The purpose of the study is to evaluate the efficacy on lung function 6 months after one course of rituximab (2 infusions) and mycophénolate mofétil (MMF) treatment compared to one course of placebo and 6 months of MMF treatment in a broad range of patients with Interstitial Lung Diseases (ILD) non-responders to a first line immunosuppressive treatment.

Inclusion Criteria:

1. Age ≥ 18 years

2. A diagnosis of ILD:

   • ILD associated with differentiated CTD or IPAF (based on internationally accepted criteria)
   • OR idiopathic ILD

3. A diagnosis of NSIP based on:

   • a histological pattern of NSIP
   • OR HRCT findings suggestive of NSIP defined as basal predominant reticular abnormalities with traction bronchiectasis, peri-bronchovascular extension and subpleural sparing, frequently associated with ground-glass attenuation

4. Patients who did not respond or relapsed or were not able to continue at least one first-line immunosuppressive treatment of ILD: corticosteroids, azathioprine, cyclophosphamide or other immunosuppressants. For the assessment of clinical response, the absence of response was defined as: either a decrease or an increase, but <10% in % predicted FVC.

5. Subjects covered by or having the rights to French social security (including CMU),

6. Written informed consent obtained from subject, with a specific check box on the Consent form of the study, understanding the risk for men and women treated with mycophenolate mofetil. And additional written consent from subject on the care and contraception agreement form for women of childbearing potential treated with mycophenolate.

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

Exclusion Criteria:

1. Known diagnosis of significant respiratory disorders (asthma, tuberculosis, sarcoidosis, aspergillosis, or cystic fibrosis) other than CTD-NSIP, IPAF-NSIP and iNSIP

2. Evidence of any clinically significant, severe or unstable, acute or chronically progressive cardiac (severe heart failure New York Heart Association Class IV or severe uncontrolled cardiac disease), other medical disease (other than NSIP) or surgical disorder, or any condition that may affect patient safety in the judgment of the investigator.

3. HRCT pattern of typical usual interstitial pneumonia (UIP)

4. For patients with idiopathic ILD, HRCT pattern of possible UIP (no evocative of NSIP)

5. Histological pattern other than pattern of NSIP

6. A first line treatment with MMF or rituximab

7. Known hypersensitivity to MMF or rituximab or sulfonamide antibiotics

8. Treatment with immunosuppressive treatments other than corticosteroids:

   • azathioprine, cyclophosphamide, methotrexate, cyclosporine, tacrolimus, leflunomide within 2 weeks (5 half-lives <= 2 weeks) prior to inclusion
   • intravenous immunoglobulins, hydroxychloroquine or other monoclonal antibody therapies (such as but not limited to etanercept, adalimumab, efalizumab, infliximab, golimumab, certolizumab) within 6 months (5 half-lives <= 6 months) prior to inclusion

9. Patients registered on a pulmonary transplantation list

10. Patients with known hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) hereditary deficiency (such as Lesch-Nyhan and Kelley-Seegmiller syndrome)

11. Pregnant or breastfeeding women, or women of child-bearing potential not using two reliable contraceptive methods (including female partners of sexually active men treated with mycophenolate) and men not using a contraceptive method (condom), or women and men having a pregnancy project during the year following randomization.

12. Patients at significant risk for infectious complications: HIV positive, other known immunodeficiency syndromes, untreated tuberculosis, hepatitis B and C or other known viral infection, infection requiring anti-infectious treatment in the preceding 4 weeks

13. Current history of substance and/or alcohol abuse

14. Deprivation of liberty, under judicial protection

15. Participation in another biomedical research with experimental drug or medical device