Co-stimulation Therapy in Rheumatoid Arthritis: Today and Tomorrow

Abstract

Abatacept is the only T cell co-stimulation modulator approved thus far for the treatment of moderate-to-severe rheumatoid arthritis (RA) and is licensed for use in patients with an inadequate response to methotrexate (MTX) and/or anti-tumor necrosis factor (anti-TNF) therapy. The upstream mechanism of action of abatacept leads to downstream effects in a variety of cell types associated with the production of autoantibodies and pro-inflammatory cytokines implicated in RA. Accumulating data also suggest effects on other cells involved in the pathogenesis of RA, including regulatory T cells and osteoclasts. Clinical trials have demonstrated that abatacept is an effective and well-tolerated treatment in RA. More recently, evidence from the Assessing Very Early Rheumatoid arthritis Treatment (AVERT) trial showed that complete drug-free remission following treatment with abatacept may be a possibility in some patients with early RA, indicating that the disease course could be altered by early intervention. Equivalent efficacy and onset of action of abatacept and anti-TNF therapy have also been demonstrated in patients with an inadequate response to MTX in the Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background methotrexate (AMPLE) trial. Together, these findings support the use of abatacept in early and established RA.

Keywords: Abatacept; CTLA-4-Ig; Co-stimulation; Rheumatoid arthritis; T cell therapy.

Fig. 1

Osteoclast differentiation and bone erosion pathways in rheumatoid arthritis showing the position that different classes of biologic agents exert their major effects [•]. Anti-rheumatic drugs are shown in blue boxes. Abatacept inhibits osteoclast differentiation by directly engaging CD80 and CD86 on the surface of osteoclast precursor cells. Figure reprinted by permission from Macmillan Publishers Ltd: Nat Rev Rheumatol. 2012;8(11):656–64, copyright (2012). IL interleukin, IL-6R interleukin-6 receptor, JAK Janus kinase, RANKL receptor activator of nuclear factor κB ligand, Syk spleen tyrosine kinase, TNF tumor necrosis factor.

Fig. 2

AVERT trial design [••]. Asterisk: Randomization stratified by corticosteroid use at baseline. Figure from Emery P, et al. Ann Rheum Dis. 2015;74(1):19–26, Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, published by the BMJ Group. AVERT Assessing Very Early Rheumatoid arthritis Treatment, CRP C-reactive protein, DAS Disease Activity Score, D/C discontinue, MRI magnetic resonance imaging, MTX methotrexate, RA rheumatoid arthritis.

Fig. 3

Percentages of patients with rheumatoid arthritis who achieved ACR20, ACR50, and ACR70 responses over 1 year by treatment group in the AMPLE trial [53]. Intent-to-treat population. Error bars show 95 % confidence intervals. Reprinted from Weinblatt ME, et al. Arthritis Rheum. 2013;65(1):28–38. © 2013, American College of Rheumatology. ACR American College of Rheumatology, AMPLE Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background methotrexate, SC subcutaneous.