Safety and Efficacy of Biologic Therapies (Ustekinumab and Vedolizumab) in the Treatment of Inflammatory Bowel Disease (IBD): A Systematic Review

Inflammatory bowel disease (IBD) is a group of chronic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), that contribute to inflammation of the gastrointestinal tract, manifesting as bloody diarrhea, fecal urgency, bloating, cramping, and weight loss. IBD manifests as an exacerbation of these symptoms, which medications with high side effect profiles can manage; consequently, many novel therapies, including biologics such as ustekinumab and vedolizumab, have been developed over the years. This systematic review aims to assess the safety and efficacy of ustekinumab and vedolizumab in treating inflammatory bowel disease based on a comprehensive analysis of relevant studies. A thorough literature search was conducted to identify randomized controlled trials, post hoc analyses, case reports, observational cohorts, and meta-analyses involving ustekinumab and vedolizumab as treatment in IBD patients. The selected studies were critically evaluated for their methodology, patient characteristics, and outcomes. The analysis involved twelve distinct studies investigating the impact of ustekinumab and vedolizumab on individuals afflicted with inflammatory bowel disease (IBD). The findings revealed a notable trend: ustekinumab displayed a propensity for yielding higher rates of clinical remission in patients with ulcerative colitis (UC). Moreover, one study underscored substantial reductions in endoscopic disease activity in patients with Crohn's disease (CD) who were on ustekinumab. Similarly, ustekinumab exhibited promising outcomes in CD patients, including swift ultrasound responses and the achievement of transmural remission, particularly among those who were new to biologic treatments. In line with this, vedolizumab demonstrated early and considerable symptomatic improvements when used to treat both UC and CD patients. While both biologics showed promising results in inducing and maintaining remission, cautious monitoring is warranted due to the potential adverse events observed in some cases. Further research with larger sample sizes and longer follow-up periods is needed to establish a comprehensive understanding of the medications' effects on IBD patients.


Introduction And Background
Inflammatory bowel disease (IBD) comprises a group of chronic, immune-mediated conditions with multifactorial etiology, the two major phenotypes being Crohn's disease (CD) and ulcerative colitis [1].It is estimated that the prevalence of inflammatory bowel disease is approximately 1 million among residents in the United States and 2.5 million among residents in Europe, and an apparent increase in its prevalence has been observed in recently industrialized nations in Asia, South America, and the Middle East, and has subsequently developed into a worldwide ailment with increasing frequency across all continents [2].Since there is no definite cure for IBD, many conventional nonbiologic therapies like aminosalicylates, corticosteroids, and immunomodulators like methotrexate have been used to control symptoms.But, over the last two decades, significant advancements have been made in managing IBD, including the introduction of novel biologic therapies [3].Among these, vedolizumab [3] and ustekinumab have emerged as promising treatment options, demonstrating efficacy in inducing and maintaining remission in patients with IBD.
Ustekinumab is a human monoclonal antibody directed against the p40 subunit of IL-23, approved for patients with IBD.At the same time, vedolizumab (VDZ) is a humanized, gut-selective monoclonal IgG1 antibody that targets the heterodimer α4β7 integrin, inhibiting migration and leukocyte adhesion [4].Both drugs belong to a group of drugs called biologic therapies [5].Vedolizumab and ustekinumab, the newer biologic therapies, have a better safety profile than immunomodulators [6].The safety and efficacy of ustekinumab and vedolizumab in treating IBD have been investigated in numerous clinical trials and realworld studies.
However, to date, a comprehensive synthesis and analysis of the available evidence on the use of these biologic agents in IBD treatment are lacking.Therefore, this systematic review aims to address this gap by critically evaluating and synthesizing the existing literature on the safety and efficacy of ustekinumab and vedolizumab in managing IBD.
We aim to provide a robust and comprehensive overview of the current evidence base by employing a systematic approach.This systematic review will encompass a comprehensive examination, meticulous selection, and critical evaluation of pertinent research studies in accordance with established protocols such as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.The selected studies will encompass randomized controlled trials, observational studies, systematic reviews/meta-analyses, and case reports, ensuring diverse evidence sources.

Review Methods
The systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 [7].

Search strategy
We used PubMed, PubMed Central, Medline, Science Direct, and Multidisciplinary Digital Publishing Institute (MDPI) to search for the relevant literature on the topic.We used the keywords, i.e., IBD, treatment, vedolizumab, ustekinumab, safety, efficacy in combination, and Booleans AND, OR, to search all databases.The keywords and the following strategy were developed to search for relevant literature in PubMed's Medical Subject Headings (MeSH) database: (("inflammatory bowel diseases/drug therapy"[Majr] OR "inflammatory bowel diseases/prevention and control"[Majr] AND "vedolizumab" [Supplementary Concept] AND "ustekinumab/adverse effects"[MeSH] OR "ustekinumab/therapeutic use" [MeSH].

Inclusion and Exclusion Criteria
We selected the articles and literature published in the last five years; we included papers written only in the English language.Our selection criteria were limited to articles and research exclusively involving adult human subjects.
Articles for which the complete text of the papers was not extracted were eliminated from the analysis.Additionally, the review did not include research that focused on pediatric age groups.Grey literature and proposal articles were also not included.We transferred the selected articles to the endnote and removed duplicate papers.Each paper was individually screened through titles and abstracts by HA (first author).In the event of a dispute regarding eligibility, the concerns were deliberated with all remaining co-authors and ultimately resolved by mutual agreement.The papers included in the shortlist underwent a subsequent evaluation process, wherein the whole text of each item was carefully analyzed.Only those articles that were deemed relevant were further considered for assessment.Applying inclusion and exclusion criteria resulted in selecting articles that met the specified criteria and narrowing down the list.

Quality Assessment of Studies
The articles selected for further consideration underwent an evaluation of their quality using appropriate instruments for quality appraisal.The screening process required the participation of all co-authors.The quality of observational studies was evaluated using the Newcastle-Ottawa method, whereas the Assessment of Multiple Systematic Review (AMSTAR) tool was employed to examine systematic reviews.The Cochrane Risk of Bias Assessment Tool (version 2) was employed to evaluate the methodological quality of the randomized controlled trials.The systematic review only included studies that met the criteria for quality appraisal.

Study Identification and Selection
A total of 499 relevant articles were collected from all databases.A total of 30 duplicate articles were excluded before conducting a thorough screening process.These articles were screened by going through titles and abstracts, and then retrieving full-text articles; 24 articles were shortlisted after this process.These 24 articles were put through quality assessment, and 12 articles were then finalized for review.The selection process is shown in the following flowchart.
The process of selecting the research papers is depicted in Figure 1 of the PRISMA flowchart.The articles were assessed for eligibility using the relevant quality assessment appraisal tools.A comprehensive analysis was conducted on a set of five randomized controlled trials.Were the patient's demographic characteristics clearly described?Yes Yes Was the patient's history clearly described and presented as a timeline?Yes Yes Was the current clinical condition of the patient on presentation clearly described?Yes Yes Were diagnostic tests or assessment methods and the results clearly described?Yes Yes Was the intervention(s) or treatment procedure(s) clearly described?Yes Yes Was the post-intervention clinical condition clearly described?Yes Yes Were adverse events (harms) or unanticipated events identified and described?No No Does the case report provide takeaway lessons?Yes Yes

TABLE 3: Quality assessment of the case reports
The eligibility of observational studies was evaluated by employing appropriate quality rating tools.The findings of the quality appraisal are presented in Table 4.

TABLE 4: Quality appraisal using the Newcastle-Ottawa Scale
The quality assessment procedure for the systematic reviews is outlined in Table 5.

Meserve et al. [21]
Did the research question and inclusion criteria for the review include components of PICO? yes Yes Did the review report contain an explicit statement that the review methods were established prior to the review, and did the report justify any significant deviations from the protocol?Yes Yes Did the review authors explain their selection of the study designs for inclusion in the review?

Outcomes Measured
The primary outcome studied from the finalized research papers was to assess the safety and efficacy of ustekinumab and vedolizumab in treating inflammatory bowel disease.The secondary outcome extracted was the efficacy of both drugs as induction and maintenance treatment for IBD, also including their safety profiles.

Study Characteristics
A total of 12 research papers were reviewed, including 5681 participants.Out of the papers selected, there were five randomized controlled trials, two systematic reviews and meta-analyses, two case reports, and three observational studies.All studies involved patients with IBD, who were either biologic therapy-naive or lacked a response to the biologic therapies.One of the trials showed that ustekinumab proved to be an effective therapy for induction and maintenance treatment in UC patients compared to placebo; two other trials exhibited the effectiveness of ustekinumab in remission of transmural inflammation and endoscopic healing by showing a reduction in the simplified endoscopic score for Crohn's disease (SES-CD) in patients of treatment-refractory Crohn's disease.In contrast, other studies proved it effective in treating perianal CD.The case reports described the leukocytoclastic reaction and Large T-cell lymphoma in patients being treated with ustekinumab over the course of their treatment.Still, no causal link was found to be associated with it since several other factors could have led to these reactions.A post hoc analysis and randomized controlled trial (RCT) proved vedolizumab to be an effective treatment for IBD in biologic naive patients compared to a placebo.At the same time, a systematic review also signified the efficacy of vedolizumab as an IBD treatment in induction and maintenance.Table 6 summarizes the findings of the studies included in the review.

Discussion
Inflammatory bowel disease is a group disorder that causes inflammation in the gastrointestinal tract.IBD includes two diseases, i.e., Crohn's disease and ulcerative colitis.There is no known etiology of this disease.Still, genetics, autoimmunity, and certain environmental triggers (e.g., smoking, stress, depression) are associated with a new incidence of IBD in patients with positive family history.Crohn's disease involves the whole gastrointestinal system, i.e., from mouth to anus, and causes transmural inflammation, whereas ulcerative colitis is mostly limited to the rectum involving the mucosa and submucosa.
Over the years, many therapies have been implemented to control and cure IBD, but no definite cure has been found; certain drugs have proved to be efficacious in controlling the symptoms and flare-ups of the disease.Commonly used therapies include amino salicylates, steroids, and immunomodulators like azathioprine and methotrexate.
Over the past decade, new drugs, i.e., biologic therapies like anti-TNF therapies, have been studied and introduced as a treatment for IBD for patients not responding to the drugs used or because of harmful side effects associated with the traditional therapies, have proved to be beneficial but refractory disease and a substantial number of non-responders still pose as a significant challenge.
Some of the new biologic therapies, like ustekinumab (an IL -23 inhibitor) and vedolizumab (a humanized monoclonal antibody), have been introduced as novel treatments for patients resistant to previous biologic therapies and refractory IBD.
In this systematic review, we have analyzed the literature and clinical trials to find out the safety profile and efficacy of ustekinumab and vedolizumab in the treatment of IBD and their efficacy in induction and maintenance of remission over the years as a secondary outcome of this review.Following is the summary of the findings discovered by carefully reviewing the selected papers.

Ustekinumab in Ulcerative Colitis (UC)
In a randomized controlled trial by Sands et al., patients receiving ustekinumab induction and maintenance therapy were randomly allocated to three groups: placebo (319 patients), ustekinumab 130 mg dose (320 patients), or ustekinumab at approximately 6 mg per kilogram (322 patients).Patient characteristics were comparable among the different trial groups in the induction and maintenance phases.The results showed significantly higher clinical remission rates (15.5% and 43.8%) compared to the placebo group (5.3% and 24%) [9].No significant difference in adverse effects was observed between the ustekinumab and placebo groups.

Ustekinumab in Crohn's Disease (CD)
In a randomized controlled trial by Rutgeerts et al., the administration of ustekinumab for both induction and maintenance therapy demonstrated a more substantial decrease in the Simplified Endoscopic Disease Activity Score for Crohn's disease (SES-CD) compared to the placebo group [10].Specifically, patients receiving ustekinumab experienced a reduction of 2.8 points from the baseline at induction until week 8, whereas patients in the placebo group only experienced a reduction of 0.7 points [10].In a retrospective cohort study by Brewer et al., ustekinumab showed promise in treating symptomatic perianal Crohn's disease, with 55.6% of patients achieving sustained response at 12 months in patients with refractory Crohn's disease [18].

Vedolizumab in Inflammatory Bowel Disease (IBD)
A post-hoc analysis by Feagen et al. ( 2019) revealed that vedolizumab demonstrated early and significant improvement in patient-reported symptoms of UC and CD, with notable response rates observed as early as week 2 [12].Similarly, in a randomized controlled trial by Vermeire et al. (2021), patients receiving vedolizumab subcutaneously showed higher rates of clinical remission and corticosteroid-free clinical remission at Week 52 compared to the placebo group [13].

Safety and Efficacy
Overall, both ustekinumab and vedolizumab demonstrated efficacy in inducing and maintaining remission in patients with UC and CD, with higher percentages of clinical remission and endoscopic mucosal healing [10].Treatment with ustekinumab partially improved Mayo scores, and CRP, lactoferrin, and calprotectin recorded at baseline in the maintenance trial in the group treated with ustekinumab.In contrast, results for these measures worsened in the placebo group [9].Adverse effects were mostly minor and comparable between treatment groups in most studies.Both the case reports presenting a leukocytoclastic reaction and Large T cell lymphoma in patients being treated with ustekinumab failed to provide any promising evidence of ustekinumab being the causative factor, as many other confounding factors would have led to these conditions in addition to ustekinumab.[16,15].No consistent factors associated with response to Ustekinumab dose escalation were found in the meta-analysis by Meserve and co-authors [21].Injection site reactions were the only notable safety concern associated with vedolizumab in the study by Vermeire et al. [13].

Differences Between Ustekinumab and Vedolizumab
Both ustekinumab and vedolizumab demonstrated efficacy in specific subsets of patients, with differences in response rates and remission rates observed in CD and UC.Ustekinumab showed higher clinical remission rates in UC compared to placebo.In contrast, vedolizumab demonstrated a better response in patients with TNF antagonist-naive CD in the study by Feagen et al. [12].

Comparison With Conventional Therapies
Ustekinumab and vedolizumab are emerging as safe and effective therapies for treating IBD; previously, anti-TNF agents also proved to be efficacious in decreasing surgery and hospitalization rates in both UC and CD patients [22].Nevertheless, a significant proportion of patients, around one-third, exhibit no response to anti-tumor necrosis factor (anti-TNF) treatments.Approximately 40% of patients who initially exhibit a positive response eventually cease to respond due to factors such as subtherapeutic drug levels, the emergence of antidrug antibodies, or the occurrence of mechanistic escape, wherein another cytokine may assume more significance in the pathogenesis of the disease [23].In addition, it is worth noting that a minority of patients may necessitate a modification in their treatment regimen as a result of experiencing side effects, such as drug-induced lupus, psoriasis, or demyelinating disease.
Compared to standard anti-TNF medicines, vedolizumab demonstrates a relatively low level of immunogenicity.When comparing patients who were administered concomitant immunosuppressant at baseline with those who were not, there was a slight decrease in the chance of producing anti-vedolizumab antibodies, with rates of 3% and 4%, respectively [24].
The immunogenicity associated with ustekinumab is notably minimal.The CERTIFI study observed that 0.7% of participants developed antibodies to ustekinumab by week 36.The maintenance IM-UNITI trial revealed a higher percentage of 2.3% by the end of the first year [25].The observed rates are significantly lower in comparison to anti-TNF medicines, such as infliximab (ranging from 0% to 83%), adalimumab (ranging from 0% to 54%), and golimumab (ranging from 0% to 19%) [26].There is significant anticipation for the release of long-term immunogenicity data pertaining to ustekinumab.

Factors Influencing Treatment Outcomes
The trial's patient selection criteria primarily focused on key factors such as biologic therapy status, disease duration, and severity.Specifically, patients considered were either biologic therapy-naive or nonresponders to previous biologics, and some had a history of resistance to all prior treatments.The impact of simultaneous treatment with corticosteroids and immunomodulators on vedolizumab therapy in IBD patients was also investigated [3].These comprehensive variables aimed to ensure a diverse and relevant patient population, providing valuable insights into the safety and efficacy of the treatments under study.As observed in the study by Feagen and co-authors, vedolizumab proved more beneficial in TNF antagonist naive patients [12].

Recommendations
The findings suggest that ustekinumab and vedolizumab are effective treatment options for IBD patients with inadequate response or loss of response to previous therapies.Further research is needed to identify factors influencing response to dose escalation in ustekinumab-treated CD patients.Both biologics showed a good safety profile, but long-term follow-up and larger studies are required to better understand their safety profiles in real-world settings.

Limitations
The identified studies contained trials that were not long enough to fully capture the efficacy of ustekinumab in the treatment of UC over the years, and the studies did not include head-to-toe comparisons with other biologic therapies.Trials that include the pediatric patient population were not included in the papers reviewed.Despite these limitations, the studies collectively provide valuable insights into the safety and efficacy of ustekinumab and vedolizumab in treating IBD.

Conclusions
The reviewed studies provide strong evidence for the safety and efficacy of ustekinumab and vedolizumab in treating IBD.However, individual patient characteristics, disease subtypes, and previous treatments may influence therapeutic response, highlighting the need for personalized treatment approaches in IBD management.Altogether, the clinical trials prove the effectiveness of ustekinumab and vedolizumab compared to placebo by significant results.Overall, ustekinumab and vedolizumab hold great promise as valuable therapeutic options for patients with IBD, but further research is warranted to optimize treatment strategies and improve.
bias of selected studies and participated in proofreading and drafting, ensuring all guidelines were met.Without the invaluable guidance and unwavering support of SK, our mentor, the successful completion of this systematic review would not have been possible; SK also participated in formulating the concept and design of the article.The final manuscript was read and approved by all authors.

FIGURE 1 :
FIGURE 1: PRISMA flowchart showing the process of article selection PRISMA -Preferred Reporting Items for Systemic Review and Meta-Analysis

Table 1
presents an overview of the databases employed in this study, together with the corresponding quantities of papers identified for each respective database.

TABLE 1 : Keywords/strategy used and the number of identified papers
IBD -inflammatory bowel disease; MeSH -Medical Subject Headings; MDPI -Multidisciplinary Digital Publishing Institute; PMC -PubMed Central

Table 3
provides a summary of the quality appraisal procedure employed for the case reports included in the study, using the Joanna Briggs Institute (JBI) critical appraisal checklist for case reports.

TABLE 5 : Quality appraisal using AMSTAR checklist
AMSTAR -Assessment of Multiple Systematic Review