The usual maintenance treatment regimen with intravenous infliximab (IFX) in patients with inflammatory bowel disease is 5 mg/kg body weight every eight weeks. However, annually 10–15% of patients who initially respond to IFX treatment experience secondary loss of response. One of the strategies available to manage this situation is treatment intensification. This includes increasing the frequency of administration (every 4 or 6 weeks) and/or increasing the dosage (10 mg/kg).1,2 Intensification of treatment achieves recovery of response in more than half of these patients. However, there are no prospective, controlled studies available to demonstrate that the two strategies are equivalent.
During the SARS-CoV-2 pandemic in 2020, most hospitals tried to minimise the exposure of immunocompromised patients to the healthcare environment. In our centre, IFX intensification was traditionally done by increasing the frequency of administration, as was done in the clinical trial that demonstrated the utility of IFX as a maintenance treatment in Crohn’s disease. In the context of the pandemic, we decided to change the intensification schedule (by increasing the interval and dose) in patients on intensified treatment due to loss of secondary response and in clinical (defined by Harvey-Bradshaw and Mayo index) and biological (defined by C-reactive protein and faecal calprotectin) remission, assuming that the change would not interfere with efficacy. This changed the regimens from 5 mg/kg every four weeks to 10 mg/kg every eight weeks or from 5 mg/kg every six weeks to 7.5 mg/kg every eight weeks.
A total of 10 patients were subject to a change of intensification regimen (Table 1). After a mean follow-up of 16 ± 6 weeks, we observed no difference in mean C-reactive protein and faecal calprotectin levels before and after the change in regimen (10.0 ± 13.3 mg/l and 5.0 ± 3.5 mg/l, p = 0.26; 160.3 ± 101.7 mg/kg and 162.7 ± 96.2 mg/kg, p = 0.97). However, three patients experienced clinical relapse, defined by recurrence of symptoms and elevation of faecal calprotectin levels, which was resolved by a return to the previous intensified regimen in two and a new dose intensification in the third. Since we do not proactively measure anti-TNF levels at our centre but do obtain regular samples for analysis if necessary, IFX levels were measured retrospectively before and after the change of regimen, with no significant differences (2.89 ± 2.42 ng/ml; 2.49 ± 2.78 ng/ml; p = 0.96). Only one patient had undetectable drug levels and elevated IFX antibody titres, despite remaining clinically stable.
Baseline characteristics of the patients according to their clinical progress after the change of regimen.
| Clinical progress after change of intensified regimen | Loss of response(n = 3) | Clinical stability(n = 7) |
|---|---|---|
| Male, n | 2 | 5 |
| Age (years), mean ± SD | 50 ± 10 | 48 ± 14 |
| Active smoker, n | 1 | 1 |
| Type of inflammatory bowel disease, n | ||
| Crohn’s Disease | 1 | 6 |
| Ulcerative colitis | 2 | 1 |
| Perianal disease, n | 1 | 1 |
| Concomitant immunosuppressive therapy, n | 2 | 6 |
| Previous intensified regimen, n | ||
| 5 mg/kg every 4 weeks | 1 | 3 |
| 5 mg/kg every 6 weeks | 2 | 4 |
| Time on intensified IFX treatment (months), mean ± SD | 46 ± 42 | 25 ± 24 |
| Pre-switch C-reactive protein (mg/l), mean ± SD | 17.8 ± 22.8 | 6.7 ± 7.04 |
| Pre-switch IFX levels (ng/ml), mean ± SD | 4.34 ± 3.0 | 2.17 ± 1.95 |
No statistically significant differences were found between groups for any of these characteristics.
Intensification of anti-TNF therapy, either by dose escalation or interval shortening, is an effective measure to address secondary loss of response. Mathematical modelling in rheumatoid arthritis patients shows that shortening the administration interval would be superior to increasing the dose of IFX, as higher and more stable blood drug levels are achieved.3 Pharmacokinetic models applied in inflammatory bowel disease show that dose or interval adjustment based on parameters such as serum albumin, patient weight and gender offers advantages over fixed dosing.4 However, a recent meta-analysis of 26 studies in patients with inflammatory bowel disease concludes that the short- and long-term response rate is similar for both strategies.5 For these reasons, the two regimens are now considered equivalent.
In our case series, the change to an intensification regimen resulted in a reduction in the use of healthcare resources (fewer day hospital sessions) and greater patient comfort, without increasing the pharmacological cost. However, despite being performed on patients in clinical and biological remission, it was accompanied by short-term treatment failure in 30% of them. We believe that the limited number of cases and the lack of evaluation of endoscopic activity do not allow us to draw firm conclusions.
In conclusion, switching from a frequency-intensified to a dose-intensified IFX regimen resulted in early loss of response in one third of patients. Comparative quality studies between the two strategies are needed.
FundingThis study did not receive any financial support.
Conflicts of interestThe authors declare the following interests/personal relationships that could be, considered conflicts of interest: AbbVie, Adacyte Therapeutics, Biogen, Celltrion, Galapagos, Gilead, GoodGut, Imidomics, Janssen, Kern Pharma, MSD, Pfizer, Roche, Samsung, Takeda, Tillots.
