Stability of infliximab dosing in inflammatory bowel disease: results from a multicenter US chart review

Abstract

Objective:

Infliximab dosing for inflammatory bowel disease (IBD) is based on patient weight and treatment response. Understanding dosing patterns may provide insight into treatment response and predictability of treatment cost. The purpose of this medical record review was to assess dose and dose frequency of infliximab maintenance treatment in patients with IBD using patient chart data.

Methods:

A retrospective chart review was conducted at 14 community gastroenterology clinics (GI clinics). Patients were aged ≥18 years, diagnosed with Crohn’s disease (CD) or ulcerative colitis (UC), and had a first infliximab administration (index date) between January 1, 2005 and September 30, 2007. At least 24 months of continuous data availability were required with dosing data collected for 12 months after initiation of infliximab therapy. Patients with biologic use and/or participation in an IBD clinical trial within 12 months before the index date were excluded.

Results:

Charts from 182 CD patients and 86 UC patients were analyzed. About half of the patients were female. Over 90% of patients initiated treatment with infliximab 5 mg/kg. Among CD patients and UC patients, respectively, 79% and 61% continued receiving this dose for maintenance therapy at stable intervals.

Limitations:

This retrospective descriptive study is limited by the type and quantity of information available in patient charts from 14 GI clinics during the first year of infliximab treatment. Further, non-anti-tumor necrosis factor medication data were intermittently collected in some charts and, therefore, did not allow for analysis.

Conclusions:

Weight-based dosing and, presumably, patient response enabled providers to find the effective infliximab dose for IBD patients. The maintenance dose and administration frequency remained stable during the initial year.

Key words::

• Anti-tumor necrosis factor therapy
• Crohn’s disease
• Inflammatory bowel disease
• Infliximab
• Ulcerative colitis

Introduction

An estimated 1 million people in the United States (US) are affected by inflammatory bowel disease (IBD), with 30,000 new cases developing every year1. The chronic condition of IBD may develop at any age, although the peak onset is 15–30 years1. IBD occurs with approximately equal frequency in men and women1.

IBD is an idiopathic condition postulated to involve an immune reaction to the gastrointestinal (GI) tract2. The two major conditions that characterize IBD are Crohn’s disease (CD), defined as a chronic relapsing and remitting disease associated with inflammation and damage of the GI tract that may affect any segment from the mouth to the anus, and ulcerative colitis (UC), characterized as a mucosal inflammatory condition of the rectum and colon2. Both are chronic conditions characterized by fever, abdominal pain, and diarrhea, with intermittent symptom frequency and severity. CD may be accompanied by fistulae and extra-intestinal manifestations (e.g., arthropathy, erythema nodosum). One meta-analysis revealed that CD is associated with a 50% increase in age-adjusted mortality over the general population3. Untreated or inadequately treated, it can also exact a large healthcare burden due to GI-related procedures, emergency room (ER) visits, hospitalizations, and surgery4. Patients with IBD have an increased risk of colorectal cancer5, and recent evidence suggests that patients with IBD may have an elevated risk of endothelial dysfunction and coronary artery disease6.

The goals of IBD therapy are induction and maintenance of remission, which may include symptomatic relief, reduction in rates of complications and surgery, and the maintenance or improvement of quality of life7–9. Traditionally, therapy has included aminosalicylates, glucocorticosteroids, and immunomodulators, including 6-mercaptopurine, azathioprine, and methotrexate. More recently, anti-tumor necrosis factor (anti-TNF) agents such as infliximab, adalimumab, and certolizumab pegol have become important components of treatment. These agents have provided new treatment options for patients with moderate to severe IBD. Infliximab, the first anti-TNF agent approved for IBD, has been shown to be effective for treatment of both CD and UC10–16, while adalimumab17–19 and certolizumab pegol20,21 have demonstrated benefits in patients with CD. For GI-related disorders, infliximab is approved by the US Food and Drug Administration (FDA) for treatment of moderately to severely active luminal CD in adult and pediatric patients, fistulizing CD in adults, and moderately to severely active UC in adults22, whereas adalimumab and certolizumab pegol are indicated only for moderately to severely active luminal CD in adults23,24.

The FDA dosing guideline for infliximab is 5 mg/kg given as an intravenous induction regimen at 0, 2, and 6 weeks, followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for CD (children and adults) and UC22. For adult patients with CD who respond and then lose their response, consideration may be given to treatment with 10 mg/kg²².

While infliximab dose escalation is clinically appropriate and within the FDA dosing parameters for some patients, it results in higher drug costs compared with the 5 mg/kg regimen. Therefore, the stability of dosing (dose and treatment interval) is of interest to certain stakeholders due to its economic implications. Further, although clinical response cannot be definitively determined based on dosing patterns, these patterns may also be generally reflective of treatment response in some cases. Research in other therapeutic areas has shown that stable dosing of a therapy may be indicative of satisfactory effectiveness, whereas dose escalation may be suggestive of suboptimal treatment response25. Thus, given the number of patients receiving treatment and the costs potentially associated with dosing changes (whether reflective of suboptimal treatment response or other factors), real-world dosing patterns and the potential economic and clinical implications represented by these dosing patterns may be an important consideration when characterizing the value of anti-TNF therapy in IBD.

Medication and administration costs can vary widely across the country based on provider contracts, rebates, etc; therefore, these data were not a focus of analysis in the context of this study. In the present study, the dosing patterns of infliximab for initiating and maintaining treatment for patients with CD and UC were examined in an observational setting. This study was conducted using a retrospective chart review from centers across the US.

Patients and methods

A retrospective medical record review was conducted at 14 community gastroenterology practices in the US. The 14 sites were selected to provide national geographic representation and variety of practice sizes and types. Data were collected through a standardized chart review form using a graphic user interface developed in Microsoft Access. Patient charts were de-identified at the study sites using a unique alpha-numeric value for each patient. A participant log sheet was developed and stored at the study site to permit the ability to match the de-identified patient marker (unique for all study participants) to the actual patient chart, allowing for future data validation should the need arise. Data collection was overseen by a healthcare professional with over 20 years of experience, including extensive experience in quality improvement and chart review studies. Chart reviewers were trained by this lead reviewer, and samples of their data collection were verified by the lead reviewer for completeness and accuracy. The lead reviewer was available to the other reviewers to answer questions throughout the data collection process.

Patients were required to be aged ≥18 years, have a documented diagnosis of CD or UC, and have an infliximab index date (date of initiation of treatment) between January 1, 2005 and September 30, 2007. At least 24 months of continuous data availability were required, including at least 12 months before and 12 months after initiation of infliximab therapy. Patients were excluded if they had evidence of biologic use in the 12 months before the infliximab index date or participated in a clinical trial for CD or UC. Patient data were collected for the 12-month period following initiation of infliximab therapy.

Data collected included IBD diagnosis information, age, gender, weight, and IBD-related complications. GI-related healthcare resource utilization (e.g., diagnostic tests, hospitalizations, ER visits, and procedures) was also captured for a separate analysis. Anti-TNF therapy was evaluated by dose, dose frequency, and reason(s) for change in dose, dose frequency, or medication (if applicable). Use of non-anti-TNF therapy (aminosalicylates, antibiotics, corticosteroids, immunomodulators, and probiotics/total parenteral nutrition) was also captured. Analytic goals included determining the mean length of time from IBD diagnosis to initiation of infliximab therapy, patient demographics at time of infliximab initiation, infliximab treatment patterns, and non-anti-TNF medication utilization. This analysis, utilizing descriptive statistics, evaluated maintenance infliximab treatment occurring subsequent to three initial infliximab induction doses. Dosing data were tracked longitudinally based on chart documentation. Dosage adjustment was defined as an increase or decrease in infliximab dose or frequency of administration during the study time frame. Stable dosage was defined as no change in dose or administration frequency. Data from patients with CD and UC were analyzed separately.

The protocol was approved by the New England Institutional Review Board. Only investigators involved in the study had access to the charts.

Results

Data were collected from 268 charts for patients who received care in 14 US gastroenterology centers. The 14 clinics were located in 12 different states across the country: Arizona, California, Colorado, Connecticut, Illinois, Kentucky, Michigan, Missouri, New York, North Carolina, Ohio, and Washington. Age and gender distribution (Table 1) were similar to findings reported for IBD patients in the overall US population1. The mean age of the CD patients was 42.2 years, the mean weight was 81.0 kg, and nearly half of the population (47.3%) were women. The mean time from CD diagnosis to infliximab treatment was 7.6 years. The mean age of the UC patients was 47.8 years, the mean weight was 80.2 kg, and, as in the CD group, nearly half (47.7%) were women. The mean time from UC diagnosis to infliximab treatment was 9.9 years.

Table 1.  Baseline patient characteristics.

	Crohn’s disease (n = 182)	Ulcerative colitis (n = 86)
Age, years	42.2 (15.2)	47.8 (14.8)
Female, %	47.3	47.7
Weight, kg	81.0 (20.0)	80.2 (19.1)
Time from diagnosis to infliximab treatment, years	7.6 (8.4)	9.9 (9.4)
Starting dose,* mg/kg
5^†  5–10  ≥10	136 (93.8%) 6^‡ (4.1%) 3^‡ (2.1%)	70 (92.1%) 4^§ (5.3%) 2^§ (2.6%)

Data are presented as mean (standard deviation) unless otherwise noted.

*Patients for whom data were evaluable (145 Crohn’s disease and 76 ulcerative colitis).

^†Changes in dosing for patients receiving 5 mg/kg are listed in Tables 3 (Crohn’s disease) and 4 (ulcerative colitis).

^‡Frequency of dosing remained stable in all patients.

^§Dose and frequency remained stable in all patients.

Crohn’s disease

A total of 182 charts were available for the CD analysis. Of these, infliximab dosing information could not be evaluated in 37 (20%) charts due to incomplete information on dose or frequency of administration, leaving 145 charts for evaluation. Dosage adjustments and the reasons for the adjustments are described in Table 2. Nine patients in the CD group required discontinuation of therapy; the charts suggest that none stopped due to intolerability. The remaining 145 evaluable charts revealed that 136 patients (94%) had therapy initiated at a dose of 5 mg/kg; of those, dose and administration frequency were stable throughout the study period in 107 patients (79%; Table 3). Documented reasons for dosage adjustment included lack of effectiveness (n = 14), adverse events (n = 1), and other reasons (n = 7) as noted in Table 2. Nine (6%) of the 145 evaluable patients had therapy initiated at higher infliximab doses (>5 to <10 mg/kg in six patients; 10 mg/kg in three patients). Among these nine patients, the dose remained stable in six patients, two patients required a decrease in dose, and one patient required an increase in dose. Frequency of administration remained stable in all nine patients.

Table 2.  Therapy adjustments noted in evaluable patient charts.

	Crohn’s disease (n = 145)	Ulcerative colitis (n = 76)
Patients requiring therapy adjustments	63 (43.4%)	36 (47.4%)
Adjustments required*
Increased dose	24	25
Decreased dose	2	4
Increased frequency of administration	13	11
Decreased frequency of administration	9	3
Discontinued therapy	9	4
Other^†	14	4
Reasons for modifications
Lack of effectiveness	14	1
Adverse events	1	1
Other^†	7	1

*Note: Some patients experienced multiple dosing adjustments, such as dose decreases, following an initial dose escalation. Therefore, the number of adjustments required is greater than the number of patients.

^†‘Other’ reason for discontinuation/modification, CD patients: weight gain; changed physicians, no reason given for change; hospitalized, missed appointment, then lost to follow-up; did not return for appointment, did not answer phone calls, and lost to follow-up; stopped when developed melanoma; stopped when developed lupus; no insurance/could not afford; discontinued treatment without explanation; no reason specified in chart. For UC patients: stopped for personal reasons; became pregnant; had osteoarthritis, wanted different medication.

Table 3.  Dose and frequency changes for Crohn’s disease patients initiated on 5 mg/kg infliximab.

	Starting frequency*
	Every 8 weeks (n = 110)	Every 6 weeks (n = 19)	Every 4 weeks (n = 7)
Dose stable	88 (80.0%)	14 (73.7%)	5 (71.4%)
Increased dose	11 (10.0%)	3 (15.8%)	0 (0.0%)
Increased frequency of administration	7 (6.4%)	0 (0.0%)	0 (0.0%)
Decreased frequency of administration	3 (2.7%)	2 (10.5%)	0 (0.0%)
Change in both dose and frequency	1 (0.9%)	0 (0.0%)	2 (28.6%)

*For maintenance therapy.

Ulcerative colitis

Eighty-six charts were available for the UC analysis. Among these, ten (12%) could not be evaluated for dosing due to incomplete information regarding dose or frequency of administration, leaving 76 charts for evaluation. Four patients in the UC group required discontinuation of therapy; the charts suggest that none stopped due to intolerability (Table 2). The remaining 76 evaluable charts revealed that 70 patients (92%) had therapy initiated at 5 mg/kg; of those, dosage and administration frequency were stable in 43 patients (61%; Table 4). Six (8%) of the 76 evaluable patients were initiated at higher infliximab doses (>5 to <10 mg/kg in four patients; 10 mg/kg in two patients), with stable dose and frequency in all six patients.

Table 4.  Dose and frequency changes for ulcerative colitis patients initiated on 5 mg/kg infliximab.

	Starting frequency*
	Every 8 weeks (n = 59)	Every 6 weeks (n = 8)	Every 4 weeks (n = 3)
Dose stable	38 (64.4%)	5 (62.5%)	0 (0.0%)
Increased dose	11 (18.6%)	1 (12.5%)	1 (33.3%)
Increased frequency of administration	5 (8.5%)	0 (0.0%)	0 (0.0%)
Decreased frequency of administration	0 (0.0%)	1 (12.5%)	1 (33.3%)
Change in both dose and frequency of administration	5 (8.5%)	1 (12.5%)	1 (33.3%)

*For maintenance therapy.

Data were collected, but not included in the final analysis, on the use of non-anti-TNF therapies (aminosalycilates, antibiotics, corticosteroids, immunomodulators, probiotics, and use of total parenteral nutrition) with the goal of determining how infliximab would affect the utilization of these therapies. Documentation of how these therapies may have been affected by anti-TNF therapy could not be adequately assessed due to the widespread practice of patient self-medicating, self-dosing, etc. to manage their symptoms.

Discussion

Over 90% of infliximab-treated patients with IBD had treatment initiated at a dose of 5 mg/kg, and 75% were maintained on a frequency of every 8 weeks. Dosing and administration frequency were stable in 79% and 61% of evaluable CD and UC patients, respectively, during the initial year of infliximab treatment. Although the majority of patients remained on a stable dose and frequency, there was evidence of both upward and downward dosage adjustments in a minority of patients, indicating that physicians may adjust the dose in certain, limited circumstances. Thus, the study findings indicate that dose and frequency is stable and consistent with FDA-approved labeling in most patients with IBD.

Research exploring the real-world dosing patterns of infliximab in IBD is limited. Waters et al.26 presented the results of a retrospective claims analysis evaluating 2118 CD patients receiving infliximab. The majority of the patients (91%) received doses that were within or less than the labeled dosing recommendation of 5 to 10 mg/kg. This research demonstrates adherence to the FDA-approved labeled dosing for infliximab in the real-world management of IBD26. Infliximab dosing patterns have also been evaluated in rheumatoid arthritis patients27; however, the applicability of these results to IBD may be limited due to differing disease characteristics and FDA dosing guidelines. Furthermore, these analyses utilized claims data, and because patient weight was not available, dosing was estimated. Therefore, additional analyses are needed to further characterize the real-world dosing of infliximab in patients with IBD. The present study furthered our understanding of infliximab dosing by demonstrating the stability and, thus, predictability of infliximab dosing in patients with CD and UC.

Given the high cost of anti-TNF agents, the effect of dosing adjustments on the cost-effectiveness of therapy should be examined. Lindsay and colleagues28 reported on the cost-effectiveness of scheduled maintenance treatment with infliximab at a dose of 5 mg/kg every 8 weeks in patients with CD. Every-8-week scheduled maintenance treatment was found to be a cost-effective treatment in terms of quality-adjusted life-years (versus standard care with immunomodulators and corticosteroids), for adult patients with active luminal or fistulizing CD. Stein and colleagues29 examined the effect of intermittent therapy followed by continuous therapy (n = 40) versus long-term continuous therapy not preceded by intermittent therapy (n = 64). Those who began on uninterrupted maintenance therapy had lower rates of CD-related hospitalization (26.5 vs. 47.5%, p = 0.03) and surgery (21.8 vs. 48.7%, p = 0.004) compared with those who had interrupted or irregular therapy before beginning scheduled maintenance therapy. Further, the rates of permanent disability were significantly lower with uninterrupted scheduled maintenance therapy (1.5 vs. 12.5%, p = 0.03). During the third year of treatment, the excess costs per patient in the group who received prior intermittent therapy compared with the scheduled maintenance therapy group amounted to $11,464 – although both cohorts were, at that time, receiving scheduled maintenance therapy.

The current study did not examine cost and effectiveness; however, given stable dosing over time, the direct drug cost for infliximab therapy may be predictable. The impact of infliximab therapy on the utilization of non-anti-TNF therapies for CD or UC was not determined in this study. A previous clinical trial30 and observational studies31 have reported decreased healthcare resource utilization (e.g., hospitalization, surgeries, GI-related procedures) after infliximab treatment for CD. Future analyses from this study will investigate resource utilization in the IBD population, inclusive of UC patients, to understand resource changes following infliximab treatment. Such information might further refine the understanding of clinical and cost considerations of infliximab in this population.

Limitations

This descriptive study is a chart review; therefore, dosing patterns reported here are based on what is available and documented in the patient’s chart. Severity of disease was not explicitly documented in patients’ medical records by the physicians and therefore did not allow further analysis by disease severity. The data reflect patient experiences from a limited number of US community GI clinics; however, results may vary by GI clinic site. Other settings (e.g., differing geographic regions, tertiary care centers) may report different results due to varying disease severity or other patient factors as well as different physician practice patterns. Data were collected, but not included in the final analysis, on the use of non-anti-TNF therapies due to intermittent documentation related to patient self-management behaviors. Additionally, the results are limited to the initial year of therapy, and other dosing findings may be reported with longer follow-up. Future studies may include patient-reported diaries to understand symptom response and titration of non-anti-TNF therapies during the course of IBD. Further, data characterizing the dosing patterns of other biologic therapies used to treat IBD might be informative to clinical and payer decision makers when interpreting these results in context.

Conclusions

The findings reported stability of infliximab dosing in most patients with IBD treated in 14 US GI clinics. Such observations provide insights for providers and may be useful for payers in understanding utilization during the first year of infliximab treatment. Given the disease chronicity of CD and UC, more observational utilization studies are warranted with longer infliximab treatment and in other IBD treatment centers. Future research may include a more complete health profile of the study patients, such as severity of their disease, confirmation of use of other medications, and pre-index resource utilization, as well as an evaluation of physician practice characteristics.

Transparency

Declaration of funding

This study was funded by Centocor Ortho Biotech Services, LLC.

Declaration of financial/other relationships

J.V. and S.M. are employed by Centocor Ortho Biotech Services, LLC. H.W. was an employee of Centocor Ortho Biotech Services, LLC, at the time at which this research was conducted and is currently employed by Ethicon, Inc. O.L. and B.L. are employed by Xcenda, LLC, which has a consultant relationship with Centocor Ortho Biotech Services, LLC. M.F. was employed by Xcenda, LLC, at the time at which this research was conducted. J.G. and D.H.A. served as scientific advisors to the project and were compensated for their review of the study design and manuscript.