Infliximab

Abstract

Infliximab is a chimaeric monoclonal antibody to human tumour necrosis factor-α (TNFα). It binds to both soluble and transmembrane forms of TNFα at picomolar concentrations in vitro. Secondary to inhibition of TNFα, infliximab reduces serum levels of inflammatory mediators and vascular endothelial growth factor, decreases the expression of chemokines in the synovial tissue and reduces lymphocyte migration into the joints of patients with rheumatoid arthritis. In 2 multicentre randomised double-blind trials conducted over 26 and 30 weeks, infliximab plus methotrexate was significantly more effective than placebo plus methotrexate according to American College of Rheumatology response criteria in patients with active rheumatoid arthritis. A substantial response to infliximab-containing regimens was evident within 2 weeks. Extension phases of these studies indicate sustained clinical efficacy for up to 54 weeks. Of considerable importance are preliminary 1-year radiographie findings that show zero median progression of joint damage in infliximab plus methotrexate recipients compared with a 7 to 8% deterioration in placebo plus methotrexate recipients. Headache, nausea, upper respiratory tract infection and infusion-related reactions are the most commonly reported adverse events with infliximab. Serious events occurred in 4.4% of infliximab versus 1.8% of placebo recipients. In the largest clinical trial, 2 patients died from disseminated infection and 3 developed new or recurrent malignancies, although the exact relationship between infliximab and these events is unknown. To date, 2 patients with rheumatoid arthritis have developed drug-induced lupus. About 10% of patients may develop antibodies to infliximab, although the clinical significance of these is presently unknown. Conclusion: Infliximab represents an important advance in the treatment of rheumatoid arthritis, with tolerability concerns raised by early studies having been eased somewhat by more recent data in larger patient numbers. If preliminary results indicating that infliximab is able to arrest joint destruction in patients with rheumatoid arthritis are corroborated, the drug will likely become an integral component of future management strategies for this difficult-to-treat condition. Infliximab is a chimaeric monoclonal antibody to human tumour necrosis factor-α (TNFα). It binds to both soluble and transmembrane forms of TNFα at picomolar concentrations in vitro but not to lymphotoxin (TNFβ). Infliximab is thought to achieve clinical benefit in patients with rheumatoid arthritis by several mechanisms secondary to TNFα blockade. Firstly, infliximab reduces serum levels of inflammatory mediators [interleukin (IL)-1β and -6] and the expression of chemokines (IL-8 and monocyte chemoattractant protein-1) in the synovial tissue. Secondly, infliximab reduces lymphocyte migration as shown by decreased movement of radiolabelled granulocytes into the joints of patients with rheumatoid arthritis. This is accompanied by increases in peripheral lymphocyte counts. Thirdly, infliximab reduces serum levels of vascular endothelial growth factor in patients with rheumatoid arthritis which may in turn reduce angiogenesis in the joint. It also reduces serum levels of metalloproteinase-3 and nitric oxide synthase activity, changes which correlate with clinical benefit in patients with rheumatoid arthritis. Infliximab is also associated with transient reductions in peripheral blood monocyte and neutrophil counts and increases in haemoglobin levels. Infliximab demonstrates dose-dependent pharmacokinetics over the dose range 1 to 20 mg/kg. No systemic accumulation of infliximab 3 or 10 mg/kg was observed when administered at 8-week intervals. Serum concentrations of infliximab appear to be sustained for longer when the drug is administered in combination with methotrexate. Eight weeks after the last of 5 × 3 mg/kg doses, serum concentrations of infliximab were approximately 2 and <0.1 mg/L with and without concomitant methotrexate, respectively. The volume of distribution (Vd) of infliximab at steady state is independent of dose, suggesting intravascular distribution. Median Vd ranges from 3 to 5L. The estimated elimination half-life of infliximab is 8 to 9.5 days. Monotherapy with infliximab, administered as a single 1 or 10 mg/kg dose, was associated with significant improvements in Paulus 20% response after 1 and 4 weeks in a randomised placebo-controlled double-blind trial in patients with active rheumatoid arthritis. In patients receiving background methotrexate, 2 multicentre randomised double-blind trials have evaluated the effects of multiple doses of infliximab 1 to 10 mg/kg administered at 4- or 8-week intervals over 26 and 30 weeks. The more recent of these studies, the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) study, is the most comprehensive analysis to date of the efficacy of infliximab in patients with refractory rheumatoid arthritis. In each of these trials, infliximab plus methotrexate was significantly more effective than placebo plus methotrexate according to American College of Rheumatology (ACR) response criteria. A substantial response to infliximab-containing regimens was evident within 2 weeks in these studies. The duration of response improved as the dosage of infliximab increased. Extension phases of these studies indicate sustained clinical response to continued infliximab therapy for up to 54 weeks. Of considerable importance are preliminary 1-year radiographic findings that show zero median progression of joint damage in infliximab recipients compared with a 7 to 8% deterioration in placebo plus methotrexate recipients. In a pooled analysis, the overall incidence of adverse events was 76% in infliximab versus 57% placebo recipients. Headache, nausea, upper respiratory tract infection and infusion-related reactions occurred most frequently. Less frequently reported adverse events included abdominal pain, pharyngitis, fever, vomiting, coughing, rash, pain, rhinitis, sinusitis, urinary tract infection, fatigue and pruritus. Serious adverse events likely to be associated with treatment occurred in 4.4% of infliximab versus 1.8% of placebo recipients; these included pneumonia and fever, dyspnoea and rash. Infection was reported in 26% of infliximab recipients versus 16% of placebo recipients after respective follow-up periods of 27 and 20 weeks. Two patients in the ATTRACT study died from infectious disease (disseminated tuberculosis and coccidomycosis) but the relationship between infliximab and these events is not known. Seven malignancies occurred in patients treated with infliximab in clinical trials. It is not clear whether infliximab contributed to the development of these malignancies; however, rates are within expectations for the populations involved. Antibodies to infliximab (ATI) can develop, although the clinical significance of these antibodies is unknown. ATI formation appears to be reduced by concomitant administration of methotrexate. In the ATTRACT trial, 3 of 27 patients who discontinued infliximab treatment were positive for the presence of ATI. Antinuclear antibodies were detected in 23% of infliximab versus 6% of placebo recipients during the ATTRACT study, whereas antibodies to doublestranded DNA were detected in 16 versus 0% of patients. Two patients with rheumatoid arthritis have developed drug-induced lupus to date. The recommended dose of infliximab for the treatment of rheumatoid arthritis is 3 mg/kg given as an intravenous infusion. Additional doses should be administered 2 and 6 weeks after the initial dose, and every 8 weeks thereafter. The drug should be administered in combination with methotrexate. Infliximab carries a warning regarding the risk of infections in patients treated with anti-TNF therapy. Caution is advised regarding the use of infliximab in patients with chronic infection or a history of recurrent infection and the drug is contraindicated in those with clinically important active infections. Infliximab should be discontinued in patients who develop serious infection, sepsis or symptoms suggestive of drug-induced lupus.