title: Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.
abstract: OBJECTIVE
  To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).
  
  
  METHODS
  In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.
  
  
  RESULTS
  The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of > or =4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti-double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells.
  
  
  CONCLUSIONS
  Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.
authors.affiliation: National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA. illeig@mail.nih.gov
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Illei
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shirota
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Yarboro
authors.forename: Jimmy
authors.initials: J
authors.lastname: Daruwalla
authors.forename: Edward
authors.initials: E
authors.lastname: Tackey
authors.forename: Kazuki
authors.initials: K
authors.lastname: Takada
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleisher
authors.forename: James E
authors.initials: JE
authors.lastname: Balow
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lipsky
mesh_terms: D000328:Adult; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D004247:DNA / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000187:drug effects* / Q000276:immunology; D011241:Prednisone / Q000008:administration & dosage; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D015415:Biomarkers; D005938:Glucocorticoids; D019947:Receptors, Interleukin-6; D004247:DNA; C502936:tocilizumab; D011241:Prednisone