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Biomarkers in interstitial lung diseases: is it possible to monitor and better treat the patients?

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Biomarkers in interstitial lung diseases: is it possible to monitor and better treat the patients?

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Biomarkers in interstitial lung diseases: is it possible to monitor and better treat the patients?

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

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