Ann Rheum Dis 2001;60:660-669 ( July )

Extended report

Effects of treatment with a fully human anti-tumour necrosis factor  monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNF in patients with rheumatoid arthritis P Barrera, L A B Joosten, A A den Broeder, L B A van de Putte, P L C M van Riel, W B van den Berg

Department of Rheumatology, University Hospital, Nijmegen, The Netherlands

Correspondence to: Dr P Barrera, Department of Rheumatology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands p.barrera{at}reuma.azn.nl

Accepted for publication 25 October 2000

OBJECTIVESTo study the short term effects of a single dose of D2E7, a fully human anti-tumour necrosis factor (TNF) monoclonal antibody (mAb), on the local and systemic homeostasis of interleukin 1 (IL1) and TNF in patients with rheumatoid arthritis (RA).
METHODSAll patients with RA enrolled in a phase I, single dose, placebo controlled study with D2E7 in our centre were studied. Systemic cytokine levels, acute phase reactants, and leucocyte counts were studied at days 0, 1, and 14 after the first administration of anti-TNF mAb (n=39) or placebo (n=11). The cellularity and the expression of IL1 and TNF in synovial tissue were studied in knee biopsy specimens obtained at baseline and at day 14 in 25 consenting patients.
RESULTSA single dose of anti-TNF mAb induced a rapid clinical improvement, a decrease in acute phase reaction, and increased lymphocyte counts in patients with active RA. The protein levels of IL1 in the circulation were low and remained unchanged, but the systemic levels of IL1 mRNA (p=0.002) and the concentrations of IL1 receptor antagonist (IL1ra) and IL6 (p=0.0001) had already dropped within 24 hours and this persisted up to day 14. Systemic levels of TNF mRNA were low and remained unchanged, though total TNF (free and bound) in the circulation increased after D2E7, probably reflecting the presence of TNF-antiTNF mAb complexes (p<0.005, at days 1 and 14). Both TNF receptors dropped below baseline levels at day 14 (p<0.005). Despite clinical improvement of arthritis, no consistent immunohistological changes were seen two weeks after anti-TNF administration. Endothelial staining for IL1 tended to decrease in treated patients (p=0.06) but not in responders. The staining for IL1 and TNF in sublining layers and vessels was mutually correlated (r_s=0.47 and 0.58 respectively, p<0.0005) and the microscopic scores for inflammation correlated with sublining TNF and IL1 scores (r_s=0.65 and 0.54 respectively, p<0.0001), though none of these showed significant changes during the study.
CONCLUSIONSBlocking TNF in RA results in down regulation of IL1 mRNA at the systemic level and in reduction of the endogenous antagonists for IL1 and TNF and of other cytokines related to the acute phase response, such as IL6, within days. At the synovial level, anti-TNF treatment does not modulate IL1 and TNF in the short term. The synovial expression of these cytokines does not reflect clinical response to TNF neutralisation.

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© 2001 by Annals of the Rheumatic Diseases
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