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Interstitial Lung Disease (ILD) Diagnostic Insights Offered by CTD Serology
Robert G Cooper Prof of Medicine (Muscle and Rheumatology)
Normal Alveolar Physiology
Contrast with ILD Pathologies Impairing Gas Transfer
Parenchymal Fibrosis (+/- inflammation) Parenchymal Inflammation (+/- PF)
Background
• ILD is a heterogeneous spectrum, causing progressive dyspnoea with lethal outcomes from respiratory failure or its cardiac complications.
• Treatment outcomes variable, and dependant on ILD subgroup phenotype.
• Problem – Differentiating between ILD subgroups can be considerably problematic.
Idiopathic Pulmonary Fibrosis (IPF), or Usual Interstitial Pneumonia (UIP)
Nonspecific Interstitial Pneumonia (NSIP)
Cryptogenic Organising Pneumonia (COP)
Acute Interstitial Pneumonia (AIP)
Respiratory-bronchiolitis-associated interstitial lung disease (RB-ILD)
Desquamative Interstitial Pneumonia (DIP)
Lymphoid Interstitial Pneumonia (LIP)
Sarcoidosis
Hypersensitivity pneumonitis
Rh Arthritis (UIP and non-UIP)
Systemic sclerosis
Myositis spectrum
Sjogren’s Syndrome
Mixed CTD
Undifferentiated CTD
Asbestos
Silica
Other dusts
Nitrofurantoin
Bleomycin
“Idiopathic” (IIP) Granulomatous CTD-ILD Environmental or medicinal exposures
The ILD Spectrum
Rare causes
Vasculitis
Langerhans cell
histiocytosis
Eosinophilic
pneumonia
Adapted from Ryerson CJ, Collard HR. Update on the diagnosis and classification of
ILD. Curr Opin Pulm Med 2013; 19: 453-459
A Classification of the ILD Spectrum
Groups
←Subgroups→ ←Subgroups→
ATS/ERS Classification Guidelines for ILD
• Subgroup diagnosis made according to occupational and clinical histories and a thorough clinical examination, in combination with “routine” serology and an HRCT.
• An idiopathic subgroup diagnosis can only be assigned if other diagnoses have been definitively excluded, but these guidelines did not dictate stringency of serology. Most chest clinics likely only test for RF, CCP and ANA, +/- ENAs
• Reliable, ILD-specific biomarkers are lacking, representing a major diagnostic issue.
American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165(2): 277-304
ILD Diagnostic Issues
• Diagnosis easy if a CTD clinically obvious (e.g erosive RA or overt SSc), or an environmental trigger easily identified (e.g silica exposure in a stone
mason).
• If history, examination and routine serology give no clue as to the “actual” diagnosis, this is of necessity assigned radiologically, i.e by HRCT
- idiopathic UIP, idiopathic NSIP, idiopathic COP etc.
But, environmental triggers may be missing and clinical signs absent or very subtle.
IPF – UIP or Probable UIP Non-Responsive to Immunosuppression
Peripheral reticular changes
CTD-ILD - Ground Glass Changes Responsive to Immunosuppression (not always)
“Ground glass” changes ----------►
HRCT as Predictor of ILD Mortality IPF vs CTD-ILD
Park JH et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med 2007; 175(7): 705-11
HRCT-Specific Problems
• When history is non diagnostic, CTD signs absent and serology unhelpful, HRCT use can still be problematic:
- HRCT images not necessarily ILD subgroup-specific.
- HRCT images may vary within ILD subgroups.
- Between-assessor variability of image reporting, so MDTs of great importance.
Idiopathic Pulmonary Fibrosis (IPF)
• Fatal in ~ 50% of cases within only 3-4 years. Aggressive corticosteroid immunosuppression is ineffective, and now proven as harmful, so now contra-indicated.
• Pirfenidone and nintedanib do slow IPF progression, but these drugs are very expensive, so can only be used in tertiary referral ILD clinics, e.g Aintree (Merseyside - NW Coast), Wythenshawe (Gt Manchester) etc.
CTD – ILD
• Generally comprise an inflammatory component (i.e “ground glass” changes) so usually responsive to steroids +/- DMARDS, at least in part. Once Rx initiated, PFTs usually stabilise, though not always.
• Role of Rituximab unclear.
• Role of anti-fibrotic drugs also unclear, but trials ongoing or planned in RA-ILD and SSc-ILD.
Diagnostic Accuracy Issues
• Between-subgroup treatment response differences mean that making an accurate diagnosis is crucial in every case, to ensure accurate delivery of either targeted immuno-suppression or targeted fibro-inhibition.
• Lack of reliable, ILD-specific, diagnostic biomarkers means that potentially dangerous diagnostic lung biopsies are still necessary.
Therapeutic Difficulties Arising Due to The Lack of ILD-Specific Biomarkers
IIP or covert CTD-ILD? Covert CTD-ILD or
IIP?
How can rheumatology help?
1999
Idiopathic
Inflammatory
Myopathies
(IIM)
Polymyositis Dermatomyositis
Juvenile
Dermatomyositis
Myositis-CTD
overlap
Malignancy
Idiopathic Inflammatory Myopathies (IIM) –
Background in 1999
Myositis is an acquired inflammatory cell infiltration in skeletal muscle, causing myalgia, fatigue and weakness, and thus disability (usually chronic). Death directly due to IIM (i.e ventilatory failure) is rare.
Infiltrations with variable numbers of CD8+ and CD4+
T-cells, with some B-cells and fewer macrophages.
Multi-system inflammation, and potentially affecting: muscle +/- lungs +/- skin +/- joints
Causative mechanisms remains poorly understood, so mechanistic research is still vital.
Mechanistic Issues in IIM in 1999 Disease Causation: Genes vs Environment
HLA-DRB1*03 (DR3)
? Viruses
Klein J & Sato A. N Eng J Med. 2000, 343:702-9
Roles of HLA and cytotoxic T-cells in IIM
Cytotoxic T-cells cause muscle cell damage and weakness
Clinical Difficulties with IIM
Many IIM mimics , so only too easy to misdiagnose other myo-pathologies as idiopathic inflammatory myositis.
Treatment responses variable, but usually incomplete, so most patients (~75%) never regain normal strength or function.
Most UK rheumatologists will only see 8-10 IIM cases in a whole career, so mechanistic research had been very difficult to undertake. So, action needed!!
UK Adult Onset Myositis Immunogenetic Collaboration (AOMIC) - Set up by RGC/WERO 2000
AOMIC - UKMYONET (RGC/WERO/HC/JL) Case Recruitment 2000-2017
- Caucasians/Non-Caucasians - Phenotype details, serum and DNA - Myositis probable/definite according to Bohan & Peter
Controls (n=537) PM/DM/OL (n >1750) IBM (n >230)
JDM* (n >350) *(JDRG collaboration LW/CP)
Aims of AOMIC - UKMYONET
Immediate - To recruit ethnically homogeneous myositis subgroup cohorts of sufficient size to enable statistically meaningful between-subgroup genetic and serological comparisons.
Longer-term - To elucidate disease mechanisms, so
as to facilitate future therapeutic developments.
Correlation of DM/(DM + PM) with UV exposure – Pathogenic role for UV?
0
10
20
30
40
50
60
70
80
90
100
0 1000 2000 3000 4000
% D
erm
ato
myo
sit
is
UV Exposure (Joules/ m2)
Guatemala
Mexico city
Guadalajara
New Delhi
Santiago
Tokyo
Seoul
Bethesda
Barcelona
Warsaw
Aachen
Nijmgen
Stockholm
Glasgow
N = 919, weighted r = 0.94, P < 4 X 10-7
(Diagram courtesy of Prof Fred Miller, NIH, USA))
Never Smokers
Ever Smokers
0
5
10
15
20
25
No SE
Single SE
Double SE
OR
Relative risks for eversmokers and neversmokers classified on presence of Shared epitope genes compared to neversmokers with no shared epitope genes (all cases are anti-citruline anti body
positive)
Never Smokers Ever Smokers
40,5
Interaction between smoking and HLA-DRB1 (SE)
in two different subsets of RA
Klareskog et al Arthritis Rheum 2006;54:38-46
Never Smokers
Ever Smokers
0
5
10
15
20
25
No SE
Single SE
Double SE
Relative Risk
Relative risks for eversmokers and neversmokers classified on presence of Shared epitope genes
compared to neversmokers with no shared epitope genes (all cases are anti -citruline anti body
negative)
Never Smokers Ever Smokers
ACPA-positive RA ACPA-negative RA
Smoke - Smoke + Smoke - Smoke +
DRB1*03 - DRB1*03 - DRB1*03 + DRB1*03 +
8
20
10
6
4
2
1
log o
dds r
atio &
95%
confidence inte
rval
Anti-Jo-1 status by smoking and HLA-DRB1*03
0.6
Chinoy H. et al, Ann Rheum Dis 2012 Jun;71(6):961-5
1.3
4.8
7.7
Index
Mechanistic Clues
Environmental triggers: E.g infections (viral), UV (light sensitivity in DM), malignancy association (CAM), smoking (Jo-1 and DR3 associated), drugs (statins) etc
Genetic and serological factors (associated):
Serological Results A large spectrum of “myositis autoantibodies”,
correlating with a large spectrum of IIM subgroups.
NXP2
Myositis-Specific and -Associated Autoantibodies (MSA and MAA)
Mi-2 (DR7)
SAE SRP
MDA5 (DR15)
TIF1-gamma (DQB1*02)
LUNG DISEASE++
SINE MYOSITIS
SKIN DISEASE++
MALIGNANCY
SEVERE MYOPATHY
Anti-synthetase
autoantibodies
PL-12
OJ
KS
PL-7
EJ
Jo-1 (DR3)
Ha
LUNG DISEASE
Zo
EIF3
5NT1A
(DR13)
IBM
CTD-IIM (MAA)
La Ro
PmScl
(DR3)
RNP
Ku HMGCoAR
(DR11)
NECROTISING
MYOPATHY
MILD DM
CALCINOSIS
Myositis specific autoantibodies Clinical phenotypes in adults and children
IIM - A Remarkable Disease Spectrum
Anti-Synthetase (DR3)
Anti-SRP Anti-Mi-2 (DR7)
Anti-TIF1g etc
Anti-synthetase
autoantibodies
PL-12
KS
OJ
EJ
Jo-1
ANTI-SYNTHETASE SYNDROME (ASS)
Anti-synthetase autoantibodies Overall frequency – 30% adult IIM patients
Myositis (PM or DM)
Raynaud’s
Arthritis (patients often initially misdiagnosed as RA)
Mechanic’s hands
Gottron’s lesions (DM only)
Fever
Interstitial Lung Disease (ILD)
Zo
Ha
PL-7
1. Yoshifuji H. Autoimmunity 2006;39:233-241.
2. Gunawardena H. Rheumatology 2009;48:607-12. Review.
DM - Heliotrope with Periorbital Oedema
DM - Gottron’s papules Erythematous to violaceous papules and plaques over the extensor
surfaces of MCP and IP joints & other large joints in a symmetric distribution.
Mechanics Hands in a Jo-1+ve Myositis Patient with ASS
Thermography - Cold Challenge Test
Nail-Fold Capillary Abnormalities (As seen by use of ophthalmoscope)
(+ 20 D Lens)
Magnifying Glass
Scleroderma - IIM - ILD Overlap
Scoring Scleroderma Skin
NXP2
MSA/MAA are also SURROGATE biomarkers of ILD
Mi-2 SAE SRP
MDA5
TIF1-gamma LUNG DISEASE++
SINE MYOSITIS
SKIN DISEASE++
MALIGNANCY
SEVERE MYOPATHY
Anti-synthetase
autoantibodies
PL-12
OJ
KS
PL-7
EJ
Jo-1
Ha
LUNG DISEASE - ILD
Zo
EIF3
5NT1A
IBM
CTD-IIM (MAA)
La Ro
PmScl
U1RNP
Ku HMGCR
NECROTISING
MYOPATHY
MILD DM
CALCINOSIS
ILD-Specific and ILD-Associated Autoantibodies (ISA and IAA)
Other SSc-specific
Abs also associated
with ILD
MDA5
Fulminant ILD – Especially in
Oriental Asians
LUNG DISEASE++
SINE MYOSITIS
Anti-synthetase
autoantibodies
PL-12
OJ
KS
PL-7
EJ
Jo-1
Ha
LUNG DISEASE - ILD
Zo
CTD-ILD (IAA)
La Ro
PmScl
U1RNP
Ku
CTD-ILD (ISA)
If ILD is the only clinical feature of a CTD, then an MSA would also represent an ISA
Clinically Amyopathic CTD-ILD:
Anti-MDA 5
• A “myositis specific” antibody, usually associates with clinically amyopathic DM (CADM).
• Also associates with a very fulminant ILD (often lethal within only weeks or months, especially so in Oriental Asians).
• Little or no response to steroids, cyclophosphamide, MMF, IVIG or Rituximab.
• Disease mechanisms unknown.
Eurimmun Line-Blot Technology Currently Available IIM and SSc Specificities
Multiple ISA/IAA autoantibodies Multiple ILD clinical phenotypes
A Growing Clinical Spectrum of ILDs
Anti-Jo-1 vs PL7 Anti-U1RNP Anti-PMScl Anti-MDA5 etc
UK-BILD Aiming to Improve Diagnostic Performance and
Provide Mechanistic Insights in ILD
Robert G Cooper (Study PI) Prof Medicine & Hon Consultant Rheumatologist
UK-BILD: The “UK Biomarkers in Interstitial Lung Disease” study.
A UK-wide cross-sectional recruitment of ILD cases comprehensive across the ILD spectrum. Has recruited ~ 2850 cases to date.
UK-BILD
• National recruitment from 38 centres.
• Case recruitment comprehensive across the ILD spectrum.
• Patients must have HRCT-proven ILD, and their investigations must have included “routine” serology.
• Samples harvested: Completed 2 page clinical pro forma and whole blood for DNA genotyping (UoM) and EDTA plasma for “serotyping” by immuno-precipitation (UoB).
UK-BILD: Case Accrual by ILD Subgroup to Nov 2017
0
100
200
300
400
500
600
700648
633
421
265
208 180
149 123 115
41 21 10 10 2 2
Idiopathic Pulmonary Fibrosis (IPF), or Usual Interstitial Pneumonia (UIP)
Nonspecific Interstitial Pneumonia (NSIP)
Cryptogenic Organising Pneumonia (COP)
Acute Interstitial Pneumonia (AIP)
Respiratory-bronchiolitis-associated interstitial lung disease (RB-ILD)
Desquamative Interstitial Pneumonia (DIP)
Lymphoid Interstitial Pneumonia (LIP)
Sarcoidosis
Hypersensitivity pneumonitis
Rh Arthritis
Systemic sclerosis
Myositis spectrum
Sjogren’s Syndrome
Mixed CTD
Undifferentiated CTD
Asbestos
Nitrofurantoin
Bleomycin
Silica
Other dusts
“Idiopathic” (IIP) Granulomatous CTD-ILD Environmental or medication exposures
The ILD Spectrum
Rare causes
Vasculitis
Langerhans cell
histiocytosis
Eosinophilic
pneumonia
Adapted from Ryerson CJ, Collard HR. Update on the diagnosis and classification of
ILD. Curr Opin Pulm Med 2013; 19: 453-459
Some IIP cases may be reclassified → CTD-ILD subgroups
Groups →
←Subgroups→ ←Subgroups→
? → CTD
? → CTD
Other Members of UK-BILD Team
• Dr Lisa Spencer (Co-I, Chest Physician, Aintree University Hospital, Liverpool, eamil: [email protected]).
• Mr Paul New (Research Associate, University of Liverpool, email: [email protected]).
• Dr Janine Lamb (Co-I, Non-Clinical Scientist heading up the Centre for Integrated Genomic Medical Research (CIGMR), University of Manchester, email: [email protected]).
• Prof Neil McHugh (Co-I, Director of Immunoprecipitation National Reference Laboratory, University of Bath, email: [email protected])
• Dr Zoe Betteridge (Non-Clinical Scientist running Immuno-precipitation Laboratory, University of Bath, email: [email protected]).
• 38 UK ILD case recruitment sites to date.
UoL
Thank you for listening
Institute of Ageing and Chronic Disease
UoLiverpool Adam Lightfoot Robert Cooper
Patients/UoManchester Janine Lamb Simon Rothwell Robert Cooper Hector Chinoy William Ollier Joanna Parkes James Lilleker Alex Oldroyd John Bowes Hazel Platt
UoBath/UKMYONET Neil McHugh Zoe Betteridge Patrick Gordon David Isenberg Mike Hanna Pedro Machado Harsha Gunawardena James Miller Paul New
EuMyonet/Euromyositis Lucy Wedderburn Gouchun Wang Louise Diedrichson Jens Schmidt
Jiri Vencovsky Paula Oakley Olivier Benveniste Ingrid Lundberg
MYOGEN/MYONET Ingrid E. Lundberg Frederick W. Miller Peter K. Gregersen Jiri Vencovsky Katalin Danko Lucy R. Wedderburn Vidya Limaye Albert Selva-O'Callaghan Michael G. Hanna Pedro Machado Lauren M. Pachman Ann M. Reed Lisa G. Rider Øyvind Molberg Olivier Benveniste Pernille Mathiesen Timothy Radstake Andrea Doria Jan De Bleecker Boel De Paepe Britta Maurer Leonid Padyukov Terrance P. O'Hanlon Annette Lee
Acknowledgements
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