Determinants of neuropsychiatric flares in patients with systemic lupus erythematosus: results from five phase III trials of belimumab

Abstract

Objective: To identify determinants of neuropsychiatric (NP) flares in patients with SLE treated for active SLE yet no ongoing severe NPSLE with non-biologic standard therapy plus belimumab or placebo.

Methods: We analysed data from five phase III trials (BLISS-52, BLISS-76, BLISS-NEA, BLISS-SC, EMBRACE; n = 3638) after exclusion of patients with baseline NP BILAG A. Factors associated with NPSLE flare, defined as a new NP BILAG A or B, were investigated using Cox regression. In a subgroup analysis, we studied patients with baseline NP BILAG E for determinants of de novo NPSLE flare. Organ damage was assessed using the SLICC/ACR Damage Index (SDI).

Results: We documented 105 (2.9%) NPSLE flares. In multivariable analysis, male sex (HR = 2.37; 95% CI: 1.31, 4.28; P = 0.004), baseline NP BILAG B-D (HR = 5.91; 95% CI: 3.86, 9.06; P < 0.001), and increasing SDI scores (HR = 1.35; 95% CI: 1.21, 1.50; P < 0.001) were strongly associated with NPSLE flare. Belimumab use yielded no association at any dose or administration form. In analysis of SDI domains, NP damage was the strongest determinant of NPSLE flare (HR = 3.25; 95% CI: 2.72, 3.88; P < 0.001), holding true for 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). Male sex was the strongest determinant of de novo NPSLE flare (HR = 3.26; 95% CI: 1.51, 7.04; P = 0.003).

Conclusion: Male sex, NPSLE history, and NP damage were strong determinants of impending NPSLE flare. No clear protection or predisposition was conferred from add-on belimumab.

Keywords: SLE; belimumab; determinants; flares; neuropsychiatric.

Figure 1.

Factors associated with NPSLE flare development in the pooled population of the belimumab trials. (A) Bars depicting proportions of patients who developed at least one NPSLE flare during follow-up in patient subgroups exposed to belimumab treatment of different dosage forms compared with patients from the same studies treated with placebo. (B) Forest plots illustrating results from univariable (left) and multivariable (right) Cox regression analysis, investigating determinants of NPSLE flare development.(+): positive levels; anti-dsDNA: anti-double-stranded DNA antibodies; anti-RNP: anti-ribonucleoprotein antibodies; anti-Sm: anti-Smith antibodies; BAFF: B-cell activating factor belonging to the TNF ligand family; C3: complement component 3; C4: complement component 4; cSLEDAI-2K: clinical SLEDAI 2000; HR: hazard ratio; Ig: immunoglobulin; IV: intravenous; LAC: lupus anticoagulant; NA: not applicable; NP: neuropsychiatric; NPSLE: neuropsychiatric SLE; SC: subcutaneous; SDI: SLICC/ACR Damage Index

Figure 2.

Factors associated with de novo NPSLE flare development. (A) Bars depicting proportions of baseline NP BILAG E patients who developed at least one de novo NPSLE flare during follow-up in patient subgroups exposed to belimumab treatment of different dosage forms compared with patients from the same studies treated with placebo. (B) Forest plots illustrating results from univariable (left) and multivariable (right) Cox regression analysis, investigating determinants of de novo NPSLE flare development in the baseline NP BILAG E population.(+): positive levels; anti-dsDNA: anti-double-stranded DNA antibodies; anti-RNP: anti-ribonucleoprotein antibodies; anti-Sm: anti-Smith antibodies; BAFF: B-cell activating factor belonging to the TNF ligand family; C3: complement component 3; C4: complement component 4; cSLEDAI-2K: clinical SLEDAI 2000; HR: hazard ratio; Ig: immunoglobulin; IV: intravenous; LAC: lupus anticoagulant; NA: not applicable; NP: neuropsychiatric; NPSLE: neuropsychiatric SLE; SC: subcutaneous; SDI: SLICC/ACR Damage Index

Figure 3.

Hazards for NPSLE flare occurrence in relation to organ damage accrual. Heat maps illustrating hazard ratios deriving from Cox regression analysis investigating associations between SDI organ domain scores and occurrence of NPSLE flares (A), as well as between SDI items and occurrence of NPSLE flares (B–H) in the entire study population (left columns) and in the baseline NP BILAG E population (right columns). Asterisks indicate statistically significant associations.HR: hazard ratio; SDI: SLICC/ACR Damage Index