The phase III VISIBLE studies investigated de novo treatment with SC vedolizumab. However, studies on switching patients that are on established maintenance treatment with IV vedolizumab to SC treatment are largely lacking. We report on a switch from IV to SC vedolizumab maintenance treatment in 89 adult IBD patients in a real-world setting with a follow-up time of 6 months and for a subgroup 12 months. Our results show that the levels of therapeutic efficacy, quality-of-life and adverse events were highly similar before as compared to after the switch with a high degree of drug persistence, and that the patients were in general very satisfied with being transferred to self-administered SC treatment.
Faecal calprotectin levels showed a statistically significant decrease for the cohort as a whole and for CD patients, while levels remained unchanged for UC patients. However, absolute levels were low and the observed decreases may not be clinically relevant. On the other hand, subclinical changes in faecal calprotectin levels are considered to precede changes in clinical disease activity[21–24] and decreases of this type may further stabilise a state of clinical remission. Drug persistence was high with 95.5% of patients remaining on treatment after 6 months, and 88.5% after 12 months. These numbers are in line with those reported for IV vedolizumab treatment, ranging from 60–95% after 12 months.[25–27]
Our evaluation of the outcome of the switch included thorough investigations of clinical disease activity, applying two activity indices for CD (patient-based HBI and PRO2-CD) and two for UC (SCCAI and PRO2-UC), analysed by both median values and by proportions of patients in remission. All of these analyses corroborated the faecal calprotectin data, showing either unchanged disease activity levels after the switch in both CD and UC patients, or as in the case of SCCAI levels, a statistically significant improvement. For the 10 patients with perianal CD, the patient-based HBI questionnaire was of particular interest since it included separate questions regarding active perianal fistula, perianal abscesses and anal fissures. At baseline, 3/10 had an active perianal disease but after the switch the number was 2/10 at follow-up. From the literature, it seems that vedolizumab may have some therapeutic effect on perianal CD in a subset of patients, but that the effectiveness overall is moderate.[28–31] Our results do not contradict this view, but one should be cautious regarding conclusions given the low number of patients with perianal CD.
We also performed a subgroup analysis of patients with limited ileal CD, which showed measurable levels of faecal calprotectin with a numerical decrease after the switch. This confirms that faecal calprotectin was an adequate readout parameter also for this subset of CD patients, which has been debated but several recent studies have shown that faecal calprotectin is a sensitive measure of disease activity also in cases with limited ileal disease.[32–35]
The SC dose of 108 mg every 2 weeks was chosen by the manufacturer with the intent to provide patients with similar average serum concentrations at steady state, as the IV dose of 300 mg every 8 weeks. However, it is unclear whether average serum concentrations directly translate into levels of therapeutic efficacy. In addition, it is possible that the altered pharmacokinetics that comes with SC administration affect the various mechanisms of action of vedolizumab (i.e. those suggested to take place in the circulation compared to within tissues) in different ways.[1–3] Although the VISIBLE studies gave us an indication as to what serum levels are common with SC vedolizumab at standard dose, the studies did not address which levels are therapeutically optimal. In our study, serum vedolizumab trough concentrations at steady state were approximately twice as high during SC as compared with IV treatment. These findings are in line with the VISIBLE studies[4,5] and the study by Ventress et al. Our results suggest an inverse relationship between serum vedolizumab trough levels and faecal calprotectin levels with vedolizumab given IV. However, after 6 months with SC vedolizumab at standard dose, this correlation was not seen. This change was primarily observed in CD patients, which also displayed a statistically significant decrease in faecal calprotectin levels after having switched to SC treatment. Our subgroup analyses of patients that had been on optimised IV dosing did not show any signs of disease worsening in terms of remission rates, clinical index scores, biomarker levels or drug persistence, after the switch to standard SC dosing. Interestingly, patients on standard IV dosing showed a statistically significant improvement in faecal calprotectin levels on SC treatment, while other outcome measures remained unchanged. Taken together, these results suggest that some patients were underdosed when being on standard IV dosing and that they were more adequately dosed (or potentially overdosed at the group level) on SC standard dosing.
Ventress et al. suggested that the first dose of SC vedolizumab should be given 28 days after the last IV dose. This was based on the assumption that the serum drug concentrations observed in the VISIBLE studies are therapeutically the most appropriate (although this has not been studied) and that the drug levels should be kept at or above this limit. With IV vedolizumab, patients' drug levels are below this limit during the entire second half of the 8-week dosing interval. There is no evidence that the limited time that serum concentrations are below the SC serum steady-state levels in the VISIBLE studies increases the risk of relapse, nor for dose-dependent toxicity, if the first SC dose is given in close proximity to the last IV dose.[36,37] Thus, with current knowledge and with support from our data we would argue that the first SC dose may be administered when the next IV dose would have been given, or earlier due to potential practical aspects.
In our cohort, the rates of adverse events were similar before and after the switch, and no serious adverse events were reported. Some of the reported symptoms, including fatigue, headache, nausea and arthralgia, were transient and lasted 1–2 days after injection. The time to the maximum serum concentration after administration of vedolizumab subcutaneously is on average 7 days with a variation between 3–14 days. Such transient reactions are thus not likely to be an effect of the drug per se but more likely representing nonpharmacological potentially immune-mediated adverse effects,[38,39] alternatively representing a nocebo effect. Investigating local injection reactions, moderate discomfort, pain or burning sensations were reported by 5%–11% of patients, and corresponding severe reactions by 1% of the patients. Conversely, 88%–94% reported none or only mild local injection reactions. These results are in line with the VISIBLE studies as well as with data for other SC biologics. SC vedolizumab contains citrate which has been pointed out to be causing pain, but studies that have addressed this issue underscore that citrate is merely one of several factors that may affect potential pain sensation at SC injection and that some of the studies attributing pain at the injection site to citrate are difficult to interpret since citrate was one of several factors modified.[42–44] Other factors that may be equally important in this context are other buffers commonly used such as phosphate and histidine, the buffer concentration, injected volume, solution temperature, pH, osmolality, needle gauge, injector device, injection speed, injection technique and low body weight.[42–44]
We also investigated various aspects of the patients' experience with the injector pen and the switch from IV to SC treatment. Overall patients found the injector pen to be user-friendly and they were very satisfied with switching to SC treatment, which was reflected in all aspects explored. However, this dataset can also be used to illuminate the group of patients, albeit small (2%–9%), that preferred IV infusions. Thus, SC administration may not be the best option for all patients. One caveat with SC treatment is that it may be more difficult to ensure patient compliance.[46,47] Hence, for patients where compliance historically has been a problem or if risk factors for non-adherence are present, IV therapy may be advisable.
Evaluations of health-related quality-of-life using the SHS instrument[13,14] showed no statistically significant differences after the switch, but there was a slight numerical trend towards improved overall quality-of-life as well as better symptom-related and social function-related quality-of-life in patients with CD. These findings underscore the high level of satisfaction regarding the switch.
The annualised cost of SC vedolizumab maintenance treatment was calculated to be 15.0% lower than for IV maintenance treatment. Another structural benefit was that nurse resources were liberated for other work tasks. This was especially valuable in times of a pandemic when the number of nurses at the outpatient clinic had to be diminished to enable staffing of Covid-19 wards. In addition, avoiding hospital visits in this context was desirable to prevent transmission of the virus.
This study had some important limitations. Firstly, there was no control group that was continued on IV treatment. Secondly, patients were not evaluated endoscopically. Lastly, anti-drug antibodies were not measured.
In conclusion, this study shows that a switch from IV to SC vedolizumab maintenance treatment can be done with maintained efficacy, safety and tolerability, including in patients on optimised IV vedolizumab dosing. In addition, patient satisfaction regarding the switch was overall high, although for a small proportion of patients IV treatment may be advisable. The appropriate window for serum vedolizumab concentration to target for combined optimal efficacy, patient convenience and cost-effectiveness during SC maintenance treatment, is still unclear and should be addressed in future studies.
This work was made possible through financial support from the Healthcare Region of Southern Sweden, and by grants to researchers in public health care from the Swedish government (ALFSKANE-539811) to Jan Marsal.
We would especially like to thank research nurses Ida Kapusta and Ann Tornberg at the Gastroenterology Outpatient Clinic at Skane University Hospital for their excellent work in managing patient contact and communication throughout the study as well as for being instrumental in the data capturing process. We would also like to thank the staff at the same outpatient clinic for facilitating this project and for all the hard work during the pandemic.
Guarantor of the article
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.
Aliment Pharmacol Ther. 2022;55(11):1389-1401. © 2022 Blackwell Publishing