Crohn’s disease is a chronic relapsing form of inflammatory bowel disease and is characterized by inflammation of the gastrointestinal tract.1 It is estimated that 1.4 million persons in the United States and 2.2 million persons in Europe have inflammatory bowel disease.2 The most recent and advanced approach to the treatment of Crohn’s disease is biologic therapy designed to neutralize the proinflammatory effects of the cytokine tumor necrosis factor (TNF)-alpha.3
In addition to infliximab, the other anti-TNFs approved by the US Food and Drug Administration (FDA) for the treatment of Crohn’s disease include adalimumab and certolizumab pegol.4,5 The focus of the current study, however, is on infliximab, which has been shown to be an effective treatment for Crohn’s disease.6-8
According to the FDA’s approved indication of infliximab for Crohn’s disease, infliximab induction consists of 5-mg/kg infusions at weeks 0, 2, and 6, followed by continued 5-mg/kg infusions every 8 weeks, with the option to escalate the dosing to 10 mg/kg on the same infusion schedule.9 As discussed in several reviews, dose escalation of infliximab has been reported in patients with Crohn’s disease.10,11
The dose escalation of infliximab has been defined as either an increase in dosage or a decrease in the dosing interval,12,13 because either approach results in an increase in the amount of infliximab that is infused during a period of multiple infusions. Studies have demonstrated the safety14 and the efficacy12 of increased infliximab doses (ie, >5 mg/kg every 8 weeks), and each method is likely to be equally effective15; however, for convenience, patients may prefer increased dosages versus decreased dosing intervals.16
Various studies indicate that increasing the dose of infliximab is a safe and cost-effective treatment pathway for patients with Crohn’s disease.17,18 Infliximab has been shown, in a recent cost analysis, to be the most cost-effective biologic for patients with Crohn’s disease who do not respond to standard therapy,17 and increasing its dose may actually result in more quality-adjusted life-years than switching to another biologic.18 Furthermore, switching from infliximab to adalimumab could result in the loss of tolerance and efficacy,19 which suggests that increasing the dose of infliximab to an effective level may be the more successful approach to treatment, especially in chronic diseases such as Crohn’s disease.
Conflicting results have been reported on the rate of infliximab dose escalation. Gisbert and Panés stated that the annual risk for the loss of infliximab response that requires dose escalation is 13% per patient-year,11 a rate which Chao and Mulani have raised some doubt about.20 Several investigations have demonstrated the rate of loss of response requiring dose escalation to be between 30% and 40%,6,13,21,22 whereas Waters and colleagues reported that 79% of patients who are new users of infliximab maintained a stable 5-mg/kg dose during the first year.23
Understanding the expected rate of dose escalation for medications such as infliximab is critical for controlling costs, managing patient expectations, spurring provider intervention, and optimizing treatment efficacy. Dose escalation will increase ingredient medication costs and may affect the treatment experience of patients. An enhanced overall understanding of the rates of infliximab dose escalation and the characteristics of patients requiring escalation may allow health plans and physicians to begin modeling algorithms that better match patients to therapy and reduce the incidence of treatment failure. Therefore, the goal of the present study was to characterize and to quantify the rate of infliximab dose escalation in a sample of patients with Crohn’s disease.
Patient data were collected retrospectively from administrative claims and from medical charts. The claims data were secured first and were used to identify the gastroenterology providers who may be willing to supply medical charts for review. The Essex Institutional Review Board approved this study.
Medical and Pharmacy Claims Data
A large mid-Atlantic managed care organization participated in this study as the health plan partner and agreed to provide claims data for its population of patients with Crohn’s disease during the calendar years 2006 through 2010. To be included in the data extraction, a member had to have a primary or a secondary diagnosis code for Crohn’s disease (International Classification of Diseases, Ninth Revision, Clinical Modification code 555.X). Three tables comprised the final database—professional, facility, and pharmacy claims. The data from a total of 27,931 unique members with Crohn’s disease were extracted.
Chart Review Data
Professional and facility claims were aggregated by physician tax identification number to identify the providers with the largest panels of patients with Crohn’s disease. Targeted providers were then solicited by telephone for recruitment into the study. Interested sites had to confirm their participation with the health plan partner and their general panel size of patients with Crohn’s disease who were also members of the health plan. All providers were offered an initial incentive of $500 for agreeing to participate in the study, as well as an additional $50 for every chart that was identified as eligible for review. The following inclusion and exclusion criteria were imposed on patient charts:
• A diagnosis of Crohn’s disease between 2006 and 2010
• Treatment with infliximab
• Age ≥18 years
• Absence of any terminal illnesses
• Absence of a thought disorder (eg, schizophrenia, schizotypal)
• Absence of an organic brain disorder and syndromes (eg, head trauma, moderate-to-severe developmental disability with cognitive impairment)
• For female patients, the absence of pregnancy.
To aid in the chart data extraction, an electronic case report form was developed that included fields for demographics, diagnoses, medications, diagnostic tests, surgical procedures, and corresponding dates. Infliximab-specific variables included the dose (mg/kg), weight (kg), administered quantity (mg), and the date of infusion. A total of 5 research staff members comprised the chart review team, with each being trained on the Health Insurance Portability and Accountability Act privacy laws and general research ethics.
As a result of variability in the medical charts composition across practices, inter-rater reliability among chart reviewers was calculated on the initial visit to each provider’s office. Any item disagreements were addressed and were corrected before additional charts were reviewed by the team. Overall, 8 gastroenterology practices and infusion centers in the mid-Atlantic area agreed to participate in the study. Charts were reviewed for a total of 161 patients with Crohn’s disease who were being treated with infliximab.
Given the variances in the number of captured infusions and in the length of their current treatment with infliximab, only patients with at least 4 infusions were retained for the main analysis in the study. Patients were grouped and were compared according to their dosing pattern into the dose-stable or dose-escalation group.
Each patient’s first episode of infliximab care, as it appeared in his or her chart, was examined for dose-escalation episode. Any lapse in therapy of 180 days or longer constituted a second episode of care,13 and such infusions were dropped from the analyses. For individual infusions for which the dose was missing, illegible, or unavailable (ie, total <5%), the dose was computed based on the administered quantity of infliximab and the patient’s weight values. If both the administered quantity and the weight were unavailable in such cases, the dose was coded as missing.
Infliximab dose escalation is typically defined as either an increase in dosing from 5 mg/kg to 10 mg/kg or a decrease in the maintenance interval from every 8 weeks to every 6 weeks.12,13 For the present study, evidence of any infliximab dose ≥7.5 mg/kg or a mean maintenance interval of 42 days or less resulted in the placement of a patient in the dose-escalation group. Maintenance infusions were determined based on physician notes, and, when unavailable, were determined by the pattern of infusion intervals during each patient’s episode of care. The patients who did not meet the dose-escalation criteria were placed in the stable-dose group.
For the complete infliximab sample, descriptive statistics (including means, standard deviations, frequencies, and percentages) were presented for the infliximab treatment-specific outcomes derived from the charts. Next, bivariate analyses were performed comparing stable-dose patients with dose-escalated patients. Chi-square tests of equality of proportions were used for categorical variables, and independent t-tests were used for scale variables. Results
A total of 925 infliximab infusions were captured from 161 patients. A total of 73 (7.9%) infusions were captured during a second episode of care and were dropped from the analyses. Descriptive statistics on the entire sample (N = 161) are listed in Table 1. The mean patient age (in rounded numbers) was 38 ± 13 years, and 75 (47%) patients were male. Within the study period, the patients’ first episode of infliximab care included a mean of 5.3 ± 2.5 infusions (range, 1-8), for a mean length of care of 255 ± 149 days. The mean medication interval during the maintenance phase of treatment was 59 ± 18 days. A total of 25 (15.5%) patients showed a lapse in their infliximab treatment, defined as a gap between any 2 infusions of 180 days. Induction infusions were identified in 27 (16.8%) samples, indicating that the majority of the captured infusion data were during the patients’ maintenance phase of treatment.
Table 2 shows the results from the infliximab-dosing analysis. Overall, 110 patients received at least 4 infusions, but 4 patients had missing dose and interval data, resulting in a total of 106 patients of the 166 patients (ie, 66%) who were qualified for the dosing analysis. Patients in both groups received a mean of 6.7 infusions.
A total of 18 (17%) patients showed evidence of dose escalation. Of the 18 patients, 9 (50%) showed a decrease in maintenance interval, whereas 12 (66.7%) showed an increase in their dosage to either 7.5 mg/kg (N = 4; 22.2%) or to 10 mg/kg (N = 8 [44.4%]). Three patients (16.7%) showed both an increase in dose and a reduction in maintenance interval.
Patients in the infliximab dose-escalation group had a significantly shorter length of therapy (257 vs 333 days, respectively; t = 2.79; P = .006) and were significantly less likely to be male (22% vs 53%, respectively; χ2[1, N = 106] = 5.82; P = .016) compared with the stable-dose patients. The majority of patients in both dose groups were in the maintenance phase of treatment (86.4% vs 77.8%, respectively; χ2[1, N = 106] = 0.86; P = .354).
The aim of the present study was to examine dosing patterns in a sample of patients with Crohn’s disease who were treated with infliximab. Existing reports of infliximab dose-escalation rates vary and complicate the estimates of costs and efficacy. Overall, the rate of infliximab dose escalation observed in the present study was within the lower range of published estimates.10 Studies focused on quantifying and describing the nature of infliximab dose escalation may be useful in the development of successful patient treatment-matching algorithms, which may ultimately help to minimize the amount of time and the expenditure lost from ineffective treatments.
A total of 8 gastroenterology sites were recruited to participate in a chart review study. These sites were targeted by an analysis of Crohn’s disease patient service and pharmacy utilization data; member patient data were provided by a large mid-Atlantic managed care organization. In all, the charts of 161 patients with Crohn’s disease who received infliximab were reviewed. As a whole, the sample appeared to be receiving infliximab treatment in accordance with the FDA-approved prescribing information, with a mean starting dose of 5.29 mg/kg and a mean maintenance interval just more than 8 weeks (59 days).
Of these 161 patients receiving infliximab, 106 patients met the inclusion criteria for the dosing analysis, the majority of whom (85%; N = 90) were in the maintenance phase of treatment. A total of 17% of the patients receiving infliximab showed evidence of dose escalation.
Patients who had dose escalation were more likely to be female and had significantly shorter lengths of therapy compared with the patients in the stable-dose group. These results are consistent with differences in sex that have been reported in patients with Crohn’s disease and the skewing of the complications of Crohn’s disease toward female patients.24,25 There was no difference between the dose-escalation and dose-stable groups with regard to the number of patients showing a lapse in therapy or regarding the proportion of patients who were captured during induction.
Although the rate of dose escalation of infliximab observed in the present study was within the lower range of published estimates, comparison across studies is difficult. Gisbert and Panés found that the risk of infliximab dose escalation was 13% per patient-year, although the authors acknowledge that patient follow-up periods varied markedly across studies.11 Other investigators have reported rates of 1-year infliximab postinduction loss of response requiring dose escalation to be between 30% and 40%.6,13,21,22
The design of the current study was distinct from previous investigations in several ways, including the focus on a single health plan, the 5-year measurement window, and the capture of infusion episodes at various time points over the maintenance phase of treatment. This study did validate previous research showing a greater proportion of increased dosages as opposed to decreased intervals (66.7% vs 50%, respectively) among the dose-escalation population16; however, the level to which physician preferences affect these results remains unknown.
Although medication ingredient costs will certainly increase with dose escalation, compliance with infliximab has already been shown to be associated with reduced emergency department and inpatient hospital utilizations, which are primary concerns to payers and to patients.26
As the SWITCH trial has previously demonstrated, some proportion of patients receiving infliximab will benefit more from persisting with and optimizing their current treatment dose than from switching to another biologic.19 This type of evidence can facilitate the development of management algorithms that maximize the cost-benefit of therapies for the treatment of Crohn’s disease.
A pilot study conducted in southern Ohio focused on the site of care of infliximab demonstrated that the collaborative efforts of the health plan, provider, and specialty pharmacy were able to formulate an intervention that reduced out-of-pocket patient costs and maintained continuity of care.27 Obviously, the first step in the current effort is to better quantify the rate of dose escalation.
It may also be worth reexamining the concept of dose escalation, because many patients who require higher doses of infliximab during the course of treatment may be better described as “dose optimized” if treatment effectiveness is achieved and maintained at the higher dose. This may also serve to remove the negative connotations associated with dose escalation.
A study by Schnitzler and colleagues that examined infliximab interventions that are aimed at keeping the disease under control demonstrated that more than 70% of patients receiving an increased dose or reinduction of infliximab were eventually able to return to the standard 5-mg/kg dose.28 In addition, approximately 60% of patients with both an increased dose and shortened interval were able to return to the standard 5-mg/kg dose and 8-week maintenance interval.28 This evidence suggests that the dose escalation of infliximab may be useful practice in the treatment of disease flares, and that reinitiating the standard dose is possible.
Several studies have previously examined factors to facilitate the maintenance of infliximab dose response; however, further testing is needed. Being a nonsmoker29 and having higher C-reactive protein levels30 may each increase the likelihood of maintained response and remission.
In the present study, being female was associated with dose escalation. Although the implication of this result is presently unclear, it is consistent with other reports of worse disease in female patients.24,25 A previous study found that young age and concomitant immunosuppressive treatment were both predictors of short-term response to infliximab.31 Ultimately, as previously stated, the goal is to successfully identify patients, early in treatment, who may be suitable for infliximab therapy to avoid the high costs associated with and to prevent the prolonged use of ineffective treatment. The formation of antibodies against infliximab is associated with a reduced duration of response to treatment.32 As of the writing of this manuscript, a study that is aimed at predicting nonresponse and loss of response to infliximab at the initial diagnosis is in the recruitment phase.33 In addition, the emerging field of pharmacogenomics has already produced early models for the prediction of infliximab response using genotypic markers.34,35
There are several limitations to the current study. As previously noted, the majority of the patient data extracted from charts did not include induction infusions, making it unfeasible to know how long patients were receiving therapy before the dose escalation. The identification of patients at their initial infusion would have assuaged this confound, but this approach was impractical, because of the need to temporally match patient charts to the claims file, and because of the use of multiple infusion centers by some patients.
In addition, although it was not the goal of the present study, the collection of greater clinical data could have allowed for an examination of the relationship between disease symptoms and dose escalation.
The majority of patient data were retrieved from medical charts, but more than 33% of patient data were restricted to the infusion worksheets within the chart, which was limited specifically to indicators of treatment with infliximab.
Also, the results of the studies that incorporate insurance claims data may only pertain to the insured population and may not apply to uninsured patients.
Finally, the dosing group sample sizes, particularly those of the dose-escalation group (N = 18), were very small, raising concerns of power and the level to which this small sample is representative of the larger population of patients with Crohn’s disease who receive infliximab therapy.
The rate of infliximab dose escalation in the present study was within the lower range of published estimates. Although additional studies utilizing larger sample sizes are needed to validate the current findings, the methodology of using administrative claims to identify sites for medical chart reviews proved to be a useful technique. Overall, the ultimate goal is to develop successful patient treatment-matching algorithms to avoid wasteful spending, to prevent the prolonged use of ineffective treatment, and to identify which cases would be best served by dose optimization versus by switching to an alternate therapeutic medication. The incorporation of patient demographics, treatments, service utilization, and even genetic data is crucial for the advancement of these efforts.
The type of evidence presented in this study is crucial for the development and modification of reimbursement policies for advanced therapeutics, including biologic agents. Specifically, this type of evidence can facilitate the development of management algorithms that maximize the cost-benefit of therapies for the treatment of Crohn’s disease. In an attempt to further reduce waste, managed care organizations may seek to reduce the number of failed trials of expensive therapeutics and begin modeling algorithms that better match patients to a therapy and reduce the probability of treatment failure. The involvement of all stakeholders is crucial to this effort.
Funding for this study was provided by Janssen Scientific Affairs, which did not participate in the management or the analysis of the data.
Author Disclosure Statement
Mr Tkacz received research support from Janssen Scientific Affairs, Dr Lofland is an employee of and has stock in Johnson & Johnson, Dr Vanderpoel is an employee of Janssen Scientific Affairs and has stock in Janssen Scientific Affairs and Johnson & Johnson, and Dr Ruetsch received research support from Janssen Scientific Affairs.
Mr Tkacz is Staff Scientist, Health Analytics, LLC, Columbia, MD; Dr Lofland is Associate Director, HECOR, Janssen Scientific Affairs, Horsham, PA; Dr Vanderpoel is Director, HECOR, Janssen Scientific Affairs, Horsham, PA; Dr Ruetsch is President, Health Analytics, LLC, Columbia, MD.
- Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605. Erratum in: Lancet. 2013;381:204.
- Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504-1517.
- Thomson AB, Gupta M, Freeman HJ. Use of the tumor necrosis factor-blockers for Crohn’s disease. World J Gastroenterol. 2012;18:4823-4854.
- Cimzia (certolizumab pegol) lyophilized powder or solution [prescribing information]. Smyrna, GA: UBC, Inc; November 2012.
- Humira (adalimumab) injection, solution [prescribing information]. North Chicago, IL: Abbott Laboratories; December 2011.
- Hanauer SB, Feagan BG, Lichtenstein GR, et al; for the ACCENT I Study Group. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.
- Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology. 2005;128:862-869.
- Panés J, Gomollón F, Taxonera C, et al. Crohn’s disease: a review of current treatment with a focus on biologics. Drugs. 2007;67:2511-2537.
- US Food and Drug Administration. Infliximab product approval information- licensing action. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm093327.htm. Accessed September 7, 2012.
- Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33:987-995.
- Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760-767.
- Lin KK, Velayos F, Fisher E, Terdiman JP. Durability of infliximab dose intensification in Crohn’s disease. Dig Dis Sci. 2012;57:1013-1019.
- Regueiro M, Siemanowski B, Kip KE, Plevy S. Infliximab dose intensification in Crohn’s disease. Inflamm Bowel Dis. 2007;13:1093-1099.
- Chaparro M, Martínez-Montiel P, Van Domselaar M, et al. Intensification of infliximab therapy in Crohn’s disease: efficacy and safety. J Crohns Colitis. 2012;6:62-67.
- Kopylov U, Mantzaris GJ, Katsanos KH, et al. The efficacy of shortening the dosing interval to once every six weeks in Crohn’s patients losing response to maintenance dose of infliximab. Aliment Pharmacol Ther. 2011;33:349-357.
- Katz L, Gisbert JP, Manoogian B, et al. Doubling the infliximab dose versus halving the infusion intervals in Crohn’s disease patients with loss of response. Inflamm Bowel Dis. 2012;18:2026-2033.
- Tang DH, Armstrong EP, Lee JK. Cost-utility analysis of biologic treatments for moderate-to-severe Crohn’s disease. Pharmacotherapy. 2012;32:515-526.
- Kaplan GG, Hur C, Korzenik J, Sands BE. Infliximab dose escalation vs. initiation of adalimumab for loss of response in Crohn’s disease: a cost-effectiveness analysis. Aliment Pharmacol Ther. 2007;26:1509-1520.
- Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut. 2012;61:229-234.
- Chao J, Mulani P. What is the rate of loss of response to infliximab therapy in Crohn’s disease? Am J Gastroenterol. 2009;104:2353-2354; author reply 2354-2355.
- de Ridder L, Rings EH, Damen GM, et al. Infliximab dependency in pediatric Crohn’s disease: long-term follow-up of an unselected cohort. Inflamm Bowel Dis. 2008;14:353-358.
- Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863-873; quiz 1165-1166.
- Waters H, Vanderpoel J, McKenzie S, et al. Stability of infliximab dosing in inflammatory bowel disease: results from a multicenter US chart review. J Med Econ. 2011;14:397-402.
- Gupta N, Bostrom AG, Kirschner BS, et al. Gender differences in presentation and course of disease in pediatric patients with Crohn disease. Pediatrics. 2007;120: e1418-e1425.
- Wagtmans MJ, Verspaget HW, Lamers CB, van Hogezand RA. Gender-related differences in the clinical course of Crohn’s disease. Am J Gastroenterol. 2001;96:1541-1546.
- Carter CT, Waters HC, Smith DB. Impact of infliximab adherence on Crohn’s disease-related healthcare utilization and inpatient costs. Adv Ther. 2011;28:671-683.
- Johnson R, Freeman EN. Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab. Am Health Drug Benefits. 2011;4(1):39-46.
- Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut. 2009;58:492-500.
- Zorzi F, Zuzzi S, Onali S, et al. Efficacy and safety of infliximab and adalimumab in Crohn’s disease: a single centre study. Aliment Pharmacol Ther. 2012;35:1397-1407.
- Reinisch W, Wang Y, Oddens BJ, Link R. C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I. Aliment Pharmacol Ther. 2012;35:568-576.
- Vermeire S, Louis E, Carbonez A, et al; for the Belgian Group of Infliximab Expanded Access Program in Crohn’s Disease. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol. 2002;97:2357-2363.
- Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601-608.
- ClinicalTrials.gov. Predictors of non-response and loss of response in IBD patients treated with anti-TNF. http://clinicaltrials.gov/ct2/show/NCT01605188. Accessed September 12, 2012.
- Hlavaty T, Ferrante M, Henckaerts L, et al. Predictive model for the outcome of infliximab therapy in Crohn’s disease based on apoptotic pharmacogenetic index and clinical predictors. Inflamm Bowel Dis. 2007;13:372-379.
- Hlavaty T, Pierik M, Henckaerts L, et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2005;22:613-626.