T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Background and objectives Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified. Design, setting, participants, & measurements Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m(2)) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab. Results Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154(+)CD4(+)CD3(+) subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%+/- 28.1% versus 78.9%+/- 16.4%; P=0.03). IFN-gamma(+)CD3(+)and IL-2(+)CD3(+) were similarly decreased in responders compared with nonresponders (0.6%+/- 0.8% versus 7.5%+/- 6.1%; P=0.003 and 0.2%+/- 0.5% versus 4.0%+/- 4.7%; P < 0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154(+)CD4(+)CD3(+), 74.8%+/- 17.2%; IFN-gamma(+)CD3(+), 7.1%+/- 7.7%; and IL-2(+)CD3(+), 7.9%+/- 10.9%; P < 0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154(+)CD4(+)CD3(+), < 83.3%(area under the curve [AUC], 0.81; 95% confidence interval [ 95% CI], 0.61 to 1.00), IFN-gamma(vertical bar) CD3(vertical bar) > 2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2(+)CD3(+)> 0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response. Conclusions We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.