Infliximab vs. Adalimumab for Crohn's disease: authors' reply

Abstract

Sirs, We agree that our cost-effectiveness analysis needs to be interpreted cautiously as we clearly state in the discussion and method sections of the article.1 As with all models, model inputs are limited by potential bias and assumptions; this was the case with our model because randomized controlled trial level evidence for infliximab dose intensification and adalimumab efficacy in infliximab secondary nonresponders was lacking at the time the model was created. With respect to the three flaws cited by Mulani and Chao:2 Response rate to infliximab dosage escalation was overestimated: The 90% response rate to dose intensification was derived from Rutgeerts’ paper comparing episodic to scheduled therapy where among patients who lost response while in the 5 mg/kg scheduled treatment group, approximately 90% re-established response after dose escalation to 10 mg/kg.3 The time to response to dose escalation is variable; however, we assumed response to occur at 4 weeks because those with a significantly longer nonresponse time (e.g. several months) would have been withdrawn from the clinical trial. One-year remission and response rates for initial responders in the infliximab arm were overestimated: In both the methods and discussion sections we clearly described the limitations of this estimate. The exact 1-year remission and response rates for dose intensification of infliximab are not clearly reported in the literature. While our response rates were based on estimates from infliximab naïve Crohn’s patients who were treated with 10 mg/kg for one year, open-label experience suggests that we may have underestimated response as up to three-fourth of Crohn’s patients who underwent dose intensification have been shown to sustain their response in the long term.4 Remission and response rates at 1 year following increase of adalimumab 40 mg from every other week to weekly were underestimated: Our remission rate for dose escalation (17%) used the entire cohort from CLASSIC II (randomized and open-label) as the denominator. The authors of the letter suggest that a remission rate of 42% would have been more appropriate because the rate is derived only from the subset of CLASSIC II cohort of patients who were dose escalated during the open-label phase.5 Although this is a reasonable assumption, the true estimate is likely in between because CLASSIC II represented infliximab-naïve rather than secondary nonresponders. Data are currently not published regarding long-term response rates for adalimumab dose escalation in infliximab secondary nonresponders. Overall, we feel that the message of our study still holds true: among Crohn’s disease patients who lose response to 5 mg/kg of infliximab, dose intensification compared to immediate adalimumab results in a marginal increase in quality-adjusted life years; however, this comes at considerable costs. Declaration of personal interests: B. Sands: Abbot Laboratories – Research grants, honoraria for speaking, scientific advisory board; Centocor – Research grants, honoraria for speaking, scientific advisory board; UCB Pharma – honoraria for speaking, scientific advisory board; Bristol-Myers Squibb – research grants, scientific advisory board; Elan Pharmaceuticals – Research grants, honoraria for speaking, scientific advisory board; Prometheus Laboratories – Research grants, scientific advisory board; Otsuka America Pharmaceuticals Inc. – Research grants, honoraria for speaking, scientific advisory board. J. Korzenik: Consulting and lecture fees from Proctor & Gamble, Shire Pharmaceuticals, Isis Pharmaceuticals, Cytokine Pharmasciences, Berlex and Centocor and research support from Danisco. A US patent entitled “Stimulating Neutrophil Function to Treat Inflammatory Bowel Disease (6500418)” was issued December 31, 2002: J. Korzenik is one of the inventors. The patent is owned by Washington University and licensed by Berlex Laboratories. G. Kaplan: Honoraria for scientific advisory board from UCB Pharma, Abbot Laboratories, and Schering Plough. C. Hur: none to declare. Declaration of funding interests: None.