Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease
Effects of Tofacitinib vs Methotrexate on Rheumatoid Arthritis Interstitial Lung Disease
Pulmonary abnormalities are present in up to 60% of patients with early rheumatoid arthritis
 (RA), and up to 10% of the patients will develop clinical interstitial lung disease (ILD).
 Recent data indicate that inhibition of Janus kinase is beneficial for this extra-articular
 manifestation. Our goal is to determine whether tofacitinib is an effective and safe
 treatment, compared to standard-of-care methotrexate, for subclinical and clinical ILD in
 patients with early RA. The study also explores disease mechanisms in lungs and joints, to
 identify potential biomarkers for diagnosis, prognosis, and response to treatment of RA-ILD.
Study objectives:

 Primary objective: Effects of tofacitinib compared to that of methotrexate on interstitial
 pulmonary abnormalities at 24 weeks.

 Secondary objectives: Effects of tofacitinib compared to that of methotrexate on pulmonary
 abnormalities and function, RA disease activity and remission rates and patient reported
 outcome measures at different time points. Frequency of adverse events.

 Exploratory objectives: Effects of tofacitinib compared to that of methotrexate on cellular
 and molecular activity profiles of clinical samples from joints and lungs.

 Study design:

 A randomized, actively controlled, open-label, assessor-blinded, multicenter 48 weeks phase
 IV trial. The study design includes an optional sub-study collecting tissue samples using
 ultrasound-guided synovial biopsies, bronchoalveolar lavage and Particles in Exhaled Air
 (PExA).

 Study population and intervention:

 Patients with early untreated RA with active and seropositive disease will be eligible for
 screening and the performance of high-resolution computed tomography (HRCT). Subjects with
 pulmonary abnormalities suggestive of RA-ILD will be randomized (1:1) to tofacitinib 5 mg BID
 (group 1) or standard-of-care methotrexate 20 mg weekly (group 2) for 48 weeks. All patients
 receive prednisone with tapering for 6 weeks. Patients with incomplete response at 24 weeks
 will escalate to combination therapy with tofacitinib+methotrexate (group 3). Intra-articular
 injections of cortisone will be allowed during the study.

 145 subjects will be included and screened (part 1), and approximately 48 subjects will be
 randomized to active treatment (part 2).
Inclusion Criteria:

 1. The subject has given written consent to participate in the study.

 2. Diagnosis of seropositive (i.e., presence of RF and/or anti-CCP antibodies) rheumatoid
 arthritis (RA) according to the ACR/EULAR 2010 criteria within 24 months.

 3. No previous treatment with disease modifying anti-rheumatic drugs (DMARDs). History of
 prednisone use is allowed but should have been discontinued 2 weeks before baseline
 measurement.

 4. Active disease with ≥2 painful and ≥2 swollen joints in 66/68 joints and CRP ≥2.0
 mg/dl

 5. Aged 18-80 years

 6. Willing to undergo HRCT and pulmonary function tests (PFTs)

 Exclusion Criteria:

 1. Current active inflammatory joint disease other than RA.

 2. Significant and/or uncontrolled cardiac, pulmonary disease, nervous system, renal,
 hepatic, endocrine or gastrointestinal disorders or severe RA which in the
 investigator's opinion would preclude patient participation.

 3. Malignancy within the past 5 years, 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.

 4. Primary or secondary immunodeficiency (history of, or currently active), including
 known history of HIV infection.

 5. Active infection (excluding fungal infections of nail beds) requiring i.v.
 anti-infectives within 4 weeks, or oral anti-infectives within 2 weeks prior to
 baseline.

 6. Women of childbearing potential not willing or able to use highly effective methods of
 birth control per ICH M3 (R2) for 28 days prior and 3 months after end of study.

 7. Pregnant or lactating women.

 8. Positive tests for hepatitis B (HBsAg or HBV DNA) or hepatitis C serology.

 9. History of herpes zoster infection during last 10 years.

 10. History of venous thromboembolism or diverticulitis.

 11. Positive tuberculosis history and/or positive Quantiferon test.

 12. Hemoglobin <90 g/L.

 13. Absolute neutrophil count < 1500 cells/uL.

 14. ASAT or ALAT >2.0 times the upper limit of normal.