Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice.

Iwao Seki,Miwa Takai-Imamura,Minoru Sasano,Hiroaki Matsuno,Tomomi Kohara-Tanaka,Satoshi Shirae,Hiroyuki Aono

doi:10.1155/2019/4176974

Iwao Seki, Miwa Takai-Imamura + Show 5 more

Open Access

https://doi.org/10.1155/2019/4176974

Copy DOI

Abstract

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.

Highlights

Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory diseases, characterized by progressive articular damage accompanied by extra-articular manifestations such as vasculitis, secondary amyloidosis, and systemic comorbidities [1, 2]
We investigated the effects of etanercept, tacrolimus, and their combined therapy on the progression of arthritis in hTNFTg mice
These findings demonstrated that concomitantly administered etanercept and tacrolimus exerted additive and/or synergistic inhibitory effects on the progression of arthritis, largely via suppression of matrix metalloproteinases (MMPs)-3 production, CD11bhigh osteoclast precursors (OCPs) mobilization, and osteoclast differentiation but did not affect antidrug antibodies (ADAs) production

Summary

Introduction

Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory diseases, characterized by progressive articular damage accompanied by extra-articular manifestations such as vasculitis, secondary amyloidosis, and systemic comorbidities [1, 2]. The use of methotrexate is recommended in combination therapy with bDMARDs because of significant clinical evidence and familiarity of rheumatologists with methotrexate as an anchor drug [4, 5]. It has been suggested that add-on tacrolimus with bDMARDs may improve the clinical outcomes, Mediators of Inflammation even when patients show inadequate responses to bDMARDs with concomitant methotrexate [8,9,10]. These findings indicate that the use of tacrolimus may be one of the valuable options for patients with contraindications for or an inadequate response to bDMARDs and/or methotrexate. The validity of concomitant therapy of bDMARDs in combination with tacrolimus for the treatment of RA has been less investigated than that in combination with other csDMARDs

Methods

Results

Discussion

Conclusion