Molecular Mechanisms in ILD in Adult Connective Tissue Disease

February 7, 2015

1

Sonye K. Danoff, MD, PhD

Co-Director, Johns Hopkins ILD/PF Program

Associate Director, Johns Hopkins Myositis Center

Molecular mechanisms in ILD in Adult Connective

Tissue Disease

ILD in sJIA Meeting, Stanford Center for Excellence in Pulmonary Biology

ILD as a manifestation of adult

CTD

• Occurs with many forms of CTD

• May be first/only manifestation of CTD

• Has variety of presentations

• Outcomes vary with presentation

• In contrast to chILD, less clearly linked to

genetics, more highly linked to exposure

• Likely differing driving mechanisms

2

Frequency of ILD varies by CTD

and by ascertainment method

CTD Prevalence PFT CT Lung

biopsy

Timing in

disease

Rheumatoid

Arthritis

1-2% of US

~2.5 million

40-50% 19% 80% Late

Lupus ~1.3 million 3-8% Late

Sjogren’s ~1 million 10-24% Late

SSc ~300,000 23-40% 70-80% Early

DM/PM ~15,000 60-90% Early

MCTD Unknown 20-60% Early

3

ILD as “Formes Frustes” of

CTD

4

Disparate Forms of ILD

5

Multiple Histopathologies in

CTD-ILD

6

Mortality: Appearances do

matter in ILD

Flaherty et al., Thorax 2003;58:143-148

NSIPNSIP

UIP

Mechanisms of lung injury in

CTD-ILD

• Antibody driven injury

• Virally triggered injury

• Cellular injury (environmental factors)

• Innocent bystander effect in malignancy

8

Antisynthetase: Unique phenotypes

associated with specific antibodiesAntibody Antigen

(tRNA

synthetase)

Prevalence in

IIM

(%)

Prevalence of

ILD

(%)

Jo-1 histidyl 25-30 66

PL-7 threonyl 2-5 78

PL-12 alanyl 2-5 90

EJ glycyl 1

OJ isoleucyl 1

KS asparaginyl 1

Zo phenylalanyl 1

Tyr tyrosyl 1

Immbert-Masseau A. Joint Bone Spine, 2003

ASAs: Potentially Causative?

• Murine Jo1 antibodies demonstrate an increase in targeted B- and T-cells

– phenotype consistent with diffuse lung and muscle inflammation

• Disease activity directly correlates with antisynthetase antibody titer

• Serve directly as chemokines and cytokines

– migration of mononuclear cells and immature dendritic cells Katsumata Y et al. J Immunology, 2007

Stone KB et al. Arth Rheum, 2007

Levine SM et al. Cur Opin Rheum, 2003

MDA5: A spectrum of ILD

• Initially described in Japanese

population as associated with CADM

with rapidly progressive ILD

11

Clinically amyopathic DM

(CADM)

12

Associated with a rapidly progressive, often fatal ILD

Fiorentino et al., Journal of the American Academy of Dermatology, 2011

Distinctive Cutaneous Phenotype

in MDA5 Dermatomyositis

MDA5–Associated Dermatomyositis:

Expanding the Clinical Spectrum

Hall et al., Arthritis Care & Research, 2013

Clearly auto-antibody is not the

whole story

• Environmental exposures: smoking

• Infectious exposures: viruses

• Medication exposures: biologics

15

Age has a critical impact on

CTD-ILD

16"The Life & Age of Woman - Stages of Woman's Life from the Cradle to the Grave", ca. 1849

Association between

autoimmunity and cancer

• Increased risk of malignancy in DM,

PM, SSc

• Evidence of antigen expression in tumor

that is recognized by autoantibody

• Resolution of autoimmunity with

treatment of tumor

17

“Autoantigen” expression in tumors

Casciola-Rosen L et al. J Exp Med, 2005

Cellular components in CTD-ILD

19

Wells & Denton, Nat Rev Rheum, 2014

Molecular mechanisms of

CTD-ILD

20Castelino &Varga Arthritis Research & Therapy 2010

With Gratitude to the Lisa Sandler Spaeth &

Fisher Foundation Funds for Pulmonary Fibrosis at JH

And The Huayi and Siuling Zhang Discovery Fund