title: Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections.
abstract: OBJECTIVE
  Late-onset neutropenia following rituximab therapy is a well-recognized side effect in lymphoma patients, but only a few cases of late-onset neutropenia have been reported in patients with autoimmune disorders. The purpose of this study was to define the incidence, clinical features, and some of the underlying mechanisms of late-onset neutropenia in relation to rituximab use in several rheumatic diseases.
  
  
  METHODS
  We conducted a retrospective analysis of a cohort of 209 consecutive patients with rheumatic diseases who had been treated with rituximab at a university hospital between June 2003 and March 2009.
  
  
  RESULTS
  Eleven patients with late-onset neutropenia were identified. The highest incidence was observed in granulomatosis with polyangiitis (Wegener's) and systemic lupus erythematosus patients (23% and 20%, respectively), whereas the incidence in rheumatoid arthritis patients was 3%. The median time to onset of neutropenia was 102 days (range 40-362 days) and coincided with the entire period of B lymphocyte depletion; this depletion was more pronounced in patients with late-onset neutropenia (P = 0.002) than in a control group of 20 matched patients without late-onset neutropenia. Serum IgM levels decreased during the same time and to a significantly greater amount in patients with late-onset neutropenia than in controls (P = 0.027). No patient with late-onset neutropenia displayed specific antineutrophil antibodies. Seven patients were hospitalized because of infections (6 with sepsis and 1 with febrile neutropenia) that required intravenous antibiotics. Six were treated with granulocyte colony-stimulating factor.
  
  
  CONCLUSIONS
  In patients treated with rituximab for rheumatic diseases, late-onset neutropenia is a clinically significant adverse event associated with marked B lymphocyte depletion and severe infections. The incidence of late-onset neutropenia appears to vary with autoimmune disease type.
authors.affiliation: Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden. daniel.tesfa@karolinska.se
authors.forename: Daniel
authors.initials: D
authors.lastname: Tesfa
authors.forename: Sofia
authors.initials: S
authors.lastname: Ajeganova
authors.forename: Hans
authors.initials: H
authors.lastname: Hägglund
authors.forename: Birgitta
authors.initials: B
authors.lastname: Sander
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Ingiäld
authors.initials: I
authors.lastname: Hafström
authors.forename: Jan
authors.initials: J
authors.lastname: Palmblad
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000009:adverse effects* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001402:B-Lymphocytes; D006801:Humans; D008212:Lymphocyte Depletion; D009503:Neutropenia / Q000139:chemically induced*; D012189:Retrospective Studies; D012216:Rheumatic Diseases / Q000188:drug therapy*; D000069283:Rituximab; D013997:Time Factors
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D000069283:Rituximab