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Crohn’s disease (CD) is a disabling chronic inflammatory bowel disease. The anti-tumour necrosis factor alpha (TNF-α) infliximab is a monoclonal mouse-human chimeric immunoglobulin that was introduced in the late 1990s. It has since been demonstrated to be an effective treatment for both luminal and fistulizing disease.1, 2 Scheduled therapy with infliximab is associated with an increased likelihood of maintaining remission, reduced likelihood of development of antibodies to infliximab (ATI), reduced number of hospitalisations and corticosteroid requirements.3, 4
Currently accepted regimen for scheduled administration of infliximab includes loading dose of 5 mg/kg at week 0, 2 and 6, followed by repeated infusions of 5 mg/kg every 8 weeks. However, 30–84% of the patents experience loss of response (LOR) to infliximab along the course of the treatment (1.4–7). It is advocated to try and induce regained response in these patients by either shortening the interval between the infusions or increasing the dose. The customary strategy and the only one reported in the framework of a controlled trial is doubling the dosage to 10 mg/kg every 8 weeks,1 although shortening the dosing interval to 4 weeks is also common.5–8 In the ACCENT 1 trial, this double-dosing policy has lead to regained response in 80–90% of patients.1 However, rather than double-dosing, many physicians reduce the dosing interval to 6 weeks in those patients who experience a shortened duration of response.9 Although this approach may be less costly and could be more convenient for the patients, requiring clinic visit every 6 weeks instead of every 4 weeks, there are sparse data to support this clinical practice or its efficacy.
Therefore, the aim of this retrospective multicentre study was to examine the efficacy of shortening the dosing interval of infliximab to every 6 weeks as compared with the conventional double-dose approach of halving the interval to every 4 weeks or escalating the dose to 10 mg/kg.
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The present study evaluated the efficacy of shortening the dosing interval of infliximab to once in every 6 weeks in patients who lost response to standard maintenance regimen, in comparison to doubling the dose or halving the dosing interval to once in every 4 weeks. There are limited data pertaining to the rates of LOR and regain of response to intensified dose. In particular, data regarding the optimal dose intensification protocol in such patients are lacking.
In the ACCENT 1 study, 29% of the patients receiving scheduled infusions of infliximab experienced worsening of symptoms requiring dose increase.1 Of these patients, 80–90% responded to the intensified dose, but the rate of 1 year sustained response to the escalated regimen was not reported due to the design of the study. Requeiro et al.7 found that in a cohort of patients who received at least eight doses of infliximab (both scheduled and episodic), 31% of the patients required dose intensification after 12 months and 54% after 30 months. Overall, 76% of these patients remained under infliximab treatment at the conclusion of follow-up, but data regarding possible additional interventions in these patients and the 1-year response rate were not reported. In a cohort of 614 patients receiving either episodic or maintenance treatment with infliximab, 50% required some change of treatment regimen including switch from episodic to scheduled treatment, shortening of dosage interval or dose escalation.5 However, data pertaining specifically to each of these policies, and the response at 12 months were not provided. Thus, to the best of our knowledge, this study is the first to assess specifically the sustained response to escalation at the clinically meaningful 12 months’ time point.
There are few systematic data regarding the shortening of the dosing interval to once every 6 weeks rather than double dosing or halving the interval. A study by Seow et al.10 in patients receiving maintenance infliximab therapy for ulcerative colitis demonstrated that in patients who had lost response to 5 mg/kg of infliximab every 8 weeks, shortening of the dosing interval to 6–7 weeks resulted in regained remission in 44% of the patients, whereas doubling the dose resulted in regained remission in 25% of the patients, but the duration of the regained remission was not reported. Magro et al.9 found that shortening the dosing interval to 6 weeks was an efficient strategy for managing LOR in CD patients receiving maintenance treatment with infliximab. However, this was a small-scale retrospective study that included only 15 patients.
Infliximab has linear pharmacokinetics with elimination half-life of 12 days and no plasma level accumulation with multiple infusions,11 so a 6-week-interval approach appears to be acceptable and safe from the pharmacological point of view. St Clair et al.12 performed a pharmacokinetic modelling for escalation of infliximab based on the cohort of rheumatoid arthritis patients. This model concluded that shortening the dose interval to every 6 weeks would increase the median serum trough level 3.5-fold compared with 2.2-fold increase in trough level after a 50% increase in infliximab dose given every 8 weeks. However, the validity of these calculations was not confirmed by actual infliximab concentration measurements, and efficacy of shortened 6-week dosing intervals was not clinically evaluated in the study.
Arguably, shortening the dosing interval to 5 mg/kg every 6 weeks is appropriate for patients with shortened response to infliximab, whereas double dosing (or interval halving) should be reserved for patients with complete or early LOR to the last infusion.8 Although this rationale is clinically sound, and has underlain physicians’ therapeutic choices for a majority of patients in our study as well, the clinical outcomes of these differing policies have not been previously investigated. Thus, we believe this study is important for being the first to compare between these two management approaches. The results suggest that escalation of the therapeutic regimen to once every 6 weeks appears to be at least as effective as doubling the dose or halving the interval, especially for patients with late postinfusion LOR (re-emerging symptoms 5–7 weeks postinfusion). This preliminary evidence supporting the validity of the 5 mg/kg/6 weeks intensification policy is also important given the significant costs incurred by these escalation regimens. In fact, based on published U.S. costs of $662/100 mg infliximab and $193 per infusion,13 keeping a 60-kg patient on 5 mg/kg/6w for 12 months would cost US$19 611 compared with US$24 990–26 148 for the double-dose strategies, amounting to a $5379–6537 savings in cost per patient per annum.
The overall rate of primary nonresponse to the first escalation was 32%, and many of the responding patients subsequently lost response to the escalated regimen within <1 year of treatment. Nevertheless, an important observation of the study is that nearly 40% of patients without a sustained response to the first escalation (either primary or secondary nonresponders) may still regain response to a second elevation of infliximab dose or further shortening of the dosing interval. Taken together, dose-intensification policy (with either one or two dose increases) results in an approximately 50% rate of sustained response at 12 months after LOR to standard maintenance therapy.
A major limitation of this retrospective study is the absence of response criteria based on clinical scoring systems. However, from the practical point of view, the patient’s report and the clinician’s decision regarding continuation or change in the therapeutic regimen probably reflects the real-life assessment of the severity of the disease and the clinical decision making. Although the involvement of several centres could contribute to heterogeneity of the clinician’s assessment of the patient’s response, it also lends further support to the wider clinical relevance of the observations as they are derived from several tertiary centres rather than any single centre with a particular policy.
As alluded to above, another possible limitation stems from a basic difference between the two groups in the sense that physicians have opted to intensify the dose to once every 6 weeks in patients reporting shortened response of 5–7 weeks to the last infusion, whereas they tended to double dose in patients experiencing little effect of the infusion whatsoever. Nonetheless, upon subanalysing the efficacy of escalation strategies for patients with late postinfusion LOR, 5 mg/kg/6w was at least as effective as double dosing. The strategies were also comparable when applied for patients with early postinfusion LOR, albeit the numbers of patients in this subanalysis were small. Thus, the present results are clinically pertinent for substantiating that the two approaches are comparable, especially for patients with late postinfusion LOR (re-emerging symptoms 5–7 weeks postinfusion). Nonetheless, a cautionary note should be placed, as this study was not designed as a non-inferiority study, and can not definitively exclude the presence of a difference – albeit small – in the efficacy of the two policies.
Finally, infliximab drug level and presence or absence of ATI were previously shown to correlate with LOR14–16 and to be helpful in directing therapy,17 but were mostly unavailable for the present study patients. Colonoscopy findings before/after dose-adjustment were also unavailable. Although these shortcomings do not affect the validity of the observations, it would be important in the future to analyse the rates of regained response by different escalation protocols in association with drug level, ATI status and endoscopic mucosal healing.
In conclusion, in patients with CD and LOR to infliximab, escalation of the infliximab dosing to once every 6 weeks appears to be at least as effective as doubling the dose or halving the dosing interval to every 4 weeks, and results in sustained response in 40% of patients. However, these preliminary data should be corroborated by a larger scale and preferably a prospective controlled study comparing the regained response rate to 5 mg/kg/6w vs. the double-dose strategy in patients with LOR to infliximab, stratified by early or late postinfusion re-emergence of symptoms.