title: High dose versus low dose fludarabine in the treatment of patients with severe refractory rheumatoid arthritis.
abstract: OBJECTIVE
  Fludarabine, a nucleoside analog that targets both resting and proliferating lymphocytes, is a promising drug for the treatment of autoimmune diseases. We conducted a 2 dose, open label clinical trial to evaluate the toxicity/safety of the fludarabine treatment and its clinical and immunological effects.
  
  
  METHODS
  Twenty-six patients with severe rheumatoid arthritis (RA) refractory to treatment with at least one slow acting antirheumatic drug were treated with intravenous fludarabine [20 mg/m2 body surface area (n=12) or 30 mg/m2 body surface area (n=14) per day for 3 consecutive days] given monthly for 6 months. Second line agents with the exception of glucocorticoids were discontinued at least 4 weeks before study entry. Measurements included toxicity and tolerability monitored at monthly intervals: efficacy, by both a 50% reduction in tender or swollen joint count and American College of Rheumatology (ACR) criteria for 20% response; and phenotypic analysis of peripheral blood mononuclear cells and T cell functional assays.
  
  
  RESULTS
  Using intention-to-treat analysis, 2 of 12 (17%) patients in the low dose and 7 of 14 (50%) in the high dose groups had 50% or greater reduction in tender and/or swollen joint count after 6 months of therapy compared to baseline (p=0.09). Two of 12 (17%) in the low dose group and 5 of 14 (36%) in the high dose group met ACR criteria for 20% improvement (p=0.28). No immediate toxicity was observed. Several infections occurred, including 4 episodes of limited Herpes zoster, which responded to standard therapy. Significant lymphopenia involving T and B cells was observed in all patients. Both naive (CD4+CD45RA+) and memory CD4+ T cells (CD4+CD45RO+) were reduced (naive > memory). No significant regeneration of naive T cells was observed, which may suggest limited thymic regenerative capacity. Fludarabine decreased the proliferative response of peripheral blood lymphocytes to mitogens, as well as the production of T cell (interleukin 2 and interferon-gamma) and monocyte derived (tumor necrosis factor-alpha and IL-10) cytokines.
  
  
  CONCLUSIONS
  Fludarabine treatment of patients with severe, refractory RA resulted in significant lymphopenia, suppression of lymphocyte function, and clinical improvement in the high dose group. There was no immediate toxicity; however, several infections occurred. Controlled trials are needed to substantiate the clinical improvement observed in this open label trial.
authors.affiliation: Clinical Investigation Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Davis
authors.forename: B J
authors.initials: BJ
authors.lastname: Fessler
authors.forename: I O
authors.initials: IO
authors.lastname: Tassiulas
authors.forename: I B
authors.initials: IB
authors.lastname: McInnes
authors.forename: C H
authors.initials: CH
authors.lastname: Yarboro
authors.forename: S
authors.initials: S
authors.lastname: Pillemer
authors.forename: R
authors.initials: R
authors.lastname: Wilder
authors.forename: T A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: J H
authors.initials: JH
authors.lastname: Klippel
authors.forename: D T
authors.initials: DT
authors.lastname: Boumpas
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D018655:Lymphocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010976:Platelet Count / Q000187:drug effects; D013997:Time Factors; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D015703:Antigens, CD; D007166:Immunosuppressive Agents; D014740:Vidarabine; C024352:fludarabine