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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Background

Infliximab (IFX) maintenance therapy for Crohn's disease (CD) is administered every 8 weeks, but inter-patient variation in optimal treatment intervals may exist.

Aim

To assess, in a prospective pilot study, the efficacy, safety and quality of life (QoL) of IFX maintenance treatment scheduled through web-based self-monitoring of disease activity.

Methods

Twenty-seven CD patients in IFX maintenance therapy were enrolled and received a standardised disease education and web-training. Using the http://www.cd.constant-care.dk concept, patients recorded their disease activity and faecal calprotectin weekly. From this, the inflammatory burden (IB) score was calculated, placing patients in the green, yellow or red zones of a ‘traffic light’ system. If placed in the yellow or red zones, the computer directed these patients to consult their physician for IFX infusion.

Results

Seventeen patients (63%) completed 52 weeks of follow-up, 6 (22%) completed 26 weeks and 4 (15%) were excluded due to loss of response, patient decision or non-adherence. In total, 121 IFX infusions were given with a median interval of 9 (range: 4–18) weeks. Only 10% of infusions were given at 8-week intervals, whereas 39% were administered with shorter and 50% with longer intervals respectively. The mean IB and the QoL remained stable during the web-treatment. One mild infusion reaction and one case of folliculitis were observed, while three patients underwent surgery.

Conclusions

The program http://www.cd.constant-care.dk appears to be a practical and safe concept for the individualised scheduling of maintenance treatment with IFX in patients with Crohn's disease. Larger studies are awaited to confirm this preliminary outcome.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Infliximab (IFX) is a chimeric human-murine monoclonal antibody that binds to both soluble and transmembrane forms of TNFα and inhibits its functional inflammatory activity. IFX was developed as a therapeutic agent for various diseases in which TNFα is known to mediate chronic inflammation. Since the initial authorisation in August 1998 in the US by the Food and Drug Administration (FDA), and by the European Medicines Agency (EMA) in September 1999 for the treatment of complicated Crohn's Disease (CD), clinical studies evaluating the efficacy of IFX have demonstrated a consistent clinical benefit in subjects with CD. In agreement with the label recommendations, IFX maintenance therapy for CD is generally prescribed at regular intervals of 8 weeks (Q8W). This therapeutic schedule is recommended as a way of preventing relapse, the formation of antibodies (Abs) to IFX and drug-related infusion reactions.[1-4] However, when IFX is infused at regular Q8W intervals after induction therapy, inter-patient variation of IFX pharmacokinetics, fluctuation in disease activity and various phenotypes are not taken into account. Furthermore, some clinical retrospective studies[5, 6] have shown that IFX-dependent patients who had their interval of administration adjusted in accordance with disease activity and their preferences responded well and had a subsequently lower surgical rate after IFX treatment.

Telemedicine systems offer an alternative monitoring and treatment method that can improve clinical outcomes, reduce delay in the initiation of treatment, increase patient access to treatment, improve patient and provider education, and reduce health care costs.[7-10]

In a recent paper, it was shown that a web-based treatment solution can optimise therapy in ulcerative colitis (UC).[11] The Constant-care concept[12] was launched by Dr Pia Munkholm in 1995, based on insights derived from epidemiological studies on pattern recognition of the disease course in IBD[13, 14] and developed as a tool to control disease activity through optimising therapy and engaging patients in the management of their disease. Constant-care consists of a web-based patient education package and a web-based disease monitoring package. The program has been shown to improve disease knowledge, adherence to treatment and to reduce clinical disease activity in patients with UC, and it was well received by patients.[11, 15]

To individualise control of the disease course and keep the disease activity at an acceptable level through treatment with IFX, the present pilot study, using the Constant-care concept as a tool for adjusting dose administration in agreement with patients needs, was proposed. IFX dose administration could be performed at intervals varying between Q4W and Q12W, according to patients' needs and taking into account their total inflammatory burden (IB) using a clinical assessment of disease activity and the results of rapidly tested faecal calprotectin (FC).

The primary objective of this study was to evaluate the efficacy and safety of the web-treatment program in terms of individualisation of IFX maintenance treatment. The secondary objectives were to assess the level of disease control and patient satisfaction during his/her participation in the study by means of measuring the frequency of uncontrolled flares, the adherence of patients to web program, and the difference between the number of Abs to IFX at study entry and at week 52 (end of study). Safety was compared to safety of conventional IFX treatment in a historical control group.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Study design

We conducted an open label, four-centre pilot study in 27 patients with CD. IFX infusions were given at a dose of 5 mg/kg with treatment frequency determined by the web-based monitoring of the IB, allowing for treatment intervals of 4–12 weeks.

Patients

Twenty-seven patients from Herlev, Hvidovre, Elsinore and Gentofte hospitals in Denmark, who were between 18 and 66 years of age, fulfilled the international diagnostic criteria for CD,[16] were classified as responders to an induction IFX therapy (indicated primarily for active luminal disease with or without concurrent perianal disease or extra-intestinal manifestations) at week 0, 2 and 6, and were planned to continue IFX maintenance therapy, were invited to participate in this study. Eligible patients were included and followed up from May 2009 through February 2011.

Web program: http://www.cd.constant-care.dk

The http://www.cd.constant-care.dk web program was founded on the ideas described previously.[15] Briefly, this is a secure program developed and provided by Dr Pia Munkholm. After receiving a disease-specific education (1.5 h) and a theoretical/practical training (1.5 h) in how to use the web program at the Patient Education Center (PEC), each patient received an individual username and password from the investigators to access the web program. The administrator part of the web program, which was only accessible to the investigators, allowed the treating physician to monitor the patients via daily checks. Patients' status appeared both on the patient and administrator parts of the web program according to a simple ‘traffic light’ system; red indicated high disease activity, yellow moderate activity and green indicated disease inactivity. This status was supplemented with patients' faecal calprotectin (FC) and quality of life (QoL) graphs.

One month after each infusion, the results of the subjective disease activity questionnaire, along with the Harvey-Bradshaw index (HBI)[17] and FC[18] were entered weekly by the patient and web-physician, respectively, into the web page, allowing the program to calculate the IB and to illustrate this via a ‘traffic light’ system. If the IB exceeded the values denoted by the yellow or red zones, the program recommended that the patients contacted the day-care hospital, and their next IFX infusion was scheduled for within 72 h. Faeces for FC measurement were collected weekly by the patient using a faeces collecting ‘Easy Sampler’ kit (container, gloves, toilet paper and a spoon). The samples were then sent by mail to the gastroenterology research laboratory at Herlev Hospital in unfrozen containers, where FC was measured by a quantitative scanning test.

Inflammatory burden components and calculation

In this study, HBI and rapidly measured FC were used to calculate the IB index, which was in turn used by the program to indicate the need or not for IFX infusion. The HBI[17] is a self-completed questionnaire with five dimensions: general well-being, abdominal pain, number of liquid stools per day, abdominal mass and complications. The total number of points scored on each question is added to compose the HBI score. To prevent a severe relapse of the disease, the scoring of HBI on the website was modified so that in our study, an HBI ≤5 was considered as inactive disease, HBI 6–7 as moderate activity and HBI ≥8 as severe disease.

Furthermore, patients were taught how to recognise specific symptoms and feel for an abdominal mass: any abnormal finding was followed up by a clinical examination. FC is expressed in mg/kg. If FC was <200 mg/kg, the FC score for the composite IB score was 0. If the FC was ≥200 mg/kg, the FC score for the composite IB score was 2.

As long as the IB scores were ≤5 – indicating that the disease was inactive or green according to the ‘traffic light’ system – no infusions were given. A yellow result indicated moderate disease activity (IB 6–7) and a red one indicated severe disease activity (IB ≥8). The graphic interpretation of the IB score and its components is illustrated in Figure 1.

image

Figure 1. Concept of http://www.cd.constant-care.dk. Patients' assessment of inflammatory burden once a week since 4th week after last infliximab infusion by a ‘traffic light’ colour score system were green = no activity, yellow = moderate activity and red = severe activity. Faecal calprotectin (FC), mg/kg: <200, green = no activity; ≥200, red = activity.

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Patients in this study were treated with IFX according to the approved EU label.[19] Participating patients had responded to induction IFX infusions (0, 2 and 6 weeks) and had subsequent maintenance treatment. If the calculated IB was >6, the next dose was recommended to be administered within a minimum of 4 weeks and maximum of 12 weeks following the last dose.

Data collection

Data on full history and demographics – age, gender, ethnicity, height and weight, smoking status, concomitant medication and disease-specific medical history – were obtained upon a patient entering the study. Data on endoscopic and radiological investigations generated up to 2 years before entering the study were retrieved from medical files, if available, to assess maximal disease extent and to validate phenotype in accordance with the Montreal Classification of localisation and behaviour.[16] Three visits (at baseline, at 6 months, and at 12 months) were performed to assess the efficacy (HBI, FC), complications and safety of therapy. At each visit, the following questionnaires were completed by all patients:

  1. S-IBDQ (Short-Inflammatory Bowel Disease Questionnaire) to determine disease-specific quality of life. The results range from 10 (worst health) to 70 (best health).[20]
  2. SF-36 (Short-Form health survey) to assess self-reported health status. This is a generic multi-purpose health survey consisting of 36 questions. It yields an eight-scale profile. The results are expressed on a scoring scale of 0– 100 for every profile, with a mean health of 50 for the Danish population.[21]
  3. HADS (hospital anxiety and depression score) to assess anxiety and depression. The questionnaire includes 14 questions: seven on anxiety (HADS-A) and seven on depression (HADS-D) to determine the mental state of the patients. The scoring results are expressed as: 0–7 normal, 8–10 borderline, ≥11 anxious and/or depressed.[22]
  4. CCKNOW (Crohn Colitis Knowledge Score) to determine the level of knowledge of the disease. This is a 30-question multiple choice questionnaire divided into four items: general IBD understanding, medication, diet and complications of IBD, with a scoring system of one point for each correct answer.[23]
  5. WPAI-CD Questionnaire (Work Productivity and Activity Impairment Questionnaire for CD) to determine the effect of CD on the patient's ability to work and to perform normal daily activities.[24]
  6. SQ (Satisfaction Questionnaire) to evaluate the web program. At the end of the study, patients completed a Visual Analogue Scale (VAS), developed to measure their satisfaction with the web program and the self-perceived influence on disease education and disease control. SQ consisted of eight questions, covering: (i) satisfaction with the web program; (ii) satisfaction with the educational component; and (iii) satisfaction with the impact of the web program on CD. A mean score above 6 on the VAS was considered a satisfactory result.[11]

Measurement of antibodies

Abs to IFX were measured at entry in the study and at the end of the study by a functional Radio ImmunoAssay at Biomonitor Inc in Copenhagen.[25]

Control patients

To compare the safety of IFX treatment between web and nonweb patients, a nonweb CD control group (historical controls) was included retrospectively from the participating centres at the end of the study. The control group patients were treated with IFX at a dose of 5 mg/kg during the same period (2009–2010) ±0.5 years and were matched 1:3 by age, gender, disease location, behaviour and indication of IFX treatment. Information regarding demographic data and IFX treatment – but not the HBI, FC and questionnaires – was retrospectively retrieved from patients' charts.

Data analysis

Standard descriptive statistical analyses were performed, including frequency distributions for categorical data and calculation of means or medians (range) for continuous variables. The Wilcoxon Signed Rank test was used to compare IB and questionnaire scores between baseline and end of follow-up and to calculate the difference in costs of IFX treatment between web-scheduled IFX infusions and out-patient clinic-scheduled IFX infusions. The frequency of Abs to IFX was analysed by Fisher's exact test. Chi-squared test and Student t test were used, when appropriate, for comparison of baseline characteristics between patients and controls. A significance level of 5% was chosen. Data analyses were performed using spss for Windows software 19.0 (www.spss.com).

Ethical considerations

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

This study was conducted after approval of the additional Protocol (nr. 13768) to the main study[11] (KA 05115) by the Danish Ethical Committee. All patients included in this study had signed an informed consent form.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

Web patients

Twenty-seven patients with CD were initially included in the study. Four patients were later excluded from the analysis due to protocol violations: non-adherence (n = 2), planning of pregnancy (n = 1) and urgent bowel resection (n = 1). Of the 23 patients included in the final analysis, 6 patients completed at least a 26-week period of follow-up online, and 17 completed the entire 52-week period of follow-up online according to the protocol (Figure 2). Baseline patient characteristics are outlined in Table 1.

image

Figure 2. Crohn's disease patients enrolled in the Constant-care study.

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Table 1. Patients' description at baseline
 Web, n = 23Controls, n = 69 P
  1. IFX, infliximab; NA, not applicable.

  2. Controls: non-web CD patients treated with IFX in 2009–2010: matched retrospectively 1:3 by age, gender, disease location, disease behaviour, IFX indication and IFX treatment period.

Gender (%)
Male10 (43)30 (44)0.594
Female13 (56)39 (56) 
Age at inclusion (years), median (range)38 (20–63)38 (18–67)0.888
Smoking (%)
Non-smoker7 (30)21 (30)0.005
Current smoker5 (22)13 (19) 
Ex-smoker11 (48)13 (19) 
Missing033 (32) 
Disease duration (years), median (range)8 (1–29)8 (0–45)0.942
Disease location (%)
Small bowel6 (26)18 (26)0.750
Large bowel13 (57)34 (49) 
Small and large bowel4 (17)17 (25) 
Disease behaviour (%)
Inflammatory13 (57)51 (74)0.022
Stricturing10 (43)12 (17) 
Penetrating06 (9) 
Surgery before web-based treatment (%)5 (22)25 (36)0.304
Concomitant medication (%)
5-ASA1 (4)00.441
Corticosteroids06 (9) 
Immunosuppressives12 (52)41 (60)0.331
Thiopurines937 
Methotrexate340.345
IFX indication (%)
Luminal disease19 (83)55 (80)0.215
Luminal & fistulizing4 (17)14 (20) 
Number of IFX infusions given prior to study enrolment, median (range)10 (3–33)6 (3–44)0.481
Inflammatory burden at baseline, median (range)2 (0–6)NA 

Infliximab treatment

In total, 121 IFX infusions were given with a median interval of Q9W (range 4–18). The median number of IFX infusions given per patient during the study period was 5 (range 2–8). Twelve (10%) infusions were given at Q8W intervals, 49 (40%) at <Q8W, while 60 (50%) were given at intervals of >Q8W. Fourteen patients (61%) had a mean interval between infusions of more than 8 weeks, 3 (13%) had fewer than 8 weeks and 6 (26%) had exactly 8 weeks.

In contrast to the varying treatment intervals, the IFX dose remained constant.

Inflammatory burden

A total of 633 IB scores were recorded during the study period, of which 504 (80%) resulted in a green ‘traffic light’ (no activity), 90 (14%) in yellow (mild to moderate activity) and 39 (6%) in red (severe activity). No statistically significant difference in IB was observed between baseline and end of follow-up (mean 2.4 vs. 2.2, P = 0.4). The median IB per infusion during web-treatment is illustrated in Figure 3.

image

Figure 3. Inflammatory burden (IB) at infliximab (IFX) infusion and 4 weeks after infusion as measured on the website. X-axis: Ranking of infusions from 1st to 8th from inclusion until end of the study. Y-axis: Scoring of IB: ≤5 no activity; 6–7 moderate activity and ≥8 severe activity. Red line: IB levels indicating need for infusion. Blue line: Patients' response to IFX therapy 4 weeks after infusion.

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QoL, general and disease-specific

No statistically significant difference in mean s-IBDQ among the 23 patients was observed between baseline and end of follow-up (55 vs. 55, P = 0.73). The evolution of mean s-IBDQ per infusion during web-treatment is illustrated in Figure 4.

image

Figure 4. Infliximab (IFX) infusions and quality of life according to the short-Inflammatory Bowel Disease Questionaire (s-IBDQ) on the day of infusion. X-axis: Ranking of infusions from 1st to 8th from inclusion until end of the study. Y-axis: Scoring of quality of life (QoL) <50 poor QoL; >50 normal QoL. Red line: The level of QoL on the day of the infusion.

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General QoL measured by SF-36 was not significantly different between baseline and end of the study when comparing mean values of physical activity (95 vs. 95, P = 0.66), role limitations due to physical health (75 vs. 87, P = 0.75), role limitations due to emotional health (100 vs. 100, P = 0.07), body pain (84 vs. 84, P = 0.43), general mental health (76 vs. 74, P = 0.53), vitality (60 vs. 75, P = 0.36), social function (87 vs. 100, P = 0.72) and general health (52 vs. 49, P = 0.86) (Figure 5).

image

Figure 5. SF-36, generic health quality of life at entry vs. end of the study (week 52) vs. Danish healthy reference levels. PF, physical activity; RP, role physical activity; BP, body pain; GH, general health; VT, vital capacity; SF, social function; RE, role emotion activity; MH, mental health.

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Anxiety and depression showed normal values in both periods of the study (median 4.0 vs. 5.0, P = 0.25 and 1.0 vs. 1.0, P = 0.91 respectively). IBD knowledge measurements showed significant improvement of general knowledge (median 17 vs. 23, P < 0.001) along with IBD knowledge (10 vs. 13, P < 0.001), IBD complications knowledge (3 vs. 4.5, P = 0.001) and IBD medication knowledge (3 vs. 4, P = 0.008), but not IBD diet knowledge (2 vs. 2, P = 0.56). According to the WPAI-CD, 70% were employed and 30% unemployed, both at baseline and at the end of the study. Among employed individuals, no significant difference was observed between baseline and end of the study in terms of work time (hours/week) missed due to CD (3 vs. 5, P = 0.35), impairment due to CD (hours/week) while working (16 vs. 14, P = 0. 96) or overall work impairment due to CD (14 vs. 15, P = 0.47). Furthermore, no differences in recent activity impairment (hours/week) due to CD from baseline to the end of follow-up was seen (16 vs. 16, P = 0. 23). The patients were highly satisfied with the web program (mean score 9.0), education (mean score 7.4) and the impact of the web program on their disease (mean score 7.7).

Antibodies to infliximab

Twenty-two (96%) patients had negative and 1 (4%) had positive Abs to IFX at baseline, while 17 (85%) had negative and 3 (15%) patients had positive Abs to IFX at the end of the study with no statistically significant difference between these two time points (P = 1.0).

Safety

Five adverse events (AEs) in four patients (17%) of the total sample were reported during the study, four of which were serious adverse events (SAEs). One AE was an infusion-related allergic reaction (urticaria), which was resolved within 15 minutes following treatment with antihistamines and did not require hospitalisation. One of the SAEs was infection (folliculitis) requiring short hospitalisation, whereas three required surgical procedures (one bowel resection and two perianal abscess drainages).

Adherence to the web program

The adherence to the web program was 86%. The total number of weeks of follow-up during the study period was 1108. During these weeks, the total possible number of web-registered weeks by patients was 624 (the number of total weeks minus 4 weeks after every IFX infusion [4 × 121]). However, the actual number of weeks for which patients registered for the web program was 534 (86%) weeks.

The excluded population & protocol deviation

Subjects 01 and 10 received only one study infusion of IFX and were later excluded from the study because of non-adherence regarding the entering of data for IB on the web program. Subject 10 experienced an AE – influenza – that required short-term hospitalisation (SAE) during the study (not included in the AEs described above). Subject 12 received only one study infusion and stopped prematurely because of planning a pregnancy (she became pregnant 6 months after the last IFX infusion): the disease was in remission during participation in the study with no AEs observed in this subject. The last excluded patient, subject 13, was admitted to hospital shortly after the first study infusion for a severe relapse demanding an urgent colon resection.

Deviation from protocol requirements regarding Q4W–Q12W infusion intervals was observed in 16 (13%) of 121 infusions, which were given after an interval of more than 12 weeks (13–18 weeks).

Cost

The total cost of 121 infusions scheduled via web program was compared to the cost of 121 IFX infusions in a hypothetical patient group whose IFX infusions were scheduled via an out-patient clinic. The DRG (Disease-Related Group) taxation system from 2010 was used in the calculations of cost effectiveness. The DRG of a web administered IFX infusion was comparable with telephone consultation carried out prior to each IFX infusion and consisted of 40 EUR in 2010.

Disease-Related Group of an out-patient-administered IFX infusion was comparable with an out-patient consultation (180 EUR). This cost was used for the out-patient-administered IFX infusion, carried out prior to IFX infusions. The median cost of one IFX infusion in web/out-patient clinic patients was: 1.937 EUR, with a range of 1.561–3.123 EUR per infusion.

We observed a significantly lower cost of web-administered IFX treatment per patient (11.502 EUR) compared with IFX treatment administered in the out-patient clinic, (12.062 EUR), P = 0.001, resulting in a total cost saving of 699 EUR per patient.

Control patients

Sixty-nine CD patients who were on maintenance therapy and receiving IFX during 2009–2010 (±0.5 years) in the participating centres were retrospectively included in the study and matched at random with the cases (1:3) by age (±5 years), gender, disease location, disease behaviour, IFX indication and IFX treatment (duration, number) prior to study enrolment. The baseline characteristics of the control group are described in Table 1.

Infliximab treatment in controls

In total, 420 IFX infusions were given during the study period, with a median interval of Q8W (range 4–16). Of these, 146 IFX infusions (36%) were given at Q8W interval, 137 (32%) <Q8W, whereas 137 (32%) were given at intervals >Q8W. The median number of IFX infusions given per patient during the study period was 7 (range 3–12). Twenty-seven patients (39%) had a mean interval between infusions of more than 8 weeks, 17 (25%) had fewer than 8 weeks and 25 (36%) had exactly 8 weeks. No significant difference in mean interval between IFX infusions was observed when comparing controls and web patients (P = 0.18).

Safety in controls

In the control group, 31 of 69 patients (45%) were registered with AEs during the study period. Of these, 21 (16 hospitalisations and 5 surgeries) were classified as SAEs. The registered surgeries were as follows: three perianal abscess drainages and two bowel resections (ileo-coecal and recto-sigmoidal). There were significantly more AEs in the control group than in the web group (45% vs. 22%, P = 0.002). However, there was no significant difference in hospitalisations (23%. vs. 22%, P = 0.57), frequency of surgical interventions (7% vs. 11%, P = 0.39) or use of corticosteroids (9% vs. 0%, P = 0.34) when comparing web-treated patients and controls respectively.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

This four centres pilot study of 27 patients with CD undergoing web-treatment with IFX was carried out to evaluate the efficacy and safety of the virtual Constant-care treatment programme for the individualisation of IFX maintenance therapy. Furthermore, we assessed the level of disease control, patient satisfaction, frequency of uncontrolled flares and adherence of patients to web-based treatment; as well as we measured Abs to IFX at study entry and at week 52, the end of the study.

Earlier self-management programs have been shown to be effective in the treatment of chronic diseases, such as asthma, diabetes mellitus and anticoagulation, and as well as in IBD.[26-32] Recently, a new web-based approach encouraging the active involvement of patients with UC in the assessment and therapy management of their disease was introduced.[11] In that study, we observed a significantly higher efficacy and adherence to therapy than among patients treated conventionally.

The goal of this study was to keep patients in clinical and biological remission (the green zone of our ‘traffic light’ system) for as long as possible. The efficacy of the web-based approach was measured by IB, which is the sum of subjective activity symptoms (HBI) and an objective marker of inflammation (FC). In our study, the IB was found to be stable during the entire study period among patients, despite the fact that treatment intervals varied considerably. This indicates that the web program guides patients to seek their infusions at the most appropriate time and that a considerable inter- and intra-patient variation in optimal treatment intervals exists. This is in contrast to current recommendations,[19] based on pivotal studies, where IFX maintenance therapy for luminal CD[4] and for fistulising CD[1] was found to be most effective when given at 8-week intervals. A study by Rutgeerts et al.,[2] a subanalysis of the ACCENT I study, comparing scheduled and episodic treatment with IFX for CD, showed that the scheduled approach (treatment every 8 weeks) was superior to episodic treatment. Our approach, however, differed in that the patients in our study scheduled their next infusion (within an allowed interval of 4–12 weeks) themselves and based on their individual clinical and biological activity. Furthermore, the infusion was given very quickly (optimally within 72 h) once the IB had increased to a level indicating disease activity. This approach may preclude the development of potential complications resulting from increased immunogenicity or uncontrolled inflammation when the therapy is given episodically as described by Rutgeerts et al.[3] Prior studies suggested that the combination of IFX and other immunosuppressive drugs is superior to IFX monotherapy[33] and the fact that approximately half of our patients were on combined therapy may contribute to the observed IB stability.

Different approaches in everyday clinical practice are observed in other studies.[5, 6, 34, 35] In a retrospective cohort study by Pedersen et al.[5] of 245 Danish-Czech CD patients treated with IFX, it was found that up to 86% of patients were on either episodic treatment with IFX or had received induction therapy only, whereas only 14% had received IFX therapy regularly, every 8 weeks, as maintenance therapy. Nevertheless, patients had high response rates on these treatment regimens (47% of patients obtained a prolonged response and 29% developed infliximab dependency). The same trend was seen in a paediatric cohort study by Duricova et al.[6]

In our study, 13% of IFX infusions were given at 13- to 18-week interval, which was a deviation from the protocol. The study protocol demanded a 4–12-week interval between infusions to avoid severe relapse, complications or the development of infusion reactions (formation of Abs to IFX). In all cases, the patients were in remission for the whole period between infusions (i.e. in the green area). One might assume that the web program itself and patients' well-being on the web program could influence the patients to make their own decision to postpone IFX infusion and not to follow the web program or web-doctor's recommendations. No AEs or loss of response were observed in these patients.

The aim of our study was to determine how patients respond to therapy when changing the interval of the therapy rather than by altering the dose. Although the Q8W is recommended, a longer dosing interval between IFX infusions seems to be beneficial in some patients. For instance, in the paediatric REACH study[36] on induction and maintenance IFX therapy, comparison of Q8W and Q12W intervals in the maintenance phase demonstrated that Q8W was superior to Q12W. Nevertheless, up to 23% of children on Q12W were in clinical remission at week 52 indicating that longer treatment intervals might be sufficient for some patients.

The efficacy of treatment with IFX seems to be influenced by the formation of Abs to IFX and the serum concentrations of IFX trough levels (TL).[25, 35, 37] In our study, the levels of Abs to IFX increased from 4% to 15% (one patient was on a <Q8W regimen and two patients on a >Q8W regimen) from the beginning to the end of the study, suggesting that our web approach was accompanied by lower levels of the drug in circulation. However, the patients did maintain a response, regardless of formation of Abs to IFX. The meaning and impact of Ab formation remains uncertain in general. Even when administering IFX at Q8W, Abs may develop.[1] IFX TL were not determined in our study, although recent studies have demonstrated that patients with higher IFX TL seem to have a better disease control in general than those with low levels.[35] However, the implications of IFX TL measurement in clinical practice, and the subsequent adjustment of IFX dose according to TL irrespective of clinical/endoscopic response for an individual patient, are still not clear. In fact, 14–27%[38, 39] of patients have good clinical responses despite sub-therapeutic IFX TL or positive IFX Abs. A present ongoing prospective study aiming to modify IFX dose according to IFX TL is expected to improve our understanding of this issue.[40]

The quality of life – both disease-specific as well as general and in terms of work productivity and activity impairment – remained stable during the web-treatment of CD patients. All patients were highly satisfied with the concept. The patients' education at the study enrolment, the E-learning program and further self-management with the use of the web program considerably increased their knowledge of IBD, medication for IBD and possible complications arising from IBD. This increase in knowledge may explain the adherence to the web program and to IFX infusions in our study.

The web-based treatment solution appeared to be safe when compared with conventionally treated control patients, where significantly more AEs/SAEs were observed. This is probably due to a better knowledge, adherence and improved disease control via web-treatment. Yet, one should bear in mind that in this study, patients were prospectively monitored and that this in itself could have lead to a better adherence and fewer adverse events.

The primary strength of this study is the evaluation of a novel web-based approach, which appears to be a promising concept for the individualisation of IFX treatment in IBD. This approach involves patients actively in their disease, allows individually scheduled treatment, and takes into account the inter-patient variation in frequency of IFX needed. Accordingly, we observed high rates of adherence to web and consequently adherence to therapy.

This study also has limitations that need considering. This is a small study with rather few selective patients (responders to IFX), and further larger scale studies are needed to confirm the promising findings of the present investigation. Such studies should randomise patients to web-based vs. conventional treatment and follow patients prospectively. Furthermore, assessment of disease activity was based on clinical symptoms combined with FC as the only objective biomarker of inflammation. C-reactive protein level was not used, neither was endoscopy/histology used to assess mucosal healing, which is an important treatment goal,[33] and therefore the observed practicality and safety of web-treatment with IFX should not lead us to forget that absence of tight monitoring of IFX-treated patients might be associated with a poor long-term disease outcome.

In conclusion, and based on our pilot open-label study, a web-based IFX treatment approach for patients with CD appears to be a practical and safe concept for the scheduling of IFX maintenance treatment to individualise treatment. Certainly, our patient-tailored treatment approach was associated with a stable IB level during maintenance treatment with IFX. However, the results of this study have to be interpreted with caution; additional studies are needed to confirm the feasibility and validity of this approach as an alternative to conventional scheduled treatment.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References

We thank our laboratory technician Vibeke Voxen Hansen and the Gastroenterology Research Lab at Herlev University Hospital for performing the FC analyses and IBD nurse Lene Neergaard for administration of IFX infusions. Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Ethical considerations
  6. Results
  7. Discussion
  8. Acknowledgement
  9. References
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