Rituximab in Rheumatoid Arthritis Lung Disease

Inclusion Criteria:

1. Diagnosis of RA according to the revised 1987 American Rheumatism Association criteria

2. Absence of clinical features suggesting infection, neoplasm, sarcoidosis, interstitiallung disease other than UIP or NSIP, other collagen vascular disease, or exposure toknown fibrogenic drugs or environmental factors

3. Diagnosis of progressive interstitial pneumonia of UIP or NSIP subtype, based on thefollowing criteria

4. Clinical symptoms consistent with interstitial lung disease with onset between 3months and 36 months prior to screening.

5. Worsening as demonstrated by any one of the following within the past year:

• > 10% decrease in Forced Vital Capacity (FVC)

• increasing infiltrates on chest X-ray or High Resolution Computed Tomography (HRCT), or worsening dyspnea at rest or on exertion

3. Diagnosis of UIP or NSIP by either of the following:

• Open or video-assisted thoracic surgery (VATS) lung biopsy showing definiteor probable UIP or NSIP

• HRCT scan showing definite or probable UIP or NSIP AND abnormal pulmonaryfunction tests (reduced FVC or decreased diffusing capacity of carbonmonoxide (DLco) or impaired gas exchange at rest or with exercise) ANDinsidious onset of otherwise unexplained dyspnea or exertion and bibasilar,inspiratory crackles on auscultation

4. FVC > 50% of predicted value at Screening

5. DLco >30% of predicted value at Screening

6. No change of disease-modifying anti-rheumatic drug (DMARD) treatment within the last 3months

Exclusion Criteria:

1. History of clinically significant environmental or drug exposure known to causepulmonary fibrosis.

2. Forced expiratory volume in one second (FEV1) FEV1/FVC ratio < 0.6 at screening (pre-or post-bronchodilator).

3. Residual volume > 120% predicted at Screening

4. Evidence of active infection

5. Any pulmonary condition other than UIP/NSIP, which, in the opinion of the siteprincipal investigator, is likely to result in the death of the patient within thenext year

6. History of unstable or deteriorating cardiac or neurologic disease

7. Pregnancy or lactation

8. Treatment with cyclophosphamide, cyclosporine, interferon gamma or beta, anti-tumornecrosis factor therapy, anti-interleukin 1 (IL1) therapy or with endothelin receptorblockers within the last 8 weeks; experimental therapy for rheumatoid arthritis

9. Creatinine > 1.5 X upper limit of normal range (ULN) at Screening

10. Hematology outside of specified limits: white blood cell (WBC) < 2,500/mm^3 orabsolute neutrophil count (ANC) < 1500

11. Hematocrit < 27% or > 59%, platelets < 100,000/mm^3 at screening

12. Positive hepatitis B or C serology

13. Any medical condition, which in the opinion of the site principal investigator, may beadversely affected by the participation in this study

14. History of recurrent significant infection or history of recurrent bacterialinfections

15. Known active bacterial, viral fungal mycobacterial, or other infection (includingtuberculosis or atypical mycobacterial disease, but excluding fungal infections ofnail beds) or any major episode of infection requiring hospitalization or treatmentwith i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeksprior to screening

16. Abnormal neurological examination reflective of central nervous disease, includingparesis, cognitive impairment and problems with coordination

17. Current enrollment in another clinical trial

18. Fever (>99.5º F)

19. History of previous rituximab administration

20. Receipt of any vaccine, particularly live viral vaccines, within 4 weeks of firststudy dose

21. Decreased Immunoglobulin G (IgG) and Immunoglobulin M (IgM) levels (below lower limitof normal range)

22. Present or past malignancy

23. History of severe allergic or anaphylactic reaction to administration of humanized ormurine monoclonal antibodies

24. Positive human immunodeficiency virus (HIV) serology