Evaluation of Efficacy and Safety of Rituximab in Patients With Progressive Interstitial Lung Disease (ILD) With Inflammatory Component: a Multicentre Double-blind Placebo-controlled Randomized Trial

Inclusion Criteria:

1. Patients ≥ 18 years old

2. Who meet at least one of the following criteria for worsening ILD within 24 months:

3. a relative decline in the FVC of >= 10% of the predicted value

4. a relative decrease in the FVC of >=5 to 10% of the predicted value AND i)worsening respiratory symptoms OR ii) an increased extent of ILD onhigh-resolution CT OR iii) a relative decrease in the DLCO of >= 15% of thepredicted value.

5. worsening of respiratory symptoms AND an increased extent of ILD onhigh-resolution CT

6. AND presence of an inflammatory component defined by

7. a previous histological pattern with lymphocyte infiltrations distant frompulmonary fibrosis to suggest an inflammatory component on pulmonary sample (for example: interstitial lymphoid aggregates with germinal centers, diffuselympho-plasmocytic infiltrations, granulomas, giant cells or centrilobularinflammation...)

8. OR a previous alveolar lymphocytosis >20% on Bronchoalveolar lavage fluid (BALF)

9. Subjects covered by the French social security system

10. Written informed consent obtained from subject

11. Ability for subject to comply with the requirements of the study

Exclusion Criteria:

1. Known diagnosis of significant respiratory disorders (asthma, tuberculosis,aspergillosis, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), ConnectiveTissue Diseases-ILD, sarcoidosis, desquamative interstitial pneumonia, pulmonaryhypertension (PAMp > 30mmHg))) or of significant severe heart failure.

2. Concomitant medical or surgical disease, clinically significant as considered by theinvestigator, serious or unstable, acute or chronically progressive, or anycondition that could affect the safety of the patient, in the opinion of theinvestigator including cardiomyopathy or heart failure.

3. Patient who can not walk more than 100 meters at 6-minutes walk test

4. HRCT profile of typical usual interstitial pneumonia (UIP)

5. Histological model of typical NSIP or definitive UIP

6. Initiation of a new therapy or with interruption/modification of therapy dosagewithin 6 weeks prior to visit 1

7. Patient who has already received a rituximab-based treatment line

8. Known hypersensitivity to rituximab, to murine proteins or other excipients orsulfonamide antibiotics.

9. Treatment with monoclonal antibodies (such as, but not limited to, etanercept,adalimumab, efalizumab, infliximab, golimumab, certolizumab) within 6 months (if 5half-lives ≤ 6 months) prior to inclusion.

10. Patients on a lung transplant list

11. Pregnant or breastfeeding women, or women of childbearing age not using a reliablemethod of contraception during the study and for 12 months following the end of thestudy treatment.

12. Patients at high risk of infectious complications: Human Immunodeficiency Virus (HIV) positive or other known immunodeficiency syndromes, hepatitis B and C (HBV,HCV), coronavirus disease (within 3 month) or other known viral infection, infectionrequiring anti-infective treatment within 4 weeks of inclusion.

13. Patients with incomplete anti-severe acute respiratory syndrome coronavirus 2vaccine regimen (according to current recommendations) and in this case who has notreceive a treatment with therapeutic antibodies anti-SARSCov2 (ex:tixagévimab/cilgavimab)

14. Patient under judicial protection, deprivation of liberty

15. Participation in other interventional research with an investigational drug ormedical device.