Efficacy and safety of low-dose interleukin-2 in combination with methotrexate in patients with active rheumatoid arthritis: a randomized, double-blind, placebo-controlled phase 2 trial

Xiaoying Zhang,Xia Zhang,Xiaozhen Zhao,Yanying Li ,Haihong Yao,Chun Li,Yin Su,Huixin Liu,Yue Yang,Limin Ren,Miao Shao,Jiali Chen,Xiaolin Sun,Ruijun Zhang,Miao Miao,Jing He,Yuebo Jin,Ru Li,Yun Li,Yuhui Li,Yun Zhou ,Tian Liu,Xu Liu,Zhanguo Li

doi:10.1038/s41392-022-00887-2

Abstract

Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR <2.6, and the change from baseline in CDAI or SDAI at week 24. Secondary endpoints included other clinical responses and safety. The primary outcomes were achieved in the per-protocol population. The improvements from baseline in CDAI and SDAI were significantly greater across time points for the Ld-IL2 + MTX group (n = 17) than for the placebo+MTX group (n = 23) (P = 0.018 and P = 0.015, respectively). More patients achieved ACR20 response in the Ld-IL2 + MTX group than those in the placebo+MTX group at week 12 (70.6% vs 43.5%) and at week 24 (76.5% vs 56.5%) (P = 0.014). In addition, low Treg and high IL-21 were associated with good responses to Ld-IL2. Ld-IL-2 treatment was well-tolerated in this study. These results suggested that Ld-IL2 was effective and safe in RA. ClinicalTrials.gov number: NCT 02467504.

Highlights

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by progressive articular destruction and is notoriously difficult to treat with poor remission.[1,2] Basic studies have shown that impaired immunological homeostasis plays a critical role in the development of RA.[3]
BMI body mass index, CCP cyclic citrullinated peptide, CDAI Clinical Disease Activity Index, CRP C reactive protein, DAS28 Disease Activity Score using 28 joints, DMARD disease-modifying anti-rheumatic drug, ESR erythrocyte sedimentation rate, health assessment questionnaire disability index (HAQ-DI) Health Assessment Questionnaire-Disability Index, HCQ hydroxycholoroquine, Low-dose interleukin-2 (Ld-IL2) low-dose interleukin-2, LEF leflunomide, MTX methotrexate, PtGA patient’s global assessment, PhGA physician’s global assessment, RA rheumatoid arthritis, RF rheumatoid factor, SASP salazosulfapyriding, SDAI Simplified Disease Activity Index, SF36 PCS Short Form-36 physical component scores, SF-36 MCS Short Form-36 mental component scores, SJC swollen joint count, TJC tender joint count, visual analog scales (VAS) Visual Analogue Scale aData are presented as Mean (SD) unless stated otherwise bP = 0.018, No other statistically significant differences were observed among two group
This randomized, double-blind, placebo-controlled clinical study provided the first evidence that Ld-IL2 further increased the efficacy of MTX

Summary

INTRODUCTION

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by progressive articular destruction and is notoriously difficult to treat with poor remission.[1,2] Basic studies have shown that impaired immunological homeostasis plays a critical role in the development of RA.[3]. Basic studies have shown that impaired immunological homeostasis plays a critical role in the development of RA.[3]. The distribution of regulatory T cells (Tregs) contributes to the disease activity of RA;[4] effector. Methotrexate (MTX) is the first-line anchor drug for RA, but it is efficacious in only 19.8–25.4% of RA patients.[1]. It was shown that 30–50% of patients need additional treatment.[8–10]. The ceiling phenomenon of low efficacy of MTX in RA is at least partially related to its interrupting effect on Tregs.[11]. A novel strategy to overcome the dilemma phenomenon of MTX is expected clinically. The deficiency of Tregs can be promoted by low-dose interleukin-2 (Ld-IL2).[12,13]. Tregs from patients with RA were reversed by exogenous IL-2 in vitro.[14]. Ld-IL2 can inhibit Th17 cell proliferation, which is associated with the development of RA.[15]. We identified factors in predicting potential responses to the treatment of LdIL2

RESULT

DISCUSSION

Findings

METHODS