1. www.bellvitgehospital.cat
Dra. Maria Molina Molina
Undad Funcional de Intersticio Pulmonar
Dirección Clínica de Enfermedades Respiratòries
Laboratorio de Investigación Neumològica. IDIBELL
Hospital Universitario de Bellvitge
Biomarkers in ILDs: is it possible to
monitor and better treat the patients?

2. The ideal biomarker in ILDs:
Objectively measured
Easily acquired (non-invasive methods)
Validity and reliability
Available for monitoring
Reflect the pathobiological mechanisms
driving disease
The information that entails improves
conventional patient care
Biomarkers in ILDs: is it possible to
monitor and better treat the patients?

3. SERUM BIOMARKERS
(diagnostic, prognostic, theragnostic)
To improve:
Diagnosis, subclinical identification, follow-up
Pharmacologic responses to a therapeutic intervention
Objectively measured
IPF
IPF-control
IPF-other ILD
TGF-β1, IL-8, VEGF, fibrocites, HSP70
HSP47 CXCL13, periostin, ECM
neoepitops, osteopontin, YKL-40
MMP3, CCL18 IGFB1, LOLX2, TNFR
alfa-defensins, ICAM-1, VCAM-1, KL-6
S100A12, SP-A, SP-D, cCK18
LPD, AGE/RAGEs
IPF-other
fibrotic
ILD
MMP-7,-8
MMP-1
MMP-28
AGE/RAGEs
Biomarkers in ILDs: is it possible to
monitor and better treat the patients?

4. Rosas IO et al. Plos medicine. 2008.54:e93
Se=96.3%
Sp=87.2%MMP7+MMP1+MMP8+IGFB1+TNFR
74 IPF
53 Control
47 Sarcoidosis
41 cHP
73 COPD
DIAGNOSTIC AND PROGNOSTIC APPROACH
Machahua C, et al. Respir Res. 2018;19:215
AGEs/RAGEs
differentiates IPF
from fNSIP (AUC =
0.987, CI = 0.959–
1.000)

5. Genomic markers: Disease Susceptibility and Outcome
Gene SNP and mutations IPF and FPF
From familial clustering (rare variant, mutations)
Surfactant protein C, A2 SFTPC, SFTPA2
Telomerase complex TERT, TERC, DKC1
ELMO domain ELMOD2
From genome-wide association studies (common variant)
Mucin 5B MUC5B
Telomerase complex TERC, TERT, DKC1, PARN, TINF2, RTEL1
Desmoplakin DSK
ATP ion transport ATP11A, FAM13A, AKT
Dipeptidyl-peptidase 9 DPP9
Toll interacting protein TOLLIP
Signal peptide peptidase SPPL2C
Angiotensin system -6AGT, ACE
From specific cohort gene studies (common variant)
SNPs -6AGT, ACE, CR1, PTGS2, FCGR, HLA-A, -B, IL-1RN, IL4, IL6, IL8, MMP1,
MMP7, MICA, PAI-1, SFPTD, TGF-β1, TNFRSF1B, CDKN1A, TP53
Better tools for genetics:
DNA studies and statistic
assessment
DIAGNOSTIC AND PROGNOSTIC APPROACH
Petrovski S, et al. Am J Respir Crit Care Med. 2017:196:82-93
Chu SG, et al. Semin Respir Crit Care Med. 2016;37:321-330
Sporadic IPF – 11.3% TERT,
RTEL1 or PARN gene mutations
> 4000 control EU – US
ancestries

6. Telomere or surfactant gene
mutations in pulmonary fibrosis
➢ Increasing lung damage versus any environmental
factor
➢ Problems for lung repair
To minimize invasive lung procedures
Newton CA et al. Eur Respir J. 2016;48:1556-158
Implications for diagnostic procedures

7. Surfactant protein gene mutations:
< 45 years, cancer, ILD childhood, newborn distress
Garcia CK. Proc Am Thorac Soc. 2011;8:158-162
Van Moorsel, et al. Am J Respir Crit Care Med. 2010;182(11):1419-25
Cogan et al. Am J Respir Crit Care Med. 2015;191(6):646-55
Seibold MA, et al. N Engl J Med. 2011;364:1503-1512
Planas L, et al 2018. Respirology. 2019
Telomerase gene mutations:
Young>Elderly, frequent family aggregation
Comorbidities: emphysema, cancer
50% UIP pattern
Systemic telomeric signs
Pulmonary phenotypes associated with genetic
variation in telomer-related genes
Hoffman TW, van Moorsel CHM, Borie R, Crestani B
Curr Opin Pulm Med. 2018;24:269-280
IPF Phenotypes

8. 2014 2016
Male, 41 years
No exposures. No symptoms, normal FVC,DLCO
Brother died, 40y, because of lung fibrosis
r.54-47delAACU TERC mutation, telomere length < 10
Newton CA et al. Eur Respir J. 2016;48:1556-158
Identifying and managing early IPF

9. Biomarcadores en Linfangioleiomiomatosis
Valores séricos de VEGF-D en suero > 800 pg/ml ayudan en
el diagnóstico de LAM y orientan en pronóstico
Hirose M, et al. PLoS One. 2019;14(2):e0212776
Cohorte LAM de Japón y
validación US

10. FVC: predictive of IPF mortality
Karimi-Shah BA, et al. New England J. 2015;372:1189-1191
…And we have some serum biomarkers that
improve predictive power

11. Planas L, et al. Respirology. 2019
Telomeric IPF disease behaviour
> 60y
> 60y+TS
< 60y
< 60y+TS
Stuart et al. Lancet Respir Med 2014

12. Herazo-Maya JD, et al. Lancet Respir Med. 2017;5:857-868
Gene expression predicting IPF outcome
52-gene risk profiles and
outcomes independent of
demographic and clinical
variables
Newton Ch et al. Front in Med. April 2018;5

13. RG Jenkins, et al. Lancet Repir Med. 2015;3(6):462–472
Matrix metalloprotease (MMP)-degraded ECM proteins: ECM neoepitopes
IPF patients = 189
Age and sex matched controls
Multicentre. Same protocol
Validating cohort
Prospective and longitudinal
Higher concentration of C1M, C3A, C3M,
C6M, CRPM in progressive IPF
IPF PROGNOSTIC APPROACH

14. Wagner CL, et al. J Clin Invest. 2018;128(12):5222-5234
TREATMENT EFFECT DEPENDING ON GENETICS
Telomere Length and Use of Immunosuppressive
Medications in Idiopathic Pulmonary Fibrosis
Molina-Molina M. Am J Respir Crit Care Med. 2019
T cell deficiency even with
functional bone morrow
The harmful effect of corticosteroids
in IPF is associated with the
presence of telomere shortening
Lung transplantation in telomerase mutation
carriers with pulmonary fibrosis
Silhan LL, et al. Eur Respir J. 2014;44(1):178-87

15. Safety, tolerability, pharmacokinetics, and pharmacodynamics of
GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary
fibrosis (FLORA): a phase 2ª randomised placebo-controlled trial
Lancet Respir Med. 2018;6:627-635
LPA (ácido lisofosfatídico): marcador teragnóstico

16. Tratamiento en otras EPID: PAP
Respir Res.2018;19:163
Proteinosis Alveolar Pulmonar autoinmune (auto-anti-GM-CSF)
Molgramostim inhalado (ensayo clínico MOL-PAP 002)
Factor estimulador de colonias granulocíticas y macrófagos
que inhibe los niveles de anti-GMCSF
Mejora Oxigenación arterial
Reduce necesidad lavado bronco-alveolar total

17. Biomarkers in ILDs: is it possible to
monitor and better treat the patients?
YES….
In Pulmonary Fibrosis and LAM
Although standards and globalization
are required to recommend its use in
clinical guidelines

18. Biomakers: Running together in the same
way but approaching from different angles
Thanks