SummaryRheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

IMPORTANCE Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options. OBJECTIVE To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population. DESIGN, SETTING, AND PARTICIPANTS A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs. INTERVENTIONS Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs). MAIN OUTCOMES AND MEASURES The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] Յ3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events. RESULTS Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with Ն3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths. CONCLUSIONS AND RELEVANCE Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety.

ObjectiveTo evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).MethodsThis 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.ResultsThe proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.ConclusionsFilgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.Trial registration numberNCT02889796.

ObjectivesTo investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure.MethodsThis 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24.ResultsThe primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was −1.0 and −0.94 with FIL200+MTX and FIL100+MTX, respectively, versus −0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments.ConclusionsFIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX.

Saccharomyces cerevisiae transcriptionally regulates the expression of the plasma membrane high affinity iron transport system in response to iron need. This transport system is comprised of the products of the FET3 and FTR1 genes. We show that Transition metals are essential for life, yet transition metals in high concentrations can be toxic. Both eukaryotes and prokaryotes tightly regulate the concentration of free intracellular metals by either regulating metal uptake or sequestration.