Infliximab (Remicade®) is a chimeric (mouse-human) antibody directed against human tumor necrosis factor (TNF). Inflixmab is FDA-approved for the treatment of rheumatoid arthritis and Crohns disease. Treatment with infliximab can result in the formation of antibodies against infliximab. The presence of these antibodies has been associated with infusion reactions in 7-19%of patients, and may also shorten the duration of the effect of infliximab when given repeatedly. Baert et al (New Engl J Med 348:601, 2003) investigated the relation between antibodies to infliximab and postinfusion infliximab concentrations, the clinical effect of infliximab, and infusion-related side effects in patients with Crohns disease.
Methods:
The study cohort consisted of 125 consecutive patients with Crohns disease who were treated with infliximab 5 mg/kg. Patients with active luminal disease received a single dose, and patients with draining fistulas received a series of 3 infusions at weeks 0, 2 and 6. For patients who responded, therapy was repeated if a relapse of disease occurred. Concomitant immunosuppressive medications and corticosteroids were allowed as indicated to control bowel disease. Immunosuppressives included azathioprine, methotrexate (MTX) and mercaptopurine. Patients were evaluated before and after each infusion.
Concentrations of infliximab and antibodies to infliximab were assayed at each visit and before each infusion by commercial ELISA. Concentrations of infliximab below 1.4 g/ml were considered negative. The cutoff value for anti-infliximab antibodies was 1.69 g/ml. Because anti-infliximab antibodies may not be measurable in the presence of infliximab, concentrations of anti-infliximab antibody were categorized as follows: 1) negative if < 1.69 g/ml and [infliximab]<1.4 g/ml; indeterminate if < 1.69 g/ml but [infliximab] > 1.40 g/ml; and, positive if > 1.69 g/ml and [infliximab] < 1.40 g/ml.
Results:
An average of 3.9 infusions (range, 1-17) per patient was administered over an average of 10 months. Antibodies against infliximab were detected in 61% of patients. An antibody concentration of > 8.0 g/ml before an infusion predicted a shorter duration of response (35 days, compared to 71 days in patients with antibody concentrations < 8.0 g/ml, p < .001), and a higher risk of infusion reactions (relative risk 2.4, p < .001). Infliximab concentrations were significantly lower at 4 weeks in patients with infusion reactions compared to those without (median, 1.2 vs 14.1 g/ml, p < .001). Patients with infusions reactions had a shorter duration of response than those without infusion reactions (38.5 vs 65 dys, p < .001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies (p < .001) and high concentrations of infliximab 4 weeks after an infusion (p < .001).
Conclusion:
Patients who develop anti-infliximab antibodies are at higher risk for developing infusion reactions, and a reduced duration of response, to treatment with infliximab. Co-treatment with an immunosuppressive drug(s) can suppress the antibody response and prolong the clinical response to infliximab.
Editorial Comments:
In clinical trials in rheumatoid arthritis (RA), infliximab treatment in the absence of methotrexate (MTX) was associated with a higher incidence of anti-infliximab antibodies and a shorter duration of action compared to co-treatment with infliximab and MTX. Consequently, the FDA guidelines for infliximab use in RA recommend co-treatment with MTX. Early treatment studies of infliximab in Crohns disease utilized a single dose and the issue of antibodies was initially not as concerning. Furthermore, some argued that propensity for developing anti-infliximab antibodies might be more likely in diseases like RA that are characterized by numerous (auto)antibodies.
The findings in this study in patients with Crohns disease, however, replicate those found in RA. Antibodies to infliximab were common in the absence of immunosuppressives, and their presence was associated with a shorter duration of drug effect and more infusion reactions. It seems likely that remicade therapy in Crohns disease will evolve towards combination therapy (remicade + immunosuppressive drug), as in RA, in patients requiring chronic treatment.
Infliximab has also been proven to be beneficial for the treatment of ankylosing spondylitis and psoriasis. It remains to be seen whether these patients will also develop anti-infliximab antibodies, but it certainly seems likely.
