Infliximab

Infliximab-Related Infusion Reactions: Systematic Review

Objective: Administration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur. Methods: We conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients. Results: We examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies. Conclusions: There is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.

Clinical Pharmacokinetics and Pharmacodynamics of Infliximab in the Treatment of Inflammatory Bowel Disease

Infliximab was the first monoclonal antibody to be approved for the treatment of pediatric and adult patients with moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC). It has been shown to induce and maintain both clinical remission and mucosal healing in pediatric and adult patients with inflammatory bowel disease (IBD) who are unresponsive or refractory to conventional therapies. The administration of infliximab is weight-based and the drug is administered intravenously. The volume of distribution of infliximab is low and at steady state ranges from 4.5 to 6 L. Therapeutic monoclonal antibodies, such as immunoglobulins, are cleared from the circulation primarily by catabolism. Median infliximab half-life is approximately 14 days. Infliximab concentration-time data in patients with CD and UC have been shown to be highly variable within an individual patient over time and between individuals by multiple population pharmacokinetic models. Covariates that have been identified to account for a part of the observed inter- and intra-individual variability in clearance are the presence of antidrug antibodies, use of concomitant immunomodulators, degree of systemic inflammation, serum albumin concentration, and body weight, which can affect the pharmacodynamic response. This article provides a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of infliximab, as well as the role of therapeutic drug monitoring in the treatment of IBD.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial

Importance: Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy.
Objective: To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM.
Design, setting, and participants: Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020.
Interventions: Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230).
Main outcome and measures: The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period.
Results: Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively.
Conclusions and relevance: Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach.
Trial registration: ClinicalTrials.gov Identifier: NCT03074656.

Infliximab and biosimilar infliximab in psoriasis: efficacy, loss of efficacy, and adverse events

Psoriasis is a chronic immune-mediated skin disease affecting multiple systems, and tumor necrosis factor-α (TNF-α) plays a significant role in the initiation and progression of the disease process. Psoriasis has a high prevalence rate in the Western world, especially in the USA and Australia; in China, although the prevalence rate is much lower, there is still a large number of patients suffering from psoriasis and its comorbidities. As TNF-α is thought to be crucial in the pathogenesis of psoriasis, specific therapy blocking TNF-α may be beneficial in the treatment of this disease. Infliximab, a murine-human monoclonal antibody, is highly efficacious in the treatment of moderate-to-severe psoriasis, with better skin clearance and faster onset of action than topical medications such as methotrexate, narrow-band ultraviolet B, and calcipotriol. Lack of adherence to infliximab therapy is mainly due to loss of response (LOR) over time and adverse events, particularly because infusion reactions are usually encountered. Anti-infliximab antibody is thought to be responsible for the LOR and infusion reactions. However, the mechanism underlying the formation of anti-infliximab antibody and its side effects remains unclear. Further studies identifying patients at risk for LOR will probably help clinicians to select the right patients for anti-TNF-α therapy and to increase the durability of the treatment. This review discusses the efficacy of infliximab as demonstrated by various clinical trials, LOR to infliximab, combatting LOR, as well as the adverse events usually faced during the use of infliximab therapy and the infliximab biosimilar Remsima^?. We hope that we can discover a better way to use infliximab in the therapy of psoriasis from the current research data.

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial

Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear.
Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM.
Design, setting, and participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019.
Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204).
Main outcomes and measures: The primary end point was clinical remission at week 30.
Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively.
Conclusions and relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates.
Trial registration: ClinicalTrials.gov Identifier: NCT03074656.