Evaluation of B lymphocyte stimulator and a proliferation inducing ligand as candidate biomarkers in lupus nephritis based on clinical and histopathological outcome following induction therapy

Abstract

ObjectivesLupus nephritis (LN) is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). B cells have a central role in the pathogenesis of SLE. B lymphocyte stimulator (BLyS) and a proliferation inducing ligand (APRIL) are pivotal in B cell homeostasis. We aimed to investigate a potential role of serum BLyS and APRIL as biomarkers in LN, especially as predictors of treatment response.MethodsSixty-four patients with active LN (52 proliferative lupus nephritis (PLN); 12 membranous LN) were included. Renal biopsies were performed at baseline and after immunosuppressive treatment. Serum levels of BLyS, APRIL and autoantibodies were measured on both biopsy occasions and in 64 individually matched controls. Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification, and scored for Activity Index and Chronicity Index. Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index.ResultsBaseline BLyS levels were significantly higher in LN patients compared with controls (p<0.001) and remained unchanged following induction treatment. APRIL levels were significantly higher in patients compared with controls at baseline (p=0.005) and decreased following treatment (p<0.001). Among PLN patients, APRIL levels decreased significantly only in responders (CR: p=0.009; HR: p=0.01). Baseline BLyS levels <1.5 ng/mL predicted treatment response, attaining a positive predictive value of 92% for CR with PLN at baseline.ConclusionsBLyS and APRIL were affected differently by immunosuppression; BLyS levels remained unchanged following therapy while APRIL levels decreased. Despite unchanged BLyS levels following therapy, low baseline levels predicted both clinical and histopathological improvement. Our data support APRIL as a candidate biomarker of renal disease activity in lupus patients with proliferative glomerulonephritis and point to low baseline BLyS levels predicting treatment response in LN, especially in PLN.

The Impact of Belimumab and Rituximab on Health‐Related Quality of Life in Patients With Systemic Lupus Erythematosus

“…From a clinical point of view, the rapid improvements following treatment with rituximab and the gradual improvements in belimumab-treated patients comprise interesting observations in the light of clinical and mech-anistic data (49,50) about the rationale for a combined treatment regimen, i.e., rituximab to induce remission and belimumab as a remission maintenance therapy. The initial remarkable decrements in MCS scores in the rituximab group may also account for the observed rapid improvements in this SF-36 component summary, in conformity with the regression toward the mean principle.…”

“…Perhaps expectedly, the amplitude of the improvements in MCS scores at month 6 displayed a slight decline at month 12 because only 1 rituximab cycle was administered. From a clinical point of view, the rapid improvements following treatment with rituximab and the gradual improvements in belimumab-treated patients comprise interesting observations in the light of clinical and mech-anistic data (49,50) about the rationale for a combined treatment regimen, i.e., rituximab to induce remission and belimumab as a remission maintenance therapy. This therapeutic strategy is currently being tested in clinical trials with larger SLE populations, and the effects on HRQoL along with clinical and immunologic outcomes are eagerly awaited.…”

Smoking and pre-existing organ damage reduce the efficacy of belimumab in systemic lupus erythematosus

“…Neither clinical evaluation nor laboratory findings can accurately reflect the histological patterns of LN. Biomarker studies have therefore been of particular interest towards the development of non-invasive diagnostic and prognostic tools, in order to avoid the potential adverse events following renal biopsies, even though they are rare and most often selflimiting [171]. It is recommended that a renal biopsy should be performed in cases of persistent proteinuria of more than 0.5 g/day, especially when accompanied by haematuria and/or cellular casts in the urinary sediment, but it could also be considered in cases of persisting isolated haematuria or pyuria after exclusion of other causes, e.g.…”

“…An obvious reason is the lack of follow-up renal biopsies at the time of the treatment evaluation. However, the importance of histology in the evaluation of the treatment outcome has been shown in studies [156,171,172] and highlighted in the European consensus statement on the terminology used in the management of lupus glomerulonephritis [167] and in a recent dialogue [228]. In studies from our group where post-treatment renal biopsies were available, we have utilised the Activity Index [181] and the 2003 ISN/RPS classification of LN [176], and proposed that complete histological response should require i. an improvement of ≥50% in the Activity Index score compared to baseline, and ii.…”

Clinical Value of Baff and April Concentrations in Systemic Lupus Erythematosus

“…I. Parodis и соавт. [56] продемонстрировали схожие с нашими результатами повышенные уровни BAFF и APRIL у пациентов с ВН и влияние иммуносупрессантов на концентрацию этих биомаркеров. Авторы определяли концентрацию BAFF и APRIL у 64 пациентов с ВН, подтвержденным по биопсии (пролиферативный нефрит выявлен у 52, мембранозный -у 12 пациентов), и у здоровых доноров (n=64).…”