Monoclonal anti‐TNFα Antibody as a Probe of Pathogenesis and Therapy of Rheumatoid Disease

Abstract

Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.

Deactivation of vascular endothelium by monoclonal anti–tumor necrosis factor α antibody in rheumatoid arthritis

“…These findings confirm and extend our previous results (16). Both the extent and duration of the decrease in serum E-selectin and ICAM-1 were dependent on the dose of cA2.…”

“…Serum ICAM-1 levels after 10 mg/kg of cA2 (median 306 ng/ml at week 4) were close to the upper limit of the range reported for normal individuals (mean 210 ng/ml, range 115-306 ng/ml [17]). Our results provide the first detailed account of a reduction in serum E-selectin and ICAM-1 as part of the response to any biologic therapy in human disease, and support our previously published preliminary data (16). There is, to date, only limited evidence showing the effects of antirheumatic drugs on endothelial cell biology.…”

“…Another possible mechanism which may account for these prolonged effects of anti-TNFa could be diminished microvascular endothelial activation, with consequent reduced leukocyte trafficking to the synovial joint. This hypothesis is consistent with our observation of increased peripheral blood lymphocyte counts in patients during the course of anti-TNFa treatment, paralleled by reduced E-selectin expression on capillaries and venules in synovial biopsies (16).…”

“…Figure 4A illustrates the change in serum Eselectin concentrations relative to preinfusion values as a function of the presence or absence of a 20% Paulus response 4 weeks after infusion of anti-TNFa (1 or 10 mg/kg). It is clear that in the group of 16 patients who did not meet the 20% Paulus criteria at this time, 7 individuals also did not exhibit any decrease in Eselectin levels (median E-selectin levels 95% relative to preinfusion values), whereas in the group of 28 patients in whom a 20% Paulus response was observed at this time, only 3 patients failed to show a reduction in E-selectin (median E-selectin levels 77%) ( P < 0.01 versus absence of 20% Paulus response, by MannWhitney U test).…”

“…In our preliminary study, we observed that preinfusion levels of serum E-selectin, ICAM-1, and VCAM-1 in RA were elevated relative to normal values, but following anti-TNFa treatment, levels of serum E-selectin, but not VCAM-1, were markedly diminished (16). We report here that serum levels of soluble Eselectin and ICAM-l, but not VCAM-l, are significantly reduced by anti-TNFa treatment in a time-and dosedependent manner in patients enrolled in a placebocontrolled double-blind trial of anti-TNFa chimeric antibody.…”