QJM Advance Access published online on February 19, 2008
QJM, doi:10.1093/qjmed/hcn006
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A pilot study of combination anti-cytokine and anti-lymphocyte biological therapy in rheumatoid arthritis
From the 1Leeds Institute of Molecular Medicine, Section of Musculoskeletal Disease, University of Leeds, 2Sir William Dunn School of Pathology, University of Oxford, 3Haematological Malignancy Diagnostic Service, 4Clinical Immunology, St James's University Hospital, Leeds, and 5Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle-Upon-Tyne, UK
Address correspondence to J.D. Isaacs, Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle-Upon-Tyne, NE2 4HH, UK. email: j.d.isaacs{at}ncl.ac.uk
Received 9 August 2007 and in revised form 2 January 2008
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Abstract |
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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 TNF
antagonist should maximize the potential of anti-T-cell mAbs to induce tolerance in RA.
Aim: To evaluate the safety of combining a TNF 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 TNF blockade. Prolonged CD4 blockade was achieved with a humanized mAb, and TNF 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 TNF 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.