To Örebro University

Background: Neuropsychiatric (NP) flares in systemic lupus erythematosus (SLE) constitute a challenging issue for the clinician on many levels as they are rather unpredictable and include severe and potentially life-threatening manifestations [1]. The identification of clinical and serological profiles predictive of NP flares would be instrumental for early detection of NP involvement, thus allowing early treatment, and hopefully resulting in improved outcomes. The B-cell depleting agent belimumab has widely shown ability to reduce rates of flare in SLE (2), but little is known on its potential benefits in the treatment of NPSLE.

Objectives: To evaluate predictors of NP flares in patients with SLE under standard therapy (ST) with or without add-on belimumab, given for active disease yet not ongoing severe NP involvement.

Methods: Data from five clinical trials of belimumab in SLE (BLISS-52 (NCT00424476), BLISS-76 (NCT00410384), BLISS-NEA (NCT01345253), BLISS-SC (NCT01484496), and EMBRACE (NCT01632241)) were used (N=3638). Flares were defined using the British Isles Lupus Assessment Group (BILAG) activity index as development of any new NP BILAG score A in patients with baseline NP BILAG score B, and development of any new NP BILAG score A or B in patients with baseline NP BILAG score C–E during a 52-week follow-up. Predictors of NP flare were investigated using univariable and multivariable Cox regression analysis. A subgroup analysis was performed to determine predictors of de novo NP flare in patients with no NP history (baseline NP BILAG E). Organ damage was assessed using the SLICC/ACR Damage Index (SDI). p values <0.05 were considered statistically significant.

Results: In total, 105 (2.9%) NP flares were documented. Of these, NP flare occurred in 52 (1.6%) patients with baseline NP BILAG E. In multivariable analysis adjusting for age, sex, ethnicity, and variables that were significant in univariable analysis, male sex (HR: 2.37; 95% CI: 1.31–4.28; p=0.004) and NP BILAG score B–D at baseline (HR: 5.91; 95% CI: 3.86–9.06; p<0.001) were highly associated with NP flare development in the pooled study population. Belimumab use displayed no clear protection at any dose or administration form. In the subgroup analysis of the baseline NP BILAG E population, male sex (HR: 3.26; 95% CI: 1.51–7.04; p=0.003) was the strongest predictor of de novo NP flare. In a separate analysis of SDI domains, the NP domain (HR: 3.25; 95% CI: 2.72–3.88; p<0.001) was the strongest predictor of NP flare, with cognitive impairment (HR: 14.29; 95% CI: 9.22–22.14; p<0.001), transverse myelitis (HR: 21.89; 95% CI: 5.40–88.72; p<0.001), and neuropathy (HR: 8.87; 95% CI: 5.59–14.09; p<0.001) mainly driving this association.

Conclusion: Current or past NP activity and established organ damage in the NP domain at baseline were the strongest predictors of NP flare in SLE patients treated for active disease yet not ongoing severe NP involvement. Whether belimumab treatment protects against NP events remains unclear and warrants future investigation.

References:

[1]Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol. 2019;15(3):137-52.

[2]Singh JA, Shah NP, Mudano AS. Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev. 2021;2(2):CD010668.