Connective Tissue Disease-

associated Interstitial Lung Disease

(CTD-ILD)
Chayanin Nitiwarangkul, M.D.
Division of Thoracic Radiology,
Department of Diagnostic and Therapeutic Radiology,
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
[email protected]

Dec, 4th 2021

Outline

• Brief introduction to CTD-ILD

• When should CTD be suspected?

• CTD-ILD vs IPAF

• Imaging of CTD-ILD

• CTD-ILD vs IPF

• Signs for differentiating CTD-ILD from IPF

What is CTD-ILD

• The major pathological features of CTD are chronic inflammation of blood

vessels and connective tissues, which can affect any organ leading to multi-
system damage.

• The lung is particularly vulnerable to such damage because anatomically it is

abundant with collagen and blood vessels.

• Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is

one of the leading causes of morbidity and mortality of CTD.

Shao T, et al. Front Immunol. 2021

Pathophysiology of CTD-ILD

Precise mechanisms that drive CTD-ILD remain unclear;

•Genetic

•Environmental

•Immunological

Shao T, et al. Front Immunol. 2021

Normal Inflammatory ILD Fibrosis
When should CTD be suspected?

• Female patients and individuals aged <50 years

• HRCT) pattern of nonspecific interstitial pneumonia NSIP or UIP(with presence

of alternative diagnosis condition)

• Presence of Raynaud’s phenomenon, skin manifestations, dryness of eyes and

mouth, and joint and muscle symptoms.

• Some imaging features may, e.g.;

• esophageal dilatation >> systemic sclerosis

• pneumomediastinum >> idiopathic inflammatory myopathy

Cottin V, et al. European Respir. 2013
CTD-ILD VS IPAF
IPAF (interstitial pneumonia with autoimmune features) (previously undifferentiated CTD-ILD (UCTD-ILD), autoimmune-featured
ILD (AF-ILD), or lung-dominant CTD (LD-CTD))

• ILD in subjects with clinical, serologic and/or morphologic (CT or surgical lung biopsy) features of autoimmunity
without characteristic CTD

• Accounting for 7–35 % of ILD

• Heterogeneous clinical characteristics; however, they are frequently in 6th to 7th decade with equal gender
predilection which is different from IPF patients who are usually older male with smoking history and more similar
to CTD-ILD

• Oldham JM, et al. studied 422 patients with either IIP or undifferentiated CTD from ILD database

• 144 (34 %) met IPAF criteria, the mean age 63.2 years, with a majority being female (52 %) and former smokers (55 %).

• The most common clinical feature was Raynaud phenomenon (27.8 %)

• The most common serologic feature was ANA positivity (77.6 %)

• The most common morphologic features were NSIP pattern on CT (31.9 %), the majority of the cohort demonstrated a UIP
pattern on CT (54.6 %) and on surgical lung biopsy (61 of 83 patients biopsied, 73.5 %)

• Prognosis: CTD-ILD > IPAF > IPF

Shao T, et al. Front Immunol. 2021
CTD with features of ILD

• Rheumatoid Arthritis (RA)

• Systemic Sclerosis (scleroderma)

• Mixed Connective Tissue Disease (MCTD)

• Myositis

• Systemic Lupus Erythematosis (SLE)

• Sjögren's syndrome
Autoantibodies and serological immune markers
PM/DM SSc RA SS MCTD
MSAs anti-Scl-70 RF Anti-SSA/Ro Anti-U1RNP
anti-Jo-1 anti-U3RNP Anti-CCP anti-SSB/La CIC
anti- PL-12 anti-U11/U12RNP C3
anti- PL-7 anti-RuvBL1/2 CH50
anti- KS anti-EIF2B
anti- OJ anti-PM-Scl
anti- EJ anti-U1RNP
anti-Zo anti-cardiolipin
anti-Ku anti-Th/To
anti-MDA5 anti-Ro52
MAAs anti-NOR90
anti-Ro52/60 nucleolar ANA
anti-U1RNP ANCA

Shao T, et al. Front Immunol. 2021

Autoantibodies

Diagnosis Autoantibody
Rheumatoid Arthritis (RA) RF, anti-CCP

Systemic sclerosis Anti-centromere antibody, anti-SCL-70

Mixed Connective Tissue Disease (MCTD) Anti-RBNP

Myositis

Anti-Jo-1, anti-aminoacyl-tRNA synthetase

(Dermatomyositis, Polymyositis, Antisynthetase syndrome)

Systemic Lupus Erythematosus (SLE) Anti-ds DNA, anti-Smith, antiphospholipid

Adapted from Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009(4):299-309
Compartment Histologic pattern RA SLE PSS PM/DM SS MCTD AS
NSIP
UIP x x x x x x
OP x x x x x x
Alveolar DAD x x x x x
parenchyma LIP x x x
CIP x x x
Lymphoid hyperplasia x x x
Alveolar hemorrhage x x x
Pleura Pleuritis/fibrosis x x x x x x
Bronchitis/bronchiolitis x x x
Airways Follicular bronchiolitis x x x
Constrictive bronchiolitis x x x
Pulmonary hypertension x x x x x x
Vessels Vasculitis x x x x
Capillaritis x
Other Other histologic findings Necrobiotic Hematoxylin Aspiration Aspiration TBGA AFBC
nodules bodies
X means presence of interstitial lung disease or interstitial lung abnormality of histologic pattern. For frequency of the pattern in each connective tissue disease, please refer to authors’ reference

Yoo H, et al. EJR. 2021

Imaging of CTD-ILD
Imaging
Common Parenchymal Manifestations of CTD-ILD
Imaging pattern RA Scleroderma SLE MDCT PM, DM, AS Sjogren

UIP ++ ++ + + + +

NSIP + ++++ + ++ ++ +

OP ++ + + + ++ -

LIP - - - - - ++

OB ++ - - - - -

AS, Antisynthetase syndrome; DM, dermatomyositis; LIP, lymphocytic interstitial pneumonitis; MCTD, mixed connective tissue disease; NSIP, nonspecific interstitial pneumonitis; OB, obliterative
bronchiolitis; OP, organizing pneumonia; PH, pulmonary hypertension; PM, polymyositis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; UIP, usual interstitial pneumonitis.
Table adapted from: Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging 2009;24(4):299-309
CTD-ILD vs IPF
CASE 1 CASE 2 CASE 3
 An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline

For adult patients with newly detected ILD of apparently unknown cause who

are clinically suspected of having IPF :

• Recommend taking a detailed history of both medication use and

environmental exposures at home, work, and other places the patient
frequently visits to exclude potential causes of ILD (motherhood statement).

• Recommend serological testing to exclude connective tissue disease

(CTD) as a potential cause of the ILD (motherhood statement).

Raghu G, et al. ATS 2018

Signs for differentiating CTD-ILD from IPF

• Straight-edge
• Anterior upper lobe
• Exuberant honeycombing
• The four corners sign*

Chung JH. et al. AJR 2018

*Walkoff L. et al. JTI 2018

Chung JH. et al. AJR 2018
 “Anterior Upper Lobe” sign
Concentration of fibrosis within the anterior aspect of the upper lobes (relative sparing of the other aspects), and concomitant
lower lobe involvement

Chung JH et al. Lung 2018

“Exuberant honeycombing” sign
Exuberant honeycomb-like cyst formation within the lungs constituting >70% of fibrotic portions of lung

Chung JH et al. Lung 2018

“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

Chung JH et al. Lung 2018

 “Four corners” sign
Focal or disproportionate inflammation and/or fibrosis
involving the bilateral anterolateral upper and posterosuperior lower lobes

Walkoff L. et al. JTI 2018

Clinical is Key!

• Making a diagnosis of IPF specifically requires the exclusion of known

causes of ILD, including autoimmune diseases, exposure to potential
inducers of chronic HP, occupational exposures, and the use of certain drugs.

• To assist the radiologist in contributing to the MDD, it is important that they

have access to relevant information on the patient’s clinical history,
exposures and the results of other tests that have been performed.

Chung JH et al. Lung 2018

Age

Gender

Signs and symptoms

Inspiratory “Velcro” crackles or “squeaks” on chest ausculta<on

Involvement of other organs that may indicate autoimmune disease

Pulmonary func<on tests (PFTs)

FVC, DLco, FEV1

Laboratory tests that may indicate autoimmune disease or hypersensi3vity pneumoni3s

Occupa<onal/environmental exposures

Smoking

Poten<al inducers of hypersensi<vity pneumoni<s e.g., birds

Exposures to compounds known to cause ILD e.g., asbestos, metal dust

Response/non-response to therapies used to treat lung disease

Use of medica<ons known to cause ILD

Family history

Features on HRCT

Features on surgical lung biopsy, if available Chung JH et al. Lung 2018

Case1: 52 YOF with rash on face and abnormal chest radiograph 
Case1: 52 YOF with rash on face and abnormal chest radiograph 
Case1: 52 YOF with rash on face and abnormal chest radiograph 
Case1: 52 YOF with rash on face and abnormal chest radiograph 
Q: What is the most likely HRCT pattern?

A: UIP >> IPF?

Case1: 52 YOF with rash on face and abnormal chest radiograph 
Age Gender Sign&Symptom

Q: What is the most likely diagnosis?

Straight-edge sign
Anterior upper lobe sign
 Case1: 52 YOF with rash on face and abnormal chest radiograph 
Age Gender Sign&Symptom

Q: What is the most likely diagnosis?

• History: 52 YOF

• Clinical: discoid rash and lupus

nephritis

• Lab: positive ANA, anti-dsDNA

• HRCT patterns: UIP with anterior

upper lobe and straight-edge sign

• Final diagnosis: SLE-related ILD

Case 2: 84 YOM with progressive dyspnea
Case 2: 84 YOM with progressive dyspnea
Case 2: 84 YOM with progressive dyspnea
Age Gender Sign&Symptom
Q: What is the most likely HRCT pattern?
A: UIP >> IPF?
Exuberant honeycombing sign Anterior upper lobe sign Straight-edge sign
 Case 2: 84 YOM with progressive dyspnea
Age Gender Sign&Symptom

Q: What is the most likely diagnosis?

• History: 84 YOM with history of
Rheumatoid arthritis

• Clinical: Arthritis at both hands

• Lab: RF +

• HRCT patterns: UIP with anterior

upper lobe, straight-edge, and
exuberant honeycombing sign

• Final Diagnosis: RA related-ILD

Thank you!