Low-dose IL-2 Reduces Disease Activity in SLE, Trial Results Suggest

Adding low-dose interleukin-2 (IL-2) to standard therapy increases responses and complete remission of lupus nephritis in patients with systemic lupus erythematosus (SLE), results of a randomized clinical trial suggest.

Patients on IL-2 had higher proportions of regulatory T cells, a subset of immune T cells associated with suppression of autoimmunity, but their immunity against infectious pathogens was not compromised, the researchers noted.

The results were published in the Annals of the Rheumatic Diseases, in a paper titled, “Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial.”

IL-2 is a cytokine – a chemical messenger used by the immune system. It has been suggested that SLE may be driven, in part, by abnormally low amounts of IL-2, which causes immune cells to misbehave. Thus, treatment with low doses of IL-2 may be therapeutic in SLE — and unlike many other SLE therapies, it wouldn’t weaken the immune system.

To test this idea, researchers conducted a Phase 2 clinical trial (NCT02465580) in which 60 patients (56 women, average age ~30 years) with SLE were given standard treatment plus either IL-2 or a placebo for 12 weeks, and were observed for a further 12 weeks after the end of treatment.

One participant in the IL-2 group withdrew from the trial because of an inability to commit to requisite visits to the hospital for follow-up.

The treatment consisted of an under-the-skin injection given every other day for two weeks, followed by a two-week break, for one cycle. The dose of IL-2 used was 1 million IU per injection.

The primary goal of the study was rate of response, as assessed by the SLE Responder Index-4 (SRI-4) at 12 weeks. While there was a trend toward better responses in the IL-2 group — 55.2% vs. 30% — this difference was not quite statistically significant, meaning it is possible that the difference between the groups was due to chance, not the treatment efficacy.

However, response rates were significant better for IL-2 at week 24 (65.5% vs. 36.7%). Other disease activity measures, like the SELENA-SLEDAI score, also suggested that adding IL-2 to standard therapy led to higher reductions in disease severity.

Furthermore, among the participants with lupus nephritis (13 in the IL-2 group and 12 in the placebo group), the complete response rate was significantly higher in the IL-2 group at both week 12 (53.85% vs. 8.33%) and week 24 (53.85% vs. 16.67%).

Patients receiving IL-2 were able to taper corticosteroids to lower amounts than those on placebo, and most had resolution of their clinical manifestations – which included rash, oral ulcers, arthritis, vasculitis (blood vessel inflammation), hair loss, and fever. Levels of SLE autoantibodies also decreased with IL-2 but not with placebo.

There were no serious adverse events in the IL-2 group, but there were two serious infections reported in the placebo group. The researchers noted that there were fewer infections overall in the IL-2 group, although this difference did not reach statistical significance. The most common side effects of IL-2 were injection site reactions, fever, and flu-like symptoms, which were generally mild and resolved without additional intervention.

The researchers also analyzed immune cells in the participants’ blood throughout the study. They found that IL-2 treatment significantly increased numbers of regulatory T cells (Tregs), which are important for helping “put the brakes” on the immune system. The researchers noted that this is a likely mechanism for the efficacy of IL-2 in SLE.

IL-2 also increased the amount of natural killer (NK) cells, which help fight infections. While treatment for lupus often makes patients more susceptible to infections, an open-label observational study (NCT02932137) suggests that IL-2 might instead protect patients from viral infections. In patients without antiviral therapy, the treatment decreased their viral load.

The researchers concluded, “Collectively, the current study provided supportive evidence that low-dose IL-2 treatment might be effective and well-tolerated in patients with SLE, which was supportive of further enlarged [randomized controlled trials] studies with multiple patient cohorts from separate clinical centers.”