Vedolizumab vs. ustekinumab as second-line ther­apy in Crohn’s dis­ease in clinical practice

Summary

Background:

Vedolizumab (VDZ) and ustekinumab (UST) have become available for the treatment of Crohn’s dis­ease (CD), however, due to limited clinical experience, the optimal treatment strategy after a failure of anti-tumor necrosis factor (anti-TNF) has yet to be elucidated. In our study, we aim to evaluate the ef­ficiency and safety of VDZ and UST as second-line clas­ses of bio­logical ther­apy in a head-to-head man­ner in comparable populations of CD patients.

Methods:

Consecutive patients with CD who have previously been treated with anti-TNF ther­apy were included. Patients were fol­lowed at regular intervals coincident with drug applications and clinical activity (HBI –  Harvey-Bradshaw Index), inflam­matory markers (C-reactive protein, fecal calprotectin) and adverse events were recorded. The primary outcome was the proportion of patients in clinical remis­sion in weeks 30– 32 (HBI ≤ 4), the clinical response in terms of HBI decrease, and the withdrawal rate.

Results:

Forty-five patients with VDZ and 50 with UST were included. Both groups were comparable in all the evaluated parameters with the exception of the male-to-female ratio and the proportion of patients with penetrat­­ing dis­ease phenotype. The proportion of patients in clinical remis­sion increased from 44.4% at baseline to 58.1% in weeks 30– 32 in the VDZ group and from 55.1% to 63.2% in the UST group; however, the increase was not statistical­ly significant. The mean paired HBI dif­ference between weeks 30– 32 and baseline reached – 1.94 ± 5.14 (p = 0.05) in the VDZ cohort and – 2.94 ± 5.91 (p = 0.01) in the UST cohort. The proportion of patients in steroid-free clinical remis­sion increased from 38.8% to 62.5% in the UST cohort (p = 0.04), and from 33.3% to 45.2% in the VDZ (p = 0.67). Six patients on VDZ and none on UST discontinued the treatment.

Conclusion:

Our study demonstrated a comparable ef­ficacy of VDZ and UST with respect to the rate of clinical remis­sion and bio­marker response; however, the steroid-spar­­ing ef­fect of UST was more prominent. There is a need for prospective randomized head-to-head trials to as­sess the optimal position of new bio­logical agents in the treatment of patients with CD.

Key Words:

inflam­matory bowel dis­eases –  bio­logical ther­apy –  vedolizumab –  ustekinumab

Introduction

Biological treatment is an established modality in the management of patients suf­fer­­ing from inflam­matory bowel dis­ease (IBD), however, only anti-tumor necrosis factor α (anti-TNF) antibodies were available for those patients for a long time. Despite their benefits in the management of IBD, anti-TNFs suf­fer from two main drawbacks: limited long-term ef­ficacy, and a relatively high risk of adverse events [1,2].

In recent years, two new bio­logical agents target­­ing dif­ferent inflam­matory pathways were granted market­­ing authorization for the treatment of Crohn’s dis­ease (CD) –  vedolizumab (VDZ) in 2014 and ustekinumab (UST) in 2016.

VDZ is a gut-selective monoclonal antibody target­­ing α4β7 integrin, which is preferential­ly expres­sed at a surface of a specific subgroup of T helper (Th) memory lymphocytes that take part in induc­­ing inflam­matory reactions in the gut [3]. It can be used to treat moderate to severe CD or UC after a failure or intolerance of conventional ther­apy or anti-TNF, and the recom­mended dos­­ing regimen in CD includes 300 mg intravenous infusion at weeks 0, 2, and 6, and then every 8 weeks with the pos­sibility of dos­­ing at week 10 in the event of insuf­ficient response.

UST is a ful­ly human monoclonal antibody target­­ing a com­mon subunit of interleukins (ILs) 12 and 23, thus block­­ing the pathway lead­­ing to the dif­ferentiation of Th cel­ls towards Th1 and Th17, which are expected to play a central role in CD pathology [4]. UST can be used to treat moderate to severe CD with inadequate response to or intolerance or contraindication of conventional or anti-TNFα ther­apy. UST treatment is initiated with a single intravenous infusion of a dose based on body weight fol­lowed by 90 mg subcutaneous injection every 8 or 12 weeks.

However, the broadened spectrum of available bio­logics is not yet accompanied by suf­ficient data from clinical practice that would ef­ficiently guide clinical decisions. Head-to-head clinical trials would provide the com­munity with the best data on the choice of bio­logics in dif­ferent phases of the dis­ease. In our single-centre observational study, we retrospectively evaluated the ef­ficiency and safety of VDZ and UST as second-line clas­ses of bio­logical ther­apy in a head-to-head man­ner in comparable populations of CD patients.

Methods

Patients

Consecutive patients with CD from a single tertiary centre who had been treated previously with anti-TNFα ther­apy (infliximab, adalimumab, or both), and in whom either VDZ or UST ther­apy was indicated between 2/ 2016 and 11/ 2018, were included. In this observational study, the patients were not matched, however, a comparison of all baseline characteristics in both cohorts was performed in order to reveal any potential significant dif­ferences between the groups.

Data col­lection

Baseline data includ­­ing age, dis­ease duration, smok­­ing status, dis­ease phenotype accord­­ing to Montreal clas­sification [5], previous CD-related surgery, and concomitant medications were recorded. The data were extracted from the CREdIT registry, the Czech national registry of bio­logical and in­novative ther­apy in IBD patients, as well as medical records, and as­ses­sed retrospectively. In our clinical practice, the patients are fol­lowed at regular intervals coincident with the drug applications. Dur­­ing each visit a blood sample is taken for analysis of the blood count and bio­chemistry, and a stool sample is col­lected for the measurement of fecal calprotectin (FC). The intervals between infusions as well as the dose of the drug were determined by a treat­­ing physician accord­­ing to the patients’ needs. The clinical response was evaluated by the Harvey-Bradshaw index (HBI), which is routinely calculated dur­­ing every visit. The need for dose optimization and the occur­rence of any adverse events dur­­ing the bio­logical treatment were recorded. At the end of the fol­low-up the presence of concomitant medication was evaluated again.

Outcome measures

Clinical remis­sion defined as HBI ≤ 4 and steroid-free clinical remis­sion were as­ses­sed at week 32 for UST and week 30 for VDZ. The clinical and bio­logical responses were evaluated as a change in HBI and a change in bio­markers (C-reactive protein (CRP) and FC) between baseline and the end of the fol­low-up. The withdrawal rate from both bio­logics due to lack of ef­ficacy and/ or adverse events was recorded.

Statistical analysis

Standard descriptive statistical analyses were performed, includ­­ing frequency distributions for categorical data and the calculation of the mean and standard deviation and/ or range for continuous variables. The dif­ferences between continuous variables at baseline were analyzed by a t-test or Man­n-Whitney test, and between week 0 and weeks 30– 32, by a Wilcoxon test. The evaluation of categorical variable dif­ference was performed by Fisher’s exact test. The statistical tests were performed us­­ing GraphPad Prism (version 8.0.1). A p-value < 0.05 was considered sta­tistical­ly significant.

Results

Patient characteristics

In total, 95 CD patients were analyzed, 45 patients were treated with VDZ and 50 with UST. The demographic and clinical characteristics of both cohorts at baseline are sum­marized in Tab. 1. Both groups were comparable in all evaluated parameters with the exception of the male-to-female ratio (75.6% females in the VDZ vs. 52.0% in the UST group; p = 0.02) and the proportion of patients with penetrat­­ing dis­ease phenotype (6.7% in the VDZ vs. 30.0% in the UST; p = 0.004).

The mean age at VDZ and UST ini­tiation was 40.5 ± 15.6 years and 37.0 ± 10.8 years and the mean dis­ease duration at that time reached 12.2 ± 8.4 years and 14.2 ± 8.5 years, respectively. Perianal dis­ease was pre­­­s­ent in about 20% of the patients and the most frequent dis­ease localization was ileocolonic. At least one previous abdominal surgery due to IBD was pre­s­ent in over two-thirds of the patients in both cohorts. Every patient had been treated previously by at least one anti-TNF agent, however, two or more dif­ferent agents were used in about 60% of the patients in both groups. Nearly one-half of the patients had concomitant im­munosuppres­sion with either methotrexate or azathioprine. Between 20 and 30% were treated with systemic corticosteroids. The baseline inflam­matory markers were similar in both groups with CRP of 11.5 mg/ L and FC of 1500 μg/ g. Clinical remis­sion was present in 44.4 and 55.1% of the patients in the VDZ and UST groups, respectively.

Treatment ef­ficacy

The proportion of patients in clinical remis­sion accord­­ing to HBI increased from 44.4 to 58.1% in the VDZ group and from 55.1 to 63.2% in the UST group, however, in neither of the groups did the dif­ference reach a statistical significance (Graph 1). The mean HBI decreased significantly between baseline and week 30 in the VDZ group (6.58 ± 4.90 vs. 4.29 ± 3.67; p = 0.03), but in the case of UST the dif­ference wasn’t significant (5.76 ± 5.00 vs. 4.68 ± 4.32; p = 0.82 (Graph 2). The mean paired HBI dif­ference between weeks 30– 32 and baseline was, however, significantly dif­ferent from zero in both bio­logics (– 1.94 ± 5.14; p = 0.05 in the VDZ cohort and – 2.94 ± 5.91; p = 0.01 in the UST cohort) (Graph 3).

The steroid spar­­ing ef­fect was well pronounced in the UST group, where the proportion of patients with systemic corticosteroids decreased from 32.0% at baseline to only 5.9% at week 32 (p = 0.01). In the VDZ group, 20.0% of the patients had systemic corticother­apy at both baseline and at week 30. The proportion of patients in steroid-free clinical remis­sion increased from 38.8% at baseline to 62.5% at week 32 in patients with UST (p = 0.04) and from 33.3 to 45.2% in the VDZ group, however, without reach­­ing statistical significance (Graph 4).

No decrease in the evaluated laboratory markers of inflam­mation was observed dur­­ing the fol­low-up period in either of the cohorts. The mean CRP at baseline and weeks 30– 32 was 11.4 ± 18.3 vs. 12.1 ± 19.4 mg/ L (p = 0.48) in the VDZ cohort and 11.5 ± 11.9 vs. 9.5 ± 11.9 mg/ L (p = 0.85) in the UST group. For FC, the measured values were 1,506 ± 1,597 vs. 1,407 ± 1,799 μg/ g (p = 0.24) and 1,569 ± 1,473 vs. 929 ± 1,475 μg/ g (p = 0.15), respectively (Graph 5 and 6).

The proportions of patients requir­­ing an intensified dos­­ing regimen was very similar at the end of the fol­low-up, reach­­ing 14.3% (5/ 35) of the patients in the VDZ group and 14.7% (5/ 34) of the patients in the UST group, however, 28.6% (14/ 42) of the patients with VDZ also received an intensified induction regimen with an infusion at week 10.

In total, 6 patients had to discontinue the ther­apy with VDZ until the end of the fol­low-up –  4 due to primary non-response and 2 after adverse reactions. In the UST group none of the patients has stopped the treatment so far.

Safety

No patient with UST had discontinued treatment due to adverse events by the end of the fol­low-up. Two patients with vedolizumab stopped ther­apy as a result of adverse events, one due to an al­lergic infusion reaction and one refused to continue with the ther­apy after newly developed acne. The patient with the al­lergic reaction was switched directly to UST. The patient with adverse skin ef­fects remained on thiopurines and started UST one year afterwards.

Twenty-four adverse events were registered in both bio­logics dur­­ing the fol­low-up (Tab. 2). This represents 117.7 adverse events per 100 patient-years in case of UST and 103.5 per 100 patient-years in VDZ. Four cases of infusion reaction occur­red in the VDZ group only. In both groups there was a single case of opportunistic mycotic infection of the esophagus and one case of molar pregnancy occur­red in a patient on UST. No patients died dur­­ing the fol­low-up.

Discus­sion

The present study performed an indirect comparison of the ef­ficacy and safety of new bio­logical agents –  VDZ and UST –  in patients with CD in a real clinical practice. Both agents were shown to have similar mid-term ef­ficacy with regard to clinical remis­sion and bio­marker response. However, more patients on UST were able to withdraw corticosteroids compared to VDZ. The safety profile was favorable, with no dif­ference between the treatment groups.

Our find­­ing of a mostly comparable ef­ficacy between VDZ and UST is in line with the previous retrospective comparative studies report­­ing similar therapeutic ef­ficacy between these agents in patients with CD [6,7]. Similarly, an indirect comparison of ran­domized control­led trials (RCTs) of VDZ and UST revealed no dif­ference regard­­ing the clinical remis­sion of induction and maintenance ther­apy in patients with previous anti-TNF failure [8]. Likewise, recent network meta-analysis of RCTs compar­­ing the relative ef­ficacy of bio­logicals, includ­­ing anti-TNFs, VDZ, and UST, as first- and second-line agents in patients with moderate to severe CD revealed no superiority of either agent (VDZ or UST) in individuals with prior exposure to anti-TNFs [9]. However, the relevance of these results for clinical practice is limited, since studies with dif­ferent patient populations and study designs were compared. Thus, only properly designed head-to-head studies may provide the optimal estimation of the therapeutic ef­ficacy of bio­logical treatments.

In our study, UST was shown to have a better steroid-spar­­ing ef­fect than VDZ. Indeed, the proportion of patients on steroids did not change dur­­ing the VDZ treatment. This is in contrast to other retrospective comparative studies, which reported similar rates of steroid-free remis­sion between VDZ and UST [6,7]. The dif­ference observed in our cohort probably indicates the ef­fect of treatment selection bias despite the similar baseline characteristics of the patients. Further, mainly prospective randomized studies should address this is­sue.

The rate of clinical remis­sion of more than 50% observed in both VDZ- and UST-treated patients in our study might seem too high compared to the results of clinical trials [10,11]. However, approximately one-half of our patients in each group were in clinical remis­sion, defined by HBI, at the start of bio­logical treatment despite high levels of bio­markers (FC, CRP), indicat­­ing the presence of active inflam­mation. This observation reflects the everyday clinical practice and points to a limitation of clinical indices in the estimation of therapeutic ef­ficacy.

The evaluation of objective markers of inflam­mation –  CRP and FC –  revealed no significant decrease dur­­ing the study in either treatment group. It is likely that the lack of therapeutic ef­ficacy observed in both cohorts results from the over­all treatment refractoriness of the study population, where all the patients were anti-TNF failures with more than one-half of them fail­­ing at least two anti-TNF agents.

The big advantage of both clas­ses of new bio­logics over anti-TNFs seems to be their good safety profile, which was also demonstrated in our study. The gut selective mechanism of the action of VDZ provides an optimal treatment option for patients with an increased risk of infectious and non-infectious complications [12,13]. Although UST has systemic ef­ficacy, the data from clinical trials, their extension observations, and cohort studies have reported favorable safety results thus far [14]. Furthermore, findings from the long-term registry of bio­logical and non-bio­logical treatment of psoriasis (PSOLAR) suggest a low risk of infectious complications in the use of UST [15].

There are several limitations to the study which have to be mentioned. Firstly, the retrospective observational design of the study precludes an adequate comparison of the treatment ef­ficacy between the bio­logicals despite similar baseline patient characteristics. Furthermore, the sample size of the cohorts was small and might have led to a lack of statistical power in some comparisons. Final­ly, the fol­low-up of the cohorts was relatively short, and no endoscopic as­ses­sment of treatment ef­ficacy was performed.

In conclusion, our study demonstrated the comparable ef­ficacy of VDZ and UST with respect to the rate of clinical remis­sion and bio­marker response. However, UST seemed to be superior to VDZ as a steroid-spar­­ing agent. There is a need for prospective randomized head-to-head trials to as­sess the optimal position of new bio­logical agents in the treatment of patients with CD.

This research was supported by IBD-Comfort Foundation.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for bio­­­­medical papers.

Submitted: 16. 2. 2019

Accepted: 19. 2. 2019

MUC. Martin Kolář

IBD Clinical and Research Centre

ISCARE I.V.F. a.s.

Jankovcova 1569/ 2c

170 04 Prague 7

Czech Republic

martin.kolar@gmail.com