title: Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis. A double-blind, placebo-controlled trial with open-label extension.
abstract: OBJECTIVE
  This pilot phase II, double-blind, placebo-controlled trial of 1 month duration, with a 2-3-month open-label extension, evaluated the safety, tolerability, biologic effects, and efficacy of interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis (RA).
  
  
  METHODS
  Forty-five RA patients were enrolled in the trial, and were randomized, after a 3-4-week disease-modifying antirheumatic drug washout, to receive a daily intravenous dose of either DAB486IL-2 or placebo (saline) for 5 days. A blinded, third-party observer evaluated arthritis activity. Clinical response was defined as > or = 25% improvement in swollen and tender joints and > or = 25% improvement in at least 2 of 6 additional parameters. The double-blind phase was 4 weeks; placebo patients could cross over to receive open-label treatment for a maximum of 3 monthly DAB486IL-2 cycles.
  
  
  RESULTS
  In the double-blind phase, 4 of 22 patients (18%) in the treated group and none in the placebo group (P = 0.05) met the criteria for clinical response. During the open-label treatment phase, 11 of 36 patients (31%) and 11 of 33 patients (33%) had a clinical response after completing 2 and 3 courses of DAB486IL-2, respectively. Adverse events included transient fever/chills (45%), nausea/vomiting (50%), elevated (< or = 3 x normal) transaminases (55%), and increased joint pain (45%). Twelve patients (8 placebo, 4 DAB486IL-2) did not complete 3 treatment cycles. No apparent differences were noted in CD4+ CD25+ cells of responders versus nonresponders, or of DAB486IL-2-treated versus placebo-treated patients.
  
  
  CONCLUSIONS
  Clinical responses were noted in patients treated with DAB486IL-2 (18%) compared with placebo (0%) in the double-blind phase. In the open-label phase, 33% of patients completing 3 monthly DAB486IL-2 cycles had improvement in arthritis activity. Further studies of IL-2 diphtheria fusion proteins are warranted to elucidate factors that may predict clinical response and define mechanism(s) of action.
authors.affiliation: Division of Clinical Immunology/Rheumatology, SRC 068, UAB Station 35294-7201, USA.
authors.forename: L W
authors.initials: LW
authors.lastname: Moreland
authors.forename: K L
authors.initials: KL
authors.lastname: Sewell
authors.forename: D E
authors.initials: DE
authors.lastname: Trentham
authors.forename: R P
authors.initials: RP
authors.lastname: Bucy
authors.forename: W F
authors.initials: WF
authors.lastname: Sullivan
authors.forename: R E
authors.initials: RE
authors.lastname: Schrohenloher
authors.forename: R H
authors.initials: RH
authors.lastname: Shmerling
authors.forename: K C
authors.initials: KC
authors.lastname: Parker
authors.forename: W G
authors.initials: WG
authors.lastname: Swartz
authors.forename: T G
authors.initials: TG
authors.lastname: Woodworth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000032:analysis; D015703:Antigens, CD / Q000032:analysis; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015415:Biomarkers; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D018501:Antirheumatic Agents; D015415:Biomarkers; C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins