Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares

Abstract

Objective: To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM).

Methods: We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6 months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes.

Results: There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only.

Conclusion: Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

Keywords: B cell; B cell targeting agents; Systemic lupus erythematosus; biomarker; flare; lupus nephritis.

Figure 1.

Kaplan Meier Survival Curves demonstrating Flare-Free Survival in Type 1 vs Type 2 episodes. Tick marks denote censored episodes. p=<0.0001 (Log-rank test). Compared to Type 1 episodes, Type 2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio = 9.0, 95% confidence interval for hazard ratio = 2.2-36.7). Median time to flare in Type 2 was 6 months.

Figure 2.

Complement C3 levels before treatment with BCA (Pre) and at event or time of censoring (Post) for Type 1 episodes (N = 17) vs Type 2 episodes (N = 9). Dotted lines denote episodes that were censored; solid lines denote episodes that resulted in flare. Horizontal dashed line indicates approximate lower limit of normal range for C3 (80mg/dL). p-values from Wilcoxon matched-pairs signed rank test.

Figure 3.

BCC (cells/μL), complement C3 (mg/dL), and UPCR (mg/mg) vs time for the patient L on Table 2. “X” marks along the trend of absolute BCC denote when CD19 measurements were taken. “RTX” along X-axis denotes receipt of a cycle of rituximab. According to our study definitions, the patient had 3 sequential LN flares with associated cutaneous vasculitis flares (marked by ∇), after she received her first RTX cycle, despite taking mycophenolate mofetil (MMF) 3000 mg/day and prednisone (10-40 mg/day). The first 2 flares responded to increased prednisone doses to 40 mg/day with taper and additional RTX cycles (2nd and 3rd respectively). However, the 3rd flare required 3 cycles of RTX (4th, 5th, and 6th) and a shortened interval between RTX cycles to 3 months for resolution. It also required IV pulse methylprednisolone 500 mg for 3 days and IV cyclophosphamide for two monthly doses after the 5th RTX cycle. No additional flares were noted while on RTX cycles every 3 months and MMF 3000 mg/day; the prednisone dose was tapered to 2 mg/day by the end of follow-up. Of note, the patient also received BLM from 11/2019 until 06/2021 when it was discontinued due to insurance reasons and lack of apparent effect beyond that of RTX.