Inflammatory bowel disease (IBD) is a lifelong disease occurring early in life which clinically contains Crohn’s disease and ulcerative colitis. The incidence and prevalence of IBD markedly increased over the second half of the 20th century, and since the beginning of the 21st century (Guan, 2019). It is projected that in the Western world, with compounding prevalence, the number of patients with IBD will grow exponentially in the next decade. Additionally, prevalence of IBD in newly industrialized countries is a fraction of that in the Western world, but the rate of the rise in incidence is steep in newly industrialized countries. In 2025, accessibility, affordability, variation in healthcare resources and the cost of biologic agents could strain healthcare systems and exacerbate disparity of care across the world (Kaplan, 2015).

Anti-tumor necrosis factor agents (anti-TNF) have been widely used for approximately 25 years now. Their integration into clinical practice has greatly advanced the treatment of IBD. This has led to an exponential increase in the number of patients that are treated with anti-TNF therapy. However, despite their proven efficacy, a considerable number of patients on anti-TNF therapy fail to respond and of those patients who initially respond to an anti-TNF agent, some discontinue therapy because they lose their response or intolerance (Eder et al., 2015; Sochal et al., 2020). Additionally, evidence suggest that patients failing an anti-TNF agent are less likely to respond to another anti-TNF biologic (Stidham et al., 2014). The calculated annual risk of loss of infliximab response in patients was found to be 13% per patient-year (Gisbert and Panés, 2009). It is important to note that anti-TNF treatment may also be discontinued due treatment-related complications such as serious infections or intolerance (Beaugerie et al., 2020). This presents a therapeutic challenge for physicians in their daily clinical practice. It is believed that non-response to primary anti-TNF treatment is often considered indicative of a patient group that is inherently more resistant to treatment, potentially due to factors such as longer disease duration or complicated disease. In some cases, patients may have been previously exposed to anti-TNF agents and demonstrated inadequate response, leading to potential immunological challenges in achieving a satisfactory response to a second agent. These considerations highlight the complexity of managing patients who do not respond to anti-TNF treatment. Currently, there are no clear guidelines regarding the appropriate therapeutic option following the failure of anti-TNF therapy. Whether the next step should be to try other anti-TNF agents or swap current anti-TNF with a drug with different mechanism of action is not clear. Physicians must carefully assess and navigate various factors, including disease characteristics, treatment history, and potential adverse events, to make informed decisions and explore alternative therapeutic options for these patients.

Vedolizumab is a humanized gut-specific monoclonal antibody targeting the α4β7 integrin leading to the inhibition of leukocyte migration from the blood to the intestinal mucosa (Luzentales-Simpson et al., 2021). Integrins are cell surface transmembrane glycoproteins that mediate cell–cell interactions and play critical roles in immune cell signaling, and trafficking. Since integrins mediate trafficking and retention of immune cells to the gastrointestinal tract, it is not surprising that they are implicated in the pathogenesis of IBD. The substantial role integrins play in IBD led to identifying the blockade of integrins or cell adhesion molecules as a therapeutic target in IBD (Gubatan et al., 2021).

Ustekinumab is a fully human monoclonal antibody that targets the p40 subunit of interleukin-12 and interleukin-23 (Benson et al., 2011). Functionally, IL-23 plays a role in the host response to pathogens as it has been observed that mucosal inflammation is dependent on IL-23 production and the development of therapies directed against IL-23 moreover substantiates the detrimental role played by this cytokine in IBD pathogenesis (Sewell and Kaser, 2022).

Both vedolizumab and ustekinumab have proven their effectiveness in randomized controlled trials enrolling anti-TNF experienced patients (Feagan et al., 2013; Sandborn et al., 2013; Feagan et al., 2016). However, some can argue that study populations in clinical trials may not accurately represent the general IBD population, which may limit the generalizability of their results (Ha et al., 2012). Additionally, despite the availability of some real-world data regarding the effectiveness and safety of ustekinumab and vedolizumab in patients with IBD after failure of or intolerance to anti-TNF therapy (Barbieri et al., 2022; Onali et al., 2022; Rayer et al., 2022), limited evidence exists with respect to real-life data in IBD from Kuwait specifically and the middle east region generally. Therefore, the aim of this study was to assess the effectiveness of vedolizumab and ustekinumab in a real-life cohort of patients with IBD who had failed to respond to an anti-TNF agent.

This study evaluated the effectiveness of ustekinumab and vedolizumab in a cohort of patients with IBD who had previously received at least one anti-TNF agent. The primary outcomes were the percentage of hospitalization, surgery, steroid-free remission, and mucosal healing, defined as Mayo score of 0 or 1 in UC and a SES-CD score of less than 3 in CD. Numerically, patients receiving ustekinumab had better clinical target outcomes than patients receiving vedolizumab after failing anti-TNF therapy. However, both agents showed effectiveness in patients with IBD after failing anti-TNF therapy.

During the GEMINI trial, vedolizumab has shown efficacy in both anti-TNF experienced and anti-TNF-naïve patients with UC (Feagan et al., 2013). A multi-center retrospective study compared the efficacy and safety of vedolizumab and infliximab in patients with UC after failing an anti-TNF agent (Hupé et al., 2020). The study included 225 patients and the authors found that compared with 26% of patients treated with infliximab, 49% of patients treated with vedolizumab as their second-line agent achieved clinical remission after a median duration of 14 weeks (p < 0.01). However, Post hoc analyses from the GEMINI 2 and GEMINI 3 trials showed that at weeks 6 and 10, clinical response rates were numerically higher in the anti-TNF-naïve patients with CD [40.3% and 48.4%] in comparison to the anti-TNF-exposed group [33.1% and 39.7%], respectively (Sands et al., 2017). Differences in clinical response rate persisted throughout week 52. Similar findings were observed in patients with UC using the post hoc analysis of efficacy data from the GEMINI 1 study. The post hoc analysis included 464 TNF-naïve patients and 367 TNF-failure and at week 6 clinical response rates to vedolizumab were numerically higher in TNF-naïve patients compared to patients who had failed anti-TNF previously (Feagan et al., 2017).

One study (Rayer et al., 2022) performed in France included patients with CD who failed a first anti-TNF drug, and treated with a second anti-TNF agent, ustekinumab, or vedolizumab as a second-line biological therapy. The authors found that the rates of steroid-free remission at weeks 14–24 were similar between the ustekinumab, vedolizumab, and second anti-TNF groups (29%, 38%, and 44%, respectively, p = 0.15). The study concluded that in the short term ustekinumab, vedolizumab, and a second anti-TNF agent demonstrated similar efficacy, as second-biological line treatment in patients with CD after failure of an initial anti-TNF agent. Another study examined the efficacy of ustekinumab in patients with refractory CD who have failed an anti-TNF agent or vedolizumab (Verstockt et al., 2019). After 24 weeks, the study found that ustekinumab showed good clinical remission rates (39.5%) but only 7% of the cohort achieved endoscopic remission.

A retrospective study examined the real-world effectiveness and safety outcomes of vedolizumab in patients with UC who had failed anti-TNF therapy in Korea (Ye et al., 2021). The study included 105 patients and authors found that within the first 14 weeks of use, vedolizumab is effective and well tolerated in the real-world setting.

Evidence from the Literature suggests an absence of difference between vedolizumab and ustekinumab after failing one anti-TNF agent in patients with CD (Pagnini et al., 2018; Singh et al., 2018; Alric et al., 2020). However, two studies favored using ustekinumab over vedolizumab because long-term remission was significantly higher in the ustekinumab group (Alric et al., 2020; Biemans et al., 2020).

A study suggested that a high proportion of patients continued on their initial biologics for 1 year and approximately half of patients were persistent after 5 years of treatment (Barbieri et al., 2022). The same study, found that patients treated with vedolizumab and ustekinumab seemed to have a higher risk of non-persistence compared to patients treated with infliximab. Authors attributed this non-persistence to be related to age and gender, in addition to those who switch/swap and those who experienced ADRs.

This study has important clinical implications. Guidance on the most appropriate second-line therapy after failing an anti-TNF agent is sparse. This study adds to evidence regarding the effectiveness of ustekinumab and vedolizumab after anti-TNF failure. Furthermore, with the increasing numbers of emerging novel therapies for IBD, it is essential to understand the best sequence of treatments in patients who have failed at least one anti-TNF agent. Randomly selecting second-line therapies for the treatment of IBD patients may lead to delays in achieving clinical response and remission.

To the best of our knowledge, this is the first study in Kuwait and middle east region to assess the efficacy of vedolizumab and ustekinumab after failing anti-TNF therapy. Additionally, the use of clinically relevant endpoints strengthens the applicability and clinical value of this study. In addition, endoscopic remission was also included as a long-term outcome which is recommended by STRIDE II guidelines (Turner et al., 2021). Furthermore, the strict inclusion criteria aid in the precise assessment of the efficacy of the second-line biologic. Moreover, long follow-up period (52 weeks) help in accurately assessing the efficacy of treatment with ustekinumab, and vedolizumab in IBD after failing anti-TNF therapy.

However, this study is not without limitations. It is a retrospective, single-center study therefore, generalization potential is limited. Furthermore, similar real world studies in Europe has been published before (Alric et al., 2020; Hupé et al., 2020; Onali et al., 2022; Rayer et al., 2022; Straatmijer et al., 2023). Additionally, given the observational nature of the present study, confounding effects cannot be completely eliminated, potential confounding factors remain a possible limitation of this study. Finally, comparison between effectiveness of vedolizumab and ustekinumab was not possible because of the small number of study subjects.

In conclusion, ustekinumab and vedolizumab were both effective in achieving clinical outcomes in patients with IBD after failing anti-TNF therapy. However, patients receiving ustekinumab had numerically higher percentages of reaching target outcomes than patients receiving vedolizumab. A prospective head-to-head trial is warranted to confirm these findings. Direct head-to-head active comparator trials, exclusively in patients with previous biologic exposure are needed in order to determine most appropriate second line therapy.