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Infliximab

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

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Summary

Abstract

Infliximab (Remicade®) is a chimeric monoclonal antibody against tumour necrosis factor (TNF)-α that has shown efficacy in Crohn’s disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2 and 6 weeks, followed by administration once every 8 weeks.

Infliximab is effective in the treatment of patients with moderately to severely active Crohn’s disease with an inadequate response to other treatment options or those with fistulising disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFα therapy, requiring cautious use of these agents in high-risk patients.

Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmacoeconomic studies are required to better ascertain the cost effectiveness of infliximab.

Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn’s disease (including fistulising disease) or rheumatoid arthritis (including early disease).

Pharmacological Properties

Infliximab acts by binding to both the soluble and the transmembrane forms of TNFα and antagonising the proinflammatory actions of TNFα. It also downregulates other proinflammatory cytokines in patients with Crohn’s disease or rheumatoid arthritis. In addition, in in vitro studies, infliximab decreased the migration of inflammatory cells to the site of inflammation by reducing levels of chemokines and endothelial adhesion molecules. Importantly, infliximab does not produce a generalised suppression of cellular immune function.

The pharmacokinetics of infliximab are linear within the therapeutic dosage range. The steady-state volume of distribution, clearance, mean residence time and elimination half-life are all dose independent in patients with rheumatoid arthritis or Crohn’s disease. Infliximab has a long elimination half-life (median 8–12 days) and is still detectable in plasma up to 12 weeks after the last dose. However, repeated treatment does not lead to any clinically relevant systemic accumulation. Concomitant administration of methotrexate in patients with rheumatoid arthritis may sustain serum infliximab concentrations for longer. The pharmacokinetic profile in paediatric patients with Crohn’s disease was similar to that in adult patients.

Therapeutic Efficacy

The usual treatment regimen for infliximab in clinical trials involved intravenous administration as a single infusion, followed by subsequent doses 2 and 6 weeks later and then every 8 weeks (or every 4 weeks in one trial) thereafter. Although a broad range of infliximab doses (1–20 mg/kg) was used in these trials, no dose-response relationship was evident and, generally, no significant added benefit was reported when using doses higher than 5 mg/kg in Crohn’s disease and 3 mg/kg in rheumatoid arthritis patients, which are the currently recommended dosages. However, some patients may benefit from increasing the dose up to 10 mg/kg; increasing the frequency of administration to once every 4 weeks may be useful in some rheumatoid arthritis patients. Infliximab treatment induced a rapid onset of clinical response both in Crohn’s disease (within 2 weeks) and rheumatoid arthritis (48 hours) patients.

In randomised, double-blind trials, single infusions of infliximab (dose range 5–20 mg/kg) were effective in the induction of response in patients with moderately to severely active Crohn’s disease. In addition, repeated treatment with infliximab 5 or 10 mg/kg during longer-term therapy (54 weeks) sustained the clinical remission achieved with single infusions. Clinical response was accompanied by endoscopic evidence of mucosal healing. Infliximab treatment was also associated with significant improvements in the health-related quality of life (HR-QOL) of patients. Similarly, in patients with fistulising disease, repeated treatment (54 weeks) with infliximab 5 mg/kg was effective in maintaining remission in patients who had responded to an initial infusion. Sustained closure and healing of fistulas was seen in these patients.

Limited data available from double-blind and noncomparative trials in paediatric patients with Crohn’s disease with or without fistulas indicate that single infusions of infliximab were effective in reducing disease activity and that repeated treatment may be effective in producing a clinical response or inducing and maintaining remission.

In a randomised, double-blind (54-week, followed by 54-week unblinded extension) trial in patients with active, methotrexate-refractory rheumatoid arthritis, infliximab (3 or 10 mg/kg) plus methotrexate was superior to methotrexate plus placebo in producing clinical response and attenuating radiographic progression of the disease. There was also a significant improvement in functional status and HR-QOL. Infliximab 3 or 6 mg/kg for 54 weeks, in combination with methotrexate, was also significantly more effective than methotrexate plus placebo in 1004 patients with early (≤3 year), methotrexate-naive rheumatoid arthritis with respect to improvements in signs and symptoms, disease progression, physical function and HR-QOL. The results of two smaller, double-blind, placebo-controlled studies using more sensitive imaging techniques (e.g. magnetic resonance imaging) have supported the notion that treatment with infliximab retarded disease progression in patients with early rheumatoid arthritis.

Tolerability

Infliximab was generally well tolerated for up to 102 weeks in clinical trials in patients with Crohn’s disease or rheumatoid arthritis, with the incidence of serious adverse events being generally similar in infliximab and placebo recipients. Infusion-related reactions are the most frequent adverse reactions to infliximab therapy. Although there appears to be no need for regular laboratory monitoring of infliximab therapy, patient monitoring, cautious use and/or discontinuation are recommended for other potentially serious adverse events possibly associated with TNFα antagonists as a class. These include tuberculosis and other serious infections, malignancy (particularly lymphoma), heart failure and CNS demyelination disorders.

Pharmacoeconomic Issues

Infliximab, like other biological agents, is a costly drug and generally more expensive than other available therapies for Crohn’ s disease. However, preliminary data have shown that it may be cost saving as a single-infusion induction regimen and cost effective as maintenance treatment of moderately to severely active Crohn’s disease. Moreover, pharmacoeconomic analyses have demonstrated that the incremental cost of infliximab maintenance therapy might be substantially offset by a reduction in other costs, such as those related to hospitalisation or surgery. In modelled cost-utility analyses, infliximab plus methotrexate was generally associated with acceptable incremental cost-effectiveness ratios relative to methotrexate monotherapy in patients with refractory rheumatoid arthritis. The cost effectiveness of infliximab in early disease has not been evaluated, but is expected to be improved when reductions with early treatment in the costs associated with the long-term disease outcomes are considered. Nevertheless, more robust pharmacoeconomic studies are needed before any conclusion may be drawn regarding the relative cost effectiveness of infliximab.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    M. Asif A. Siddiqui & Lesley J. Scott

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  1. M. Asif A. Siddiqui
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Correspondence to M. Asif A. Siddiqui.

Additional information

Various sections of the manuscript reviewed by: H. Asakura, International Medical Information Center, Shinjukuku, Tokyo, Japan; F. Breedveld, Department of Rheumatology, Leiden University Hospital, Leiden, The Netherlands; T. Ikawa, Osaka Rehabilitation Hospital, Osaka, Japan; P.J. Rutgeerts, Gastroenterology Section, Faculty of Medicine, University of Leuven, Leuven, Belgium; S. Schreiber, Department of General Internal Medicine and Institute for Clinical Molecular Biology, Christian-Albrechts-University, Schittenhelmstrasse, Kiel, Germany; W.S. Selby, Department of Medicine, University of Sydney, Sydney, Australia; G. Valesini, Division of Rheumatology, La Sapienza University, Rome, Italy.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘infliximab’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE and EMBASE search terms were ‘infliximab’ and (‘Crohn disease’ or ‘rheumatoid arthritis’). AdisBase search terms were (‘infliximab’ or ‘anti-tnf-monoclonal-antibody’) and (‘Crohn’s disease’ or ‘rheumatoid arthritis’). Searches were last updated 19 September 2005.

Selection: Studies in patients with Crohn’s disease or rheumatoid arthritis who received intravenous infliximab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Infliximab, Crohn’s disease, rheumatoid arthritis, pharmacodynamics, pharmacokinetics, therapeutic use, pharmacoeconomics, tolerability.

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Siddiqui, M.A.A., Scott, L.J. Infliximab. Drugs 65, 2179–2208 (2005). https://doi.org/10.2165/00003495-200565150-00014

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