Biologic therapies and JAK inhibitors have become central to the treatment of moderate-to-severe ulcerative colitis. However, implementation and sequencing vary considerably between countries. In the Netherlands, specific considerations such as cost-efficiency, historical use of agents like cyclosporin and 6-thioguanine, and the national healthcare insurance shape treatment preferences. An adaptation of the ECCO guideline to the Dutch context is needed to align with local practice and ensure sustainable, evidence-based care.

Summary of Findings

See Supplementary file in the study article (Raine, 2022) for GRADE conclusions and number of included studies per comparison.

Description of studies

Table 3 indicates the number of included studies, including references, per comparison. The assessment of the risk of bias is summarized in the risk of bias tables in the supplementary file by Raine (2022). 

Table 3. Included studies per comparison with regard to biological/JAKi treatment in the ECCO guidelines on treatment of ulcerative colitis (Raine, 2022)

Results

Results described below are adopted from Raine (2022).

_{Note: Next to the included RCTs as described above, also other studies (inc. observational studies) are described. These were not used for calculating the level of evidence of the PICO outcome.}

TNFα-remmers

Induction therapy

We identified nine suitable RCTs that compared anti-TNF agents [infliximab, adalimumab, golimumab] with placebo in patients with moderately-to-severely active UC [see SoF Table 12, available as Supplementary data at ECCO-JCC online] (Rutgeerts, 2005; Kobayashi, 2016; Jiang, 2015; Xian-Janssen, 2015; Reinisch, 2011; Sandborn, 2012; Sandborn, 2014a; Sandborn, 2014b; Suzuki, 2014; Hibi, 2017). Patient eligibility required an inadequate response to or intolerance of conventional therapies, which were defined as corticosteroids, immunomodulators, or both in most studies, although three RCTs also permitted inadequate response to or intolerance of oral 5-ASA alone (Rutgeerts, 2005; Sandborn, 2014a; Hibi, 2017). Our meta-analysis revealed evidence of efficacy for induction of clinical remission [RR: 2.23; 95% CI: 1.81–2.76] and clinical response [RR: 1.56; 95% CI: 1.38–1.76]. We found data supporting efficacy for mucosal healing [RR: 1.49; 95% CI: 1.32–1.68], which is closely related to but defined differently from the outcome of interest used in this guideline [endoscopic response]; evidence was therefore downgraded due to indirectness. There was no difference in terms of AEs when analysed regardless of treatment duration [RR: 0.84; 95% CI: 0.64–1.09]. Safety data for anti-TNF agents from large cohort studies were generally reassuring (Kirchgesner, 2018; Kirchgesner, 2020; Lemaitre, 2017).

Studies that directly compared anti-TNF agents are not available. Two network meta-analyses (Bonovas, 2018; Singh, 2020) that performed indirect comparisons concluded that infliximab is superior to adalimumab for the induction of clinical remission [OR: 2.10; 95% CI: 1.21–3.64 (Bonovas, 2018) and OR: 2.10; 95% CI: 1.16–3.79 (Singh, 2020), respectively]. The first network meta-analysis also concluded that infliximab is superior to adalimumab and golimumab for induction of clinical response [OR: 2.01; 95% CI: 1.36–2.98 and OR: 1.67; 95% CI: 1.08–2.59, vs adalimumab and golimumab, respectively] and for induction of mucosal healing [OR: 1.87; 95% CI: 1.26–2.79 and OR: 1.75; 95% CI: 1.13–2.73, vs adalimumab and golimumab, respectively] (Bonovas, 2018). For patients with a history of previous failure of biologic therapy, there are limited data to guide treatment selection. Subgroup analysis of a phase 3 trial suggests that the clinical effects of induction therapy with adalimumab were markedly lower in patients with previous anti-TNF agent exposure [and non-significantly different from placebo] (Sandborn, 2012). A previous systematic review of cohort studies identified eight studies that reported the efficacy of adalimumab when used after infliximab in UC. However, meta-analysis was not possible, due to study heterogeneity (Gisbert, 2015). In patients with a history of previous infliximab therapy randomised to either adalimumab or vedolizumab, rates of clinical remission and endoscopic response were not significantly different (Sands, 2019). There are extremely limited data on the use of anti-TNF agents in other biologic sequences. A key question is whether to combine an anti-TNF agent with an immunomodulator. The combination of infliximab with azathioprine is more effective than infliximab alone (Panaccione, 2014). Similar RCT-level data do not exist for adalimumab in combination with thiopurine therapy in UC, although cohort studies suggest a possible benefit for this combination (Targownik, 2020) and pharmacokinetic benefits have been reported in patients with Crohn’s disease (Kennedey, 2019). For patients experiencing loss of response to a first anti-TNF agent used as monotherapy and with evidence of anti-drug antibodies, there is clear RCT evidence in favour of addition of a thiopurine to prevent formation of anti-drug antibodies to the second anti-TNF agent (Roblin, 2020). The optimal time point for the introduction of anti-TNF therapy has yet to be defined. Unlike in Crohn’s disease, no post-hoc analysis has demonstrated increased efficacy of anti-TNF agents used early in the UC disease course. Factors predicting severe or complicated disease, such as young age at first diagnosis, extensive disease, and high inflammatory burden, have been proposed to identify patients who may benefit from early treatment escalation (Peyrin-Biroulet, 2016) although the benefits of this approach have not been demonstrated in any strategy trial.

Maintenance therapy

We performed a meta-analysis of data extracted from 10 placebo-controlled RCTs of anti-TNF agents [infliximab, golimumab, adalimumab] for the maintenance of remission in adult patients with moderately-to-severely active UC [SoF Table 16, available as Supplementary data at ECCO-JCC online] (Rutgeerts, 2005; Kobayashi, 2016; Jiang, 2015; Xian-Janssen, 2015; Reinisch, 2011; Sandborn, 2012; Sandborn, 2014a; Sandborn, 2014b; Suzuki, 2014; Hibi, 2017; Janssen, 2014). Anti-TNF agents were effective for the maintenance of clinical remission [RR: 1.98; 95%CI: 1.60–2.45], steroid-free clinical remission [RR: 2.86; 95% CI: 1.67– 4.90], improvement in quality of life [QoL] [RR: 1.71; 95% CI: 1.27–2.32], and sustained clinical remission [RR: 2.76; 95% CI: 1.78–4.28]. The risk of SAEs was not different between anti-TNF agents and placebo [RR: 0.84; 95% CI: 0.64–1.09]. Evidence was also sought for endoscopic remission and biochemical remission; however, data were insufficient. Large-scale cohort studies support the safety of these drugs (Kirchgesner, 2018; Kirchgesner, 2020; Lemaitre, 2017).

Vedolizumab

Induction therapy

Two placebo-controlled RCTs were identified that addressed our PICO question. These included 620 patients with moderately-to severely active UC treated with vedolizumab or placebo; induction of clinical remission, induction of clinical response, and SAEs were reported [Feagan, 2013; Motoya, 2019]. Patients were followed up to 6–10 weeks [SoF Table 13, available as Supplementary data at ECCO-JCC online]. We included these two studies in a meta-analysis. Clinical remission was achieved more often in patients receiving vedolizumab compared with placebo [RR: 2.14; 95% CI:1.03–4.43]. Although the direction of effect for clinical response was the same as for clinical remission, the difference between patients treated with vedolizumab and those receiving placebo was not significant [RR: 1.51; 95% CI: 0.99–2.29]. Rates of SAEs in patients treated with vedolizumab were not significantly different from those receiving placebo [RR: 0.71; 95% CI: 0.39–1.30]. Safety data from large cohort studies also confirmed this favourable safety assessment.112 Evidence was also sought for endoscopic response and biochemical remission; however, data were insufficient. Of note, rates of endoscopic remission at Week 6 in the GEMINI I phase 3 induction study were 40.9% for vedolizumab-treated patients compared with 24.8% for placebo-treated patients [p = 0.001] (Feagan, 2013). In contrast, endoscopic remission rates at Week 10 in a Japanese phase 3 induction study did not differ significantly between vedolizumab- and placebo treated patients [36.6% vs 30.5%, p = 0.32] (Motoya, 2019). The overall quality of evidence was low. The quality of evidence was low for clinical remission due to serious inconsistency and imprecision. The quality of evidence was moderate for clinical response due to serious inconsistency. The inconsistency for both outcomes was due to heterogeneity in outcomes between the two RCTs. The quality of evidence for SAEs was moderate due to serious imprecision. However, the overall recommendation was graded as strong, considering the overall evidence available combined with the favourable safety profile of vedolizumab in both RCT and cohort studies.

Maintenance therapy

We identified three RCTs that included 441 patients treated with intravenous vedolizumab or placebo, which reported on maintenance of clinical remission and sustained clinical remission in adult patients with moderately-to-severely active UC who responded to induction therapy [SoF Table 18, available as Supplementary data at ECCO-JCC online] (Feagan, 2013; Motoya, 2019; Sandborn, 2020; Feagan, 2017). Patients in these trials were followed up for 52–60 weeks. We performed a meta-analysis of results from these trials. Clinical remission was more common in induction responders who subsequently received vedolizumab compared with placebo [RR: 2.37; 95% CI: 1.74–3.23]. Likewise, sustained clinical remission was also more common in patients receiving vedolizumab maintenance therapy compared with placebo [20.7% vs 9.4%; RR: 2.16; 95% CI: 1.34–3.50]. The quality of evidence for these outcomes was moderate to high. The rate of SAEs across five studies involving 1288 patients was not significantly different between vedolizumab and placebo [RR: 0.71; 95% CI: 0.39–1.30]. The quality of evidence for this outcome was moderate due to serious imprecision arising from sparse data. Nevertheless, the safety profile of vedolizumab has been established in a large cohort study (Kirchgesner, 2020). In particular, the rate of serious infections in patients with UC appeared lower in those treated with vedolizumab than with anti-TNF agents, after adjusting for baseline differences [including comorbidities]. More recently, a double-dummy placebo-controlled RCT evaluated both intravenous and subcutaneous preparations of vedolizumab in patients with moderately-to-severely active UC, who had responded to open-label intravenous vedolizumab induction therapy (Sandborn, 2020). Clinical remission, endoscopic improvement, and sustained clinical remission were significantly more frequently observed with subcutaneous vedolizumab than with placebo. The study was not powered to compare intravenous and subcutaneous preparations, although all outcomes were numerically similar between these two groups. SAEs occurred at similar frequencies in all three groups, and no distinct safety signals were observed with the subcutaneous preparation.

Vedolizumab vs. adalimumab

One RCT compared the efficacy and safety of vedolizumab with those of adalimumab over a 1-year period in patients with moderately-to severely active UC [SoF Table 19, available as Supplementary data at ECCO-JCC online] [Sands, 2019a]. A significantly higher percentage of patients in the vedolizumab group than in the adalimumab group achieved clinical response [RR: 1.46; 95% CI: 1.29‒1.67], clinical remission [RR: 1.39; 95% CI: 1.10‒1.76), and endoscopic remission [RR:1.43; 95% CI: 1.17‒1.75]. There was a numerical trend in favour  of vedolizumab for biochemical remission [RR: 1.22; 95% CI: 0.96‒1.54]. Corticosteroid-free clinical remission occurred in a numerically lower percentage of patients in the vedolizumab group than in the adalimumab group [RR: 0.58; 95% CI: 0.32‒1.05]. Of note, the quality of evidence for steroid-free clinical remission was low, as evidence relied on sparse data and the confidence intervals were very wide. Incidence rates of infections and serious infections occurred at similar frequencies with vedolizumab and with adalimumab [RR: 0.80; 95% CI: 0.55‒1.17]. It is important to note that dose escalation was not permitted with either drug, despite evidence of improved maintenance outcomes with dose escalation for both drugs (Feagan, 2013; Colombel, 2020; Wolf, 2014).

Ustekinumab

Induction therapy

A single RCT compared ustekinumab with placebo for induction therapy in patients with moderately-to-severely active UC [SoF Table 15, available as Supplementary data at ECCO-JCC online] (Sands, 2019b). Patients were required to have not responded to or been intolerant to previous biologic or conventional therapy [defined as corticosteroid). Of these, 51.1% of randomised patients had previously failed treatment with an alternative biologic, including 16.6% who failed treatment with both an anti-TNF agent and vedolizumab. The study demonstrated the benefit of ustekinumab [6 mg/kg] over placebo in induction of clinical remission [15.5% vs 5.3%; RR: 2.91; 95% CI: 1.72–4.94], clinical response [61.8% vs 31.3%; RR: 1.97; 95% CI: 1.64–2.37], and endoscopic improvement [27.0% vs 13.8%; RR: 1.96; 95% CI: 1.41–2.72]. At completion of induction, the change in mean Inflammatory Bowel Disease Questionnaire [IBDQ] score from baseline was greater in those receiving ustekinumab [6 mg/kg] than in those receiving placebo [35.0 vs 16.16; p <0.001]. Median change in faecal calprotectin from baseline also showed a more significant reduction in the treatment arm [-1368.26 vs 17.92; p <0.001]. SAEs did not differ between ustekinumab [6 mg/kg] and placebo [5.2% vs 7.9%;RR: 0.67; 95% CI: 0.39–1.17]. Clinical and endoscopic benefit compared with placebo was observed for patients with and without previous biologic failure. An indirect network meta-analysis did not reveal a statistical difference between ustekinumab and anti-TNF agents or tofacitinib for clinical and endoscopic outcomes in patients naïve to biologic therapy but suggested a possible benefit of ustekinumab over adalimumab or vedolizumab for patients with previous anti-TNF exposure (Singh, 2020).

Maintenance therapy

A single RCT compared ustekinumab with placebo for maintenance therapy in UC in patients who responded to ustekinumab induction therapy (Sands, 2019b). The study revealed that maintenance treatment with ustekinumab, at approved dosing of 90 mg subcutaneously every 8 weeks, offers benefit when compared with placebo in maintenance of clinical remission [RR: 1.82; 95% CI: 1.33–2.49] and maintenance of steroid-free clinical remission [RR: 1.79; 95% CI: 1.30– 2.47], at Week 44. Although data were not available for endoscopic improvement, we used data for the closely related endpoint of endoscopic remission and found benefit compared with placebo [RR: 1.79; 95% CI: 1.36–2.36]. There was a reduction in mean faecal calprotectin for those who remained on ustekinumab during the maintenance period [-434.9 vs 813.3]. The benefits of ustekinumab were also reflected by the IBDQ scores in patients who completed the maintenance study [3.9 vs -15.7]. SAEs did not occur more frequently in the treatment arm [5.2% vs 7.9%; RR: 0.67; 95% CI: 0.39–1.17]. In addition to 8-weekly dosing, the study also evaluated 12-weekly maintenance therapy. Twelve-weekly dosing also showed statistically significant superiority over placebo for clinical remission [RR: 1.60; 95% CI: 1.16–2.21], steroid-free clinical remission [RR: 1.61; 95% CI: 1.16–2.24], and endoscopic remission [RR: 1.53; 95% CI: 1.14–2.04]. Compared with 8-weekly dosing, rates were numerically lower, but this did not reach statistical significance. The differences between outcomes with 8-weekly and 12-weekly dosing were greater in patients with a history of previous biologic failure (Sands, 2019b).

Tofacitinib

Induction therapy

We performed a meta-analysis of data from two RCTs relevant to our PICO question. These included 1220 patients with moderate to-severe UC who previously had an inadequate response, loss of response, or were intolerant to either conventional therapy [mesalamine plus steroids or thiopurines] or a biologic agent who were treated with tofacitinib or placebo [SoF Table 14, available as Supplementary data at ECCO-JCC online] (Sandborn, 2012; Sandborn, 2017). There was evidence for efficacy in induction of clinical response [RR: 1.79; 95% CI: 1.49–2.14], clinical remission [RR: 3.26; 95% CI: 1.95–5.43], and endoscopic response [RR: 5.18; 95% CI: 2.12–12.69]. However, the evidence regarding endoscopic response was downgraded due to indirectness and imprecision [low number of events]. Data on biochemical remission were insufficient. SAEs were comparable [RR: 0.70; 95% CI: 0.45–1.08], although the evidence was also downgraded due to imprecision. Further safety data are available from post-marketing studies of tofacitinib [discussed under maintenance therapy below]. A previous meta-analysis of RCTs on tofacitinib showed similar positive data for clinical and endoscopic endpoints in both the subgroup of patients naïve to anti-TNF agents and the subgroup with previous anti-TNF agent exposure. There were no significant differences in estimates of effect sizes between these subgroups. This was reflected in the findings of indirect network meta-analyses that did not find evidence of a statistical difference between tofacitinib and anti-TNF agents or ustekinumab for clinical and endoscopic outcomes in patients naïve to biologic therapy (Bonovas, 2018; Singh, 2020) but suggest a possible benefit over adalimumab or vedolizumab for patients with previous anti-TNF agent exposure (Singh, 2020).

Maintenance therapy

We identified one RCT that reported outcomes in 593 patients treated with tofacitinib or placebo as maintenance therapy (Sandborn, 2017). For patients who responded to induction therapy, tofacitinib at a dose of 5 or 10 mg twice daily was superior to placebo in maintaining clinical remission [RR: 3.37; 95% CI: 2.23–5.10] and endoscopic remission [RR: 3.88; 95% CI: 1.90–7.95] in patients with moderate-to-severe UC who had an adequate response to the induction scheme. However, the evidence regarding endoscopic remission was downgraded due to imprecision [low number of events]. Sustained clinical remission [RR: 4.71; 95% CI: 2.51–8.84], corticosteroid-free remission [RR: 2.54; 95% CI: 1.39–4.65], and improvement in QoL [RR: 2.55; 95% CI: 1.93–3.37] were also superior. The evidence regarding corticosteroid-free clinical remission was also downgraded due to imprecision. Data on biochemical remission were insufficient. SAEs for tofacitinib therapy in RCTs were comparable to placebo [RR: 0.70; 95% CI: 0.45–1.08]. The evidence was again downgraded due to imprecision.  However, an increased risk for infections was observed [OR: 1.56; 95% CI: 1.18–2.06]. Most of the serious infections were of bacterial origin, including community-acquired pneumonia and urinary tract and skin infections. A separate meta-analysis of the safety profile of Janus kinase inhibitors across multiple inflammatory diseases showed a particularly high risk of viral infections, especially herpes zoster [RR: 6.53; 95% CI: 0.86–49.58] (Olivera, 2020). This signal was also observed in a pooled analysis of safety data from the tofacitinib development program in UC [incidence rate 4.1 events per 100 person-years; 95% CI: 3.1–5.2] (Sandborn, 2019) although most cases were uncomplicated and associated with a single dermatome. This risk appears to be dose dependent and is more common with 10 mg twice daily dosing than 5 mg twice daily (Sandborn, 2019). A large cohort study in rheumatoid arthritis suggested that the rates of herpes zoster appear higher with tofacitinib than with anti-TNF agents; this risk appeared to be especially significant in older patients or in those receiving concomitant corticosteroid therapy (Curtis, 2016). A safety study of tofacitinib in patients with rheumatoid arthritis, aged ≥50 years and with at least one known cardiovascular risk factor, revealed a significantly increased risk of venous thromboembolism [VTE] in patients treated with 10 mg twice daily tofacitinib compared with patients treated with anti-TNF agents. This risk was not observed in patients treated with 5 mg twice daily tofacitinib (PRAC, 2019). Although data are sparse, VTE has been reported in patients with VTE risk factors who participated in the UC development program (Sandborn, 2019b). Considering these findings, the European Medicines Agency recommended using tofacitinib at the lowest efficacious dose and avoiding tofacitinib 10 mg twice daily as maintenance treatment for patients with known VTE risk factors. In this regard, 140 UC patients treated with tofacitinib 10 mg twice daily for at least 2 consecutive years, and in sustained remission for ≥6 months, were randomized to continue with the same dose or de-escalate to 5 mg twice daily. After 6 months, clinical remission rates were 77% and 90% for the 5 mg twice daily and 10 mg twice daily groups, respectively. No differences in AEs or SAEs were detected between the two groups, although herpes zoster cases were numerically higher in the 10 mg twice daily group (Vermeire, 2021). Further post-marketing surveillance data suggest that tofacitinib use is also associated with an increased risk of cardiac events and malignancies (EMA, 2021).

For the current module, the 2022 ECCO Guidelines on Therapeutics in Ulcerative colitis: Medical Treatment were adapted (Raine, 2022). With regard to treatment with biologicals and JAK-inhibitors, a systematic review of the literature was performed for the PICO questions/comparisons described below. See Table 1 below for an overview of the investigated comparisons.

Table 1. Investigated PICO questions (systematic literature search) with regard to biological/JAKi treatment of the two ECCO guidelines on treatment of ulcerative colitis (Raine, 2022)

Table 2. PICO

Relevant outcome measures

The ECCO guideline panel considered clinical response for induction, clinical response for maintenance, clinical remission for induction, clinical remission for maintenance, steroid free clinical remission, improvement in quality of life, endoscopic remission, SAEs, AEs leading to treatment discontinuation, need for surgery, surgical site infection SSI postoperative morbidity, non-septic postoperative morbidity, 30-day mortality, need for recurrent intervention, pouch failure, continence, urgency, histology proven dysplasia or cancer and female fertility as critical outcome measures for decision making; and sustained clinical remission, biochemical improvement, biochemical remission, sexual function, improvement in work productivity, endoscopic response, histologic healing, AEs, immunogenicity drug levels, length of hospital stay, reduced pain, improved cosmesis and bowel movement frequency as important outcome measures for decision making.

A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.

The guideline panel did not report minimal clinically (patient) important differences for the outcome measures.

Search and select (Methods)

A systematic literature search was performed using the following bibliographic databases: Embase.com, Pubmed/Medline and Cochrane Central databases. All databases were searched until February 2020 for systematic reviews, RCTs and observational studies (for all PICO questions). The search strategies and number of records for all PICO questions (including PICO questions not on biological or JAKi treatment or other disease manifestations) can be found in the supplementary files of the ECCO guidelines (Raine, 2022).

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23. Laharie, D. et al. Infliximab plus azathioprine versus azathioprine alone for steroid-dependent ulcerative colitis (the SUCCESS trial): a randomised, controlled, open-label trial. Lancet Gastroenterol. Hepatol. 7, 827–837 (2022).
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