Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study.

OBJECTIVES: Disease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab (BEL) and one cycle of rituximab (RTX). METHODS: In this phase 3, double-blind BLISS-BELIEVE trial (GSK Study 205646), patients with active SLE initiating subcutaneous BEL 200 mg/week for 52 weeks were randomised to intravenous placebo (BEL/PBO) or intravenous RTX 1000 mg (BEL/RTX) at weeks 4 and 6 while stopping concomitant immunosuppressants/tapering corticosteroids; standard therapy for 104 weeks (BEL/ST; reference arm) was included. PRIMARY ENDPOINT: proportion of patients achieving disease control (SLE Disease Activity Index-2000 (SLEDAI-2K) ≤2; without immunosuppressants; prednisone equivalent ≤5 mg/day) at week 52 with BEL/RTX versus BEL/PBO. Major (alpha-controlled) secondary endpoints: proportion of patients with clinical remission (week 64; clinical SLEDAI-2K=0, without immunosuppressants/corticosteroids); proportion of patients with disease control (week 104). Other assessments: disease control duration, anti-dsDNA antibody, C3/C4 and B cells/B-cell subsets. RESULTS: The modified intention-to-treat population included 263 patients. Overall, 16.7% (12/72) of BEL/PBO and 19.4% (28/144) of BEL/RTX patients achieved disease control (OR (95% CI) 1.27 (0.60 to 2.71); p=0.5342) at week 52. For major secondary endpoints, differences between BEL/RTX and BEL/PBO were not statistically significant. Anti-dsDNA antibodies and most assessed B cells/B-cell subsets were lower with BEL/RTX versus BEL/PBO. Mean disease control duration through 52 weeks was significantly greater with BEL/RTX versus BEL/PBO. CONCLUSIONS: BEL/RTX showed no superiority over BEL/PBO for most endpoints analysed; however, it led to significant improvements in disease activity markers compared with BEL/PBO. Further investigation of combination treatment is warranted. TRIAL REGISTRATION NUMBER: NCT03312907.

Changes in regional brain morphology in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric lupus (NPSLE) is a severe and potentially life-threatening condition, reported to occur in 25%-70% of patients with systemic lupus erythematosus (SLE). Brain imaging, especially magnetic resonance imaging, is frequently used to diagnose or exclude overt cerebral pathologies such as edema, hemorrhage, and central thrombosis. More advanced imaging techniques have been applied to demonstrate subtle changes in regional cerebral blood flow and brain structure. We investigated changes in regional gray-matter (GM) volume in SLE patients without neurological manifestations and NPSLE patients at an acute stage of the disease. METHODS: Using high-resolution structural images and voxel-based morphometry (VBM), we investigated regional GM volume in 20 NPSLE patients (within 2 weeks of the acute manifestation), 18 SLE patients without neurologic and/or psychiatric manifestations, and 18 healthy controls. RESULTS: VBM analyses revealed several regions of GM atrophy in various parts of the brain in NPSLE and SLE patients. GM atrophy was seen in both groups in the temporal and parietal lobes and was most pronounced in the posterior thalamus bilaterally. Both groups showed an increase in regional GM volume in the posterior parahippocampal gyrus. CONCLUSION: Our data suggest that changes in regional brain morphology are present in acute NPSLE, but also in SLE (as compared to controls), which might be indicative of a subclinical neurodegenerative process. Further research is needed to investigate whether specific neuropsychiatric symptoms are related to these changes.

Perfusion-weighted MR imaging in cerebral lupus erythematosus.

RATIONALE AND OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a diagnostically challenging, severe, and life-threatening condition, which is currently lacking a "gold standard." Our aim with this study is to look for magnetic resonance (MR) perfusion differences in NPSLE, SLE, and healthy control (HC) patients and correlate our findings with clinical parameters. MATERIALS AND METHODS: Twenty-four NPSLE patients, 21 SLE patients, and 21 HC underwent dynamic susceptibility contrast enhanced MR perfusion using a 3-T scanner. Nine prospectively selected intracranial regions of interest were placed in white and gray matter and the cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) values were calculated. Subjects underwent clinical evaluation with SLEDAI and serum antibodies. RESULTS: The SLE patients had higher CBF and CBV compared to the HC overall (P = .01) and in specific areas (P = .03-.048). SLE patients with signs of active disease (elevated SLEDAI and anti-double-stranded DNA) had significantly elevated CBV, CBF, and MTT in the posterior cingulate gyrus (P = .01-.02). No significant difference was seen in the magnetic resonance perfusion measurements of NPSLE patients compared to SLE and HC, although the NPSLE patients also showed higher CBV variability compared to the SLE (P = .0004) and HC cohort (P < .0001). CONCLUSION: SLE patients have increased CBV and CBF compared to healthy controls. The SLE patients with clinical markers for active disease have elevated CBV, CBF, and MTT in the posterior cingulate gyrus. NPSLE patients show increased variability in perfusion measurements, which may explain why susceptibility contrast enhanced MRI has not yet provided a specific target for NPSLE.