Objective. The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 ؋ 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower-dose regimen (2 ؋ 500 mg) of RTX. Our aim was to compare the efficacy and safety of low-and high-dose RTX and to test the noninferiority of the low-dose regimen. Methods. A systematic literature review searching for randomized controlled trials (RCTs) and cohort studies comparing low-and high-dose RTX for RA was conducted using the Embase, PubMed, Cochrane Library, and Web of Science databases. The primary end points were the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70 responses and the Disease Activity Score in 28 joints (DAS28) at 24 and 48 weeks. The secondary end points were patient-reported outcomes (PROs; Health Assessment Questionnaire, Short Form 36, and Functional Assessment of Chronic Illness Therapy-Fatigue scores) and adverse events. Noninferiority of low-dose RTX was tested using different approaches, one of which was based on the fixed margin method. Results. In total, 6 RCTs and 2 cohort studies were identified. Four RCTs were included in the meta-analysis of efficacy outcomes, which showed no significant differences in the primary outcomes between low-and high-dose RTX. Noninferiority criteria of low-dose RTX were met for the ACR20, ACR50, DAS28, and PROs (at 24 and 48 weeks). Serious adverse events did not differ significantly. The results of 2 additional RCTs and a meta-analysis of 2 cohort studies corroborated the results of the meta-analysis of RCTs. Conclusion. Low-dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for RA.

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We have shown recently that TACE transactivates epidermal growth factor receptor (EGFR), and induces ERK phosphorylation (ERK‐P) and cellular proliferation upon 5‐HT2A receptor stimulation in renal mesangial cells.In this study our aim was to identify kinases responsible for TACE phosphorylation and potential activation during inter‐receptor cross‐talk. We detected robust threonine phosphorylation of TACE as early as 6 minutes following 5‐HT stimulation using a phospho‐threonine/proline antibody. This suggested phosphorylation of threonine 375, as this is the only threonine next to a proline present in the cytoplasmic tail of TACE. Using chemical inhibitors (naltrindole and PDK1/Akt/Flt dual pathway inhibitor) we showed that ERK phosphorylation is PDK1 dependent. Additionally, a MAPK cascade seems to have a role in TACE phosphorylation in that a MEK inhibitor (10 μM of PD989059) significantly attenuated 1 μM 5‐HT‐induced TACE phosphorylation. To study kinase‐induced activation of the enzyme we used a quenched fluorogenic TACE substrate. We found attenuation of 5‐HT‐induced TACE activity in PD989059‐pretreated cells. No serine phosphorylation of TACE upon 5‐HT stimulation was detected. Our data suggest that (1) either MEK itself or members of the MAPK family can be (directly or indirectly) responsible for TACE phosphorylation and activation during inter‐receptor crosstalk, and (2) multiple kinases contribute to TACE phosphorylation.This work was supported by NIH DK070054‐03 to M.G., T32 DK07752‐08 to C.L.R., NIH NCCR P20 RR016434 to P.G., NIH R01 DK55524 to L.M.L. and REAP from the VA Research Service.