How does infliximab work in rheumatoid arthritis?

Abstract

Since the initial characterization of tumor necrosis factor alpha (TNFalpha), it has become clear that TNFalpha has diverse biologic activity. The realization that TNFalpha plays a role in rheumatoid arthritis (RA) has led to the development of anti-TNF agents for the treatment of RA. Infliximab, a chimeric monoclonal antibody that specifically, and with high affinity, binds to TNFalpha and neutralizes the cytokine, is currently approved for the treatment of RA and Crohn's disease, another immune-inflammatory disorder. In addition to establishing the safety and efficacy of infliximab, clinical research has also provided insights into the complex cellular and cytokine-dependent pathways involved in the pathophysiology of RA, including evidence that supports TNFalpha involvement in cytokine regulation, cell recruitment, angiogenesis, and tissue destruction.

Figure 1

Efficacy, pharmacokinetics, and antibody incidence of infliximab. Efficacy of infliximab as (a) monotherapy (closed symbols) and (b) in combination with methotrexate (open symbols) based on Paulus 20% criteria; infliximab 1 mg/kg (closed triangle ▲, open triangle △), infliximab 3 mg/kg (closed diamond ◆, open diamond ◇), infliximab 10 mg/kg (closed square ■, open square □), and placebo plus methotrexate (closed circle ●). Arrows indicate the infusion times of infliximab and placebo. (c) Pharmacokinetics of infliximab alone (closed symbols) or with methotrexate (open symbols); infliximab 1 mg/kg (closed triangle ▲, open triangle △) infliximab 3 mg/kg (closed diamond ◆, open diamond ◇), and infliximab 10 mg/kg (closed square ■, open square □). (d) Incidence of anti-infliximab antibodies; infliximab alone (closed symbols) and infliximab plus methotrexate (open symbols). Panels a, b, and c, adapted with permission from Maini et al. [10]; panel d, data from Maini et al. [10]. Copyright 1999. American College of Rheumatology.

Figure 2

Effect of infliximab on IL-6 concentrations. (a) Circulating IL-6 concentrations in patients treated with a single infusion of infliximab or placebo on Day 0; infliximab 1 mg/kg (closed triangle ▲), infliximab 10 mg/kg (closed square ■), and placebo (open circle ○). ^*P < 0.05, ^**P < 0.01, ^***P < 0.001 compared with placebo. (b) The relationship between the reduction in circulating IL-6 by Day 3 and the reduction in C-reactive protein (CRP) over the same period (r = 0.59, P < 0.002). Adapted with permission from Charles et al. [19]. Copyright 1999. The American Association of Immunologists.

Figure 3

Effect of infliximab on circulating IL-1ra in patients treated with a single infusion of infliximab or placebo on Day 0. Infliximab 1 mg/kg (closed triangle ▲), infliximab 10 mg/kg (closed square ■), and placebo (open circle ○). ^*P < 0.05, ^**P < 0.01, ^***P < 0.001 compared with placebo. Adapted with permission from Charles et al. [19]. Copyright 1999. The American Association of Immunologists.

Figure 4

Histologic scores, expression of chemokines and adhesion molecules and lymphocyte counts before and after single infusion of infliximab. (a) and (b) Histologic scores of knee synovial biopsies before (shaded bar) and after (open bar) treatment by chemokine or adhesion molecule. (c) Circulating lymphocytes; infliximab 10 mg/kg (closed square ■), infliximab 1 mg/kg (closed triangle ▲), and placebo (open circle ○). (d) Change in serum E-selectin concentrations; infliximab 1 mg/kg (closed triangle ▲), infliximab 10 mg/kg (closed square ■), and placebo (open circle ○). Panel a, data from Taylor PC et al. [26]; panel b, data from Tak PP et al. [24]; Panels c and d, adapted with permission from Paleolog et al. [25]. Copyright 1996, American College of Rheumatology.

Figure 5

Gamma camera images of the knees and of the hands of a rheumatoid patient. Images were taken 22 hours after a bolus injection of autologous radiolabeled (¹¹¹Indium) granulocytes before and after a single 10 mg/kg intravenous bolus of infliximab. Adapted with permission from Taylor et al. [26]. Copyright 1999, American College of Rheumatology.

Figure 6

Serum VEGF concentrations at baseline and following a single infusion of infliximab in patients with active rheumatoid arthritis. Infliximab 1 mg/kg (closed triangle ▲), infliximab 10 mg/kg (closed square ■), and placebo (open circle ○). Adapted with permission from Paleolog et al. [29]. Copyright 1998, American College of Rheumatology.