Since the publication of the latest Dutch IBD guideline in 2009, numerous new medication options have become available  for the treatment of Crohn’s disease. Yet, in daily clinical practice , the positioning and optimal use of these various therapeutic agents remain unclear. In June 2024 the ECCO guideline for Crohn’s disease was published, describing the same topic.

Summary of Findings

See Supplementary file in the study article 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 Gordon (2024). 

Table 3. Included studies per comparison with regard to biological/JAKi treatment performed by the two working groups of the ECCO guidelines on treatment of Crohn's disease (Gordon, 2024)

Results

Results described below are adapted from Gordon (2024).

Infliximab

Induction therapy

The efficacy of infliximab monotherapy for induction therapy in patients with active CD was evaluated in one small [n = 108], randomised, placebo-controlled trial comparing a single infusion of infliximab 5 mg/kg [n = 27], 10 mg/kg [n = 28], or 20 mg/kg [n = 28] with placebo [n = 25]. In this trial, standard dosing of infliximab [5 mg/kg] was superior to placebo for inducing clinical response at Week 12 [RR: 4.01; 95% CI: 1.29–12.44]. Superiority of infliximab was not observed for clinical remission at Week 12 [RR: 3.70; 95% CI: 0.87–15.80]. Endoscopic endpoints were not reported. Although safety was evaluated in this study, AEs were pooled for all dosing schemes of infliximab, precluding any conclusion on the safety profile of standard dosing of infliximab, with the level of certainty further affected by sparse data (Targan, 1997). Following the pivotal trial of Targan. (1997), the ACCENT I trial established the induction dosing time points of Week 0 followed by Week 2 and Week 6 (Hanauer, 2022).

Maintenance therapy

No separate meta-analysis has focused primarily on the outcomes of infliximab maintenance therapy in patients with CD. Two landmark RCTs were published more than 20 years ago and were pooled for the purpose of this guideline (Hanauer, 2022; Rutgeerts, 2006). In total, 408 patients who clinically responded to one dose of infliximab [CDAI decrease ≥ 70] were included. After 44 weeks, the overall likelihood of achieving clinical remission with infliximab [5 or 10 mg/kg every 8 weeks] over placebo was 2.15 [95% CI: 1.52–3.05]. Mucosal healing [defined as absence of mucosal ulceration] was assessed at 54 weeks in one RCT showing superiority of infliximab over placebo [RR: 7.00; 95% CI: 1.02–48.10] (Rutgeerts, 2006). However, patients in the placebo group received episodic doses of infliximab In the pivotal trials, AEs [RR: 0.97; 95% CI: 0.88–1.07], SAEs [RR: 0.86; 95% CI: 0.65–1.14], and serious infections [RR: 0.85; 95% CI: 0.36–2.00] were not different between infliximab and placebo (Hanauer, 2022; Rutgeerts, 2006). In a network analysis performed in the framework of a Cochrane collaboration, the dose-adjusted OR for severe AEs for infliximab was 1.13 [95% CI: 0.79–1.62] (Singh, 2011). Evidence for clinical and endoscopic outcomes for infliximab maintenance therapy was downgraded due to imprecision [sparse events] and indirectness [since the 10 mg/kg dose is higher than the standard maintenance dose of 5 mg/kg] in the two pivotal RCTs. This led to an overall assessment of the level of evidence as low.

Combination therapy, induction

The SONIC RCT (Colombel, 2010) compared the efficacy of infliximab combined with azathioprine over infliximab monotherapy in patients naïve to both therapies, who failed to respond to steroids or 5-ASA. Combination therapy resulted in higher rates of clinical remission at Week 26 when compared with infliximab monotherapy [RR: 1.64; 95% CI: 1.07–2.53]. Combination therapy was also more likely to result in mucosal healing at this time point [RR: 1.82; 95% CI: 1.01– 3.26]. There were significantly lower rates of SAEs in those receiving combination therapy [RR: 0.56; 95% CI: 0.32– 0.97 with no difference in total AEs. In addition, several prospective (Kenndey, 2019) and retrospective observational studies Luber, 2021; Targownik, 2020; Kapizioni, 2024)  and a network meta-analysis have also suggested the benefit of combination therapy with azathioprine over infliximab monotherapy (Rui, 2021). Combination therapy with azathioprine appears to improve efficacy by enhancing pharmacokinetic features of infliximab (Colombel, 2019).

Combination therapy, maintenance

For patients who achieved clinical remission after induction with combination therapy with infliximab and immunomodulator, two RCTs provide data on combination therapy versus monotherapy within the maintenance period; these are the SONIC trial (Colombel, 2010) for combination of infliximab with azathioprine, and the COMMIT trial (Feagan, 2014) for combination of infliximab with methotrexate. Meta-analysis of these data revealed higher rates of mucosal healing [RR: 1.46; 95% CI: 1.00–2.13] and improved patient-reported outcomes, measured as change in Inflammatory Bowel Disease Questionnaire [IBDQ] score from baseline (mean difference [MD]: 4.8; 95% CI: 2.23–11.83]) Although resulting in numerically higher efficacy rates, combination therapy was not superior in clinical response [RR: 1.21; 95% CI: 0.96–1.53], clinical remission [RR: 1.25; 95% CI: 0.97–1.61], or steroid-free clinical remission [RR: 1.15; 95% CI: 0.85–1.55]. SAEs were less frequent with combination therapy [RR: 0.66; 95% CI: 0.41–0.98], whereas total AEs [RR: 1.01; 95% CI: 0.94–1.09] were similar between groups.

More recently, infliximab has been licensed for subcutaneous [SC] maintenance administration after two intravenous [IV] induction dosing at week 0 and 4. This decision was based on pharmacokinetic and safety data comparing maintenance SC dosing every 2 weeks with IV dosing (Schreiber, 2021). Subsequent RCT data have demonstrated the superiority of maintenance SC infliximab versus placebo for clinical and endoscopic endpoints among responders to IV infliximab induction therapy, demonstrating that this formulation is an effective option for responders to IV induction (Colombel, 2023). Multiple cohort studies have reported the effectiveness and safety of switching patients already established on standard doses of IV maintenance infliximab to SC maintenance dosing (Smith, 2022). Future recommendations on infliximab combination therapy may change with emerging evidence on the efficacy, pharmacokinetics, and immunogenicity of SC infliximab (D’Haens, 2023).

Combination therapy, de-escalation

The combination of anti-TNF therapy with a thiopurine is associated with adverse long-term safety signals in terms of risk of both serious infection and malignancy (Kirchgesner, 2020; Feagan, 1995). This raises questions regarding potential de-escalation of treatment for patients in stable remission. The recent SPARE trial investi­gated clinical relapse in CD patients in steroid-free clinical remission for a minimum 8 months under combined infliximab and immunomodulator therapy, who either continued com­bination therapy or stopped infliximab or immunosup­pressive therapy (Louis, 2023). In this study with 211 randomised CD patients, clinical remission was significantly more often maintained over 2 years of follow-up when combination therapy was de-escalated to infliximab monotherapy [63/69; 91%] when compared with immunomodulator monotherapy [46/71; 65%] [RR: 1.41; 95% CI: 1.17-1.7]. There were no significant differences in clinical relapse rates, endoscopic outcomes, or pharmacokinetic outcomes between the group continuing combination therapy and those discontinuing immunomodulator therapy. AEs occurred at a similar fre­quency across treatment groups.

In general, a higher risk of lymphoma exists when anti-TNF agents are combined with conventional immunosup­pression, although the absolute rates remain very low and are estimated at 1.9 per 10 000 patient-years in a meta-analysis consisting of almost 9000 patients included in the SEER data­base (Siegel, 200). Finally, in patients with immunogenic failure towards a first anti-TNF agent, the addition of thiopurines during switch to a second anti-TNF agent increases efficacy and reduces immunogenicity (Roblin, 2020).

Adalimumab

Induction therapy

A meta-analysis of pooled data on adalimumab versus placebo from three RCTs (Chen, 2020; Hanauer, 2006; Sandborn, 2007) involving 680 patients with moderate-to-severe CD, who did not achieve adequate response or were intolerant to corticosteroids and/or immunosuppressants, demonstrated efficacy for induction of clinical remission [RR: 3.58; 95% CI: 2.42– 5.29] and clinical response [RR: 1.98; 95% CI: 1.47–2.67] within 4 weeks of therapy initiation. Limited endoscopic data were available for the induction period only in one study; the data showed a significant trend towards enhanced mucosal healing [RR: 30.51; 95% CI: 1.87–498.81]. However, this evidence was downgraded due to high imprecision arising from sparse data (Rutgeerts, 2012). There was no difference in AEs between those receiving adalimumab or placebo during the induc­tion period [RR: 0.91; 95% CI: 0.75–1.11] (Chen, 2020; Hanauer, 2006; Sandborn, 2007). Rates of SAEs with adalimumab were also not significantly different from placebo [RR: 0.29; 95% CI: 0.09–0.96], but evidence was downgraded due to imprecision from sparse data (Chen, 2020; Hanauer, 2006; Sandborn, 2007). Data revealed improved QoL based on the IBDQ within 4 weeks of therapy initiation[RR: 0.91; 95% CI: 0.75–1.11]. A Cochrane review based on three RCTs revealed similar re­sults for clinical remission, response, improvement in QoL, and AEs during the first 4 weeks of therapy (Abbass, 2019).

Maintenance therapy

Data from three RCTs in individuals with moderate-to-severe CD, who responded to induction therapy [CHARM, EXTEND 1, CLASSIC-II], demonstrated effi­cacy of adalimumab 40 mg SC every 2 weeks over placebo for maintenance of clinical remission [RR: 2.70; 95% CI: 1.75–4.19] at 52–56 weeks of follow-up (Rutgeerts, 2012; Colombel, 2007; Sandborn, 2007). Outcomes of clinical response [RR: 2.01; 95% CI: 1.14–3.55], but not corticosteroid-free remission [RR: 2.32; 95% CI: 0.62-8.63], were also improved with adalimumab( Colombel, 2007; Sandborn, 2007).  RCT data on endoscopic outcomes are more limited, but suggest efficacy of adalimumab relative to placebo in endoscopic remission [RR: 9.14; 95% CI 2.21–37.80], endoscopic response [RR: 14.22; 95% CI: 1.93–104.98], and mucosal healing [RR: 31.00; 95% CI: 1.90–506.95] (Rutgeerts, 2012). Based on a post-hoc analysis of a single, placebo-controlled trial, QoL improvement was greater with adalimumab [RR: 1.32; 95% CI: 1.11–1.62] (Panaccione, 2010). Regarding safety during the maintenance period, pooled clinical trial data indicated that adalimumab was associ­ated with fewer SAEs than placebo [RR: 0.57; 95% CI: 0.39–0.83], and associations with any AE [RR: 1.00; 95% CI: 0.86–1.15] and serious infections were comparable [RR: 0.79; 95% CI: 0.34–1.79] (Rutgeerts, 2012; Colombel, 2007; Sandborn, 2007). In a network analysis per­formed in the framework of a Cochrane collaboration, the dose-adjusted OR for SAEs for adalimumab was 1.01 [95% CI: 0.64–1.59] (Singh, 2011).

Combination therapy, induction

Only one open-label RCT [the DIAMOND trial] (Matsumoto, 2016) studied the use of combination therapy of adalimumab with a thiopurine when compared with adalimumab monotherapy for the induction of clinical remission in patients naïve to both therapies. In this trial, combination therapy was not superior to adalimumab monotherapy for inducing clinical remission at Week 26 [primary endpoint] [RR: 0.95; 95% CI: 0.78–1.15]. However, combination therapy was associated with endoscopic improvement at Week 26 [RR: 1.32; 95% CI: 1.06–1.65], although this benefit was lost by Week 52. There was no increase in AEs leading to discontinuation associated with combination therapy [RR: 1.03; 95% CI: 0.60–1.78].

Combination therapy, maintenance

The Week 52 maintenance outcomes of the DIAMOND trial demonstrated no clinical benefit of combination therapy in clinical remission [RR: 1.07; 95% CI: 0.91–1.25], clinical response [RR: 0.95; 95% CI: 0.78–1.15] (Matsumoto, 2016; Hisamatsu, 2019) steroid-free clin­ical remission [RR: 0.97; 95% CI: 0.851.12] (Hisamatsu, 2019) endoscopic response [RR: 1.20; 95% CI: 0.89–1.62] (Watanabe, 2018) mucosal healing [RR: 1.77; 95% CI: 0.82–3.82] (Watanabe, 2018) SAEs [RR: 0.25; 95% CI:  0.01–5.00], or any AE [RR: 0.81; 95% CI: 0.47–1.38] (Matsumoto, 2016; Hisamatsu, 2019). Likewise, a meta-analysis that included retrospective studies also revealed that combination therapy was not superior to monotherapy for maintenance of remission [OR: 1.08; 95% CI: 0.79–1.48, p = 0.48] (Kopylov, 2014). More recently, post-hoc analysis of six RCTs [CLASSIC-I, GAIN, CHARM, EXTEND, ULTRA 1, and ULTRA 2] demonstrated no efficacy benefits with immunomodulator and adalimumab combination therapy when compared with adalimumab monotherapy in CD pa­tients with inadequate disease control on immunomodulatory therapy (Colombel, 2017). The DIAMOND study included patients naïve to adalimumab. In the case of immune-mediated loss of re­sponse to a first anti-TNF, RCT evidence suggests that com­bination therapy is of benefit with the second anti-TNF (Roblin, 2020). Additionally, the observational PANTS study demonstrated a significant reduction in anti-adalimumab antibody devel­opment with adalimumab combination therapy in anti-TNF-naïve patients [HR: 0.44; 95% CI: 0.31–0.61] (Kennedy, 2019) suggesting that some patients may benefit from combination therapy with adalimumab and a thiopurine, depending on genetic predisposition (Sazonovs, 2020). Therefore, combining adalimumab with an immunomodulator should be considered in high-risk groups, including those with prior immunogenic failure to other anti TNFs.

Ustekinumab

Induction therapy

One systematic review and meta-analysis pooled the results from RCTs in which ustekinumab was compared with placebo for induction of remission in adult patients with moderately to severely ac­tive luminal CD (MacDonald,2016). Four trials involving 1947 patients treated with different ustekinumab IV doses or equivalent pla­cebo reported on induction outcomes at 6 weeks (Sandborn, 2012; Feagan, 2016; Rutgeerts, 2018; Sandborn, 2008). Data were extracted and a meta-analysis was performed, demonstrating  efficacy in clinical response [RR: 1.56; 95% CI: 1.38–1.57] and clinical remission [RR: 1.76; 95% CI: 1.40–2.22]. Two substudies (Rutgeerts, 2018; Li, 2019) involving 252 patients revealed that more pa­tients receiving ustekinumab achieved endoscopic improve­ment compared with placebo [47.7% vs 29.9%, RR: 1.60; 95% CI: 1.13–2.26] and a reduction in the mean global hist­ology activity scores [from 10.4 ± 7.0 to 7.1 ± 5.9; p < 0.001] at 8 weeks. A more recent RCT (Sandborn, 2022) investigating the efficacy and safety of guselkumab in CD, in which ustekinumab was administered in a reference arm [63 patients], reported similar results at 12 weeks. Two studies (Sands, 2018; Sandborn, 2021) reported on the effect of ustekinumab on health-related QoL. The RR was 2.42 [95% CI: 1.27–4.61] for achieving PRO-2 remission, 2.14 [95% CI: 1.27–3.62] for IBDQ remission, and 1.86 [95% CI: 1.33– 2.59] for IBDQ response at 12 weeks (Sandborn, 2022). Similarly, signifi­cantly greater proportions of patients receiving ustekinumab had clinically meaningful IBDQ and SF-36 score improve­ment at 8 weeks compared with placebo in a pooled ana­lysis of two pivotal RCTs. One study reported pooled safety results of phase 2/3 RCTs on any AEs or SAEs after induc­tion [1653 patients] (Sands, 2018). The pooled RR of any AEs was not significantly different between ustekinumab and placebo [53.8% vs 56.1%, RR: 0.96; 95% CI: 0.89–1.03]. Similarly, the pooled RR of any SAEs and of any serious infection were not significantly different between ustekinumab and placebo [4.5% vs 6.2%, RR: 0.72; 95% CI: 0.51–1.02; and 1.1% vs 1.2%, RR: 0.95; 95% CI: 0.45–2.01, respectively]. The rate of antidrug antibody formation was < 5% (Hanauer, 2020). Finally, a meta-analysis (Rubín de Célix, 2022) of 63 observational studies [8529 patients] reported that 60% [95% CI: 54–67%, I2 = 93%] of patients who received ustekinumab achieved clinical response, 37% [95% CI: 28–46%, I2 = 97%] achieved clinical remission, and 33% [95% CI: 27–40%, I2 = 86%] achieved corticosteroid-free clinical remission at 8–14 weeks, replicating the results of RCTs in a real-world setting of refractory patients with CD.

Maintenance therapy

One RCT in­cluded patients with moderate-to-severe CD who responded to ustekinumab induction therapy. Patients were re-randomised to receive ustekinumab 90 mg [either every 8 weeks or every 12 weeks] or placebo. More patients receiving ustekinumab when compared with those receiving placebo were in clin­ical remission over a 44-week follow-up [51% vs 35.9%, RR: 1.42; 95% CI: 1.10–1.84] (Feagan, 2016) and at Week 56 [50.2% vs 27.7%; RR: 1.83; 95% CI: 1.35–2.47] (Hanauer, 2020; Sanbron, 2019). The same study showed that more patients receiving ustekinumab were also in corticosteroid-free clinical remission over a 44-week follow-up [44.7% vs 29.8%, RR: 1.50; 95% CI: 1.12–2.02] and after 56 weeks of treatment [44.7% vs 22.1%; RR: 2.02; 95% CI: 1.43–2.86 (Feagan, 2016; Hanauer, 2020; Sanbron, 2019). Similar results were shown for clinical response. There are limited placebo-controlled trial data from a subgroup analysis on endoscopic remission [total SES-CD score ≤ 2] and mucosal healing [complete absence of any mucosal ulcerations among patients who presented with ulceration in at least one ileocolonic segment at induction]. There was no statistically significant difference in mucosal healing [RR: 3.13; 95% CI: 0.40–24.53] or endoscopic remis­sion [RR: 2.61; 95% CI: 0.32–21.08] between ustekinumab and placebo (Rutgeerts, 2018). Nevertheless, outcome data from a large randomised trial comparing treatment with ustekinumab every 8 weeks with adalimumab every 2 weeks showed similar endoscopic outcomes between the two groups (Sands, 2022). In addition, post-hoc analyses showed that ustekinumab im­proved health-related QoL compared with placebo (Sands, 2018). A pooled safety analysis from phase 2/3 studies showed that there was no statistically significant difference between placebo- or ustekinumab-treated patients for SAEs [RR: 1.03; 95% CI: 0.85–1.26] and serious infections [RR: 1.57; 95% CI: 0.98–2.51] for a mean follow-up of 48 weeks (Sandborn, 2021).

Ustekinumab versus adalimumab

Induction therapy

The SEAVUE trial [phase 3b] (Sands, 2022) was an active com­parator randomised trial that used a ‘treat-through’ design to compare the effectiveness and safety of ustekinumab and adalimumab monotherapy in biologic-naïve adult pa­tients with moderately to severely active CD. Of note, the threshold of endoscopic disease required for trial inclusion was lower compared with several other studies [requiring at least one, single ulcer of any size]. The primary endpoint was the proportion of patients in clinical remission [CDAI score < 150] at Week 52. A total of 386 patients were en­rolled and randomly assigned to receive ustekinumab [n = 191] or adalimumab [n = 195]. Ustekinumab induction was approximately 6 mg/kg IV on Day 0, followed by main­tenance of 90 mg SC at Week 8, and then 90 mg SC once every 8 weeks. Adalimumab induction was 160 mg SC on Day 0, 80 mg SC at Week 2, followed by maintenance of 40 mg SC at Week 4, and then once every 2 weeks. Study treatments were administered as monotherapy and without dose modifications. Both monotherapies were effective for induction of remission at Week 16 [ustekinumab 57% vs adalimumab 60%, difference -3%, 95% CI: -13 to 7; nom­inal p = 0.55] and demonstrated comparative efficacy [RR: 0.95, 95% CI: 0.80–1.13]. Response rates at 16 weeks were similar between agents [72% vs 73%, respectively], with moderate-quality evidence. Safety outcomes for both groups did not show significant differences.

Maintenance therapy

When considering maintenance outcomes at Week 52, 64.9% [124/191] of patients receiving ustekinumab every 8 weeks versus 61.0% [119/195] of patients receiving adalimumab every 2 weeks were in clinical remission [RR: 1.06, 95% CI: 0.91–1.24] (Sands, 2022). Similarly, corticosteroid-free clinical remission was achieved in 61% of the ustekinumab group and 57% of the adalimumab group [RR: 1.06, 95% CI: 0.90–1.25]. Both treatment groups showed similar endoscopic response [ustekinumab 42% vs adalimumab 37%, RR: 1.14, 95% CI: 0.88–1.47] and endoscopic remission rates  [ustekinumab 29% vs adalimumab 31%, RR: 0.93, 95% CI: 0.67–1.28] at Week 52 (Sands, 2022). Overall, the safety profile was similar between groups for AEs [RR: 1.03, 95% CI 0.93–1.14] and SAEs [RR: 0.82, 95% CI 0.22–3.00]. However, the numerical proportions of patients in the ustekinumab group [34%] who experienced infections was lower than in the adalimumab group [41%], although rates of serious infections were similar (Sands, 2022).

Risankizumab

Induction therapy

Two placebo-controlled RCTs were identified (D’Haens, 2022). The two studies included a total of 889 patients with moderately to severely active CD, with evaluable outcome data after exposure to either three IV doses of 600 mg risankizumab [Weeks 0, 4, and 8] or placebo, with primary outcome measures captured at Week 12. Clinical response and clinical remission were achieved more often in patients receiving risankizumab compared with placebo [RR: 1.79, 95% CI: 1.47–2.17 and RR: 1.95, 95% CI:1.57–2.43, respectively]. Endoscopic response and endoscopic remission were achieved with risankizumab more often than placebo [RR: 2.96, 95% CI: 2.17–4.05 and RR: 3.22, 95% CI: 1.93– 5.38, respectively]. Rates of any AEs in patients treated with risankizumab occurred statistically less often than in patients receiving placebo [RR: 0.85, 95% CI: 0.62–1.17]. SAEs and serious infections occurred less often in risankizumab-treated patients [RR: 0.45, 95% CI: 0.3–0.67 and RR: 0.21, 95% CI: 0.07–0.65, respectively].

Maintenance therapy

Clinical responders to risankizumab from the two phase 3 induction trials were re-randomised in a single maintenance therapy trial (D’Haens, 2022). A total of 141 evaluable participants received 360 mg risankizumab SC every 8 weeks, and 164 partici­pants received SC placebo (Ferrante, 2022). Compared with placebo, more patients treated with risankizumab achieved clinical remis­sion [51.8% vs 39.6%, RR: 1.31, 95% CI: 1.02–1.67] or endoscopic response [46.8% vs 22.0%, RR: 2.13, 95% CI: 1.52–2.99] at Week 52 (Ferrante, 2022; Ferrante, 2023). A higher proportion of patients on risankizumab maintenance also achieved clinical response, endoscopic remission, and ulcer-free endoscopy after 1 year of therapy. The overall incidence of any SAEs or serious infec­tions were similar across study groups.

Vedolizumab

Induction therapy

Four RCTs involving 1126 patients treated with vedolizumab or placebo reported on clinical and safety outcomes in adult pa­tients with moderately to severely active luminal CD at 6–10 weeks. (Sandborn, 2013; Feagan, 2008; Sands, 2014). Data were extracted and a meta-analysis was per­formed. Vedolizumab was superior to placebo in induction of clinical response [RR: 1.59, 95% CI: 1.32–1.91] and clinical remission [RR: 2.00, 95% CI: 1.51–2.66]. Endoscopic out­come data were not assessed. The pooled RR of any AEs was not significantly different between vedolizumab and placebo [62% vs 53.8%, RR: 1.15, 95% CI: 0.88–1.51]. Similarly, the pooled RR of SAEs was not significantly different between vedolizumab and placebo [9.0% vs 9.2%, RR: 0.99, 95% CI: 0.68–1.44].

A meta-analysis (Macaluso, 2023) of 74 observational studies [13 663 patients] reported that 56% [95% CI: 51–61%, I2 = 89%] of the patients who received vedolizumab exhibited clinical response, 36% [95% CI: 32–40%, I2 = 85%] achieved clin­ical remission, 30% [95% CI: 25–34%, I2 = 87%] achieved corticosteroid-free clinical remission, and 29% [95% CI: 19–42%, I2 = 58%] achieved mucosal healing at 6–16 weeks, replicating the results of RCTs in a real-world setting of re­fractory patients with CD.

Maintenance therapy

Maintenance therapy with vedolizumab was investigated in three RCTs in patients with moderate-to-severe CD who had responded to induction therapy. Vedolizumab was ad­ministered IV at 300 mg every 8 weeks in two studies (Sandborn, 2013; Watanabe, 2020) and SC at 108 mg every 2 weeks in one study (Vermeire, 2022). Following 52–60 weeks of maintenance therapy, vedolizumab was superior to placebo in achieving clinical remission [RR: 1.55, 95% CI: 1.25–1.91], with 44.7% [197/441] of pa­tients receiving vedolizumab in clinical remission when compared with 27.1% [81/299] of patients receiving pla­cebo. Moreover, vedolizumab was effective at maintaining steroid-free clinical remission [RR: 2.23, 95% CI: 1.44– 3.44]; this endpoint was achieved in 39.0% [71/182] of patients receiving vedolizumab compared with 16.3% [21/129] of patients receiving placebo. Again, no endo­scopic data were generated during the registrational trials, although endoscopic outcomes have been collected during open-label clinical trials and cohort studies (Danese, 2019). Vedolizumab showed a similar incidence of AEs [RR: 0.96, 95% CI: 0.86–1.08], SAEs [RR: 0.98, 95% CI: 0.67–1.44], and ser­ious infections [RR: 0.32, 95% CI: 0.09–1.13] compared with placebo through Week 52–60. Similar safety signals were observed in the GEMINI long‐term safety study that followed CD patients exposed to IV vedolizumab every 4 weeks for a median of 32 months [range 0.03–100.3] (Loftus, 2020).

Upadacitinib

Induction therapy

Two RCTs re­ported outcomes for a total 1021 patients who were random­ised in a 2:1 ratio to receive either 45 mg/day of upadacitinib or placebo for 12 weeks (Loftus, 2023). We meta-analysed outcomes from these trials. A significantly higher percentage of patients re­ceiving upadacitinib achieved clinical remission than those who received placebo [44.4% vs 25.1%, p < 0.001] and endo­scopic response [40.2% vs 8.4%, p < 0.001]. Significantly higher proportions of patients on upadacitinib achieved clinical response, steroid-free remission, and endoscopic re­mission when compared with placebo. The overall incidence of safety outcomes was similar between patients exposed to upadacitinib and placebo.

Maintenance therapy

Clinical responders from the induction RCTs were re-randomised to receive daily upadacitinib 15 mg [n = 169], upadacitinib 30 mg [n = 168], or placebo [n = 165] (Loftus, 2023). When compared with placebo, maintenance therapy with upadacitinib, 15 mg once daily and 30 mg once daily by Week 52, resulted in significantly higher rates of clinical remission [37.3% and 47.6% vs 15.1%, respect­ively, p < 0.001 for both comparisons], endoscopic response [35.5% and 40.1% vs 7.3%, respectively, p < 0.001 for both], and remission [19.1% and 28.6% vs 5.5%, respect­ively, p < 0.001 for both].  A higher proportion of patients on upadacitinib main­tenance achieved clinical response and steroid-free clinical remission with improved QoL. Efficacy outcomes were all numerically higher in the group receiving higher doses of maintenance therapy, although this should be viewed against safety and cost considerations. The overall incidence of any SAEs or serious infections were similar across study groups. Herpes zoster infection was reported in 4.0% of patients re­ceiving maintenance treatment with 15 mg upadacitinib and 7.2% of patients receiving 30 mg upadacitinib, compared with 4.7% in the placebo group. No adjudicated cardiovas­cular events were reported. One case of hepatic vein throm­bosis concurrent with exacerbation of CD was reported in a patient receiving 30 mg upadacitinib.

For the current module, the 2024 ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment were adapted (Gordon, 2024). With regard to treatment with biologicals and JAK-inhibitors, a systematic review of the literature was performed for the PICO questions/comparisons described below. Systematic literature searches were performed by two separate working groups. Working group 1 focused on the induction of remission. Working group 2 focused on the maintenance of remission. See Table 1 below for an overview of the investigated comparisons per working group.

_{Note: Both working groups also performed searches for the efficacy of certolizumab and filgotinib versus placebo. These questions were not further considered, as neither is registered in the Netherlands for adults with Crohn’s disease.}

Table 1. Investigated comparison (systematic literature search) with regard to biological/JAKi treatment performed by the two working groups of the ECCO guidelines on treatment of Crohn's disease (Gordon, 2024)

Table 2. PICO

Relevant outcome measures

Working group 1

The ECCO guideline panel considered clinical response, clinical remission, SAEs, endoscopic response as critical outcome measures for decision making; and quality of life, steroid-free remission, AEs, serious infections and endoscopic remission as important outcome measures for decision making.

Working group 2

The ECCO guideline panel considered clinical response, clinical remission, quality of life, steroid-free remission, SAEs and endoscopic remission as critical outcome measures for decision making; and biochemical remission, AEs, serious infections, endoscopic response and mucosal healing 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; minimally relevant for patients) 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. Both databases were searched from until Januari-March 2023 (depending on the PICO) for systematic reviews, RCTs and observational studies. For the following comparisons (which were new in the current ECCO guidelines), searches were performed from unlimited date: risankizumab/upadacitnib/filgotinib versus placebo, ustekinumab versus adalimumab and adalimumab/infliximab monotherapy versus combination therapy. For all other PICO questions, searched were performed from 1 April 2018 as the searches of the previous ECCO guidelines from 2020 were performed at that date. Detailed search strategies per PICO are available in the supplementary file of the ECCO guidelines (Gordon, 2024).

After deduplication a total of 14123 records were founds for all PICO questions (including PICO questions not on biological or JAKi treatment). The number of records per PICO question are also available from the supplementary file of the ECCO guidelines.

1. Abbass M, Cepek J, Parker CE, et al. Adalimumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2019;2019:CD012878.
2. Abraham B, Wu J, Vermeire S, Melmed G, Ungaro R, Charabaty A, Moses R, Chan-Diehl F, Paulissen J, Zhu B, Barnes EL, Ehrlich AC, Rubin DT. Efficacy and Safety of Mirikizumab in the Treatment of Moderately to Severely Active Ulcerative Colitis Regardless of Baseline Modified Mayo Score: Results From the Phase 3 LUCENT Trials. Crohns Colitis 360. 2025 Jan 8;7(2):otaf002. doi: 10.1093/crocol/otaf002. PMID: 40260308; PMCID: PMC12010086.
3. Anjie SI, Gecse KB, Meloni CM, Vidal-Itriago A, Löwenberg M, D'Haens GR. Immunogenicity and Efficacy of Subcutaneous Infliximab Monotherapy vs Combination Therapy in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2025 May 14:S1542-3565(25)00409-4. doi: 10.1016/j.cgh.2025.03.021. Epub ahead of print. PMID: 40378993.
4. Chen B, Gao X, Zhong J, et al. Effcacy and safety of adalimumab in Chinese patients with moderately to severely active Crohn’s disease: results from a randomized trial. Therap Adv Gastroenterol 2020;13:1756284820938960.
5. Colombel JF, Adedokun OJ, Gasink C, et al. Combination therapy with infiximab and azathioprine improves infiximab pharmacokinetic features and effcacy: a Post Hoc Analysis. Clin Gastroenterol Hepatol 2019;17:1525–32.e1.
6. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52–65.
7. Colombel JF, Jharap B, Sandborn WJ, et al. Effects of concomitant immunomodulators on the pharmacokinetics, effcacy and safety of adalimumab in patients with Crohn’s disease or ulcerative colitis who had failed conventional therapy. Aliment Pharmacol Ther 2017;45:50–62.
8. Colombel JF, SB H, Sandborn W, Sands BE, et al. CT-P13 SC 3.8. DOP86 Subcutaneous infiximab [CT-P13 SC] as maintenance therapy for Crohn’s disease: a phase 3, randomised, placebo controlled study [LIBERTY-CD]. J Crohns Colitis 2023;17:i161–2.
9. Colombel JF, Sandborn WJ, Reinisch W, et al.; SONIC Study Group. Infiximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383–95.
10. Danese S, Sandborn WJ, Colombel JF, et al. Endoscopic, radiologic, and histologic healing with vedolizumab in patients with active Crohn’s disease. Gastroenterology 2019;157:1007–18.e7.
11. D’Haens G, Reinisch W, Schreiber S, et al. Subcutaneous infiximab monotherapy versus combination therapy with immunosuppressants in infammatory bowel disease: a Post Hoc Analysis of a Randomised Clinical Trial. Clin Drug Investig 2023;43:277–88.2022;399:2200–11.
12. D’Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet 2022;399:2015–30.
13. Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate in combination with infiximab is no more effective than infiximab alone in patients with Crohn’s disease. Gastroenterology 2014;146:681–8.e1.
14. Feagan BG, Sandborn WJ, Gasink C, et al.; UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016;375:1946–60.
15. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol 2008;6:1370– 7.
16. Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet 2022;399:2031–46.
17. Ferrante M, Irving PM, Abreu MT, et al. Maintenance risankizumab sustains induction response in patients with Crohn’s disease in a randomised phase 3 trial. J Crohns Colitis 2023;18:416–23.
18. Gordon H, Biancone L, Fiorino G, et al. ECCO guidelines on inflammatory bowel disease and malignancies. J Crohns Colitis 2023;17:827–54.
19. Hanauer SB, Feagan BG, Lichtenstein GR, et al.; ACCENT I Study Group. Maintenance infiximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9.
20. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody [adalimumab] in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006;130:323–33; quiz 591.
21. Hanauer SB, Sandborn WJ, Feagan BG, et al. IM-UNITI: three-year effcacy, safety, and immunogenicity of ustekinumab treatment of Crohn’s disease. J Crohns Colitis 2020;14:23–32.
22. Hanauer SB, Sands BE, Schreiber S, Danese S, Kłopocka M, Kierkuś J, Kulynych R, Gonciarz M, Sołtysiak A, Smoliński P, Srećković S, Valuyskikh E, Lahat A, Horyński M, Gasbarrini A, Osipenko M, Borzan V, Kowalski M, Saenko D, Sardinov R, Lee SJ, Kim S, Bae Y, Lee S, Lee S, Lee JH, Yang S, Lee J, Lee J, Kim JM, Park G, Sandborn WJ, Colombel JF. Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: Two Randomized Phase 3 Trials (LIBERTY). Gastroenterology. 2024 Oct;167(5):919-933. doi: 10.1053/j.gastro.2024.05.006. Epub 2024 May 23. PMID: 38788861.
23. Hisamatsu T, Matsumoto T, Watanabe K, et al.; DIAMOND study group . Concerns and side effects of azathioprine during adalimumab induction and maintenance therapy for Japanese patients with Crohn’s disease: a subanalysis of a prospective randomised clinical trial [DIAMOND Study]. J Crohns Colitis 2019;13:1097–104.
24. Kapizioni C, Desoki R, Lam D, et al. Biologic therapy for infammatory bowel disease: Real-world comparative effectiveness and impact of drug sequencing in 13,222 patients within the UK IBD BioResource. J Crohns Colitis 2024;18:790–800.
25. Kennedy NA, Heap GA, Green HD, et al.; UK Infammatory Bowel Disease Pharmacogenetics Study Group. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4:341–53.
26. Kirchgesner J, Lemaitre M, Carrat F, Zureik M, Carbonnel F, Dray-Spira R. Risk of serious and opportunistic infections associated with treatment of infammatory bowel diseases. Gastroenterology 2018;155:337–46.e10.
27. Kopylov U, Al-Taweel T, Yaghoobi M, et al. Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn’s disease: a systematic review and meta-analysis. J Crohns Colitis 2014;8:1632–41.
28. Li K, Friedman JR, Chan D, et al. Effects of ustekinumab on histologic disease activity in patients with Crohn’s disease. Gastroenterology 2019;157:1019–31.e7.
29. Loftus EV, Feagan BG, Panaccione R, et al. Long-term safety of vedolizumab for infammatory bowel disease. Aliment Pharmacol Ther 2020;52:1353–65.
30. Loftus EV Jr, Panés J, Lacerda AP, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. N Engl J Med 2023;388:1966–80.
31. Louis E, Resche-Rigon M, Laharie D, et al.; GETAID and the SPARE-Biocycle research group. Withdrawal of infiximab or concomitant immunosuppressant therapy in patients with Crohn’s disease on combination therapy [SPARE]: a multicentre, open label, randomised controlled trial. Lancet Gastroenterol Hepatol 2023;8:215–27.
32. Luber RP, Dawson L, Munari S, et al. Thiopurines and their optimisation during infiximab induction and maintenance: A retrospective study in Crohn’s disease. J Gastroenterol Hepatol 2021;36:990–8.
33. MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2016;11:Cd007572.
34. Macaluso FS, Ventimiglia M, Orlando A. Effectiveness and safety of vedolizumab in infammatory bowel disease: a comprehensive meta-analysis of observational studies. J Crohns Colitis 2023;17:1217–27.
35. Matsumoto T, Motoya S, Watanabe K, et al.; DIAMOND study group. Adalimumab monotherapy and a combination with azathioprine for Crohn’s disease: a prospective, randomized trial. J Crohns Colitis 2016;10:1259–66.
36. Panaccione R, Feagan BG, Afzali A, Rubin DT, Reinisch W, Panés J, Danese S, Hisamatsu T, Terry NA, Salese L, Van Rampelbergh R, Sahoo A, Vetter ML, Yee J, Han C, Frustaci ME, Wan KYY, Yang Z, Johanns J, Andrews JM, D'Haens GR, Sands BE; GALAXI 2 & 3 Study Group. Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn's disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, placebo and active comparator-controlled, double-blind, triple-dummy trials. Lancet. 2025 Jul 26;406(10501):358-375. doi: 10.1016/S0140-6736(25)00681-6. Epub 2025 Jul 17. PMID: 40684778.
37. Rautakorpi J, Kolehmainen S, Löyttyniemi E, Björkesten CA, Arkkila P, Sipponen T, Salminen K. Switching to Subcutaneous Infliximab Maintenance Therapy Is Effective in Patients with Inflammatory Bowel Disease. Dig Dis Sci. 2025 Apr;70(4):1457-1466. doi: 10.1007/s10620-025-08876-5. Epub 2025 Feb 13. PMID: 39946070; PMCID: PMC11972210.
38. Roblin X, Williet N, Boschetti G, et al. Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Gut 2020;69:1206–12.
39. Rubín de Célix C, Chaparro M, Gisbert JP. Real-world evidence of the effectiveness and safety of ustekinumab for the treatment of Crohn’s disease: systematic review and meta-analysis of observational studies. J Clin Med 2022;11:4202.
40. Rubin DT, Allegretti JR, Panés J, Shipitofsky N, Yarandi SS, Huang KG, Germinaro M, Wilson R, Zhang H, Johanns J, Feagan BG, Hisamatsu T, Lichtenstein GR, Bressler B, Peyrin-Biroulet L, Sands BE, Dignass A; QUASAR Study Group. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025 Jan 4;405(10472):33-49. doi: 10.1016/S0140-6736(24)01927-5. Epub 2024 Dec 17. PMID: 39706209.
41. Rui M, Fei Z, Wang Y, et al. Will the inducing and maintaining remission of non-biological agents and biological agents differ for Crohn’s disease? The evidence from the network meta-analysis. Front Med [Lausanne] 2021;8:679258.
42. Rutgeerts P, D’Haens G, Targan S, et al. Effcacy and safety of retreatment with anti-tumor necrosis factor antibody [infiximab] to maintain remission in Crohn’s disease. Gastroenterology 1999;117:761–9.
43. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infiximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest Endosc 2006;63:433–42; quiz 464.
44. Rutgeerts P, Gasink C, Chan D, et al. Effcacy of ustekinumab in inducing endoscopic healing in patients with Crohn’s disease. Gastroenterology 2018;155:1045–58.
45. Rutgeerts P, Van Assche G, Sandborn WJ, et al; EXTEND Investigators. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 2012;142:1102–11.e2.
46. Sands BE, Han C, Gasink C, et al. The effects of ustekinumab on health-related quality of life in patients with moderate to severe Crohn’s disease. J Crohns Colitis 2018;12:883–95.
47. 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. Gastroenterology 2014;147:618–27.e3.
48. Sands BE, Irving PM, Hoops T, et al. Ustekinumab versus adalimumab for induction and maintenance therapy in biologic-naive patients with moderately to severely active Crohn’s disease: a multicentre, randomised, double-blind, parallel-group, phase 3b trial. Lancet.
49. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut 2007;56:1232–9. 89. Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab sustains clinical remission and overall clinical beneft after 2 years of therapy for Crohn’s disease. Aliment Pharmacol Ther 2010;31:1296–309.
50. Sandborn W, Sands B, Colombel JF, et al. Effcacy of ustekinumab in Crohn’s disease at maintenence Week 56: IM-UNITI study. J Crohns Colitis 2019;13:S274.
51. Sandborn WJ, Gasink C, Gao LL, et al.; CERTIFI Study Group. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med 2012;367:1519–28.
52. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infiximab: a randomized trial. Ann Intern Med 2007;146:829–38.
53. Sandborn WJ, Feagan BG, Fedorak RN, et al.; Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 2008;135:1130–41.
54. Sandborn WJ, D’Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn’s disease: induction results from the Phase 2 GALAXI-1 Study. Gastroenterology 2022;162:1650–64.e8.
55. Sandborn WJ, Feagan BG, Rutgeerts P, et al.; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711–21.
56. Sandborn WJ, Feagan BG, Danese S, et al. Safety of ustekinumab in inflammatory bowel disease: pooled safety analysis of results from phase 2/3 studies. Inflamm Bowel Dis 2021;27:994–1007.
57. Sazonovs A, Kennedy NA, Moutsianas L, et al.; PANTS Consortium. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infiximab and adalimumab in patients with Crohn’s disease. Gastroenterology 2020;158:189–99.
58. Schreiber S, Ben-Horin S, Leszczyszyn J, et al. Randomized controlled trial: subcutaneous vs intravenous infiximab CT-P13 maintenance in infammatory bowel disease. Gastroenterology 2021;160:2340–53.
59. bSiegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol 2009;7:874–81.
60. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev 2011;2011:CD008794.
61. Smith PJ, Critchley L, Storey D, et al. Effcacy and safety of elective switching from intravenous to subcutaneous infiximab [CT-P13]: a multicentre cohort study. J Crohns Colitis 2022;16:1436–46.
62. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997;337:1029–35.
63. Targownik LE, Benchimol EI, Bernstein CN, et al. Combined biologic and immunomodulatory therapy is superior to monotherapy for decreasing the risk of infammatory bowel disease-related complications. J Crohns Colitis 2020;14:1354–63.
64. Vermeire S, D’Haens G, Baert F, et al. Effcacy and safety of subcutaneous vedolizumab in patients with moderately to severely active Crohn’s disease: results from the vISIBLE 2 Randomised Trial. J Crohns Colitis 2022;16:27–38.
65. Versteegh, M., Idema, D. L., Huygens, S., Jenniskens, K., Pierik, M., Römkens, T., ... & Damen, J. A. (2025). Comparative efficacy of all available pharmaceutical therapies for moderate to severe Crohn’s disease: a systematic review and network meta-analysis. Gastro Hep Advances, 100764.
66. Versteegh, M. M., Huygens, S. A., Bermejo, I., Grimm, S., Pierik, M., Römkens, T., ... & Wahab, P. (2025a). Cost–Utility Analysis of Treatment Sequences for Moderate-to-Severe Crohn’s Disease. PharmacoEconomics, 1-13.
67. Versteegh, M. M., Huygens, S. A., Bermejo, I., Grimm, S., Pierik, M., Römkens, T., ... & Wahab, P. (2025). Cost–Utility Analysis of Treatment Sequences for Moderate-to-Severe Crohn’s Disease. PharmacoEconomics, 1-13.
68. Watanabe K, Matsumoto T, Hisamatsu T, et al.; DIAMOND study group. Clinical and pharmacokinetic factors associated with adalimumab-induced mucosal healing in patients with Crohn’s disease. Clin Gastroenterol Hepatol 2018;16:542–9.e1.
69. 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 Gastroenterol 2020;55:291–306.