CTD ILDs.

Dr. Suresh Kumar Yogi
III Year Post Graduate Student
Dr. S.N. Medical Collage

Background
 The term interstitial lung disease (ILD), in general ,
implies the clinical manifestation of inflammatory-
fibrotic infiltration of the alveolar walls ( septa)
resulting in profound effects on the capillary
endothelium and the alveolar epithelial lining cells.

 ILD refers to a heterogeneous collection of more than
one hundred distinct lung disorders
 Commonly, interstitial lung disease (ILD) presents
with-
 Dyspnea on exertion,
 Diffuse bilateral infiltrates on chest imaging,
 Restriction with diffusion impairment on physiologic
testing.

INTRODUCTION
 Interstitial lung diseases (ILD) are common pulmonary
complications of the CVDs
 Approximately 15% of patients with an interstitial lung
disease have an underlying connective-tissue disease. [1]
 Almost all autoimmune conditions have been associated
with the occurrence of ILD.
 ILD may be the initial manifestation of a connective-tissue
disease. [2]
 It has been suggested that some patients who have ILD but
who do not meet clinical criteria for connective-tissue
disorders may have a lung-predominant form of a
connective-tissue disease. [3]

 Collagen-vascular diseases (CVDs) are a heterogeneous
group of autoimmune disorders characterized by the
presence of auto antibodies.
 Include-
Progressive systemic sclerosis (PSS),
Rheumatoid arthritis
Dermatomyositis (DM)/ Polymyositis (PM),
Sjögren syndrome (SS)
Systemic lupus erythematosus
Ankylosing spondylitis (AS),
Mixed connective-tissue disease (MCTD)

Interstitial lung diseases associated with CTD
CTD Frequency of ILD
(%)
Comment
Systemic sclerosis
Rheumatoid arthritis
Polymyositis/dermatomyosit
is
Sjögren’s syndrome
Systemic lupus
erythematosus
Mixed connective tissue
disease
45 (clinically
significant)
20 to 30
20 to 50
Up to 25
2 to 8
20 to 60
More common in diffuse
disease; topoisomerase-1
antibodies
Increased risk with cigarette
smoking
More common with anti-
synthetase antibodies
-
Usually in patients with
multisystem disease
_
Castelino and Varga Arthritis Research & Therapy 2010, 12:213 http://arthritis-
research.com/content/12/4/213

Pathophysiology
 The pathogenesis of connective-tissue diseases is
unknown.
 The role of autoimmunity in ILD associated with
connective-tissue disorders such as systemic sclerosis,
SLE, and RA is well established. [4]

 Histological subtypes in ILD associated with
CTD including-
 Usual interstitial pneumonia (UIP),
 Nonspecific interstitial pneumonia (NSIP),
 Organizing pneumonia,
 Diffuse alveolar damage,
 Lymphoid interstitial pneumonia (LIP),
 ILD related to CTD may be associated with pulmonary
hypertension.

 Classification of histological and radiological patterns
developed for idiopathic interstitial pneumonias,
applied to connective tissue disease-associated
interstitial lung disease
American Thoracic Society/European Respiratory and Society. International
Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonia. Am J
Respir Crit Care Med 2002; 165: 277-304.

Pattern Histology CT features
UIP
NSIP
OP
DAD
LIP
UIP Subpleural and peripheral fibrosis.
Temporal and spatial heterogeneity.
Scattered fibroblastic foci and
honeycombing are key features.
Uniform interstitial involvement by variable
degrees of fibrosis and inflammation.
Honeycombing is rare.
Connective tissue plugs within small airways
and air spaces (Masson bodies). In its ‘pure’
form, little or no inflammation or fibrosis in
the surrounding interstitium.
DAD In the acute phase: hyaline membranes,
edema.
In the organizing phase: airspace and
interstitial organization.
Bronchiolocentric lymphoid tissue
hyperplasia
Basal, subpleural reticulation and
honeycombing; traction bronchiectasis;
little, if any, ground-glass attenuation.
Bilateral patchy ground-glass opacities
admixed with reticulation and traction
bronchiectasis /bronchiolectasis. Little or
no honeycombing. Usually,predominantly
basal.
Airspace consolidation, with a
predominantly basal/peripheral or peri-
bronchovascular distribution.
Bands with air bronchograms and a
perilobular pattern can also be seen.
Acute phase: diffuse ground-glass opacities
and consolidation in dependent areas.
Organizing, phase : reticular pattern,
traction bronchiectasis and architectural
distortion
Ground-glass attenuation is the
predominant finding, with thin-walled
cysts frequently present. Lung nodules and
septal thickening may also be seen

Pattern of ILD in connective tissue disease
CTD ILD ILD PATTERN
SSc
RA
PM-DM
Sjo¨ gren’s
SLE
++++
++
+++
++
+
NSIP>>>UIP
UIP>NSIP>OP=DAD
NSIP=OP>DAD>UIP
NSIP>LIP>OP=UIP=DAD
NSIP>DAD=LIP=OP=UIP

Risk factors for the development of CTDs
 Genetic susceptibility – Many individuals are predisposed
genetically to develop CTDs; a genetic predisposition is
found in persons with SS, including familial clustering and
an association with human leukocyte antigen (HLA)-Dw2
and HLA-Dw3; AS is strongly associated with HLA-B27 [5, 6]
 Hormonal influence – Pregnancy exacerbates various
CTDs, including SLE and RA, suggesting that hormones
(especially estrogen) play an important role[7]
 High titers of rheumatoid factor (RF) and the presence of
rheumatoid nodules – associated with an increased
prevalence of pulmonary fibrosis in persons with RA
 Cigarette smoking (>25 pack-year) – increases the risk of
ILD in patients with RA[8]

Etiology
 The exact cause of CTDs is unknown.
 Role of inflammatory mediators
A wide variety of cytokines identified in bronchoalveolar lavage (BAL)
fluid appear to contribute to the cascade of inflammation in the
lungs. [9] The most striking of these are the following:
 Interleukin (IL)–8 (a neutrophil chemoattractant and activator)
 Tumor necrosis factor-α (TNF-α, an early cytokine involved in many
pathologic processes)
 Macrophage inflammatory protein-1α (a cytokine that is important in
neutrophil chemotaxis)
 RANTES (regulated on activation normal T-cell expressed and
secreted, a cytokine that is important in T-cell and eosinophil
recruitment and activation)
 Transforming growth factor-β (TGF-β)
 Endothelin-1

 Infections- in SLE, Epstein-Barr virus (EBV)
 Immunologic factors
 Genetic factors-association between diffuse lung
disease and human leukocyte antigens like HLA-
DR3,HLA-DR52a,HLA-DRB1*11 and HLA-DPB1*1303
 Environmental factors-
 Drugs such as hydralazine, procainamide, and D-
penicillamine can induce SLE-like responses in
humans
vitamin D deficiency was associated with reduced lung
function in patients with connective tissue disease and
may play a role in the pathogenesis of ILD. [21]

Epidemiology
 RA is a common disease, with a worldwide prevalence
of approximately 1% and an annual incidence of
approximately 3 in 10,000 adults. [10,11]
 SS affects 1 in 1250 individuals. [12] PSS and limited SD
affect 1 in 5,000-20,000 individuals
 SLE affects approximately 1 in 2000 individuals.[13]

 CVDs are rare in children; the primary peak age of
onset is middle age.
 SLE, RA, PM/DM, SS, and MCTD are more common
in females.
 DM affecting older individuals (ie, >50-60 years) may
be associated with malignancy.
 RA occurs predominantly in women but RA-related
ILD is more common in middle-aged men.
 AS is more common in men, with a male-to-female
ratio of 3:1.

Interstitial Lung Disease in India.
Results of a Prospective Registry.
 Conclusions:
Hypersensitivity pneumonitis was the most common
new-onset ILD in India, followed by CTD-ILD and
idiopathic pulmonary fibrosis;
 CTD-ILD. A total of 151 patients had CTD-ILD; mean age
was 50.8 (SD, 13.8) years and most were women (73.5%) . A
total of 54.3% had nonspecific interstitial pneumonia
(NSIP), whereas 31.8% had usual interstitial pneumonia
(UIP) . Rheumatoid arthritis was the most common
specific CTD (38.4%) followed by scleroderma (22.5%) .
Mean FVC among patients with CTD-ILD was 56.6%
predicted (SD, 20.6).
Singh, Collins, Sharma, et al.: ILD in India: The ILD-India Registry

CLINICAL HISTORY
 Typical presentation of ILD Is nonspecific
 Dyspnea on exertion or cough,
 Diffuse bilateral infiltrates on chest imaging,
 Restriction with diffusion impairment on physiologic
testing.

Workup
 A thorough history is key for the diagnosis of collagen-
vascular diseases (CVDs).
 History of occupation, environmental exposures,
radiation exposure, and drug use
 History of smoking
 Detailed family history- like SLE
 Physical Examination

Systemic
symptoms
CTD
Dermatological Heliotrope rash, Gattron’s papule,
mechanic’s hand.
history of skin tightness and thickening,
telangiectasias, Raynaud’s phenomenon, or
digital pitting.
Malar rash, photosensitivity skin reaction,
or hair loss.
Dermatomyositis
Systemic sclerosis
(scleroderma)
SLE
Gastrointestinal Esophageal motility problems as acid
reflux (chest burning or pressure, cough
after meals, regurgitation of food)
Systemic sclerosis and
polymyositis,
Musculoskeletal Arthralgias,morning stiffness, joint
swelling and erythema, and deformities
Swollen fingers (“sausage digits”)
Rheumatoid arthritis,
Sjögren syndrome, or
mixed connective
tissue disorder.
systemic sclerosis
and polymyositis
Ophthalmologic Dry eyes or the use of eye drops may
uncover sicca syndrome,
history of uveitis
Sjögren syndrome
SLE or sarcoidosis

Digital tip infarction
cutaneous calcium deposits
(calcinosis cutis)
Salt & Pepper Skin - Hyper and
hypopigmentattion seen in systemic
sclerosis.
Matted telangiectasia common in
scleroderma. (Image courtesy of
Dr. Lorinda Chung.)
sclerodactyly, a thickening of
the skin
Courtesy of Vandana Mehta Rai MD, and C Balachandran MD via Derma tology
Online Journal

Heliotrope rash in woman with
dermatomyositis.
Gottron papules and nail-fold
telangiectasia in patient with
dermatomyositis.
Classic malar rash
(butterfly rash) in SLE
mechanic’s hand.
Swollen fingers (“sausage
digits)

Investigations
 Chest x-ray - either normal or Diffuse bilateral
infiltrates
 Physiological testing
Restriction
reduced FVC
reduced DLCO
 HRCT
 6MWT

CXR changes:
1. Reticulonodular shadowing
2. Loss of volume
3. Widespread/ bilateral

 Antibodies to be ordered in suspected CTD –ILD
 Order in all patients with ILD
 ANA
 RA
 ANCA
 Specific antibodies
ANA immunoblot-
 Anti Scl-70,
 Anti JO-1,
 Anti CCP,
 U1RNP,
 Ro La

ref.. Murray & nadel’s textbook of respiratory medicine

Conclusion
•Serum KL-6 levels were increased in patients with CTD-ILD and had a positive
correlation with ILD severity as measured using a semiquantitative CT grading scale,
whereas serum KL-6 levels had a negative correlation with PFT parameters. Serum
KL-6 could be a clinically useful biomarker in screening and evaluating CTD-ILD.
•Among the patients diagnosed with CTDs with possible ILD manifestations,
the serum KL-6 level was significantly higher in patients with ILD than in those
without ILD.
• Serum KL-6 concentrations lower than 275.1 U/Ml were able to differentiate the
absence of ILD

CT Features of the Usual Interstitial Pneumonia Pattern: Differentiating
Connective Tissue Disease–Associated Interstitial Lung Disease From
Idiopathic Pulmonary Fibrosis
 Specific CT signs that are more common in UIP associated with CTD-ILD than
in UIP associated with IPF.
 Anterior upper lobe sign - concentration of fibrosis within the anterior
aspect of the upper lobes (with relative sparing of the other aspects of the
upper lobes) and concomitant lower lobe involvement.
 Exuberant honeycombing sign - exuberant honeycomb-like cyst formation
within the lungs constituting greater than 70% of fibrotic portions of lung .
 Straight-edge sign-isolation of fibrosis to the lung bases with sharp
demarcation in the craniocaudal plane without substantial extension along the
lateral margins of the lungs on coronal images .
 Read More: https://www.ajronline.org/doi/full/10.2214/AJR.17.18384

Fig. 1—65-year-old woman with connective tissue disease. unenhanced chest CT
images show substantial degree of reticulation, traction bronchiectasis and
bronchiolectasis, and honeycombing within upper lobes, mostly concentrated in
anterior aspect consistent with anterior upper lobe sign.
Fig. 2—52-year-old man with connective tissue disease. A and B, unenhanced
chest CT images show substantial degree of reticulation and subpleural
honeycombing within upper lobes, mostly concentrated in anterior aspect
consistent with anterior upper lobe sign.
Axial (A) sagittal (B)
Axial (A)
sagittal (B)

Fig. 3—61-year-old woman with known connective tissue disease. A and B, Axial unenhanced chest CT images show
peripheral- and basilar-predominant pulmonary fibrosis pattern characterized primarily by florid honeycombing
consistent with exuberant honeycombing sign.
Fig. 4—57-year-old woman with known connective tissue disease. A and B, Axial unenhanced chest CT
images show peripheral- and basilar-predominant pulmonary fibrosis pattern characterized primarily by
florid honeycombing consistent with exuberant honeycombing sign.

Fig. 5—49-year-old woman with connective tissue disease. Coronal
unenhanced chest CT image shows basilar-preponderant pulmonary fibrosis
characterized by ground-glass opacity and reticulation and traction
bronchiolectasis. Along
lateral aspect of lungs, fibrosis does not extend superiorly along chest wall but
rather forms fairly straight interface between fibrosis and normal lung
orthogonal to lateral chest wall surface, consistent with straight-edge sign.
Fig. 6—31-year-old man with connective tissue disease. Coronal
unenhanced chest CT image shows basilar preponderant pulmonary
fibrosis characterized mainly by large degree of honeycombing
(exuberant honeycombing sign).
Along lateral aspect of lungs, fibrosis does not extend superiorly
along chest wall but rather forms fairly straight interface between
fibrosis and normal lung orthogonal to lateral chest wall surface,
consistent with straightedge sign.

The role of lung ultrasound in the
diagnosis of interstitial lung disease
 Abstract: Current data have shown that lung ultrasound
(LUS) is an emerging tool in the diagnosis of interstitial
lung disease (ILD) by evaluating numbers of B-lines,
pleural irregularities and nodules or consolidations. These
features can distinguish between ILD and others different
pulmonary conditions (i.e., patients with heart failure or
end-stage renal disease accompanied by pulmonary
congestion). Although there is not a standardized approach
for diagnosis of ILD by LUS examination and most studies
has been made on rheumatologic patients, we discuss
utility of LUS in detecting ILD and its correlation to
classical radiological finding, especially to high-resolution
computed tomography (HRCT).

Sonographic interstitial syndrome.
Multiple, separated B-lines
Black arrow indicates the pleura and
white arrows show lung comets
associated with thickened irregular
pleural lines.
Falcetta A, Leccardi S, Testa E, et al. The role of lung ultrasound in the diagnosis of
interstitial lung disease. Shanghai Chest. 2018 May 28;2(5).

Ultrasound in the Assessment of Pulmonary
Fibrosis in Connective Tissue Disorders:
Correlation with High-Resolution Computed
Tomography
Conclusion. study demonstrates that US B-line assessment may be a
useful and reliable additional imaging method in the evaluation of PF in
patients with CTD.
DOI: https://doi.org/10.3899/jrheum.120104

Dose and duration of steroid treatment
Disease Initial dose of prednisolone Duration of therapy
Sarcoidosis 20-40 mg/day 6-9 months
Hypersensitivity
pneumonitis
0.5mg/kg/day 6-9months
CTD-ILDs 0.75-1 mg/kg/day 12-24months
Idiopathic NSIP 0.75-1 mg/kg/day 12-24 months
COP 0.5 mg/kg/day 6 months
RB-ILD, DIP Smoking cessation first, if no
response , 0.5mg/kg/day
6 months
Acute exacerbations Methylprednisolone pulse 1gm/day
x 3 f/b 0.75-1 mg/kg/day
AIP Methylprednisolone pulse 1gm/day
x 3 f/b 0.75-1 mg/kg/day
Plus cyclophosphophamide

PROGNOSIS
 CVD-associated ILD causes significant morbidity and
mortality.
 Most forms of CVD-related ILD have a better prognosis
than idiopathic ILD. An exception is RA-related ILD with
UIP findings. [35, 36]
 However, CVDs are more indolent in progression than IPF.
 Mortality is high in patients with CVD who develop ILD
and pulmonary hypertension.

 PM/DM and systemic sclerosis are associated with higher
mortalities than other CVDs.
 The 3-year survival rate for patients with systemic sclerosis
and pulmonary hypertension is 56%.
 In patients with RA and SLE who develop ILD, mortality is
3-4 times higher than that in the general population
 RA- ILD has approximately 5 years median survival.

 Indicators of poor survival-
 Diffusing capacity of the lung for carbon monoxide
(DLCO) below 50% of predicted
 PM/DM-associated ILD with normal creatine kinase
values, negative anti-Jo antibody findings, and pulmonary
hypertension[37, 39]
 Male sex and lung fibrosis in RA-related ILD [40]
 Patients with SD – Antitopoisomerase and
antiribonucleoprotein polymerase antibodies are
associated with pulmonary hypertension.

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