Uzzo Martina, Schumacher Helmut, Steffgen Juergen, Deutschel Simone, Jayne David, Bajema Ingeborg
University of Milano-Bicocca, Monza, Italy, and University of Groningen, University Medical Center, Groningen, The Netherlands.
Statistical Consultant, Ingelheim, Germany.
Arthritis Rheumatol. 2025 Jun;77(6):696-704. doi: 10.1002/art.43076. Epub 2025 Jan 28.
A phase 2 trial tested different doses of the anti-CD40 monoclonal antibody BI 655064 as an add-on therapy to the standard of care in patients with class III or IV lupus nephritis (LN) with active disease. A post hoc analysis showed a potential benefit of the higher tested doses (180 and 240 mg) versus a low dose (120 mg) or placebo. We investigated whether the treatment effect of BI 655064 on kidney outcomes may be modified by the presence of glomerular monocytes, a target for this drug with a well-known role in LN pathogenesis.
One hundred one renal biopsies of patients with LN enrolled in the BI 655064 trial were scored centrally. The estimated glomerular filtration rate (eGFR), spot urine protein/urine creatinine ratio (UP/UC), and complete renal response (CRR) were evaluated over 52 weeks. Patients were divided according to a "better" or "worse" performance than the average of all patients in the cohort, predicted by a mixed model for repeated measurements. Logistic regression models adjusted for potential confounders were used to assess the association between different treatment doses and outcomes according to the presence or absence of monocytes.
A higher BI 655064 dose (180 or 240 mg) was associated with better outcomes of UP/UC and CRR when glomerular monocytes were present in kidney biopsy samples (odds ratio [OR] 3.66 [95% confidence interval (CI) 1.09-12.3], P = 0.04; OR 4.58 [95% CI 1.24-16.9], P = 0.02). A trend toward improved eGFR was also observed in these patients (at 52 weeks, P = 0.08).
In LN kidney biopsy samples with glomerular monocytes, high-dose BI 655064 treatment improved proteinuria at 52 weeks and resulted in a higher CRR compared to biopsy samples without glomerular monocytes. Histologic features may guide the choice of treatment for individual patients with LN.
一项2期试验测试了不同剂量的抗CD40单克隆抗体BI 655064作为活动性疾病的III或IV级狼疮性肾炎（LN）患者标准治疗的附加疗法。一项事后分析显示，与低剂量（120 mg）或安慰剂相比，较高测试剂量（180和240 mg）具有潜在益处。我们研究了肾小球单核细胞的存在是否会改变BI 655064对肾脏结局的治疗效果，肾小球单核细胞是该药物的一个靶点，在LN发病机制中具有众所周知的作用。
对参与BI 655064试验的LN患者的101份肾活检标本进行集中评分。在52周内评估估计肾小球滤过率（eGFR）、随机尿蛋白/尿肌酐比值（UP/UC）和完全肾脏缓解率（CRR）。根据重复测量的混合模型预测，将患者按照表现比队列中所有患者的平均水平“更好”或“更差”进行分组。使用针对潜在混杂因素进行调整的逻辑回归模型，根据单核细胞的存在与否评估不同治疗剂量与结局之间的关联。
当肾活检样本中存在肾小球单核细胞时，较高剂量的BI 655064（180或240 mg）与更好的UP/UC和CRR结局相关（优势比[OR] 3.66 [95%置信区间（CI）1.09 - 12.3]，P = 0.04；OR 4.58 [95% CI 1.24 - 16.9]，P = 0.02）。在这些患者中还观察到eGFR有改善趋势（在52周时，P = 0.08）。
在有肾小球单核细胞的LN肾活检样本中，与没有肾小球单核细胞的活检样本相比，高剂量BI 655064治疗在52周时改善了蛋白尿，并导致更高的CRR。组织学特征可能指导个别LN患者的治疗选择。
