Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab

Authors

  • Klaus Bendtzen,

    Corresponding author
    1. Institute for Inflammation Research, Rigshospitalet National University Hospital, and BioMonitor ApS, Copenhagen, Denmark
    • Institute for Inflammation Research IIR7521, Rigshospitalet National University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
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    • Dr. Bendtzen has received consulting fees and/or honoraria (less than $10,000) from Wyeth Denmark and Schering-Plough Denmark and owns stock in BioMonitor ApS. Dr. Geborek has received consulting fees and/or honoraria (less than $10,000) from Wyeth Sweden, Schering-Plough Sweden, and Abbott, Sweden.

  • Pierre Geborek,

    1. Lund University Hospital, Lund, Sweden
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    • Dr. Bendtzen has received consulting fees and/or honoraria (less than $10,000) from Wyeth Denmark and Schering-Plough Denmark and owns stock in BioMonitor ApS. Dr. Geborek has received consulting fees and/or honoraria (less than $10,000) from Wyeth Sweden, Schering-Plough Sweden, and Abbott, Sweden.

  • Morten Svenson,

    1. Institute for Inflammation Research, Rigshospitalet National University Hospital, and BioMonitor ApS, Copenhagen, Denmark
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  • Lotta Larsson,

    1. Lund University Hospital, Lund, Sweden
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  • Meliha C. Kapetanovic,

    1. Lund University Hospital, Lund, Sweden
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  • Tore Saxne

    1. Lund University Hospital, Lund, Sweden
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  • This publication reflects only the authors' views; the European Community is not liable for any use that may be made of the information herein.

Abstract

Objective

Infliximab, an anti–tumor necrosis factor α (anti-TNFα) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability.

Methods

To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-infliximab antibody, and a functional one for measurement of TNFα binding due to infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed.

Results

Trough serum infliximab levels after the first 2 intravenous infusions of infliximab at 3 mg/kg varied considerably between patients (range 0–22 μg/ml). At this stage, only 13% of the patients were anti-infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of infliximab. Indeed, low infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of infliximab at the early stage of treatment and later development of anti-infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect.

Conclusion

Development of anti-infliximab antibodies, heralded by low preinfusion serum infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate infliximab therapy.

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