Rheumatol Ther. 2020 DOI: 10.1007/s40744-019-00192-5In this study examining the effect of FIL on a panel of biomarkers, FIL down-modulated several key inflammatory mediators of signalling pathways in RA - independent of MTX background therapy. This confirmed the strong network effects of the JAK1 node in autoimmunity, matrix and cartilage degradation, angiogenesis, and leukocyte adhesion and recruitment. Biomarkers key to RA pathophysiology were measured at baseline, Wk4 and Wk12 in FIL 100 mg, FIL 200 mg or PBO treatment groups from two phase 2b studies: DARWIN1 (FIL+MTX) and DARWIN2 (FIL mono). Lymphocyte subpopulations were also quantified at baseline, weeks 1, 2, 4, 8, and 12 by flow cytometry. FIL induced significant, dose-dependent reductions in various RA pathogenesis biomarkers including IL-6 and its downstream target SAA, which are indicative of JAK1 signalling inhibition. Biomarker modulations were independent of MTX co-medication. FIL also displayed effects on immune factors common to TOF and BARI which included transient increases in total lymphocyte count and a sustained elevation in B-cell numbers – despite significant reductions in B-cell chemoattractant and survival/activation markers, CXCL13 and BAFF. Study limitations included measuring systemic cytokine levels as a surrogate for local processes and confining immunophenotyping to major immune cell types.