Outcome of Patients With Lupus Nephritis Treated With an Anti-CD40 Monoclonal Antibody According to Kidney Biopsy Features

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Figure 1

Patient selection chart. According to the International Society of Nephrology/Renal Pathology Society 2003 classification, patients with class III or IV LN were included, and the coexistence of class V was allowed. A cohort of 101 patients was eligible for the study (see text for further details). Patients had been previously randomized in four groups, as per the BI 655064 phase 2 trial protocol (2:1:1:2): 32 patients were in the placebo arm, 16 were in the 120‐mg BI 655064 arm, 18 were in the 180‐mg BI 655064 arm, and 35 were in the 240‐mg BI 655064 arm. For analytical purposes, we combined patients belonging to the placebo and the low‐dose 120‐mg BI 655064 groups (48 patients) as well as those in the high‐dose 180‐ and 240‐mg BI 655064 groups (53 patients). LN, lupus nephritis.

Figure 2

The impact of different treatment doses on UP/UC and eGFR mean profiles over 52 weeks in patients with (A and C) and without (B and D) monocytes in kidney biopsy samples. UP/UC and eGFR mean profile over 52 weeks were adjusted for the previously identified variables (interstitial fibrosis, karyorrhexis, pseudothrombi for UP/UC, infiltration of granulocytes, and endocapillary hypercellularity for eGFR). When we evaluated kidney biopsy samples containing glomerular monocytes, the UP/UC mean profile over 52 weeks differed in the high‐dose (180 and 240 mg) and low‐dose (120 mg) and placebo groups, reaching statistical significance at the end of follow‐up (at 52 weeks, P = 0.057) (A). In contrast, the UP/UC trend over 52 weeks was similar in the two treatment groups when we evaluated biopsy samples with no glomerular monocytes (at 52 weeks, P = 0.92) (B). When we evaluated kidney biopsy samples containing glomerular monocytes, the eGFR mean profile over 52 weeks differed in the high‐dose and low‐dose and placebo groups. Despite the lack of statistical significance, the trend suggested a benefit of the higher doses at the end of follow‐up (at 52 weeks, P = 0.075) (C). In contrast, the eGFR trend at 52 weeks was similar in the two treatment groups when we evaluated biopsy samples with no glomerular monocytes (at 52 weeks, P = 0.98) (D). eGFR, estimated glomerular filtration rate; UP/UC, spot urine protein/urine creatinine ratio.