Piantoni Silvia, Regola Francesca, Masneri Stefania, Merletti Michele, Lowin Torsten, Airò Paolo, Tincani Angela, Franceschini Franco, Andreoli Laura, Pongratz Georg
Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Department of Rheumatology and Hiller Research Center for Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany.
Front Pharmacol. 2021 May 21;12:666971. doi: 10.3389/fphar.2021.666971. eCollection 2021.
Patients with systemic lupus erythematosus (SLE) show increased serum levels of tumor necrosis factor (TNF)/TNF receptor (R) superfamily member, e.g. BAFF (B lymphocyte stimulator). Belimumab, a monoclonal antibody against soluble BAFF, is used for treatment of SLE. Although B cells are the main target, a BAFF-dependent T-cell activation pathway also plays a role. High levels of anti-DNA antibodies and low complement at baseline are known predictors of response to Belimumab. To explore the association of circulating lymphocytes and serum levels of B- cell related TNF/TNFR superfamily members with response to Belimumab in SLE patients. Twenty-one SLE patients received Belimumab. Clinical evaluation and laboratory tests were performed at baseline, at 6 and 12 months. TNF super-family members (BAFF, APRIL, sBCMA, sCD40L, sTACI, TWEAK) were tested by high-sensitivity ELISA in all patients, and lymphocyte immunophenotyping was performed by flow cytometry in ten subjects. SLE-disease activity was assessed by SLEDAI-2K score. Linear regression modeling was used to investigate parameters influencing SLEDAI-2K and anti-dsDNA antibody titers over time and for predictive models. Clinical improvement was observed in all patients. A global reduction of circulating B cells, especially naïve, was detected, without variation in the T-cell compartment. All TNF family members decreased, whereas APRIL remained constant. The increase in serum levels of C3 ( = 0.0004) and sTACI ( = 0.0285) was associated with a decrease of SLEDAI-2K. The increase of C4 ( = 0.027) and sBCMA ( = 0.0015) and the increase of CD8 T cells ( = 0.0160) were associated with a decrease, whereas an increase of sCD40L in serum ( = 0.0018) and increased number of CD4 T cells ( = 0.0029) were associated with an increase, in anti-dsDNA antibody titers, respectively. Using stepwise forward inclusion, the minimal model to predict SLEDAI-2K response at 12 months included BAFF ( = 3.0 - 07) and SLEDAI-2K ( = 7.0 - 04) at baseline. Baseline APRIL levels also showed an association, although the overall model fit was weaker. In our real-life cohort, baseline serum levels of BAFF were the best predictor of response to Belimumab, confirming post-hoc results of the BLISS study and suggesting the utility of this particular biomarker for the identification of patients who are more likely to respond.
系统性红斑狼疮（SLE）患者血清中肿瘤坏死因子（TNF）/TNF受体（R）超家族成员水平升高，如B淋巴细胞刺激因子（BAFF）。贝利尤单抗是一种针对可溶性BAFF的单克隆抗体，用于治疗SLE。虽然B细胞是主要靶点，但BAFF依赖的T细胞激活途径也发挥作用。基线时抗DNA抗体水平高和补体水平低是已知的贝利尤单抗治疗反应的预测指标。为了探讨SLE患者循环淋巴细胞和B细胞相关TNF/TNFR超家族成员血清水平与贝利尤单抗治疗反应的相关性。21例SLE患者接受了贝利尤单抗治疗。在基线、6个月和12个月时进行了临床评估和实验室检查。所有患者均通过高灵敏度ELISA检测TNF超家族成员（BAFF、增殖诱导配体（APRIL）、可溶性B细胞成熟抗原（sBCMA）、可溶性CD40配体（sCD40L）、可溶性跨膜激活剂和钙调素亲环素配体相互作用分子（sTACI）、肿瘤坏死因子样弱凋亡诱导因子（TWEAK）），并对10名受试者进行了流式细胞术淋巴细胞免疫表型分析。采用SLE疾病活动指数2000（SLEDAI-2K）评分评估SLE疾病活动度。使用线性回归模型研究随时间影响SLEDAI-2K和抗双链DNA（dsDNA）抗体滴度的参数以及预测模型。所有患者均观察到临床改善。检测到循环B细胞总体减少，尤其是初始B细胞，而T细胞亚群无变化。所有TNF家族成员均下降，而APRIL保持不变。血清C3水平升高（P = 0.0004）和sTACI升高（P = 0.0285）与SLEDAI-2K降低相关。C4升高（P = 0.027）和sBCMA升高（P = 0.0015）以及CD8 + T细胞增加（P = 0.0160）与抗dsDNA抗体滴度降低相关，而血清中sCD40L升高（P = 0.0018）和CD4 + T细胞数量增加（P = 0.0029）分别与抗dsDNA抗体滴度升高相关。采用逐步向前纳入法，预测12个月时SLEDAI-2K反应的最小模型包括基线时的BAFF（P = 3.0×10 - 07）和SLEDAI-2K（P = 7.0×10 - 04）。基线APRIL水平也显示出相关性，尽管总体模型拟合较弱。在我们的真实队列中，基线血清BAFF水平是贝利尤单抗治疗反应的最佳预测指标，证实了BLISS研究的事后结果，并表明该特定生物标志物在识别更可能有反应的患者方面的实用性。
