januse kinase inhibition with filgotinib to silence autoreactive b cells in rheumatoid arthritis

Conditions: Rheumatoid Arthritis

Summary: to investigate the effect of filgotinib on phenotype, b cell receptor (bcr) usage and functional parameters of circulating b cells expressing acpa in patients with acpa-positive ra that show incomplete response to standard, medium-dose methotrexate (mtx) monotherapy.

b cells expressing anti citrullinated protein antibodies (acpa) in patients with rheumatoid arthritis (ra) display an activated, proliferative phenotype. experimental data indicate that acpa and acpa-expressing b cells are actively involved in driving the disease process in ra. the present study is based on the hypothesis that targeted intervention with filgotinib as a means to interfere with the activation of b cells in early, active, acpa-positive ra can reverse the activated, proliferative phenotype of citrullinated antigen-specific b cells.

Eligibility criteria:
inclusion criteria: each patient must: * have a diagnosis of ra and must have fulfilled the revised 2010 eular/acr criteria for classification of ra prior to initiation of first-line treatment. * have a positive test for the presence of anti-citrullinated protein antibodies (acpa) in serum with a value of at least 200 u/ml, as determined by routine clinical assay. * have moderate to highly active disease defined by a disease activity score evaluating 28 joints (das28) ≥ 3.2 or, correspondingly, an sdai score of \> 11. * have used methotrexate monotherapy at a stable, maximally tolerated dose once weekly for at least 3 months; concomitant glucocorticoid therapy is allowed if at a stable dose of ≤ 7.5 mg prednisolon equivalent within 30 days prior to entry in the study. * have adequate hematologic function (anc ≥ 4000 cells/μl, platelet count ≥ 150000/μl, and haemoglobin ≥ 10 g/dl (corresponding to 6.2 mmol/l) * have a serum creatinine clearance of \> 15 ml/min. * be at least 18 years of age * if female and of childbearing potential, agree to: comply with effective contraceptive measures, use adequate contraception since the last menses and use adequate contraception during the study * be willing to undergo pre-treatment screening for latent tuberculosis infection by chest x-ray and mantoux testing as well as serological screening for chronic viral hepatitis infection. as an alternative for the mantoux test, a standardized ifn-gamma release assay may be used to assess latent tuberculosis infection. * be able and willing to give written informed consent prior to entry in the study exclusion criteria: any patient who: * has ever been treated with rituximab or another b-cell depleting agent * has been treated with a biological dmard (except rituximab) or a targeted synthetic dmard within 6 months prior to entry in the study * has received intra-articular or systemic glucocorticoid injections within 30 days prior to baseline or requires narcotic analgesics other than those accepted by the investigator for analgesia (e.g. paracetamol, nsaids, codeine, tramadol) * receives concomitant treatment with a csdmard other than methotrexate * has been tested negative for acpa * is in clinical remission as defined by a disease activity score evaluating 28 joints (das28) ≤ 2.6 or, correspondingly, an sdai ≤ 3.3 * has evidence of a medical condition which represents a contra-indication for initiation of either a tnf-alpha inhibitor or a janus kinase inhibitor, as outlined in the spcs of either adalimumab and/or filgotinib. * has liver function abnormality (ast and/or alt ≥ 3 x upper limit of normal range) * has concurrent treatment with an experimental drug or who has participated in another clinical trial with an investigational drug within 30 days prior to study entry * has past or current history of solid or haematological neoplasms, except for curatively treated non-melanoma skin cancer, adequately treated in situ carcinoma of the cervix or another cancer curatively treated and with no evidence of disease for at least 10 years * is pregnant or a currently nursing woman * is female and of childbearing potential, unwilling to use adequate contraceptive measures during the study.

Keywords: autoreactive b cells immunological remission anti citrullinated protein antibodies