title: A pilot study of combination anti-cytokine and anti-lymphocyte biological therapy in rheumatoid arthritis.
abstract: BACKGROUND
  Immunological tolerance in humans using anti-T-cell monoclonal antibodies (mAbs) may be hampered by a pro-inflammatory microenvironment. All clinical trials of such therapies in rheumatoid arthritis (RA), however, have selected patients with active disease at baseline. Concurrent neutralization of inflammation with a TNFalpha antagonist should maximize the potential of anti-T-cell mAbs to induce tolerance in RA.
  
  
  OBJECTIVE
  To evaluate the safety of combining a TNFalpha antagonist and CD4 mAb in RA.
  
  
  METHODS
  An iterative pilot study focused on the safety of such combination therapy.
  
  
  METHODS
  Eight poor prognosis, seropositive RA patients were treated with combined CD4 and TNFalpha blockade. Prolonged CD4 blockade was achieved with a humanized mAb, and TNFalpha blockade with a p55 TNF receptor fusion protein.
  
  
  RESULTS
  There was a low incidence of classical first-dose reactions to the CD4 mAb, possibly reflecting concomitant TNFalpha blockade. An unusual anaphylactoid reaction was seen, however, and one patient developed a probable allergic reaction after several infusions. Skin rashes were common, as previously reported with CD4 mAb monotherapy. No serious infections were documented during follow-up, despite CD4+ lymphopenia in some patients. Most patients appeared to demonstrate improved RA disease control after the study. After 17-49 months after therapy, one patient was in remission, one remained off disease modifying anti-rheumatic drugs and five had stable disease, three on previously ineffective doses of methotrexate.
  
  
  CONCLUSIONS
  We report, for the first time in man, immunotherapy with a combination of an anti-cytokine and an anti-T-cell reagent. We witnessed an unusual first-dose reaction but there were no significant infectious complications.
authors.affiliation: Leeds Institute of Molecular Medicine, Section of Musculoskeletal Disease, University of Leeds, UK.
authors.forename: A W
authors.initials: AW
authors.lastname: Morgan
authors.forename: G
authors.initials: G
authors.lastname: Hale
authors.forename: P R U B
authors.initials: PR
authors.lastname: Rebello
authors.forename: S J
authors.initials: SJ
authors.lastname: Richards
authors.forename: H-C
authors.initials: HC
authors.lastname: Gooi
authors.forename: H
authors.initials: H
authors.lastname: Waldmann
authors.forename: P
authors.initials: P
authors.lastname: Emery
authors.forename: J D
authors.initials: JD
authors.lastname: Isaacs
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D015704:CD4 Antigens / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha