Belimumab Nearly Doubled Non-GC Remission and LLDAS Rates in SLE Post-Hocs

When the glucocorticoid (GC) dose component was excluded from definitions of remission and low disease activity in systemic lupus erythematosus (SLE), belimumab outperformed placebo at both targets by approximately 50% on a relative basis — and attainment rates were roughly double those previously observed using full definitions — according to a post hoc analysis of 5 pooled Phase 3 trials published in RMD Open.¹

The findings, from primary author Ioannis Parodis, MD, PhD, Associate Professor of Rheumatology, at Karolinska Institutet, and colleagues, address a recognized methodological gap in the belimumab trial program: the pivotal Phase 3 studies (BLISS-76, BLISS-52, North East Asia, BLISS-SC, and EMBRACE; conducted 2006–2018) predated the establishment of Definition Of Remission In SLE (DORIS) and Lupus Low Disease Activity State (LLDAS) as formal treatment targets and lacked mandated GC tapering protocols — a standard component of contemporary SLE management that was not yet guideline-endorsed at the time.¹

Post-Hoc Analyses of Trials Lacking Mandated GC Tapering Protocols

The analysis pooled individual patient data from 3,086 adults with active, seropositive SLE across the 5 trials (belimumab, n = 1,869; placebo, n = 1,217). Patients received belimumab 10 mg/kg/month intravenously or 200 mg/week subcutaneously, or placebo, both added to standard therapy. Because GC tapering was not mandated — and over half of all patients were on prednisone equivalents >7.5 mg/day at baseline — the investigators created modified endpoint definitions stripping the GC dose component: non-GC-DORIS (requiring clinical SLEDAI = 0 and Physician's Global Assessment [PGA] <0.5) and non-GC-LLDAS (requiring SLEDAI-2K ≤4, no major organ activity, no new disease features, and PGA ≤1), with attainment compared from week 4 through week 52.¹

At week 52, non-GC-DORIS attainment was 18% with belimumab versus 13% with placebo (risk ratio [RR], 1.44; 95% CI, 1.20–1.71; P <.001). Non-GC-LLDAS attainment was 32% versus 21% (RR, 1.50; 95% CI, 1.32–1.71; P <.001). Differences emerged by week 20 for non-GC-DORIS and week 24 for non-GC-LLDAS and were maintained to week 52.¹

For context, the corresponding week 52 rates with full definitions in the prior integrated post hoc analysis were 8% vs 6% for DORIS remission and 17% vs 10% for LLDAS — indicating the modified non-GC definitions approximately doubled attainment in both arms, confirming that the GC dose criterion is a primary driver of attainment difficulty in these historical datasets.¹

Across subgroups, differences between belimumab and placebo were generally larger in patients with higher baseline disease activity. In the SLEDAI-2K ≥10 subgroup, non-GC-DORIS RR was 1.58 (95% CI, 1.22–2.04; P = .001) and non-GC-LLDAS RR was 1.68 (95% CI, 1.40–2.03; P <.001). In the SLEDAI-2K <10 subgroup, the non-GC-DORIS difference did not reach statistical significance (RR, 1.27; 95% CI, 0.99–1.62; P = .086), though non-GC-LLDAS remained significant (RR, 1.32; 95% CI, 1.11–1.57; P = .009). By ethnic subgroup, statistically significant belimumab advantages were observed for Asian and White patients; results were numerically but not statistically in favor of belimumab for Black/African American and Indigenous American patients.¹

Non-GC Definitions ≠ Treatment Targets

The authors caution that the non-GC-DORIS and non-GC-LLDAS definitions used in this analysis should not be adopted as clinical treatment targets, as they may classify patients as meeting remission or low disease activity criteria despite ongoing dependence on moderate-to-high GC doses.¹ Rather, the findings are interpreted as evidence that the original belimumab trial data may have underestimated the drug's true effect on these outcomes, and that adherence to current guidelines recommending GC minimization (target ≤5 mg/day prednisone equivalent per 2023 EULAR recommendations) could result in higher real-world attainment rates — a hypothesis supported by a recent retrospective Spanish multicenter study reporting DORIS remission and LLDAS rates of 36% and 62%, respectively, at week 52 in belimumab-treated patients.¹

As a post hoc analysis, the findings are hypothesis-generating and subject to the limitations inherent in pooling trials that were not designed to assess these endpoints. GC use was not protocol-mandated in either direction, introducing potential confounding. Three co-authors are employees of GSK, which funded the original Phase 3 trials; the post hoc analysis was funded by Parodis's research group through Swedish academic sources.¹

Belimumab and Kidney Function Preservation in Lupus Nephritis

Separately, RheumatologyLive also recently spoke with Richard A. Furie, MD, Chief of the Division of Rheumatology at Northwell Health and Professor of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, about a post hoc analysis of the BLISS-LN Phase 3 trial (NCT01639339) presented at European Alliance of Associations for Rheumatology (EULAR), held June 3-6 in London, United Kingdom. The analysis restricted the BLISS-LN population to an MMF subgroup with ISN/RPS class III or IV ± V lupus nephritis — approximately 60% of the original cohort (n = 135 belimumab; n = 136 placebo) — to better align with other B-cell therapy LN trial populations. In that subgroup, the eGFR slope from month 6 through week 104 was −1.4 mL/min/1.73 m² per year with belimumab versus −6.6 mL/min/1.73 m² per year with placebo. Belimumab also showed greater improvements in urine protein-to-creatinine ratio responder rates, eGFR change from baseline, anti-dsDNA, anti-C1q, C3, and C4 biomarkers, and lower risk of kidney-related events or death through week 104. The analysis was descriptive, and design differences across LN trials limit cross-study comparisons.³

"The name of the game with any part of your body is to maintain integrity of that particular organ, especially the kidney," Furie said. "This speaks to eGFR slope — perhaps one day it will be a primary endpoint for our studies, just like it is in non-lupus nephritis conditions."³

References

1. Parodis I, Lindblom J, Levy RA, et al. Belimumab outperforms placebo for attainment of modified DORIS remission and LLDAS without the glucocorticoid component: a post hoc analysis of five phase III SLE trials. RMD Open. 2026;12:e006624. doi:10.1136/rmdopen-2025-006624

2. Parodis I, Lindblom J, Levy RA, et al. Attainment of remission and low disease activity after treatment with belimumab in patients with systemic lupus erythematosus: a post-hoc analysis of pooled data from five randomised clinical trials. Lancet Rheumatol. 2024;6:e751–761. doi:10.1016/S2665-9913(24)00179-3

3. Furie RA. Belimumab added to MMF standard therapy and kidney function outcomes in lupus nephritis: a post hoc analysis of the BLISS-LN phase 3 trial. Presented at: European Alliance of Associations for Rheumatology (EULAR) European Congress of Rheumatology; June 3–6, 2026; London, UK.