGE et al. [39] retrospectively 2% with pulmonary hypertension) [49]. The threshold of
analysed a cohort of 55 patients with IPF (mean age 60 yrs, 41 alveolar nitric oxide concentration was defined using a
males) who had been evaluated for lung transplantation receiver operating curve. Alveolar nitric oxide concentrations
including right heart catheterisation. As lung transplantation at baseline .5.3 ppb were associated with an increased risk of
alters the natural course of the disease, transplant events were 10% decrease in total lung capacity or FVC from baseline or
censored over the follow-up period. This study demonstrated death (HR 6.06, 95% CI 2.36-15.53; p,0.001), irrespective of
that pulmonary hypertension at baseline and acute exacerba-
tions of IPF were associated with increased mortality.
FVC values or the presence of ILD at baseline [49]. Thus, in a
population of systemic sclerosis patients, the alveolar nitric c
EUROPEAN RESPIRATORY REVIEW VOLUME 22 NUMBER 127 29
CLINICAL YEAR IN REVIEW: ILD V. COTTIN

oxide concentration accurately identifies patients with a high 62% of them with a UIP pattern at chest computed tomography,
risk of developing lung function deterioration or death. indicating that clinical and/or biological features of CTD may
Whether this noninvasive biomarker may also help to identify be associated with ILD even with a typical UIP pattern at
candidates for early initiation of appropriate treatment imaging. Furthermore, patients with autoimmune-featured ILD
requires further investigation. were younger than IPF counterparts, were more likely to be
females, and less frequently had a UIP pattern at imaging.
The impact of diagnosing CTD in a patient with ILD (CTD-ILD) However, the 5-yr overall survival was similar in patients with
has long been debated, with recent findings suggesting that autoimmune-featured ILD and in those with IPF (52% versus
CTD-ILD may have a better prognosis than IPF, with the notable 48%, respectively), although it was significantly higher in those
exception of patients with rheumatoid arthritis and a usual with ILD associated to one defined CTD (95%, p,0.01) [54]. In a
interstitial pneumonia (UIP) pattern at imaging [50]. This post hoc subgroup analysis, patients with autoimmune-featured
concept has gained further support from a large study of data ILD and a high titre of antinuclear antibodies (o1:1,280) had a
derived from The Health Improvement Network, a large greater survival than their counterparts. This observation
primary care database in the UK, involving 446 general suggests that future refinement of clinical and biological criteria
physicians from 2000 to 2009 [51]. Mortality rates were compared for so-called autoimmune-featured ILD (or undifferentiated
between the groups using Cox regression, adjusting for age, sex ILD) may identify a subset of patients with more clinical, and
and year of diagnosis. 324 individuals with CTD-ILD had better especially prognostic, relevance.
survival (median survival 6.5 yrs) than 2,209 individuals with
pulmonary fibrosis and absence of CTD (median survival In a similar approach, CORTE et al. [56] retrospectively studied
3.1 yrs) (HR 0.76, 95% CI 0.620.92), although with significant 101 patients (38% females) with idiopathic interstitial pneu-
mortality in both groups (124 versus 230 deaths per 1,000 person- monia who had a surgical lung biopsy between 1979 and 2005.
yrs, respectively) [51]. The median survival was 8.8 yrs in Two major findings were reported in this study. First, the
patients with systemic sclerosis-ILD, 6.6 yrs in rheumatoid authors demonstrated that the proportion of patients with
arthritis-ILD and 5.6 yrs in other CTDs (p50.0217) [51]. One idiopathic interstitial pneumonia who were diagnosed with
limitation of the study was that IPF was considered a clinical undifferentiated CTD were dependent on the criteria used.
syndrome diagnosed in primary care, with possible confusion When the stringent criteria described by MOSCA et al. [57] was
with other idiopathic interstitial pneumonia of less severe applied, 21% of patients with nonspecific interstitial pneumo-
outcome; histopathological data were not available. However, nia and 13% with IPF were diagnosed with undifferentiated
only incident cases were included, limiting bias. It is likely that CTD, while the proportion was 71% and 36%, respectively,
the widespread use of high-resolution computed tomography when the less specific diagnostic criteria of KINDER et al. [52]
(HRCT), the increased awareness of pulmonary complications of was applied. Using the criteria of KINDER et al. [52] did not add
CTD, and the multidisciplinary approach of patients with CTD value to prognostic evaluation once the histological pattern
have contributed to milder cases of ILD being diagnosed. had been taken into account [56]. This further underlines that a
standardised definition of undifferentiated CTD based on
Significant overlap exists between patients with CTD-ILD and prediction of histological pattern and/or prognosis is still
those with idiopathic ILD. Current guidelines recommend lacking. Secondly, this study confirmed the link between a
evaluation of patients with ILD for underlying CTD using both histological pattern of nonspecific interstitial pneumonia and
clinical evaluation and measurement of a variety of auto- the context of CTD. Although the diagnosis of nonspecific
antibodies. While a defined and well-characterised CTD is interstitial pneumonia continues to require surgical lung
occasionally diagnosed in this setting, a subset of patients biopsy, a clinical algorithm predictive of a histological
present with symptoms and/or autoimmune features sugges- diagnosis of nonspecific interstitial pneumonia was suggested
tive of an autoimmune condition, but do not fulfil international based on HRCT appearance (typical or not typical of IPF/UIP),
diagnostic criteria for a given CTD. These patients are sex and age, and Raynauds phenomenon. In patients with
currently considered to have undifferentiated CTD [52], also HRCT features not typical of IPF, the presence of either a
referred to by other authors as lung-dominant CTD [53]. compatible demographic profile (e.g. females aged ,50 yrs) or
Undifferentiated CTD is associated with a higher prevalence of Raynauds phenomenon was highly specific for a histolo-
nonspecific interstitial pneumonia pattern, female sex and pathology of nonspecific interstitial pneumonia and was
younger age, although with unclear survival relevance [52, 53]. associated with improved survival [56].
The prevalence and characteristics of autoimmune features The potential value of anti-cyclic citrullinated peptide anti-
were studied prospectively in 200 subjects with ILD [54]. IPF bodies has been demonstrated in 74 patients who had
was diagnosed according to the 2002 international criteria [55], respiratory symptoms in the absence of existing rheumatoid
and CTD was diagnosed following American College of arthritis or other CTD, three of whom eventually developed
Rheumatology criteria. Patients received a questionnaire and articular manifestations of rheumatoid arthritis during a
underwent comprehensive serology testing. They were con- median follow-up of 449 days [58]. The implication of anti-
sidered as having autoimmune-featured ILD if they had at cyclic citrullinated peptide antibodies in patients with lung
least one sign or symptom suggestive of a CTD and at least one disease but no established rheumatoid arthritis requires
serologic test reflective of an autoimmune process, yet did not fit further investigation.
criteria for CTD [54]. Of note, autoimmune features included
some that are poorly specific for CTD, e.g. gastro-oesophageal Overall, these studies indicate that clinical and/or biological
reflux and low titre auto-antibody. Autoimmune-featured ILD features of CTD may be associated with ILD, even in the case of
was identified in 32% of incident patients evaluated for ILD, typical UIP pattern on chest HRCT. So-called undifferentiated

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V. COTTIN CLINICAL YEAR IN REVIEW: ILD

CTD is associated with a histological pattern of nonspecific 2 Wuyts WA, Agostini C, Antoniou K, et al. The pathogenesis of
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STATEMENT OF INTEREST 21 King TE Jr, Brown KK, Raghu G, et al. Build-3: A randomized,
V. Cottin has received fees for speaking from Intermune, Boehringer controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J
Ingelheim and Actelion, and has participated as an investigator to Respir Crit Care Med 2011; 184: 9299.
clinical trials sponsored by Intermune, Boehringer Ingelheim and 22 Zisman DA, Schwarz M, Anstrom KJ, et al. A controlled trial of
Actelion, and as member of a steering committee for a clinical trial sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med
sponsored by Boehringer Ingelheim. 2010; 363: 620628.
23 Muller-Quernheim J, Wells A. Evidence-based recommendations
in idiopathic pulmonary fibrosis: a year is a long time in interstitial
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