Inflammatory bowel disease is a group of chronic non-specific intestinal inflammatory diseases. UC is one such disease with a partly understood pathogenesis. Reportedly, genetic susceptibility, immunomodulatory dysfunction, microbiota, environment, and other factors contribute to intestinal inflammatory response. UC is characterized by continuous and superficial mucosal inflammation which extends to the proximal colon, leading to ulcers, massive bleeding, toxic megacolon, and fulminant colitis when the lesions are severe (Chang, 2020). The increasing number of UC patients worldwide has rendered it a common disease of the digestive system (Ng et al., 2017). The disease and its related complications (infection, thrombosis, malignant tumors, etc.) impose a huge medical and economic burden on the patient’s family and society (Alatab et al., 2020).

The main objective of UC treatment is to achieve clinical remission and mucosal healing (Cazzato et al., 2021). At present, commonly used drugs, such as 5-aminosalicylic acid (5-ASA), hormones, and immunosuppressants, can relieve the symptoms of patients without terminating the mucosal inflammatory activity and disease development. Moreover, severe short-term (systemic immunosuppression and risk of opportunistic infections) and long-term (Cushing’s syndrome, diabetes, and osteoporosis) adverse effects limit their application (Na and Moon, 2019). Over the past 2 decades, the emergence of biological agents (i.e. anti-tumor necrosis factor (TNF), anti-α4β7 integrin, anti-IL12/23) and small molecule drugs (SMDs) (i.e. Janus kinase (JAK) inhibitors, sphingosine 1-phosphate (S1P) receptor modulators), has shown potential of inducing and maintaining the clinical remission and mucosal healing of UC (Pouillon et al., 2016; Kim and Cheon, 2017).

Consequently, the treatment of moderate to severe UC has shown promising results. Various randomized controlled trials (RCTs) studies have confirmed the efficacy and safety of these drugs (Suzuki et al., 2015; Suzuki et al., 2014; Sands et al., 2019a; Sandborn et al., 2012; Sandborn et al., 2017; Sandborn et al., 2014; Sandborn et al., 2020; Sandborn et al., 2021; Danese et al., 2022); however, comparative studies of these drugs are limiting. In an ideal world physicians would like to select the most efficacious and least toxic drug upfront. While conventional meta-analysis has a limited scope, network meta-analysis performs direct and indirect comparisons of evidence to rank and compare the efficacy and safety of multiple interventions and to select an optimal intervention. Therefore, we conducted a network meta-analysis to compare the efficacy and safety of different drugs, providing a basis for selecting clinical treatments for moderate to severe UC.

In this updated systematic review and network meta analysis combining direct and indirect evidence from the RCTs of biologics (infliximab, adalimumab, vedolizumab, ustekinumab, and golimumab), SMDs (tofacitinib, upadacitinib, and ozanimod), and immunosuppressors (AZA and tacrolimus), we made several key observations. First, although all approved agents are effective, upadacitinib was ranked highest in terms of induction and maintenance. Second, the safety of vedolizumab is unequivocal compared to other active interventions, as it has the lowest rate of AE, followed by upadacitinib. Of note, upadacitinib had the lowest incidence of SAE. Third, when compared to infliximab alone, infliximab combined with AZA can enhance efficacy while potentially increasing the incidence of adverse events, particularly serious adverse events. As compared with previous estimates, this study expanded the scope of the search to include traditional drugs, biologics, and small molecule drugs. Although only two studies, Lawrance et al. (2017) and Panaccione et al. (2014), had conventional drugs that met the criteria, Lawrance et al. (2017) had to be excluded from the mesh analysis due to its small sample size. This study included high-quality RCTs characterized by low heterogeneity and a rigorous methodology. The updated analysis has key strengths with inclusion of a head-to-head trial comparing vedolizumab and adalimumab (Sands et al., 2019b), which forms a more connected network, and provides more robust. Additionally, it analyzed both the induction and maintenance phases, conducting a subgroup analysis (treat straight-through vs rerandomization of responders) on the outcome indicators during the maintenance phase, which enhances the overall persuasiveness of the results. With limited head-to-head trials, this information can inform clinical practice and guidelines directly and facilitate shared decision making for management of patients with moderate–severe ulcerative colitis.

Our results confirm several prior observational comparative effectiveness studies, individual patient level analyses of clinical trials, and indirect treatment comparison network meta-analyses suggesting higher efficacy and effectiveness of infliximab over adalimumab and golimumab (Bonovas et al., 2018; Singh et al., 2018; Singh et al., 2017; Singh et al., 2020b). This may be related to differences in pharmacokinetics and bioavailability with different dosing schema (weight-based vs fixed dose) and route of administration. Infliximab binds to TNF-α at the site of inflammation by intravenous administration, thereby inhibiting inflammation with maximum bioavailability. Therefore, it can induce immediate clinical responses in patients with moderate to severe UC. After subcutaneous administration, adalimumab and golimumab exhibit slow absorption and distribution. Consequently, they are not preferred treatment options during the induction period (Sandborn et al., 2012). Our findings also support the observation in the recent head-to-head VARSITY (Sands et al., 2019b) trial that vedolizumab is more effective than adalimumab for long-term maintenance of clinical remission and endoscopic improvement. Vedolizumab selectively blocks the binding of α4β7 integrin to MAdCAM-1, thereby inhibiting the further migration of lymphocytes into the lamina propria and intestinal lymphoid tissue without blocking the inflammatory active lymphocytes (Li et al., 2018). Therefore, it shows poor efficacy in the induction phase. Once effective, it shows a sustained anti-inflammatory response. Moreover, vedolizumab is highly safe owing to its unique mechanism of action and its excellent ability to maintain clinical remission and endoscopic mucosal improvement makes it highly competitive for application in patients with primary and secondary non-responsive, or refractory UC than infliximab.

The formation of anti-drug antibodies leads to a reduction in serum concentrations of infliximab, which is a major reason for primary or secondary non-response in some patients. In patients with Crohn’s disease or rheumatoid arthritis, the combination of immunomodulators and infliximab had been observed to reduce the production of anti-drug antibodies and increase serum trough levels of infliximab (Klotz et al., 2007; Ruffolo et al., 2010). Our study also confirms that the combination of AZA and infliximab improves efficacy in UC patients, although the reasons for this change remain unclear. Perhaps the most informative results from our analysis is the first confirmation of the dominance of JAK inhibitors in treating moderate to severe UC. This is increasingly relevant given the high rates of primary nonresponse or secondary loss of response to initial biologic therapy, and is an often-faced clinical scenario for which there is limited guidance. We observed that upadacitinib was significantly more effective than other biologic therapies for induction and maintenance. Upadacitinib is a small molecule drug characterized by non-immunogenicity and high bioavailability. At the same time, upadacitinib is more selective than tofacitinib, exhibiting a greater inhibitory effect on JAK1 than on JAK2 and JAK3. This selectivity reduces some adverse events associated with JAK2 and JAK3 inhibition while improving efficacy (Napolitano et al., 2022). Findings from these indirect comparisons need to be interpreted with caution because these trials did not always mirror clinical practice. We acknowledge that there is a paucity of head-to-head trials to truly inform comparative efficacy and safety. However, it is important to note that across trials of therapy, key inclusion/exclusion criteria, outcome definitions, and patient and clinical characteristics, co-interventions were comparable across trials, which facilitated this network meta-analysis.

Besides inherent limitations of individual trials, there were limitations to our analyses. Most of the included trials relied on local investigators for endoscopic reading of endoscopic disease activity for trial recruitment and outcome assessment, whereas trials of tofacitinib, upadacitinib and ozanimod included blinded central readers, which can influence absolute event rates. There were differences in timing of outcomes assessment in induction and maintenance,and time-dependent variability in efficacy could not be analyzed in detail. At the same time, the follow-up times for AEs and SAEs are also somewhat inconsistent, which may potentially bias safety results.

Integrating findings from this meta-analysis and other studies, current evidence favors upadacitinib or infliximab as the preferred agents for induction and upadacitinib or vedolizumab as the preferred agents for maintenance in patients with moderate to severe UC. However, in addition to the quality of evidence, several other factors are important for facilitating shared decision-making and developing a personalized treatment strategy for each patient. These factors include the balance of the risk–benefit profile, specific patient attributes, the clinical judgment and experience of the treating physicians, patients’ values and preferences, as well as the costs and resources available. These considerations also shape healthcare policy regarding the positioning of different agents. Pragmatic head-to-head trials are warranted to optimally inform the relative positioning of newly available agents in clinical practice.

In a systematic review and network meta-analysis, we found upadacitinib showed the best efficacy and safety in to be ranked highest in patients with moderate to severe ulcerative colitis. More trials of direct comparisons are needed to inform clinical decision making with greater confidence.