Vedolizumab-associated Nasopharyngitis in the Treatment of Inflammatory Bowel Disease: A Systemic Review and Meta-analysis of Randomized Placebo-controlled Trials

doi:10.21203/rs.3.rs-2980756/v1

Download PDF

Research Article

Vedolizumab-associated Nasopharyngitis in the Treatment of Inflammatory Bowel Disease: A Systemic Review and Meta-analysis of Randomized Placebo-controlled Trials

https://doi.org/10.21203/rs.3.rs-2980756/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Vedolizumab is a new biologic therapy that selectively inhibits α4β7 integrin in the gut to alleviate inflammation, making it a promising treatment option for inflammatory bowel disease. This meta-analysis investigated the correlation between vedolizumab treatment and nasopharyngitis incidence, as well as the effect of different formulations on nasopharyngitis occurrence. Six randomized, double-blind, placebo-controlled clinical trials demonstrated that the incidence of nasopharyngitis adverse events in the vedolizumab group was higher than that in the placebo control group, and the intravenous formulation group had a higher incidence than the placebo group. However, subcutaneous administration did not increase the incidence of nasopharyngitis adverse events. Vedolizumab may be a promising treatment option for inflammatory bowel disease, but the potential risk of nasopharyngitis should be considered, especially for intravenous formulation.

Vedolizumab

inflammatory bowel disease

nasopharyngitis

ulcerative colitis

Crohn's disease

Vedolizumab is a novel monoclonal antibody drug that selectively blocks the interaction between integrin α4β7 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thereby inhibiting lymphocyte entry into intestinal tissue and reducing intestinal inflammation. Since only lymphocytes with integrin α4β7 on their surface can travel to intestinal tissue, the drug does not affect the immune function and inflammatory response of other tissues and organs^[1–3]. Therefore, Vedolizumab has a high safety profile in the treatment of ulcerative colitis and Crohn's disease, but its therapeutic efficacy varies among individuals^[4].

Inflammatory Bowel Disease (IBD) is a group of diseases characterized by chronic inflammation of the intestines, including Ulcerative Colitis (UC) and Crohn's Disease (CD). The etiology of the disease is not yet fully understood, but it is known that genetic factors, environmental factors, and immune system abnormalities may all contribute to its development^{[5, 6]}. The clinical manifestations of IBD vary due to individual differences, with common symptoms including abdominal pain, diarrhea, constipation, anemia, and weight loss. The incidence and epidemiological characteristics of the disease also vary depending on geographical region, race, age, and other factors^{[7, 8]}. Currently, a variety of approaches are used for comprehensive and individualized treatment of IBD, including medication, surgery, and nutritional support^[9].

Drugs used to treat inflammatory bowel disease (IBD) primarily include 5-aminosalicylic acid drugs, immunosuppressants, biologics, and steroids. However, each drug has its limitations in treatment. For example, although steroid hormones have a significant effect on treating IBD, the biggest limitations are drug tolerance and dependence. Long-term use can lead to osteoporosis, diabetes, infection, and other complications^[10]. The use of immunosuppressants to treat IBD can also inhibit the immune system, increasing the risk of infection^{[11, 12]}.

Nasopharyngitis refers to chronic inflammation of the nasal and pharyngeal mucosa, which is typically caused by bacteria, viruses, allergens, and other factors. In many clinical trials assessing the safety of vedolizumab, it has been observed that nasopharyngitis is a relatively common adverse event. Given the increasing focus on respiratory infections due to the COVID-19 pandemic and the growing use of vedolizumab. The aim of this study is to evaluate whether there is a correlation between the use of vedolizumab and the incidence of nasopharyngitis during treatment, and to compare the effects of different formulations on the incidence of nasopharyngitis.

2.1 Literature search strategy

This study used Pubmed and Web of Science (Medline database) as search engines to identify relevant studies published up to February 2023. MeSH terms and keywords were used during the search process, including "Inflammatory bowel disease," "Ulcerative colitis," and "Crohn's disease.", “vedolizumab”, “Nasopharyngitis”, “Adverse Events”.

2.1.1. Inclusion criteria.

Randomized clinical trials (RCT);

Used a placebo as the control group.

Patients with inflammatory bowel disease.

2.1.2. Exclusion criteria.

Duplicate literature;

Systematic review or meta-analysis;

Non-randomized controlled study or review;

Irrelevant study results or missing data;

2.2. Data extraction

The data from the eligible clinical studies were extracted using the following criteria: title, author, publication date, total number of participants, number of participants in the experimental group, total number of adverse reactions in the experimental group, number of adverse reactions related to nasopharyngitis, number of participants in the control group, total number of adverse reactions in the control group, total number of adverse reactions, route of administration, treatment phase, and whether combination therapy was used.

2.2 Literature quality and risk of bias assessment

This study was systematically reviewed in strict accordance with the requirements of the AMSTAR quality evaluation form, the quality of the selected articles was strictly controlled, and the risk of bias tool was used to assess the risk of bias in randomized trials.

2.3 Statistical Analysis

The study used binary data analysis to assess the correlation between Vedolizumab and nasopharyngitis, as well as subgroup analysis of the correlation between administration routes and nasopharyngitis occurrence. Results were expressed as the relative risk (RR) and 95% confidence intervals (CIs). Heterogeneity was determined using the I² statistic, where I² ≥ 50% indicates significant heterogeneity. If no heterogeneity was present, the Mantel-Haenszel fixed-effects model was used to calculate the combined RR. All statistical analyses were conducted using Review Manager (RevMan) 5.4.1^[13].

A total of 1392 articles were identified through literature search, using databases including PubMed and Web of Science. Duplicate articles were first screened, resulting in 423 articles being excluded. The remaining 969 articles were further screened by title and abstract, and 20 articles were selected for full-text review. After a comprehensive review of the 20 clinical trials, six trials were finally included in the study. Reasons for exclusion included irrelevant data, low quality non-randomized controlled trials, and missing data. The screening process of the study is presented in Fig. 1.

3.1 Characteristics of the included studies and Systematic review

During the process of successfully screening 6 articles, the articles were evaluated strictly according to the AMSTAR quality assessment tool (Fig. 2), with the aim of selecting articles that met the quality requirements as much as possible. The subjects of the 6 studies^{[4, 14–18]} were all patients with inflammatory bowel disease and required clinical evidence of inflammatory bowel disease. Placebo-controlled studies were conducted in which patients were grouped according to the principles of randomization and double-blindness. Among them, 2 studies^{[15, 17]}used vedolizumab subcutaneous injection, while the remaining 4 studies^{[4, 14, 16, 18]}used vedolizumab intravenous injection. Before data analysis and synthesis, the quality of the studies was assessed using the Cochrane risk of bias tool, as shown in Fig. 3.

All included studies reported cases of adverse events related to nasopharyngitis. Figure 4 shows the total number of participants, the number of control and experimental groups, and the mode of administration in each study. Three studies^{[4, 14, 15]} investigated the use of Vedolizumab in patients with ulcerative colitis or ulcerative colitis. The other three studies^[16–18] investigated the use of Vedolizumab in the treatment of Crohn's disease. It is worth noting that although all included studies provided data on the incidence of nasopharyngitis in the experimental and control groups, and some mentioned that the occurrence of nasopharyngitis had some correlation, there was no statistical analysis presented to support this claim.

3.3 Meta-analysis and meta-regression

3.3.1 Association of vedolizumab with nasopharyngitis adverse events

The incidence of nasopharyngitis adverse events was investigated in six clinical trials of vedolizumab for inflammatory bowel disease. A meta-analysis (Fig. 5) showed that the incidence of nasopharyngitis adverse events in the vedolizumab experimental group was higher than that in the placebo control group (RR = 1.38, 95%CI: 1.08–1.76), Z = 2.56 (P = 0.01 < 0.05), indicating that there was a statistical difference between the experimental group and the control group. It can be statistically considered that vedolizumab monoclonal antibody is correlated with the occurrence of nasopharyngitis, indicating that the use of vedolizumab monoclonal antibody can increase the incidence of nasopharyngitis. According to the Cochrane systematic evaluation, the heterogeneity in the study was acceptable (I²=39% <50%). Figure 6 shows that the studies were relatively evenly distributed on both sides of the midline, so it can be considered that there was little publication bias.

3.3.2 Correlation between the mode of administration of vedolizumab and nasopharyngitis

Two studies^{[15, 17]} used subcutaneous formulations as the experimental group, and the other four studies^{[4, 14, 16, 18]} used intravenous injection as the administration method. A meta-analysis (Fig. 7) showed that the incidence of nasopharyngitis adverse events in the experimental group using intravenous formulations was higher than that in the placebo control group (RR = 1.46, 95%CI: 1.11–1.92), Z = 2.70 (P = 0.007 < 0.05), indicating that there was a statistical difference between vedolizumab using intravenous formulations and nasopharyngitis, and there was a certain correlation. However, the statistical analysis results of the subcutaneous formulation group showed that when vedolizumab was administered by subcutaneous injection, it did not cause an increase in the incidence of nasopharyngitis adverse events (RR = 1.07, 95%CI: 0.61–1.85), Z = 0.23 (P = 0.82 > 0.05), indicating that there was no statistical difference between subcutaneous formulations and nasopharyngitis. Figure 8 shows that there was little publication bias in the study.

Vedolizumab is a novel biological agent that inhibits lymphocyte migration by targeting intestinal adhesion molecule α4β7, giving it selective and targeted characteristics. Compared with traditional drugs for treating inflammatory bowel disease, multiple clinical studies^{[16, 19, 20]} have demonstrated the significant efficacy and safety of vedolizumab for ulcerative colitis and Crohn’s disease. However, vedolizumab also has some limitations in its application, such as vedolizumab may be ineffective for some inflammatory bowel disease patients^[21], and the incidence of adverse events may increase during drug use. Therefore, when applying vedolizumab to treat inflammatory bowel disease, individualized selection and management are needed according to the specific situation of patients to achieve optimal therapeutic effects.

In this meta-analysis study, six randomized, double-blind, placebo-controlled clinical trials were finally determined, which evaluated the incidence of nasopharyngitis adverse events during vedolizumab and placebo use. This study showed that vedolizumab can significantly increase the incidence of nasopharyngitis. However, in a subgroup analysis on the correlation between vedolizumab administration method and nasopharyngitis incidence rate, it was found that when subcutaneous formulations were used as experimental groups compared with placebo control groups, there was no significant increase in nasopharyngitis adverse events numbers, as Hu Q's study results^[22] showed that vedolizumab using subcutaneous injection maintained clinical efficacy induced by intravenous infusion in IBD patients without increasing safety risks. Therefore, combined with the statistical results of this subgroup analysis, it can be speculated that intravenous injection of vedolizumab can increase the incidence rate of nasopharyngitis adverse events, while subcutaneous injection has little effect on nasopharyngitis incidence rate and has higher safety.

Although the studies included in this study were all double-blind, randomized, placebo-controlled multicenter trials, there were still some limitations. Since the incidence rate of adverse events of drugs is influenced by the dose, administration method, patient characteristics and disease type used, and the six clinical studies included were conducted in specific geographical locations and populations, this may limit the generalizability of the results. Secondly, the sample size and study design of different studies were different, so there may be some heterogeneity, which may also lead to inconsistency of results. In addition, some literature did not fully describe the dose and course of treatment drugs, which may affect the analysis results.

In summary, the meta-analysis results of this study showed that in vedolizumab for treating inflammatory bowel disease studies, the incidence rate of nasopharyngitis adverse events in the vedolizumab experimental group was higher than that in the placebo control group. Compared with the placebo control group, the incidence rate of nasopharyngitis adverse events in the intravenous injection vedolizumab experimental group was significantly higher than that in the subcutaneous injection experimental group. However, the number of studies included in the analysis was obviously small, but it is believed that with the popularization of vedolizumab worldwide, more and more clinical trials will be carried out, which will continuously improve its statistical analysis results.

Author’s Contributions:

Zicheng Liao carried out research project establishment, literature search, literature screening, statistical analysis, writing articles, and making charts.

Funding

No funding was obtained for this study.

Conflict of Interest Statements

I declare that I have no financial or personal relationships that may have inappropriately influenced me in writing this article. Additionally, I confirm that this manuscript has not been published elsewhere and is not under consideration by any other publication.

Data Availability Statement

The data used in this study were obtained from previously published articles, which are properly cited and referenced in the manuscript. The author did not directly generate or collect the data themselves. All relevant information regarding the data sources, including the article titles, authors, journal names, and publication years, has been provided in the references section of the manuscript.

von Andrian UH, Engelhardt B.Alpha4 integrins as therapeutic targets in autoimmune disease[J].N Engl J Med.2003,348(1):68-72.
Arihiro S, Ohtani H, Suzuki M, et al.Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease[J].Pathol Int.2002,52(5-6):367-74.
Fedyk ER, Wyant T, Yang LL, et al.Exclusive antagonism of the α4 β7 integrin by vedolizumab confirms the gut-selectivity of this pathway in primates[J].Inflamm Bowel Dis.2012,18(11):2107-19.
Feagan BG, Rutgeerts P, Sands BE, et al.Vedolizumab as induction and maintenance therapy for ulcerative colitis[J].N Engl J Med.2013,369(8):699-710.
Xavier RJ, Podolsky DK.Unravelling the pathogenesis of inflammatory bowel disease[J].Nature.2007,448(7152):427-34.
Baumgart DC, Sandborn WJ.Crohn's disease[J].Lancet.2012,380(9853):1590-605.
Ng SC, Shi HY, Hamidi N, et al.Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies[J].Lancet.2017,390(10114):2769-78.
Loftus EV, Jr.Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences[J].Gastroenterology.2004,126(6):1504-17.
Kaser A, Zeissig S, Blumberg RS.Inflammatory bowel disease[J].Annu Rev Immunol.2010,28:573-621.
Ma C, Lee JK, Mitra AR, et al.Systematic review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for inflammatory bowel disease[J].Aliment Pharmacol Ther.2019,50(1):5-23.
Wright EK, Ding NS, Niewiadomski O.Management of inflammatory bowel disease[J].Med J Aust.2018,209(7):318-23.
Holmer A, Singh S.Overall and comparative safety of biologic and immunosuppressive therapy in inflammatory bowel diseases[J].Expert Rev Clin Immunol.2019,15(9):969-79.
Review Manager (RevMan) [Computer program]. Version 5.4. The Cochrane Collaboration, 2020.
Motoya S, Watanabe K, Ogata H, et al.Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study[J].PLoS One.2019,14(2):e0212989.
Sandborn WJ, Baert F, Danese S, et al.Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis[J].Gastroenterology.2020,158(3):562-72.e12.
Sandborn WJ, Feagan BG, Rutgeerts P, et al.Vedolizumab as induction and maintenance therapy for Crohn's disease[J].N Engl J Med.2013,369(8):711-21.
Vermeire S, D'Haens G, Baert F, et al.Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn's Disease: Results From the VISIBLE 2 Randomised Trial[J].J Crohns Colitis.2022,16(1):27-38.
Watanabe K, Motoya S, Ogata H, et al.Effects of vedolizumab in Japanese patients with Crohn's disease: a prospective, multicenter, randomized, placebo-controlled Phase 3 trial with exploratory analyses[J].J Gastroenterol.2020,55(3):291-306.
Sands BE, Feagan BG, Rutgeerts P, et al.Effects of vedolizumab induction therapy for patients with Crohn's disease in whom tumor necrosis factor antagonist treatment failed[J].Gastroenterology.2014,147(3):618-27.e3.
Vermeire S, Loftus EV, Jr., Colombel JF, et al.Long-term Efficacy of Vedolizumab for Crohn's Disease[J].J Crohns Colitis.2017,11(4):412-24.
Dulai PS, Boland BS, Singh S, et al.Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients With Crohn's Disease[J].Gastroenterology.2018,155(3):687-95.e10.
Hu Q, Tang XZ, Liu F, et al.Vedolizumab subcutaneous formulation maintenance therapy for patients with IBD: a systematic review and meta-analysis[J].Therap Adv Gastroenterol.2023,16:17562848231166227.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Vedolizumab-associated Nasopharyngitis in the Treatment of Inflammatory Bowel Disease: A Systemic Review and Meta-analysis of Randomized Placebo-controlled Trials

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and Methods

2.1 Literature search strategy

2.1.1. Inclusion criteria.

2.1.2. Exclusion criteria.

2.2. Data extraction

2.2 Literature quality and risk of bias assessment

2.3 Statistical Analysis

3. Results

3.1 Characteristics of the included studies and Systematic review

3.3 Meta-analysis and meta-regression

3.3.1 Association of vedolizumab with nasopharyngitis adverse events

3.3.2 Correlation between the mode of administration of vedolizumab and nasopharyngitis

4. Discussion

Declarations

References

Additional Declarations

Status:

Version 1