Anti-B-cell therapy in RA-ILD

Prior treatment

• Women of childbearing potential i.e. any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential” defined as: women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g. hysterectomy, bilateral oophorectomy, or bilateral salpingectomy)) not willing or able to use highly effective methods of birth control (resulting in a low failure rate of less than 1% per year when used consistently and correctly) from 14 days prior to IMP administration, throughout the duration of the study and up to 6 months after end-of-study (i.e. 12 months after last RTX/Placebo IMP dose).
• Subjects with current or recent (≤30 days prior to baseline) participation in a clinical trial with an investigational product.
• Subjects with previous treatment with anti-B cell targeted therapy for RA.
• Subjects with active infection (excluding fungal infections of nail beds) requiring hospitalization and/or i.v. anti-infectives ≤ 4 weeks, or oral anti-infectives* ≤ 2 weeks prior to baseline. *Prophylactic anti-viral therapy for chronic Hepatitis B and valaciclovir for Herpes Simplex type 2 are exempt (see exclusion criteria 6 and 7).
• Subjects with biologic or targeted synthetic DMARDs, anti-fibrotic therapy or cyclophosphamide ≤ 12 weeks prior to baseline.

Other illness

• Subjects with other chronic rheumatic disease, except for secondary Sjögrens syndrome.
• Subjects with severe congestive heart failure (NYHA class 4) or severe uncontrolled heart disease.
• Subjects with any significant comorbidity or disorder (including clinically significant pathological lab results) that according to the investigator will preclude study participation.
• Subjects with any other factors (such as significant psychiatric or mental disorder, alcohol or other substance abuse, language barriers) that will make adherence to the protocol difficult.
• Subjects with hypersensitivity towards murine proteins or excipients of rituximab drugs.
• Subjects with a history of severe infection(s) including but not limited to disseminated and/or recurrent severe Herpes Simplex or Herpes Zoster infections.
• Subjects with suspected or diagnosed active or latent tuberculosis and/or positive QuantiFERON (or TB-spot) test. Subjects with latent tuberculosis can be included if successfully treated or have initiated prophylaxis therapy ≥ 1 months of baseline.

Lab values

• Subjects with absolute neutrophil count <1.5 x10^9/L.
• Subjects with absolute thrombocyte count <75 x10^9/L.
• Subjects with chronic hepatitis B without proper prophylactic therapy. Subjects with chronic hepatitis B can be included only if monitored with Hepatitis B DNA, aminotransferases (ALT and AST) every 12 weeks and treated with anti-viral drug for at least 7 days before RTX infusion and for at least 18 months after last RTX infusion.

Age

• Subjects with a history of malignancy ≤ 5 years prior to baseline (except for successfully treated cervical carcinoma in situ, basal cell and squamous cell carcinoma of the skin, with no evidence of recurrence or metastatic disease for at least 3 years).

Other

• Subjects with asthma or COPD with FEV1/FVC < 0.7.
• Subject who is, or wish to become, pregnant or lactating during and ≤ 6 months after the study.
• Subjects with inborn error of immunity or acquired severe immunodeficiency including but not limited to total immunoglobulin G < 6g/L.

• The subject has given their written consent to participate in the trial.
• The subject is an adult with rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) positive RA fulfilling the 2010 ACR/EULAR RA classification criteria.
• The subject has radiographic signs of ILD (defined as non-dependent abnormalities in ≥5% of a lung zone (upper, middle or lower) including ground glass opacities, reticulations, lung distortion, traction bronchiectasis, honey combing and non-emphysematous cysts) on a chest high resolution computed tomography (HRCT) scan (reviewed and concluded by two thoracic radiologists in consensus).
• The subject has pulmonary function ≥ 50 %pFVC and 40-80 %pDLCO. Participants may be asymptomatic or symptomatic with respect to ILD.
• The subject has a stable background conventional synthetic (cs) disease modifying anti-rheumatic drug (DMARD) therapy with or without a low dose prednisone since ≥ 12 weeks prior to baseline.