Introduction 1 2 3 4 5 6 7 8 9 10 11 11 The purpose of our study was to determine the safety and efficacy of RTX therapy in the treatment of children with severe SLE. Over the course of 7 years, we retrospectively assessed the indications and responses to RTX therapy in a cohort of children with active SLE that was refractory to conventional therapies or who had clinical indications prohibiting the use of more toxic immunosuppressant drugs. Patients and methods A retrospective analysis was performed on a cohort of 51 patients diagnosed with SLE and lupus nephritis who received their care at Holtz Children’s Hospital, University of Miami Miller School of Medicine, between January 1996 and June 2007. The study was approved by the institutional review board, with waiver of consent authorization, and all subjects were assured anonymity in compliance with the Health Insurance Portability and Accountability Act (HIPAA). The medical records were reviewed for patients’ demographic characteristics, age at diagnosis, prior and current medical treatments, type of lupus nephritis and serologic and clinical response to therapy. 12 Clinical protocol 2 2 Lupus disease activity index and serology 13 Lupus nephritis and renal disease activity 14 15 16 2 17 Statistical methods P Results Patients’ demographics During the period of observation 18 patients were treated with RTX for at least one course of two to four doses. There were 16 female patients and two male patients. Mean age at the time of diagnosis of SLE was 10.7 ± 2.5 years (range 7 to 14 years). Mean duration of disease prior to treatment with RTX was 3.1 ± 2.5 years (range 2 months to 8 years). Age at the time of first RTX treatment was 14.2 ± 3.3 years, and current age at the time of this report was 17 ± 5.0 years. 1 18 Table 1 F M H B HT CYC CyA AZT MMF IVIG CS HXQ FR PR Patient Gender Age at diagnosis (years) Race Indication for rituximab Nephritis class a Upr/cr (mg/mg) Outcome Before RTX After RTX 1 F 12.0 B Nephritis, serositis, Coomb’s (+) anemia, CYC-toxicity IV CYC, MMF 13.0 0.1 FR 2 M 10.0 W Nephritis, serositis, CS toxicity IV CYC, MMF 2.1 0.6 PR 3 F 11.0 B Nephritis, serositis, Coomb’s(+) anemia, CYC- toxicity sepsis IV CYC, MMF 4.0 1.7 PR 4 F 8.0 H Pulmonary HT, nephritis, Coomb’s(+) anemia IV-V CYC, MMF, IVIG 2.6 0.2 FR 5 F 12.0 B Ophthalmic vasculitis, nephritis IV-V CYC, AZT 0.4 0.1 FR 6 F 14.0 B Nephritis, Coomb’s(+) anemia, CS toxicity NA CYC, AZT, MMF, IVIG 0.6 0.3 PR 7 F 12.0 B Nephritis, serositis, CYC-toxicity sepsis IV-V CYC, AZT, MMF, IVIG 2.6 NA Died 8 F 12.0 B Nephritis, serositis, Coomb’s(+) anemia IV CYC, AZT, IVIG 3.6 1.9 PR 9 F 14.0 B Nephritis, serositis, ataxia, miliary tuberculosis III IVIG 1.7 0.2 FR 10 F 7.0 H Nephritis, serositis, arthritis, CYC-toxicity sepsis IV CYC, MMF, IVIG 3.0 0.7 PR 11 F 12.8 H Nephritis, serositis, arthritis, obesity V MMF 9.7 0.2 FR 12 F 7.0 B Nephritis, thrombocytopenia, CYC toxicity IV-V CYC, AZT, MMF, IVIG, CyA 5.4 0.2 FR 13 F 7.0 B Nephritis, Coomb’s(+) anemia, skin vasculitis IV MMF 1.5 0.2 FR 14 M 12.5 H Nephritis, serositis, arthritis, CYC-toxicity sepsis III CYC, MMF, IVIG 2.3 0.8 PR 15 F 13.0 B Nephritis, arthritis, skin vasculitis, Coomb’s(+) anemia IV CYC, MMF, IVIG 6.8 0.9 PR a All three patients on hemodialysis responded positively to the RTX therapy. Patient HD-1 had Raynaud’s syndrome and finger necrosis; her symptoms resolved, and she recently received a transplant, 4 years after RTX treatment. Patient HD-2, who had been on ventilator support with pneumonitis, pleuritis and carditis for 1 month prior to receiving RTX, recovered and has been stable on hemodialysis as an outpatient for >4 years since RTX therapy. Patient HD-3, after 3 years on hemodialysis, developed debilitating chorea with increased lupus serology. She did not respond to anti-convulsant therapy. The chorea resolved within weeks of the RTX therapy. She remains on dialysis without recurrence of chorea. B-cell depletion and re-population 1 Fig. 1 P  2 Table 2 NS Parameter Before rituximab therapy After rituximab therapy P Total lymphocyte count 1044 ± 596 1734 ± 1535 NS CD4+ lymphocytes 344 ± 217 556 ± 264 NS CD19+ lymphocytes 243 ± 223 74 ± 71 0.005 Immunoglobulin IgG 1603 ± 848 1596 ± 1055 NS Immunoglobulin IgM 273 ± 514 283 ± 531 NS Upr/cr (mg/mg) 4.0 ± 3.5 0.6 ± 0.6 0.001 Serum albumin (g/dl) 2.6 ± 0.7 3.5 ± 0.6 0.001 Scr (mg/dl) 1.2 ± 0.4 0.6 ± 0.2 0.001 2 86 ± 32 144 ± 37 0.0003 2 79 ± 26 13 ± 20 <0.0001 SLEDAI-2K score 47 ± 19 25 ± 14 0.0004 Lupus activity and auto-antibody response 2 2 Fig. 2 Panel a 13 Panel b Panel c Panel d P  1 2 2 P Adverse events Staphylococcus aureus 3 Patient #13 had systemic vasculitis and class IV lupus nephritis. Since she was only 7 years of age, it was decided to treat her with intravenous administration of Solu-Medrol followed by weekly RTX for four doses and concurrent mycophenolate mofetil (MMF) as induction therapy. She responded well to RTX, with resolution of her proteinuria and clinical remission of the lupus nephritis. However, she developed symptoms of cerebral vasculitis, with seizures and a cerebral infarct, demonstrated by magnetic resonance imaging (MRI) after her fourth dose of RTX. She was treated with intravenously administered gamma globulin (IVIG) and two doses of cyclophosphamide. Her neurologic deficits resolved and her vasculitis reversed, as demonstrated by MRI. She remains in remission of the lupus nephritis and cerebritis 6 months after RTX therapy. Mild adverse reactions occurred in approximately half the patients and included pruritis, nausea, or malaise associated with the infusions. These became less when hydrocortisone was added to the pre-medication regimen and the infusion rate was slowed to 6 to 8 hours. Discussion 8 19 21 19 22 11 23 8 24 25 26 27 27 18 28 11 22 In conclusion, RTX therapy offers a potential innovation in the current treatment regimens for children with aggressive SLE that includes both renal and extra-renal manifestations. The development of a randomized controlled treatment protocol for induction and maintenance therapy in pediatric patients is very much warranted.