Interstitial Pneumonia with Autoimmune Features. Where are we?

1. Interstitial Pneumonia with Autoimmune Features. Where are we? CLAUDIA RAVAGLIA – FORLI (ITALY) PORTO – 23/24 MARCH 2018

2. Autoimmune or rheumatologic “flavour” Patients diagnosed with IIP can have certain, often subtle, features that suggest an underlying autoimmune process without meeting established diagnostic criteria for any characterizable CTD • clinical features in the absence of serologic abnormalities • highly specific serum autoantibody without typical systemic or extra-thoracic findings. • radiologic or histopathologic features suggesting an underlying CTD in the absence of extra-thoracic clinical or serologic findings

3. Autoimmune or rheumatologic “flavour” • UCTD-ILD (= Undifferentiated CTD associated ILD) • Lung-dominant CTD • Autoimmune-featured ILD • Different (overlapping) diagnostic criteria and terms • Lack of consensus over nomenclature and classification criteria • Limited ability to conduct prospective studies

4. ERS/ATS Task Force =international, multidisciplinary panel of CTD-ILD experts • 13 pulmonologists • 4 rheumatologists • 1 radiologist • 1 pathologist

5. IPAF statement: start point • A RESEARCH statement (IPAF was not a validated diagnosis) • AIMS: • To explore FORME FRUSTES of CTD-ILDs (described in several clinical series with no standardized definitions) • To COLLECT DATA to catch important INFORMATION: disease epidemiology, pathophysiologic mechanisms of disease, prognostic and therapeutic implications … • To CREATE a CONSENSUS-DERIVED NOMENCLATURE • To FACILITATE the design and conduct of CLINICAL STUDIES • It is “the first draft” -> need to be validated, improved, etc. ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD

6. IPAF statement: definition • ILD with no known causes • Combination of other features suggestive of an underlying systemic autoimmune condition but not characterized CTD • Clinical (extra-thoracic) • Serologic (specific antibodies) • Morphologic (radiological, hystopathologic, physiological) • At least one feature of two domains • The term “connective tissue disease” was specifically avoided due to concerns that such labelling gives a false impression that these individuals have a defined CTD ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD

7. ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD

8. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

9. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

10. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

11. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

12. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

13. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

14. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

15. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

16. Since the statement a lot of retrospective studies have been published to describe the phenotype and natural history of cohorts of patients with IPAF

18. 1. Can IPAF be considered a diagnosis? • Any clinical utility? • Well defined etiopathogenesis? • Well known natural history? • Prognostic significance – predictors of mortality? • Therapeutic implications?

20. FVC 56 patients IPAF. 71% female. Mean age 55 years. UIP pattern (HRCT) : 9% Chartrand et al. 2016

21. 27 death during follow-up. No UIP pattern on CT scan Pulmonary Medicine (2017) 17:111

22. 27 death during follow-up. No UIP pattern on CT scan Pulmonary Medicine (2017) 17:111

23. Retrospective study. 422 UCTD-ILD, IIP, undifferentiated ILD. IPAF criteria -> 144 IPAF. Comparing outcome of IPAF patients with IPF and CTD-ILD outcome. Oldham et al.

24. Retrospective study. 422 UCTD-ILD, IIP, undifferentiated ILD. IPAF criteria -> 144 IPAF. Comparing outcome of IPAF patients with IPF and CTD-ILD outcome. Oldham et al.

26. IPAF with UIP has the same mortality as IPF IPAF without UIP has the same mortality as CTD-ILD Oldham et al.

27. Retrospective study. 101 IPAF patients. IPAF non-UIP IPAF-UIP If we make a distinction between UIP and non-UIP, does IPAF designation really help us? IPF Kelly B et al. Respirology(2018)

28. Oldham ERJ

29. In the modified IPAF group there were also patients with UIP pattern => patients with UIP pattern can also have more favorable prognosis depending on clinical and other morphological features UIP does not exclude IPAF

31. IPAF patients can develop a CTD

32. IPAF patients can develop a CTD Importance of longitudinal surveillance for evolution to CTD among those with IPAF and those with IIP in general

33. 2. Best definition of clinical/serological domain • Some countries have the rheumatologist in the MDM • However, often the rheumatologist does not see patients (just join the meeting) • Competence of respiratory physician (who describes patient to the rheumatologist) may be limited in evaluating these features • Patients with suspected IPAF could be evaluated jointly by a rheumatologist and a respiratory physician in a CTD-ILD clinic!

34. Not included in the clinical domain (*) • Alopecia • Photosensitivity • Oral ulcers • Weight loss • Sicca symptoms • Myalgia or arthralgia alone • Oesophagealdismotility • Younger age • Female sex (*) less-specific symptoms, ubiquitous and not nearly as specific for CTD

35. Not included in the clinical domain (*) • Joint pain alone • Alopecia • Photosensitivity • Oral ulcers • Weight loss • Sicca symptoms • Myalgia or arthralgia • Oesophagealdismotility • Younger age • Female sex BUT RISK TO EXCLUDE PATIENTS WITH “AUTOIMMUNE FLAVOUR”! (*) less-specific symptoms, ubiquitous and not nearly as specific for CTD

36. Included in the clinical domain (*) • Mechanic Hands • Gottron’s sign • Distal digital tip ulceration (*) highly specific items for definite CTD or even pathognomonic features for well definite CTDs

37. Included in the clinical domain (*) • Mechanic Hands • Gottron’s sign • Distal digital tip ulceration BUT RISK TO CONSIDER AS IPAF INCOMPLETE FORMS OF CTD THAT ARE IN TURN AT HIGH RISK OF CLINICAL EVOLUTION (*) highly specific items for definite CTD or even pathognomonic features for well definite CTDs

38. Included in the serological domain (*) • ENA specificities • anti-DsDNA • Anti-tRNA-synthetase antibodies BUT RISK TO CONSIDER AS IPAF INCOMPLETE FORMS OF CTD THAT ARE IN TURN AT HIGH RISK OF CLINICAL EVOLUTION (*) highly specific items for definite CTD or even pathognomonic features for well definite CTDs

39. Anti-tRNA-synthetase antibodies • Some patients with anti-tRNA-synthetase Abs are considered CTD-ILD and not IPAF even in absence of systemic features of CTD • And viceversa • Could identify a sub-group with different outcome? • It is crucial to better standardize Idiopathic Inflammatory Myopathies classification * Anti-CADM-140-Ab (= anti MDA5) is associated with clinically amyopathic DM (bad survival) * Anti-Ku Ab is not part of the IPAF criteria! NIEHS. Classification Criteria Study: The International Myositis Classification Criteria Project.

40. Temporal clustering and combination of elements • There is sometimes temporal clustering between the development of lung disease and the onset of a number of systemic features suggestive of autoimmunity. • In the statement temporal linkage is not taken into account • The simultaneous or near-simultaneous development of IPAF features in two domains must surely increase the likelihood of biological linkage between these features. * This may also apply to clinical features (such as sicca symptoms and gastro-esophageal reflux) that are compatible with, but less specific for, autoimmune disease and are excluded from the IPAF clinical domain. Luppi F, Wells A. ERJ 2016

41. 3. Best definition of morphological domain Lung biopsy in IPAF could be appropriate: • Chest imaging pattern on HRCT is atypical for an underlying CTD • Chest imaging pattern on HRCT is atypical for an IIP • Chest imaging pattern on HRCT suggests malignancy or infection • A specific pattern cannot be identified by HRCT

42. PATIENTS CATEGORIZED AS “IPAF” WHO HAD UNDERGONE SURGICAL LUNG BIOPSY (SLB)

43. In-Hospital Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the United States • Mortality 1.7% for elective procedures • Mortality 16% for non-elective procedures • Risk factors: • Age • Comorbidities • Open surgery • Provisional diagnoses of IPF or CTD-ILD Hutchinson JP et al. AJRCCM 2016

44. Mortality 0.1% (1 of 994 patients) TLCB mortality VATS mortality Ravaglia C, Bonifazi M, Wells AU et al. Respiration 2016

45. Potential role of cryo in IPAF pts? There are no data regarding cryo in IPAF

46. Multi-compartment designation • In predominantly restrictive ILD, it is often obvious that there is coexisting airflow obstruction • In predominantly restrictive ILD, it is often obvious that there is coexisting pulmonary vasculopathy • Which are the elements that justify a multi-compartment designation?

47. We don’t know which are the better functional indexes of obstruction in these patients? • FEV1/FVC 0.70 or RV/TLC? • We don’t know which are the better functional indexes of pulmonary hypertension? • KCO ? FVC/DLCO >1.6? Definite PH? What is “disproportionate PH”? • How can we adjust airflow obstruction to the presence/absence of emphysema on HRCT?

48. In conclusion • IPAF a “provisional” diagnostic entity • Natural history – Prognostic factors • Role of immunosuppression and anti-fibrotic therapy in IPAF (particularly those with the more fibrotic patterns of ILD) • Better definition of diagnostic criteria, in particular of the multi-compartment designation • Consider the temporal linkage of the domains • Possible role of cryobiopsy in IPAF