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Infliximab

A Review of its Use in Crohn’s Disease and Rheumatoid Arthritis

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Summary

Abstract

Infliximab is a chimaeric monoclonal antibody which binds to and inhibits the activity of tumour necrosis factor-α (TNFα), a cytokine which is involved in the development of both Crohn’s disease and rheumatoid arthritis. In patients with treatment-resistant Crohn’s disease, infliximab was significantly more effective than placebo in the relief of symptoms. 50 to 89% of patients responded to infliximab and most of them also achieved remission. Patients showed signs of relapse 8 to 12 weeks after a single infusion but responded to additional infusions of the drug. Infliximab was also effective in closing the fistulae in 68% of patients with fistulising Crohn’s disease; the response rate with placebo was 26%.

Infliximab achieved a clinical response in 44 to 81% of patients with refractory rheumatoid arthritis. Following a single infusion, symptom recurrence was evident after 6 to 12 weeks, but subsequent infusions re-established a clinical response. Concurrent methotrexate appeared to prolong the effects of infliximab in this patient group.

Anti-infliximab and anti-double-stranded DNA antibodies developed in some patients, particularly those who received multiple infusions of infliximab. Acute adverse events consistent with hypersensitivity occurred in some patients who received multiple infusions of infliximab. Infection occurred slightly more frequently with infliximab than with placebo.

Conclusions: Infliximab appears to be an effective therapy for patients with treatment-resistant or fistulising Crohn’s disease or refractory rheumatoid arthritis. The tolerability, long term efficacy and optimal dosage regimen need to be further defined in comparative trials before the full potential of infliximab is realised in these patients.

Pharmacodynamic Properties

Tumour necrosis factor-α (TNFα) is present at elevated levels in inflamed tissues and is thought to play a central role in the pathogenesis of Crohn’s disease and rheumatoid arthritis. Infliximab is a mouse-human chimaeric monoclonal antibody which binds to and blocks the function of human TNFα. Consistent with blockade of TNFα, intravenous infliximab resulted in reduced expression of TNFα-regulated chemokines, endothelial adhesion molecules and interleukins in patients with Crohn’s disease or rheumatoid arthritis. A 25 to 50% decrease in peripheral monocyte counts was observed in some patients who received infliximab, but resolved within a few weeks.

Patients who received multiple infusions of infliximab were more likely to develop anti-infliximab antibodies than those who received single infusions, but concurrent methotrexate or higher doses of infliximab markedly reduced the antiinfliximab response. Anti-double-stranded DNA (anti-dsDNA) antibodies also developed in patients more frequently after multiple than after single infusions of infliximab.

Pharmacokinetic Properties

Serum infliximab concentrations increased in proportion with higher doses, and the median volume of distribution was 3.0 L with infliximab 5 mg/kg. Eight weeks after patients received infusions of infliximab 1 to 20 mg/kg, serum infliximab was detectable only in patients who received ≥10 mg/kg. Concurrent methotrexate tended to increase serum concentrations of infliximab.

The elimination half-life of infliximab was 9 to 10 days in patients with either Crohn’s disease or rheumatoid arthritis. This is longer than that reported for intact mouse monoclonal antibodies, but shorter than that reported for native human antibodies.

Clinical Use in Crohn’s Disease

In 8- to 48-week clinical trials involving 9 to 107 patients with treatment-resistant Crohn’s disease, infliximab 5 to 20 mg/kg achieved a clinical response [defined as a reduction in Crohn’s disease activity index (CDAI) score of ≥70 points] in 50 to 89% of patients. In the only fully reported, placebo-controlled trial, single infusions of infliximab 5, 10 or 20 mg/kg achieved a clinical response in 50 to 81% of patients with Crohn’s disease compared with 17% of patients with placebo. Remission (defined as a CDAI score <150) was achieved in 27 to 50% of patients who received infliximab compared with 4% of patients who received placebo in this study. There was no dose-response pattern with infliximab 5, 10 and 20 mg/kg, although the 1 mg/kg dose was associated with a lower clinical response rate.

Patients with treatment-resistant Crohn’s disease generally responded to a single infusion of infliximab by week 2, the earliest time-point reported, and exhibited maximum improvement by week 4 to 6. Disease activity started to return after approximately 8 to 12 weeks. A longer overall duration of response was achieved with multiple infusions of infliximab. To date, a maximum of 5 infusions have been administered with an associated duration of effect of at least 44 weeks.

In patients with fistulising Crohn’s disease, infliximab was significantly more effective than placebo on the basis of closure of fistulae. At least 50% of fistulae were closed during ≥2 consecutive visits in 68% of patients who received infliximab 5 mg/kg compared with 26% of placebo recipients. In 55% of infliximab recipients, all fistulae were closed.

Clinical Potential in Rheumatoid Arthritis

In 4- to 26-week trials, single doses of infliximab 1 to 20 mg/kg achieved a clinical response in 44 to 81% of patients with rheumatoid arthritis refractory to ≥1 disease-modifying antirheumatic drug (DMARD), based on the Paulus 20% or American College of Rheumatology criteria (range 7 to 81 evaluable patients). In 1 trial, pain score, swollen joint count and C-reactive protein (CRP) levels were improved by 63, 61 and 45%, respectively, 4 weeks after patients received a single infusion of infliximab 10 mg/kg.

The response to infliximab was apparent 1 week after infusion and reached a maximum after approximately 3 weeks. The median duration of the Paulus 20% response after a single infusion of infliximab 10 mg/kg was 8 weeks in 1 trial. Patients who were re-infused with infliximab after responding to an initial infusion and subsequently relapsing continued to respond similarly. However, the duration of the response was reduced with each successive infusion administered after relapse in a noncomparative trial in 7 patients; after 1, 2, 3 or 4 infusions, the median response duration was 12, 9.1, 8.3 and 7.7 weeks, respectively. Concurrent methotrexate therapy improved the duration of the response to multiple infusions of infliximab.

Tolerability

Adverse events associated with infliximab were usually mild and resolved spontaneously. Acute, infusion-related adverse events suggestive of hypersensitivity (urticaria, somnolence, pruritus, chills, fever, headache, facial flushing, chest pain, dyspnoea and/or nausea) occurred in 6 to 38% of patients who received multiple infusions of infliximab and were more common in patients with anti-infliximab antibodies. Such events were not reported in recipients of a single infusion of infliximab. The incidence of infection was slightly higher in patients who received infliximab than in placebo recipients. Other adverse events, at least possibly related to treatment, included hypertension, rigors, rash, headache and eczema. Two patients developed symptoms of systemic lupus erythematosus after multiple infusions of infliximab, and in 1 patient this was correlated with the development of anti-dsDNA antibodies. Five patients developed lympho-proliferative disorders after receiving infliximab, but the data did not establish a relationship between this adverse event and treatment.

Dosage and Administration

Infliximab is indicated for the management of moderate to severe, active Crohn’s disease which does not respond to conventional therapies, and for fistulising Crohn’s disease. The recommended dose in patients with treatment-resistant Crohn’s disease is a single, 2-hour intravenous infusion of infliximab 5 mg/kg. In patients with fistulising Crohn’s disease, intravenous infusions of infliximab 5 mg/kg administered at 0, 2 and 6 weeks are recommended. Currently, no formal dosage recommendations are available for the administration of infliximab in patients with rheumatoid arthritis. In clinical trials in patients with refractory rheumatoid arthritis, the most effective doses of infliximab were 3 and 10 mg/kg, and clinical responses were maintained when infusions of infliximab were administered every 4 or 8 weeks.

Because some infliximab recipients with Crohn’s disease or rheumatoid arthritis have developed anti-dsDNA antibodies, hypersensitivity-type reactions or anti-infliximab antibodies, infliximab should be used with caution in patients with pre-existing anti-dsDNA antibody titres and in those who have previously received mouse or mouse-human monoclonal antibodies.

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Onrust, S.V., Lamb, H.M. Infliximab. BioDrugs 10, 397–422 (1998). https://doi.org/10.2165/00063030-199810050-00006

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