Sarcoidosis whats new Dominique Valeyre EA 2363 Universit

Sarcoidosis: what’s new? Dominique Valeyre EA 2363, Université Paris 13, Sorbonne Paris Cité AP-HP, site Avicenne, Bobigny Pneumo. Trieste 04/17/2018

COI disclosure • No COI with this presentation • Member of scientific advisory boards on IPF treatment (Bohringer-Ingelheim, Roche) • Support for transportation and acomodation in ATS, ERS and CPLF scientific meetings • Fees for lectures on « sarcoidosis » in « avancées de pneumologie » (Astra) and on ILDs (ISIS France)

Selected themes and articles Epidemiology – – Duchemann B et al ERJ 2017; 50 Rossides M et al. ERJ 2018; 51 Severe pulmonary sarcoidosis – – – Kirkil G et al Chest 2017 Uzunhan Y et al. ERJ 2017; 49 Boucly A et al. ERJ 2017; 50 CVD risk in sarcoidosis (Ungraet ERJ 2017) Phenotypes of sarcoidosis – – Schupp ERJ 2018 Mana Medicine 2017 Treatment – – Broos CE et al. ERJ 2018; 51 Khan Respir Med 2017 Heidelberger JAMA Dermatology 2017 Schimmelpenninck Respir Med 2018 Réhabilitation – Lingner H et al. Respiration 2018 Etiology/pathogenesis (m. Tor pathway; Th 17. 1; mi. RNA; microbiome) – – Linke M, Weicchart T Nat Immunology 2017 Broos C ERJ 2018 Ascoli C AJRCMB 2018 Zimmermann ERJ 2017

Epidemiology of sarcoidosis

ILD (including sarcoidosis) epidemiology in a multiethnic county of greater Paris B Duchemann ERJ 2017

Seine Saint Denis population > 15 years old (1 194601 inhabitants) ILD cases N Prevalence (/105) n Incidence (/105/year) All identified cases 1170 97. 9 232 19. 4 Reviewed cases 848 71. 0 219 18. 3 ILDs of known cause 260 21. 8 77 CTDs/vasculitis 145 12. 1 39 Pneumoconioses 42 3. 5 9 Drug-induced ILD 31 2. 6 14 Hypersensitivity pneumonitis 28 2. 3 11 Radiation induced pneumonitis 7 0. 6 1 0. 1 Others * 7 0. 6 2 0. 3§ 145 12. 14 52 IPF 98 8. 2 33 NSIP 20 1. 7 10 Desquamative interstitial pneumonia 10 0. 8 3 Organizing pneumonia 9 0. 8 1 Unclassified (despite SLB) 6 0. 5 5 Respiratory bronchiolitis with ILD 2 0 Lymphoid interstitial pneumonia 0 0. 0 Sarcoidosis 361 30. 2 58 4. 9 Particular ILDs 22 1. 8 10 Lymphangioleiomyomatosis 9 0. 8 4 Chronic idiopathic eosinophilic pneumonia 5 0. 4 1 Pulmonary Langerhans cell histiocytosis 4 0. 3 2 Pulmonary alveolar proteinosis 2 0. 2 1 Others † 2 0. 2 2 0. 1 60 5. 0 22 1. 8 34 2. 9 13 1. 1 Idiopathic interstitial pneumonias 6. 5 3. 3 0. 8 1. 2 0. 9 4. 4 2. 8 0. 3 0. 1 0. 4 0. 0 0. 8 0. 3 0. 1 0. 2 Undetermined diagnosis Differential diagnosis between IPF and NSIP B Duchemann Eur Respir J 2017

ILD prevalence Duchemann Eur Respir J 2017

ILD incidence B Duchemann Eur Respir J 2017

ILD prevalence according to age and sexe Duchemann Eur Respir J 2017

Impact of geographical origin in ILD epidemiology Table 3: Odd ratio by geographical origin for the main etiological diagnoses (multinomial logistic regression analysis, reviewed cases) Geographical origin Diagnosis Europeans Afro-Caribbeans Maghrebi Others Sarcoidosis OR (95% CI) p-value 1 NA 2. 972 (1. 615 -5. 468) < 0. 001 1. 822 (1. 118 -2. 970) 0. 016 1. 727 (0. 792 -3. 769) 0. 170 IPF OR (95% CI) p-value 1 NA 0. 604 (0. 163 -2. 241) 0. 451 1. 418 (0. 824 -2. 440) 0. 208 0. 288 (0. 036 -2. 303) 0. 240 CTDs/vasculitis ILDs OR (95% CI) p-value 1 NA 4. 383 (2. 210 -8. 693) < 0. 001 1. 767 (1. 032 -3. 027) 0. 038 2. 191 (0. 931 -5. 157) 0. 073 Duchemann Eur Respir J 2017

Sarcoidosis epidemiology is variable prevalence US 141/105 AA 49/105 Cauc UK F/M origin F>>M 5/105 France 32/105 All 10/105 Cauc Sweden 160/105 Japan incidence 4. 9/105 F>M Africa>Maghr eb>Europe M>F 1/105 Arkema ERJ 2016; Baughman Ann ATS 2016; Gribbin Thorax 2006 Morimoto ERJ 2008; Duchemann ERJ 2017

Sarcoidosis mortality in Sweden: a population-based cohort study National patient register in Sweden - cohort study - only 30% with sarcoidosis mention on death certificate - increase of all cause mortality (+62%) - associated to initial treatment - ≠ Ungrasaert Mayo Clinic Proc 2016 Rossides ERJ 2018

Walsh Lancet RM 2014

Walsh Lancet RM 2014

Kirkil Chest 2017

Uzunhan ERJ 2017

Uzunhan ERJ 2017; Godet Chest 2016

Uzunhan ERJ 2017

Uzunhan ERJ 2017

Conclusions for CPA-sarcoidosis • Occurs in advanced pulmonary sarcoidosis (often with pulmonary masses) • Association with prior intensive mould occupational exposure • Mortality mainly caused by advanced pulmonary fibrosis (>20% at CT, PH, CPI, Walsh algorithm) more than CPA

Survival at 1, 3, 5 yrs=93, 74, 55% Boucly et al ERJ 2017

IS to consider when compression by active lymphadenopathy or persistance of active vascular lesions (PET +++)

Schupp ERJ 2018

Mana Medicine 2017

Ungrasert ERJ 2017

Daily home spirometry to detect early steroid treatment effects in newly pulmonary sarcoidosis Broos ERJ 2018

GC adverse effects Khan Respir Med 2017 • Retrospective monocentric study of new sarcoidosis cases 105 GC+ vs 49 GC • Criteria: diabetes, BMI, HTN, hyperlipidemia, bone density, ophtalmologic complications; any complication; new abnomality or worsening of a previous abnormality • Predisposing factors: age, sexe, origin • End-point: time elapsed before any event; each event

Results • • Risk of adverse events x 2. 35 in group GC+ Linked with cumulated doses or duration of GC Predisposing factors: age and preexisting trouble Most significant effects on: BMI and HTN

Khan Respir Med 2017

Khan Respir Med 2017

Impact of inflammation/DMARDs on CVD in sarcoidosis Ungraert ERJ 2017

Efficacy and safety of infliximab biosimilar inflectra in sarcoidosis Schimmelpenninck Respir Med 2018 • • Retrospective study: n=29 (main indication: lung) Dose 5 mg/kg Duration 6 months Response +: SUV max; s. IL-2 R; FVC; HRQOL 4 infectious episodes (not severe) No need for interruption of treatment Conclusion: – Far cheaper – Short-term efficacy and safety of inflectra • Unresolved questions – Long-term immunisation? – Effet of serial change of biosimilars?

Heidelberger JAMA Dermatology 2017

Aknowledgements • Avicenne + P 13 (EA 2363) – H Nunes; Y Uzunhan; D Bouvry; O Freynet; F Jeny – C Planès; PY Brillet; M Brauner; D Piver; M Kambouchner; JF Bernaudin • Equipes de génétique (A Calender; Y Pacheco); immunologie (M Miyara; G Gorochov); épidémiologie (I Annesi-Maesano; PA Rosental; N Nathan); modèles (C Planès; V Besnard; F Jeny) • Groupe GSF, groupe de travail officiel de la SPLF