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Introduction <p>The development of anti-drug antibodies against tumor necrosis factor inhibitors, such as infliximab and adalimumab, is a major cause of therapeutic failure in patients with immune-mediated inflammatory diseases (IMIDs). However, immunogenicity responses are heterogeneous, and drug exposure can be restored in selected cases through individualized management.</p> Aim <p>To evaluate the clinical management and pharmacokinetic (PK) outcomes of immunogenicity in IMIDs treated with infliximab or adalimumab, by assessing its prevalence and phenotypes, associated factors, and the effectiveness of therapeutic interventions in reversing its PK impact.</p> Method <p>This retrospective cohort study included 997 patients treated with infliximab (n = 278) or adalimumab (n = 719). Immunogenicity was defined by detectable anti-drug antibodies and/or undetectable serum drug levels. Patients were stratified into three phenotypes based on anti-drug antibody titers and serum concentrations. Therapeutic drug monitoring guided clinical decision-making in cases of suspected treatment failure, immunogenicity, or subtherapeutic exposure, in accordance with institutional protocols. PK reversal was defined as the reappearance of detectable drug levels after intervention without switching therapy.</p> Results <p>Immunogenicity was identified in 240 patients (24.1%), more frequently among those treated with infliximab (28.4%) than with adalimumab (22.4%; <i>p</i> = 0.064). Multivariable analysis confirmed treatment with infliximab (OR: 1.43; 95% CI: 1.04–1.97) and prior immunogenicity (OR: 3.69; 95% CI: 1.50–9.11) as risk factors, while concomitant immunosuppressants were protective (OR: 0.62; 95% CI: 0.45–0.84). Among 77 patients managed actively, PK reversal was achieved in 76.7%. The rate of reversal was higher with adalimumab (80.0%) than with infliximab (62.5%; <i>p</i> = 0.039), and in patients with undetectable antibodies and low drug concentrations (Group 3) than in those with low-level antibodies (77.5% vs 50.0%; <i>p</i> = 0.024). Dose intensification and supervised administration were effective in achieving PK reversal (79.2% and 70.8%, respectively). Median serum drug concentrations increased significantly after intervention in both groups (<i>p</i> &lt; 0.001).</p> Conclusion <p>Therapeutic drug monitoring–guided interventions tailored to immunogenicity phenotype can restore drug exposure in a substantial proportion of patients treated with tumor necrosis factor inhibitors. Recognition of reversible immunogenicity is essential for optimizing long-term therapeutic success and avoiding premature drug discontinuation. </p>

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Immunogenicity phenotypes and reversal of pharmacokinetic impact in anti-TNF–treated immune-mediated diseases: a real-world study

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Rocío Guzmán-Laiz,
  • Carles Iniesta-Navalón,
  • Manuel Ríos-Saorín,
  • Lorena Rentero-Redondo,
  • Irene Garcia-Masegosa,
  • Rebeca Añez-Castaño,
  • Elena Urbieta-Sanz

摘要

Introduction

The development of anti-drug antibodies against tumor necrosis factor inhibitors, such as infliximab and adalimumab, is a major cause of therapeutic failure in patients with immune-mediated inflammatory diseases (IMIDs). However, immunogenicity responses are heterogeneous, and drug exposure can be restored in selected cases through individualized management.

Aim

To evaluate the clinical management and pharmacokinetic (PK) outcomes of immunogenicity in IMIDs treated with infliximab or adalimumab, by assessing its prevalence and phenotypes, associated factors, and the effectiveness of therapeutic interventions in reversing its PK impact.

Method

This retrospective cohort study included 997 patients treated with infliximab (n = 278) or adalimumab (n = 719). Immunogenicity was defined by detectable anti-drug antibodies and/or undetectable serum drug levels. Patients were stratified into three phenotypes based on anti-drug antibody titers and serum concentrations. Therapeutic drug monitoring guided clinical decision-making in cases of suspected treatment failure, immunogenicity, or subtherapeutic exposure, in accordance with institutional protocols. PK reversal was defined as the reappearance of detectable drug levels after intervention without switching therapy.

Results

Immunogenicity was identified in 240 patients (24.1%), more frequently among those treated with infliximab (28.4%) than with adalimumab (22.4%; p = 0.064). Multivariable analysis confirmed treatment with infliximab (OR: 1.43; 95% CI: 1.04–1.97) and prior immunogenicity (OR: 3.69; 95% CI: 1.50–9.11) as risk factors, while concomitant immunosuppressants were protective (OR: 0.62; 95% CI: 0.45–0.84). Among 77 patients managed actively, PK reversal was achieved in 76.7%. The rate of reversal was higher with adalimumab (80.0%) than with infliximab (62.5%; p = 0.039), and in patients with undetectable antibodies and low drug concentrations (Group 3) than in those with low-level antibodies (77.5% vs 50.0%; p = 0.024). Dose intensification and supervised administration were effective in achieving PK reversal (79.2% and 70.8%, respectively). Median serum drug concentrations increased significantly after intervention in both groups (p < 0.001).

Conclusion

Therapeutic drug monitoring–guided interventions tailored to immunogenicity phenotype can restore drug exposure in a substantial proportion of patients treated with tumor necrosis factor inhibitors. Recognition of reversible immunogenicity is essential for optimizing long-term therapeutic success and avoiding premature drug discontinuation.