To Örebro University

Background: In patients with systemic lupus erythematosus (SLE), renal involvement is associated with high morbidity, and renal flares are major contributors to poor long-term prognosis. Identification of patients at risk of developing renal flares despite immunosuppressant therapy is imperative to optimise management.

Objectives: To identify predictors of renal flares in patients receiving treatment for active extra-renal SLE.

Methods: Data from BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS Northeast Asia (NEA; NCT01345253), and BLISS-SC (NCT01484496) were used (N=3225). The trials included patients with active, seropositive SLE and excluded active severe renal SLE. Participants were assigned to belimumab or placebo, on top of non-biologic standard therapy. We investigated anti-dsDNA, anti-Sm, anti-ribosomal P, and anti-cardiolipin (aCL) antibodies, low C3 and low C4 levels, B cell activating factor (BAFF), serum albumin, serum creatinine, and proteinuria at baseline as potential predictors of renal flares during a 52-week follow-up. We used Cox regression models to evaluate traditional disease features as predictors of renal flares in the pooled trial population. We also performed subgroup analysis of belimumab and placebo recipients. Covariates in the adjusted models included age, sex, ethnicity, body mass index, organ damage, baseline extra-renal activity (SLEDAI-2K score excluding renal and immunological descriptors), current or former renal SLE history (renal BILAG A–D), baseline use of glucocorticoids, antimalarials, and immunosuppressants, and use of belimumab.

Results: The mean age of the study population was 36.7 years, 94% were women, 54.6% had current or former renal involvement at baseline, and 192 developed a renal flare after a median follow-up time of 197 (IQR: 85–330) days from baseline. Patients with current or former renal involvement at baseline displayed a >9-fold increased hazard to develop a new renal flare (HR: 9.4; 95% CI: 5.0–17.7; P<0.001). In the pooled study population, baseline serum albumin (adjusted HR 0.9; 95% CI: 0.9–0.9; P<0.001), proteinuria (adjusted HR: 1.3; 95% CI: 1.2–1.4; P<0.001), and low C3 levels (adjusted HR: 1.8; 95% CI: 1.3–2.5; P<0.001) were robust determinants of subsequent renal flare occurrence; similar associations were found in the belimumab and placebo subgroups. Furthermore, we observed an association between anti-dsDNA positivity and renal flare development in univariable models (HR: 2.1; 95% CI: 1.4–3.2; P<0.001 in the pooled population), which attenuated in multivariable models (Figure 1). Positive levels of anti-Sm antibodies were associated with renal flare occurrence in the placebo (adjusted HR: 2.9; 95% CI: 1.5–5.6; P=0.002) but not in the belimumab subgroup, whereas anti-ribosomal P antibodies were associated with renal flare development in belimumab-treated (HR: 2.8; 95% CI: 1.5–5.0; P<0.001) but not in placebo-treated patients. Finally, positive levels of aCL antibodies (any isotype) predicted renal flare development in the belimumab group (adjusted HR: 1.8; 95% CI: 1.1–2.8; P=0.020) but yielded a negative association in the placebo group (adjusted HR: 0.4; 95% CI: 0.2–0.9; P=0.028).

Conclusion: Current or former renal involvement, high baseline proteinuria levels, hypoalbuminaemia, and C3 consumption were robust determinants of imminent renal flares. Beyond anti-dsDNA, anti-ribosomal P and aCL antibody positivity may prove valuable early signals of imminent renal flares in patients treated with belimumab. Anti-Sm positivity predicted imminent renal flares in patients treated with non-biological standard therapy, but not in belimumab-treated patients, assumably due to benefit conferred from belimumab in anti-Sm positive individuals, as shown previously [1].

Reference: [1]Parodis I, et al. Int J Mol Sci. 2020; 21(10):3463