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



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.



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-γ(+)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-γ(+)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-γ(+)CD3(+)<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.



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.
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Chang-Yien
CY
Chan
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Isaac Desheng
ID
Liu
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Lourdes Paula
LP
Resontoc
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Kar-Hui
KH
Ng
Biostatistics Unit, Medicine Dean's Office, National University of Singapore, Singapore.
Yiong-Huak
YH
Chan
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Perry Yew-Weng
PY
Lau
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Mya
M
Than
Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California; and.
Stanley C
SC
Jordan
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore.
Kong-Peng
KP
Lam
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Wee-Song
WS
Yeo
Department of Paediatrics, Yong Loo Lin School of Medicine and.|Department of Paediatric Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
Hui-Kim
HK
Yap
D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000032:analysis; D065095:Calcineurin Inhibitors / Q000627:therapeutic use; D002648:Child; D005260:Female; D005500:Follow-Up Studies; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D011237:Predictive Value of Tests; D011239:Prednisolone / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy; D012372:ROC Curve; D000069283:Rituximab / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000737:chemistry* / Q000502:physiology; D055815:Young Adult
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D017252:CD3 Complex; D015704:CD4 Antigens; D065095:Calcineurin Inhibitors; D007155:Immunologic Factors; D007376:Interleukin-2; D023201:CD40 Ligand; D000069283:Rituximab; D007371:Interferon-gamma; D011239:Prednisolone
Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Lymphocyte Activation; Prednisolone; ROC Curve; Rituximab; T-Lymphocyte Subsets; nephrotic syndrome; proteinuria