IBD: Measuring Infliximab and Human Anti-Chimeric Antibodies
IBD: Measuring Infliximab and Human Anti-Chimeric Antibodies
Objectives: Human anti-chimeric antibodies (HACAs) and subtherapeutic infliximab concentrations are associated with decreased duration of response. We evaluated the clinical utility of measuring HACA and infliximab concentrations.
Methods: The medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured were reviewed to determine whether the result affected clinical management.
Results: One hundred fifty-five patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). HACAs were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of 17%. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86% of patients whereas changing to another anti-TNF agent had a response of 33%. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76% of the time and had no evidence of active inflammation by endoscopic/radiographic assessment 62% of the time.
Conclusions: Measurement of HACA and infliximab concentration impacts management and is clinically useful. Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent.
Infliximab (Remicade, Centocor, Horsham, PA) is a chimeric monoclonal IgG1 antibody against tumor necrosis factor (TNF) that is effective for the treatment of Crohn's disease and ulcerative colitis. Treatment with infliximab can result in immunogenicity and the formation of human anti-chimeric antibodies (HACAs), also known as antibodies to infliximab. The incidence of HACAs has been shown to be as high as 37–61% in patients receiving episodic infliximab. Scheduled infliximab therapy decreases the incidence of HACAs to 6–16%. Concomitant immunosuppressive therapy also decreases the formation of HACAs, but this may only be important in those receiving episodic therapy. Immunogenicity to infliximab is not a unique phenomenon related to its chimeric structure, as treatment with any exogenous protein can lead to the development of antibodies. In fact, similar rates of antibodies have been reported in patients treated with adalimumab and certolizumab pegol.
Some have questioned whether the presence of antibodies to anti-TNF agents directly correlates with decreased efficacy. Comparisons can be drawn from the rheumatoid arthritis literature. Several groups have shown that the development of antibodies to infliximab and adalimumab correlates with not only decreased drug concentrations but also decreased clinical response. In inflammatory bowel disease (IBD), studies have shown that there is a shorter duration of clinical response in patients with detectable HACA concentrations. A subgroup analysis of a larger randomized controlled trial showed a trend toward decreased remission in patients who underwent episodic therapy and had detectable antibodies.
The clinical efficacy of infliximab may be dependent not only on the absence of HACA but also on infliximab concentrations. In a study of Crohn's disease patients on scheduled maintenance infliximab therapy, patients with detectable trough concentrations had a higher rate of clinical remission, a lower serum C-reactive protein (CRP) concentration, and a higher rate of endoscopic improvement. HACAs have also been associated with an increased risk of infusion reactions, which in turn can also lead to decreased infliximab concentrations.
Although the associations between clinical efficacy and infusion reactions with infliximab concentrations and HACA status have been described, the clinical utility of these tests in routine practice remains unclear. The clinical indications for measuring HACA and infliximab concentrations in patients with IBD have not been previously assessed. Furthermore, the optimal patient management based on the results of testing has not been clearly elucidated. We retrospectively studied the utility of measuring HACA and infliximab concentrations and compared subsequent clinical management and response. We propose a treatment algorithm based on the results of testing.
Abstract and Introduction
Abstract
Objectives: Human anti-chimeric antibodies (HACAs) and subtherapeutic infliximab concentrations are associated with decreased duration of response. We evaluated the clinical utility of measuring HACA and infliximab concentrations.
Methods: The medical records of patients with inflammatory bowel disease (IBD) who had HACA and infliximab concentrations measured were reviewed to determine whether the result affected clinical management.
Results: One hundred fifty-five patients had HACA and infliximab concentrations measured. The main indications for testing were loss of response to infliximab (49%), partial response after initiation of infliximab (22%), and possible autoimmune/delayed hypersensitivity reaction (10%). HACAs were identified in 35 patients (23%) and therapeutic infliximab concentrations in 51 patients (33%). Of 177 tests assessed, the results impacted treatment decisions in 73%. In HACA-positive patients, change to another anti-tumor necrosis factor (TNF) agent was associated with a complete or partial response in 92% of patients, whereas dose escalation had a response of 17%. In patients with subtherapeutic infliximab concentrations, dose escalation was associated with complete or partial clinical response in 86% of patients whereas changing to another anti-TNF agent had a response of 33%. Patients with clinical symptoms and therapeutic infliximab concentrations were continued at the same dose 76% of the time and had no evidence of active inflammation by endoscopic/radiographic assessment 62% of the time.
Conclusions: Measurement of HACA and infliximab concentration impacts management and is clinically useful. Increasing the infliximab dose in patients who have HACAs is ineffective, whereas in patients with subtherapeutic infliximab concentrations, this strategy may be a good alternative to changing to another anti-TNF agent.
Introduction
Infliximab (Remicade, Centocor, Horsham, PA) is a chimeric monoclonal IgG1 antibody against tumor necrosis factor (TNF) that is effective for the treatment of Crohn's disease and ulcerative colitis. Treatment with infliximab can result in immunogenicity and the formation of human anti-chimeric antibodies (HACAs), also known as antibodies to infliximab. The incidence of HACAs has been shown to be as high as 37–61% in patients receiving episodic infliximab. Scheduled infliximab therapy decreases the incidence of HACAs to 6–16%. Concomitant immunosuppressive therapy also decreases the formation of HACAs, but this may only be important in those receiving episodic therapy. Immunogenicity to infliximab is not a unique phenomenon related to its chimeric structure, as treatment with any exogenous protein can lead to the development of antibodies. In fact, similar rates of antibodies have been reported in patients treated with adalimumab and certolizumab pegol.
Some have questioned whether the presence of antibodies to anti-TNF agents directly correlates with decreased efficacy. Comparisons can be drawn from the rheumatoid arthritis literature. Several groups have shown that the development of antibodies to infliximab and adalimumab correlates with not only decreased drug concentrations but also decreased clinical response. In inflammatory bowel disease (IBD), studies have shown that there is a shorter duration of clinical response in patients with detectable HACA concentrations. A subgroup analysis of a larger randomized controlled trial showed a trend toward decreased remission in patients who underwent episodic therapy and had detectable antibodies.
The clinical efficacy of infliximab may be dependent not only on the absence of HACA but also on infliximab concentrations. In a study of Crohn's disease patients on scheduled maintenance infliximab therapy, patients with detectable trough concentrations had a higher rate of clinical remission, a lower serum C-reactive protein (CRP) concentration, and a higher rate of endoscopic improvement. HACAs have also been associated with an increased risk of infusion reactions, which in turn can also lead to decreased infliximab concentrations.
Although the associations between clinical efficacy and infusion reactions with infliximab concentrations and HACA status have been described, the clinical utility of these tests in routine practice remains unclear. The clinical indications for measuring HACA and infliximab concentrations in patients with IBD have not been previously assessed. Furthermore, the optimal patient management based on the results of testing has not been clearly elucidated. We retrospectively studied the utility of measuring HACA and infliximab concentrations and compared subsequent clinical management and response. We propose a treatment algorithm based on the results of testing.
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