- Top of page
- Materials and Methods
- Ethical considerations
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). The Constant-care concept 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.
- Top of page
- Materials and Methods
- Ethical considerations
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. 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, based on pivotal studies, where IFX maintenance therapy for luminal CD and for fistulising CD was found to be most effective when given at 8-week intervals. A study by Rutgeerts et al., 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. Prior studies suggested that the combination of IFX and other immunosuppressive drugs is superior to IFX monotherapy 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. 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.
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 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. 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. 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.
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, 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.