A pilot study of combination anti-cytokine and
anti-lymphocyte biological therapy in rheumatoid arthritis
A.W. MORGAN1, G. HALE2, P.R.U.B. REBELLO2, S.J. RICHARDS3, H.-C. GOOI4,
H. WALDMANN2, P. EMERY1and J.D. ISAACS5
From the1Leeds 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,
Received 9 August 2007 and in revised form 2 January 2008
Background: Immunological tolerance in humans
using anti-T-cell monoclonal antibodies (mAbs) may
be hampered by a pro-inflammatory microenviron-
ment. 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 TNFa antag-
onist should maximize the potential of anti-T-cell
mAbs to induce tolerance in RA.
Aim: To evaluate the safety of combining a TNFa
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
and TNFa blockade. Prolonged CD4 blockade was
achieved with a humanized mAb, and TNFa
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 TNFa blockade. An unusual
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 documen-
ted 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
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.
Anti-cytokine therapies are effective agents for
reducing inflammation and preventing joint destruc-
tion in patients with RA. Current data, however,
suggest that long-term treatment will be necessary
when using these drugs, with the attendant risk of
In contrast, data from
animal models suggests that the combination of
anti-cytokine and anti-T-cell therapy may provide
longer term benefit from brief courses of therapy.
TNFa blockade,2and anti-CD3 therapy provided
particularly robust responses when combined with
Address correspondence to J.D. Isaacs, Musculoskeletal Research Group, Institute of Cellular Medicine,
Newcastle University, Framlington Place, Newcastle-Upon-Tyne, NE2 4HH, UK. email: email@example.com
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Q J Med 2008; 101:299–306
doi:10.1093/qjmed/hcn006Advance Access published on 19 February 2008
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