Reddy Venkat, Martinez Lina, Isenberg David A, Leandro Maria J, Cambridge Geraldine
University College London, Rayne Institute, London, UK.
Hospital General Universitario, Gregorio Marañón, Madrid, Spain.
Arthritis Care Res (Hoboken). 2017 Jun;69(6):857-866. doi: 10.1002/acr.22993. Epub 2017 Apr 24.
B cell-depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with systemic lupus erythematosus (SLE). The aim of this observational study was to document long-term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice.
We included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti-dsDNA antibodies, over a median of 48 months most recent followup. Flow cytometry was used prospectively to assess B cell phenotypes in 17 of 57 patients.
Twelve patients (21%) had persistent IgM hypogammaglobulinemia (<0.4 gm/liter), and 4 of 57 (5%) had low IgG (<7 gm/liter) at the most recent followup (range 12-144 months). This was not associated with serious adverse events or high anti-double-stranded DNA (anti-dsDNA) antibodies (>1,000 IU/ml; normal <50 IU/ml). Factors predictive of low serum IgM included baseline serum IgM ≤0.8 gm/liter (receiver operator curve analysis) and subsequent therapy with mycophenolate mofetil (MMF; odds ratio 6.8, compared with other immunosuppressants). In patients maintaining normal IgM levels (9 of 17), the frequency of circulating IgD+CD27+ B cells was significantly higher (P = 0.05). At 12 months after rituximab, 7 of 30 SLE patients with baseline anti-dsDNA ≤1,000 IU/ml had lost seropositivity.
Lower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti-dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE.
基于利妥昔单抗的B细胞清除疗法是系统性红斑狼疮（SLE）患者难治性疾病的一种治疗选择。这项观察性研究的目的是通过在常规临床实践中对接受利妥昔单抗治疗的SLE患者的血清免疫球蛋白水平进行随访，记录其对B细胞功能的长期影响。
我们纳入了57例连续接受利妥昔单抗及联合/序贯免疫抑制剂治疗的SLE患者，并在最近一次随访的中位时间48个月内测量了血清总IgG、IgM、IgA以及IgG抗双链DNA抗体。前瞻性地使用流式细胞术评估了57例患者中17例的B细胞表型。
在最近一次随访（随访时间为12 - 144个月）时，12例患者（21%）存在持续性IgM低丙种球蛋白血症（<0.4 g/升），57例中有4例（5%）IgG水平较低（<7 g/升）。这与严重不良事件或高抗双链DNA（抗dsDNA）抗体（>1000 IU/ml；正常<50 IU/ml）无关。预测血清IgM水平低的因素包括基线血清IgM≤0.8 g/升（接受者操作特征曲线分析）以及随后使用霉酚酸酯（MMF）进行治疗（与其他免疫抑制剂相比，优势比为6.8）。在维持正常IgM水平的患者（17例中的9例）中，循环IgD + CD27 + B细胞的频率显著更高（P = 0.05）。在利妥昔单抗治疗12个月后，30例基线抗dsDNA≤1000 IU/ml的SLE患者中有7例血清学转为阴性。
较低的基线血清IgM水平以及序贯使用MMF可预测SLE患者在接受利妥昔单抗治疗后出现IgM低丙种球蛋白血症，但这与抗dsDNA抗体水平升高或感染风险增加无关。这为临床医生在SLE患者的利妥昔单抗及序贯免疫抑制治疗方面提供了有用的指导。
