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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 TNFα antagonist should maximize the potential of anti-T-cell mAbs to induce tolerance in RA. Aim: To evaluate the safety of combining a TNFα antagonist and CD4 mAb in RA. Design: 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 TNFα blockade. Prolonged CD4 blockade was achieved with a humanized mAb, and TNFα 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 TNFα 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. © The Author 2008. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved.

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299 - 306