Adding sirolimus to standard-of-care (SoC) therapy significantly improves clinical and serological outcomes in patients with active systemic lupus erythematosus (SLE), according to the SIRIUS* trial presented at EULAR 2026.
“Our study provides robust evidence that sirolimus is an effective and safe add-on therapy for active SLE and supports its consideration as a valuable treatment option in clinical practice,” said Dr Mengtao Li from Peking Union Medical College Hospital, Beijing, China.
Li and his team conducted a multicentre, double-blind, placebo-controlled trial involving 146 patients with active SLE (clinical SLEDAI-2K** score ≥4 with serological activity) who had inadequate response to SoC treatments, recruited from six centres in China. Participants were randomly assigned to receive either sirolimus 1.5 mg once daily (n=70) or a matching placebo (n=75) for 24 weeks in addition to SoC therapy.
At week 24, a significantly higher proportion of sirolimus-treated patients achieved a Systemic Lupus Erythematosus Responder Index 4 (SRI-4) response, the primary endpoint, than those treated with placebo (52.9 percent vs 22.7 percent; p<0.001). [EULAR 2026, abstract LB0006]
Notably, sirolimus recipients showed higher SRI-4 response rates as early as week 4 (27.1 percent vs 18.7 percent; p=0.224), which persisted through week 12 (48.6 percent vs 20 percent; p<0.001), than the placebo recipients.
Secondary endpoints
From baseline to week 24, patients treated with sirolimus vs placebo achieved significant improvements in SLE disease activity, as shown by a greater decrease in SLEDAI‑2K (–4.7 vs –1; p<0.001) and PGA*** (and –0.38 vs –0.18; p=0.009) scores, and a higher BICLA+ response rate (60 percent vs 32.2 percent; p=0.003).
Furthermore, the sirolimus group exhibited a marked improvement in immunological markers relative to the placebo group, as shown by a greater increase in complement C3 and C4 levels (mean change from baseline, 0.26 vs 0.02 g/L and 0.08 vs 0.01 g/L, respectively; p<0.001 for both), and a more substantial decline in anti-dsDNA antibody titres (–89.3 vs 51.1 IU/mL; p<0.001).
This clinical benefit observed with sirolimus over placebo was also consistently observed across all other secondary efficacy endpoints, such as higher rates of clinical remission (14.3 percent vs 4 percent; p=0.041) and LLDAS++ (24.3 percent vs 10.7 percent; p=0.030).
Significantly higher response rates for SRI-5 (40 percent vs 17.3 percent; p=0.002) and SRI-6 (40 percent vs 16 percent; p=0.001) were also observed with sirolimus than with placebo.
Safety
Adverse events occurred in 97.3 percent of patients receiving sirolimus compared with 86.7 percent of those receiving placebo, with similar infection rates observed in both groups (25.7 percent vs 26.7 percent).
Metabolic side effects were more frequent with sirolimus, but were manageable, than with placebo (60.3 percent vs 26.4 percent for hypertriglyceridemia and 42.7 percent vs 9.8 percent for elevated total cholesterol).
Nevertheless, sirolimus was well tolerated, with no new safety signal identified, Li noted.
New treatment option?
In this study, “sirolimus represents a potent and well-tolerated oral therapeutic option for active SLE, particularly in patients with inadequate response to standard therapy,” Li noted.
“This is the first multicentre randomized controlled trial to demonstrate that targeting the mechanistic target of rapamycin (mTOR) pathway with sirolimus significantly improves multiple composite response indices (SRI-4, BICLA) and promotes clinical remission and LLDAS in patients with active SLE,” said Li.
“These findings are important to establish mTOR+ inhibition as a therapeutic choice for SLE,” the researchers added.