The results of this systematic review showed that most of the pediatric data on the effectiveness and safety of vedolizumab for the treatment of IBD were descriptive and the evidence were inadequate, as all the studies included were case series without randomized controlled trails (RCTs).
Overall, we found 0%-35% of CD patients achieved clinical remission in short-term therapy, compared to that of 20%-64% in UC patients. During maintenance therapy, 17%-73% of CD patients and 20%-77% of UC/IBD-U patients achieved clinical remission. Approximately one-third to one half of CD patients and 20%-75% of UC/IBD-U patients had clinical response with quite small sample size. These findings might suggest that lower therapeutic response was achieved in CD compared with UC, which was consistent with previously published studies in adults. Randomized controlled trials of GEMINI 1 and 2 found that compared with CD, the response and remission rates in UC were higher at both 6 weeks (47.1% and 16.9% vs. 31.4% and 14.5%) and 52 weeks (56.6% and 41.8% vs. 39.0% and 43.5%) [10, 11]. Canadian and Hungarian real-world cohorts also showed significantly greater clinical remission and response rate for UC compared with CD [31, 32]. However, opposite results reported by Gabriele et al, cohort in Italy showed better results for CD patients, with higher clinical response and remission rate compared with UC at 14 weeks (85% and 69% vs. 52% and 30%), 24 weeks (84% and 61% vs. 56% and 26%) and 52 weeks (59% and 45% vs. 25% and 20%) [33]. The difference in clinical response and remission rate could be attributed to quite small sample size and differences in patients baseline characteristics variability: the characteristic of patients involved varied in IBD phenotype, disease severity at vedolizumab initiation, disease duration.
Steroid-free remission, whether clinically or endoscopically is an important treatment goal for pediatric IBD [20, 34], as corticosteroids have potentially serious side effects associated with long term use including linear growth restriction, and osteopenia amongst many others [35]. In a meta-analysis on adult population, approximately one-quarter of CD or UC achieved CS-free clinical remission at 14 weeks, while 31% of CD and 42% of UC of that at 12 months [36]. Our study seemingly showed similar results. In our study, we found 0%-19% of CD and 20%-44% of UC/IBD-U patients achieved CS-free clinical remission at 14 weeks. Higher rate was identified for UC (40%-71%) compared with CD (13%-33%) at 22 weeks. However, opposite results existed. In a real-world study by Fabiana et al, better results for CD were identified at any follow-up time [ie, between 8-12 weeks 53.6% vs.18.7% (UC); 30 weeks 56.5% vs. 25% (UC); 52 weeks 53.6% vs. 35.4%(UC)], as much more CS ongoing UC were initially involved [45.8% vs. 24.6%(CD)] [37].
Although mucosal healing is a critical IBD therapy goal associated with sustained clinical remission, it is too burdensome for children to frequently undergo endoscopy. Therefore, only two studies of small sample size reported mucosal healing rates ranging from 17%-39% for CD and 15%-34% for UC/IBD-U with median follow-up time over 6 months. In addition, the definition of mucosal healing is still controversial. Most investigators agree that an endoscopic Mayo subscore of 0 for UC, and simple endoscopic score for Crohn’s disease (SES-CD) 0-2 for CD [20]. However, one study involved in our review defined mucosal healing more strictly, including a composite of both endoscopic (macroscopic) and histologic indices [29]. In adult population, mucosal healing rates are reported as 21.2-41.9% for CD and 15%-57.1% for UC regardless of patients’ baseline characteristics [31–33, 38].
Whether anti-TNF-experienced or not is the factor influencing the outcome of vedolizumab treatment has been disputed. Two post hoc analyses from the GEMINI studies assessed the efficacy of vedolizumab in CD and UC based on previously anti-TNF experienced patients [39, 40]. Results showed for CD, there were higher response and remission rates in patients who were anti-TNF-naïve compared with anti-TNF-experienced, and the advantages persisted to week 52 [39]. In UC patients, similar outcomes were found. Compared to placebo, patients naïve to anti‐TNF had higher rates of response than patients with anti‐TNF failure at week 6, whereas during maintenance therapy, there were no significant difference with placebo in both groups and between the two groups [40]. In contrast, however, some real-world clinical studies indicated that there was no impact of previous anti‐TNF exposure on response or maintenance of remission though the sample size of TNF–naïve patients were small [31, 41]. Chaparro et al found the remission rates of patients who were anti-TNF naïve, with failure to 1 anti‐TNF and failure to >1 anti‐TNF at week 14 were 57.6%, 51.2% and 44% respectively [41]. And study by Kotze et al demonstrated that previous failure to anti‐TNF agents was not associated with the efficacy of vedolizumab [31]. More interestingly, study by Mader showed previous treatment with anti-TNF agents was associated with a significantly lower efficacy of VDZ in UC but not in CD patients [42]. This might be attributed to longer disease duration for anti-TNF-experienced UC patients. In pediatric population, Jossen et al found higher rates of both endoscopic and histologic remission in anti-TNF-naïve patients compared to those who were anti-TNF-experienced (66% vs. 42%, 52% vs 33%, respectively) [29]. However, authors admitted these anti-TNF-naïve patients had slightly less severe disease at baseline compared with the anti-TNF-experienced patients. Therefore, this question deserves further investigation in the future.
With respect to safety, phase 2 and 3 trials showed a favorable safety profile of vedolizumab, with similar AEs incidence rate compared with placebo [43, 44]. Safety data from real-world cohort studies reported the total AE incidence rate was 23.6%, with infectious complication rate 7.8% [44]. In pre-marketing clinical trials, the most frequently reported AEs were respiratory tract infection [21.2/100 person-years (PYs)] and abdominal pain (12.1/100 PYs) [43, 44]. And real-world data showed respiratory tract infection (3.6%) and arthralgia (3.1%) were most common AEs [44]. Our findings were basically consistent with those from adult populations. The most prevalent AEs were respiratory tract infection and nausea and vomiting. Nevertheless, one study reported by Conrad et al reported 38% (8/21) experienced 12 serious adverse events that required hospitalization [25].
There are several limitations in our review. Initially, there was a significant heterogeneity in study design, including the threshold criteria of patients involved and definitions of remission, response and mucosal healing. Most studies used Pediatric Crohn’s Disease Activity Index (PCDAI) or Pediatric Ulcerative Disease Activity Index (PUCAI), but weighted Pediatric Crohn’s Disease Activity Index (wPCDAI), short Pediatric Crohn’s Disease Activity Index (shPCDAI) or partial Mayo score were also used. As to mucosal healing, endoscopic assessment alone was agreed by majority of investigators, but Jossen et al also evaluated histological changes [29]. Moreover, all the studies included were case series, some reported the data prospectively while the others used a retrospective approach, which may result in significant differences in clinical decision. In addition, there was no placebo-controlled trial with a standard protocol, which meant the effectiveness was not necessarily attributed to the intervention. The recurrent nature of CD additionally weakens the assessment of causal relationships between interventions and outcomes. Nevertheless, vedolizumab for pediatric patients is usually applied to patients with severe disease or those who are refractory to conventional therapies, which are unlikely to have spontaneous relief.
In spite of the above-mentioned shortcomings, we performed a comprehensive literature search. Although no RCTs were included, case series of vedolizumab therapy seemed to represent ‘real-world’ experience of pediatric population in different areas and medical centers and provide a deeper understanding of vedolizumab in heterogenous and more complex patient populations. Besides, the role of case series evidence in systematic reviews of health care interventions is especially suitable for reviews of rapidly developing pharmacological interventions and supporting evidence on safety, when case series are usually the only available clinical evidence [45] .