Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported

Balestro, Elisabetta

Braccioni, Fausto

Calabrese, Fiorella

Cozzi, Franco

Lunardi, Francesca

Nordio, Beatrice

Polverosi, Roberta

Sfriso, Paolo

English

PubMed

Francesca Lunardi

Elisabetta Balestro

Beatrice Nordio

Franco Cozzi

Roberta Polverosi

Paolo Sfriso

Fausto Braccioni

Fiorella Calabrese

Springer - Publisher Connector

CASE REPORT Open Access
Undifferentiated connective tissue disease
presenting with prevalent interstitial lung
disease: Case report and review of literature
Francesca Lunardi1, Elisabetta Balestro2, Beatrice Nordio2, Franco Cozzi3, Roberta Polverosi1, Paolo Sfriso3,
Fausto Braccioni2 and Fiorella Calabrese1*
Abstract
Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms
suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective
tissue disease. Lung involvement can complicate the course and management of the disease, often determining a
worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported.
We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical
sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia
(NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening
which then detected Raynaud’s phenomenon and positivity of antinuclear antibodies. After a multidisciplinary
discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with
UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident
first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial
lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct
diagnosis.
Background
The term undifferentiated connective tissue disease
(UCTD) is used to define clinical entities characterised
by features suggestive of CTD which do not meet the
classification criteria of the American College of Rheu-
matology for a specific single disease, such as systemic
lupus erythematosus, systemic sclerosis, polymyositis/
dermatomyositis, and Sjögren’s syndrome [1-9]. UCTD
can evolve in these patients over time.
As only a few reports have described lung involvement
during UCTD the natural history still remains unknown
and unpredictable. Interstitial lung disease (ILD) with a
histological pattern of non specific interstitial pneumo-
nia (NSIP) has recently been reported to be the most
frequent lung manifestation [10-13], usually responsible
for progression and adverse outcome of the disease.
Lung involvement as the first clinical manifestation of
UCTD is rarely reported. We discuss the case and
review the associated literature of UCTD.
Case Presentation
Clinical summary
A 50-year-old non-smoking female textile worker after a
flu-like episode started to suffer from dry cough and pro-
gressive dyspnoea. Chest radiography showed parenchy-
mal pulmonary opacity in the lower posterior segment of
the right haemithorax and bilateral interstitial thickening
of the lower pulmonary segment. The patient was there-
fore treated with antibiotics and steroids but the clinical
and radiological manifestations did not improve.
Computed tomography (CT) scan of the lungs three
months later revealed a ground glass pattern in the apical
segment of the upper and lower lobes. Lymphadenopathy
in the paratracheal space was also observed (Figure 1).
The laboratory results showed an increased level of
inflammatory parameters (erythrocyte sedimentation
* Correspondence: fiorella.calabrese@unipd.it
1Department of Diagnostic Medical Sciences and Special Therapies,
University of Padua, Padua, Italy
Full list of author information is available at the end of the article
Lunardi et al. Diagnostic Pathology 2011, 6:50
http://www.diagnosticpathology.org/content/6/1/50
© 2011 Lunardi 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/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
rate: 78 mm; C-reactive protein: 5.7 mg/dl; Fibrinogen:
492 mg/dl), without any other positive tests (e.g. rheuma-
toid factor). The pulmonary function test showed a
restrictive pattern (vital capacity: 1.59 L, 50% predicted;
total lung capacity: 3.94 L, 75% predicted) with a reduc-
tion in the single breath diffusion capacity of carbon
monoxide (TLCO/VA 0.84 mmol/min/kPa/l, 52% pre-
dicted). Arterial oxygen tension at rest was normal (pH:
7.44; pO2: 92.4 mmHg; pCO2: 38.8 mmHg). A six-minute
walking test revealed oxygen desaturation (87%) with
severe dyspnoea (BORG scale 5/10). Bronchoscopy with
combined bronchoalveolar lavage and transbronchial
biopsies were performed, but they provided no significant
additional information.
Open lung biopsy was performed and based on a histo-
logical diagnosis of non specific interstitial pneumonia
(NSIP) an accurate immunological follow-up was required.
The assay of a larger panel of autoantibodies showed
only positivity of antinuclear antibodies (ANA), at titer
1/160. The other investigated antibodies (such as anti-
ENA, anti-DNAds, anti-centromere, anti-cyclic citrulli-
nated peptide and anti-tRNA synthetases) were all
negative. Finally, a nailfold capillaroscopy (NFC) was
recommended and showed the presence of minor capil-
lary changes characteristic of a nonspecific pattern
(Figure 2). Clear-cut signs of Raynaud’s phenomenon
(RP) were then reported during rheumatologic follow-
up. After a multidisciplinary discussion (pneumologist,
radiologist, pathologist and rheumatologist) a final diag-
nosis of NSIP associated with UCTD was made.
Therefore, the patient was discharged and started a
treatment regimen of oral cyclophosphamide (100 mg/
die) and prednisone (25 mg/die) for 12 months. The
combination was then stopped and the patient was fol-
lowed only with low dose of corticosteroids.
Up to now, over a follow-up period of three years, the
clinical picture and the pulmonary function test remain
stable and no definitive CTD has developed.
Pathological findings
Low-magnification microscopy showed an uniform
alveolar septa thickening by cellular infiltrate and fibro-
sis. At higher magnification, the alveolar septal intersti-
tium was expanded by mild inflammation and collagen
deposition with minimal honeycomb changes. No fibro-
blastic foci and active fibrosis were seen and patchy
lymphoid aggregates were occasionally visible. The inter-
stitial chronic inflammation consisted of lymphocytes and
some plasma cells. Increased macrophagic infiltration was
seen in some alveolar spaces. The appearance was consis-
tent with the fibrosing variant of NSIP (Figure 3). Organis-
ing pleuritis with mesothelial hyperplasia was present.
Medial vessel thickening was particularly seen in remo-
delled lung areas.
Conclusions
Up to 25% of patients who show clinical and laboratory
features of systemic autoimmune diseases do not fulfil
the classification criteria of ACR for a specific CTD and
they are considered to have a distinct clinical entity,
called UCTD [1,4,7,8]. The definition is still under
debate, although it is becoming more definite. In 1999
and 2006 Mosca et al. reviewed the literature and
Figure 1 Computed tomography scan of the lung. A: Axial CT
scan shows right paratracheal linfoadenopathy B: Axial HRCT scan
shows septal interlobular thickening with ground glass opacities at
the lower lobes.
Figure 2 Capillaroscopy images. Abnormal capillary shape with
winding and acrocyanotic capillaries.
Figure 3 Histological pattern in lung biopsy. Panoramic view
showed interstitial inflammatory cell infiltration sometimes
aggregated in follicular pattern (arrows). Vessel remodelling
(arrowhead) is also well seen (original magnification, haematoxylin-
eosin stain: 40x).
Lunardi et al. Diagnostic Pathology 2011, 6:50
http://www.diagnosticpathology.org/content/6/1/50
Page 2 of 4
proposed that preliminary classification criteria for
UCTD include the following: at least one clinical mani-
festation of CTD, positive ANA results, and a disease
duration of at least three years [4,8].
It may be difficult to distinguish these conditions from
early phases of defined diseases such as systemic lupus
erythematosus, systemic sclerosis and others. The nat-
ural history of these rare entities is variable: a high per-
centage of patients with UCTD maintain an
undifferentiated clinical course and do not evolve to a
distinct CTD, whereas some patients can evolve over
time [4,7,8,11].
Laboratory test screening is essential to identify mar-
kers that may suggest a systemic, autoimmune disease,
or specific organ involvement. In fact, about 90% of the
patients with UCTD show positive ANA [1,5]. Capillaro-
scopy is useful to detect abnormalities in capillary shape
and blood flow, which suggest features of Raynaud’s
phenomenon.
The onset of UCTD is similar to most CTDs, peaking
in the middle years of life. There are no specific signs or
symptoms of UCTDs because these entities present
manifestations common to other CTDs. The main clini-
cal features at onset of UCTD are arthritis and arthral-
gia, Raynaud’s phenomenon, pleuritis and pericarditis,
xerostomia and xerophtalmia, leukopenia, esophageal
involvement, fever and myositis [1,9,14]. Major organ
involvement is unusual and the lung has been reported
as a late complication, often determining a worse out-
come [15].
Recently an ATS working group described idiopathic
NSIP as a distinct entity that occurs mostly in middle-
aged women who never smoked and who often have
positive serologic tests (antinuclear antibodies or rheu-
matoid factor) [16].
The typical histological findings of NSIP detected in
our patient who also presented the clinical phenotype
(middle-aged, non-smoking woman) suggested an addi-
tional careful investigation for an accurate rheumatolo-
gic evaluation and follow-up.
Kinder et al. recently showed that the majority of
patients (88%) who met the UCTD criteria had distinct
radiological and pathological features of NSIP, thus
emphasizing that this pattern is peculiar of the disease
[10]. The same group more recently highlighted the
concept that patients with UCTD and lung involvement
have improved pulmonary function during the follow-
up, as in our case [11] compared to other unfavourable
interstitial diseases as idiopathic pulmonary fibrosis.
Lung involvement usually appears as a complication in
established UCTD. There is only a recent study which has
demonstrated that NSIP may be the first clinical manifes-
tation of the disease [13], as in our case. The prospective
study by Romagnoli et al. demonstrated that more than
50% of patients diagnosed with NSIP showed an autoim-
mune disease, as UCTD, in their follow-up. In particular,
UCTD was detected in 22% of NSIP patients [13].
In conclusion, we have described a case of a patient
with UCTD whose first clinical manifestation was lung
involvement. UCTD should be considered when NSIP is
diagnosed even in cases with evident first clinical mani-
festations of severe respiratory dysfunction.
A multidisciplinary approach with the intervention of
pneumologists, radiologists, pathologists and rheumatol-
ogists is recommended to achieve a correct diagnosis.
Consent
Written informed consent was obtained from the patient
for publication of this case report and any accompany-
ing images. A copy of the written consent is available
for review by the Editor-in-Chief of this journal.
Acknowledgements
The authors thank Judith Wilson for English revision. This study was
supported by the Italian Ministry of Instruction, University and Research.
Author details
1Department of Diagnostic Medical Sciences and Special Therapies,
University of Padua, Padua, Italy. 2Department of Cardiac, Thoracic, and
Vascular Sciences, University of Padua, Padua, Italy. 3Department of Clinical
and Experimental Medicine, University of Padua, Padua, Italy.
Authors’ contributions
BN and EB were involved in the clinical assessment of the patient and in
paper writing, FL in morphological description and paper writing, FC and PS
in rheumatological investigations, FB in clinical assessment, RP in radiological
evaluations, FC in pathological diagnosis and paper writing.
All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 4 April 2011 Accepted: 7 June 2011 Published: 7 June 2011
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doi:10.1186/1746-1596-6-50
Cite this article as: Lunardi et al.: Undifferentiated connective tissue
disease presenting with prevalent interstitial lung disease: Case report
and review of literature. Diagnostic Pathology 2011 6:50.
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Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: Case report and review of literature

Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported.We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia (NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening which then detected Raynaud's phenomenon and positivity of antinuclear antibodies. After a multidisciplinary discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct diagnosis

LUNARDI, FRANCESCA

BALESTRO, ELISABETTA

NORDIO, BEATRICE

COZZI, FRANCO

POLVEROSI, ROBERTA

SFRISO, PAOLO

CALABRESE, FIORELLA

F. Braccioni

Archivio istituzionale della ricerca - Università di Padova

Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: case report and review of literature.

Abstract Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported. We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia (NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening which then detected Raynaud's phenomenon and positivity of antinuclear antibodies. After a multidisciplinary discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct diagnosis.</p

Sfriso Paolo

Polverosi Roberta

Cozzi Franco

Nordio Beatrice

Balestro Elisabetta

Lunardi Francesca

Braccioni Fausto

Calabrese Fiorella

Directory of Open Access Journals

Diagnostic Pathology

Abstract
          Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported.
          We describe a case of a female patient who developed significant respiratory dysfunction as the principal clinical sign. Video-assisted thoracoscopy was performed and a histological pattern of nonspecific interstitial pneumonia (NSIP) was found. A pathological diagnosis suggested careful follow-up with extensive immunological screening which then detected Raynaud's phenomenon and positivity of antinuclear antibodies. After a multidisciplinary discussion (pneumologist, radiologist, pathologist and rheumatologist) a final diagnosis of NSIP associated with UCTD was made. The diagnosis of UCTD should be considered when NSIP is diagnosed even in cases with evident first clinical manifestations of severe respiratory dysfunction. A multidisciplinary approach in the field of interstitial lung disease with NSIP, also including rheumatologic expertise, is fundamental to achieve a prompt and correct diagnosis.</jats:p

Crossref

A: Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project.

Chida K: Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respir Med

Defining unclassificable connective tissue diseases: incomplete, undifferentiated, or both? J Rheumatol

Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD.

Early undifferentiated connective tissue disease. V. An inception cohort 5 years later: disease remissions and changes in diagnoses in well established and undifferentiated connective tissue diseases.

Idiopathic NSIP: an interstitial lung disease associated with autoimmune disorders? Eur Respir J

Inês L: Undifferentiated connective tissue disease: a seven-center cross-sectional study of 184 patients. Clin Rheumatol

King TE Jr: Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med

Szegedi G: Five-year follow-up of 665

Szegedi G: Five-year follow-up of 665 Hungarian patients with undifferentiated connective tissue disease (UCTD). Clin Rheumatol

Undifferentiated connective tissue disease-associated interstitial lung disease: changes in lung function. Lung

Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin Rheumatol

Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol

Undifferentiated connective tissue diseases (UCTD). Autoimmun Rev

Undifferentiated connective tissue diseases: the clinical and serological profiles of 91 patients followed for at least 1 year. Lupus

Willkens RF: Early undifferentiated connective tissue disease. II. The frequency of circulating antinuclear antibodies in patients with early rheumatic diseases.

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Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: Case report and review of literature

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