Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial

Abstract

Objectives: Open-labelled clinical trials suggested that low-dose IL-2 might be effective in treatment of systemic lupus erythematosus (SLE). A double-blind and placebo-controlled trial is required to formally evaluate the safety and efficacy of low-dose IL-2 therapy.

Methods: A randomised, double-blind and placebo-controlled clinical trial was designed to treat 60 patients with active SLE. These patients received either IL-2 (n=30) or placebo (n=30) with standard treatment for 12 weeks, and were followed up for additional 12 weeks. IL-2 at a dose of 1 million IU or placebo was administered subcutaneously every other day for 2 weeks and followed by a 2-week break as one treatment cycle. The primary endpoint was the SLE Responder Index-4 (SRI-4) at week 12. The secondary endpoints were other clinical responses, safety and dynamics of immune cell subsets.

Results: At week 12, the SRI-4 response rates were 55.17% and 30.00% for IL-2 and placebo, respectively (p=0.052). At week 24, the SRI-4 response rate of IL-2 group was 65.52%, compared with 36.67% of the placebo group (p=0.027). The primary endpoint was not met at week 12. Low-dose IL-2 treatment resulted in 53.85% (7/13) complete remission in patients with lupus nephritis, compared with 16.67% (2/12) in the placebo group (p=0.036). No serious infection was observed in the IL-2 group, but two in placebo group. Besides expansion of regulatory T cells, low-dose IL-2 may also sustain cellular immunity with enhanced natural killer cells.

Conclusions: Low-dose IL-2 might be effective and tolerated in treatment of SLE.

Trial registration number: ClinicalTrials.gov Registries (NCT02465580 and NCT02932137).

Keywords: Autoimmune diseases; cytokines; systemic lupus erythematosus; t cells; treatment.

Figure 1

Patient enrolment and treatment assignments. Consolidated standards of reporting trials diagram was based on the 65 contacted SLE patients. Sixty of the patients were enrolled into two arms. Arm 1 (n=30), the IL-2 group, received three treatment cycles. Each cycle included subcutaneous IL-2 administration at a dose of 1 million IU every other day for 2 weeks (a total of seven doses) and a following 2-week break. Participants in arm 2 (n=30), the placebo group, started treatment with the same procedure as arm 1. mITT, modified intention-to-treat; N, no of patients.

Figure 2

Clinical response of SLE patients after treatment with low-dose IL-2 and placebo. (A) The SRI-4 response rate of patients receiving low-dose IL-2 (red) or placebo (blue) treatment during the 12-week treatment and 12-week follow-up period. Grey areas indicate the periods on IL-2 or placebo therapy. (B) SELENA-SLEDAI scores during the 24 weeks. (C) Complete remission (CR) rate in patients with lupus nephritis. (D) Proportion of patients achieving corticosteroid reduction by ≥50% from baseline to 24 weeks. (E) Levels of albumin at week 0, 12 and 24. (F) Proteinuria per 24 hours (24-UPE) of patients with lupus nephritis from baseline to 24 weeks. (G, H) The percentages of patients achieving normal levels of C3 and C4 in the 24 weeks. *p<0.05. The actual data of the results are listed in online supplementary table S13–20 (online supplementary table S13 for (A), online supplementary table S14 for (B), online supplementary table S15 for (C), online supplementary file 1 for (D), online supplementary table S17 for (E), online supplementary table S18 for (F), online supplementary table S19 for (G) and online supplementary file 1 for (H)). SRI-4, SLE Responder Index-4.

Figure 3

Dynamics of immune cell subsets in SLE during IL-2 treatment. (A, B, C) Changes in percentages of CD4⁺ T cell, CD8⁺ T cell and Treg cells at every visit. (D, E) Dynamics of total NK cells and CD56^bri NK in SLE patients during 24 weeks. The actual data of the results are listed in online supplementary table S21. Treg, regulatory T.