Summary and Certainty of Evidence We did not identify any new RCT that provided direct evidence for combination immunomodulator-TNF antagonist therapy in moderate-to-severe UC since the last guideline.56 The UC-SUCCESS trial provides direct evidence for this recommendation.80 This RCT randomized patients with moderate-to-severe UC to receive infliximab alone (n ¼ 77), azathioprine alone (n ¼ 76), or a combination of both agents (n ¼ 78). At week 16, the primary end point of corticosteroid-free clinical remission was achieved by 39.7% of patients receiving combination therapy compared with 22.1% of infliximab-treated patients and 23.7% of azathioprine-treated patients. A higher rate of mucosal healing was observed in the combination therapy group (62.8%) compared with infliximab (54.6%) or azathioprine (36.8%). This translated to an absolute difference in clinical remission rate of 170 per 1000 for combination therapy compared with infliximab alone (Table 13) and 159 per 1000 for combination therapy compared with immunomodulator alone (Table 14). Benefits and Harms In the UC-SUCCESS trial, there was no difference in the rate of serious infections between the combination therapy group compared with those receiving infliximab monotherapy (OR, 0.33; 95% CI, 0.01–7.86). In observational studies, there was a higher risk of lymphoma with combination therapy compared with TNF antagonist monotherapy. In a national study from France, the risk of lymphoma was higher in patients receiving combination therapy compared with TNF-antagonist monotherapy (HR, 2.53; 95% CI, 1.35–4.77) or thiopurine monotherapy (HR, 2.35; 95% CI, 1.31–4.22).25 Thus, the increase in efficacy with combination therapy must be balanced against the risk of therapy-related adverse events. Patients, particularly with more moderate (rather than severe) disease, may reasonably elect to use TNF antagonist monotherapy over combination therapy balancing risks and benefits. Rationale and Implementation Considerations In addition to direct evidence from the UC-SUCCESS study, indirect evidence in support of combination therapy is also derived from moderate-to-severe CD. In the landmark SONIC trial of immunomodulator-naïve patients with CD, a combination of azathioprine and infliximab therapy was associated with higher rates of corticosteroid-free clinical remission at week 26 compared with those receiving infliximab or azathioprine alone.80 Although the COMMIT trial did not demonstrate benefit of methotrexate added to infliximab in patients with CD, patients receiving combination therapy had a higher infliximab trough level and lower rates of anti-infliximab antibody positivity.81 Thus, it is reasonable to infer, given their similar broad mechanisms of immunosuppression, that there is an additive benefit to use of methotrexate in combination with TNF antagonists. There are less direct data demonstrating the benefit of combination therapy with adalimumab or golimumab. In the DIAMOND trial, a combination of azathioprine and 1332 Singh et al Gastroenterology Vol. 167, Iss. 7 GUIDELINES Table 14.GRADE Evidence Profile Comparing Infliximab þ Immunomodulators vs Immunomodulator Monotherapy for Achieving Steroid-Free Remission in Patients With Moderate-to-Severe Ulcerative Colitis Outcomes Study event rates [n/N (%)] Relative effect, RR (95% CI) Absolute effecta No. of participants (studies) Quality of the evidence (GRADE)b Risk with immunomodulator Risk with combination therapy Combination therapy with infliximab þ immunomodulators compared with immunomodulator monotherapy for moderate-to-severe UC Achieving clinical remission (CRITICAL) 18/79 (22.8%) 31/80 (38.8%) 1.70 (1.04–2.78) 159 more per 1000 (from 9 more to 406 more) 159 (1 RCT) ⨁⨁⨁c MODERATE NOTE. No trial of maintenance therapy comparing TNF antagonists þ immunomodulators vs immunomodulator monotherapy was identified. a Absolute effects estimated based on the following placebo rates across trials: induction of clinical remission w10%; maintenance of clinical remission w15%. b GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. c Rated down for imprecision because optimal information size not met (<200 events). Table 13.GRADE Evidence Profile Comparing Infliximab þ Immunomodulators vs Infliximab Monotherapy for Achieving Steroid-Free Remission in Patients With Moderate-to-Severe Ulcerative Colitis Outcomes Study event rates [n/N (%)] Relative effect, RR (95% CI) Absolute effecta No. of participants (studies) Quality of the evidence (GRADE)b Risk with infliximab monotherapy Risk with combination therapy Combination therapy with infliximab þ immunomodulators compared with infliximab monotherapy for moderate- tosevere UC Achieving clinical remission (CRITICAL) 17/78 (21.8%) 31/80 (38.8%) 1.78 (1.08–2.94) 170 more per 1000 (from 17 more to 423 more) 158 (1 RCT) ⨁⨁⨁c MODERATE NOTE. No trial of maintenance therapy comparing TNF-a antagonists þ immunomodulators vs TNF-a antagonist monotherapy was identified. a Absolute effects estimated based on the following placebo rates across trials: induction of clinical remission w10%; maintenance of clinical remission w15%. b GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. c Rated down for imprecision because optimal information size not met (<200 events). December 2024 AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis 1333 GUIDELINES adalimumab treatment was associated with higher rates of endoscopic response compared with adalimumab monotherapy.82 Given similar rates of immunogenicity across the different TNF antagonists, we extrapolated the benefit of combination therapy to all agents within this class. It has been hypothesized that achieving adequate biologic trough levels may reduce the need for combination therapy in patients receiving TNF antagonist therapy.83 This has not been examined prospectively. Similarly, there may be greater benefit to combination therapy in patients genetically predisposed to developing anti-drug antibodies to TNF antagonists.84 Question 6: In adult outpatients with moderate-to-severe UC, what is the efficacy of combination therapy with immunomodulator (thiopurines, methotrexate) and non-TNF antagonist biologic agents (vedolizumab, ustekinumab, mirikizumab, risankizumab, guselkumab) in comparison to non-TNF antagonist biologic (vedolizumab, ustekinumab, mirikizumab, risankizumab) monotherapy for induction and maintenance of clinical remission? Recommendation: In adult outpatients with moderate-to-severe UC, the AGA makes no recommendation in favor of, or against. the use of non-TNF antagonist biologics in combination with an immunomodulator over nonTNF antagonist biologic alone. [No recommendation, knowledge gap] Summary and Certainty of Evidence Since the last guideline in 2020, multiple observational studies and indirect evidence from 1 randomized trial provided evidence for this recommendation. In a multicenter study of patients with IBD initiating vedolizumab or ustekinumab, there was no difference in remission rates at 1 year between those on combination therapy and on monotherapy.85 A meta-analysis that included 33 studies (6 RCT and 28 cohort studies) identified no difference in clinical outcomes in patients with combination therapy with vedolizumab (OR, 0.84; 95% CI, 0.68–1.05) or ustekinumab (OR, 1.1; 95% CI, 0.87–1.38).86 In contrast to these data, in the VIEWS trial, which randomized patients with UC on combination vedolizumab and thiopurine treatment to continuation of dual therapy or withdrawal, cessation of thiopurine was associated with no difference in clinical relapses (P ¼ .12), but a modestly higher fecal calprotectin (P ¼ .003) and lower rates of histologic remission (P ¼ .03).87 Benefits and Harms There are limited data on the safety of combination immunomodulator and non-TNF antagonist biologic therapy. Subgroup analyses from RCTs, as well as data from observational studies, do not suggest an increase in risk of serious infections or malignancy with combination therapy for non-TNF antagonist biologic therapy. However, these studies have mostly lacked longer-term follow-up data. Rationale and Implementation Considerations Mechanistically, there are several reasons why combination therapy may be less necessary with non-TNF antagonist biologic therapies. First, both vedolizumab and anti-IL agents have lower immunogenicity than TNF antagonists.88,89 In addition, for vedolizumab, receptor saturation is already noted at low trough saturations. However, immunomodulators may have an independent benefit, especially for preventing relapse. Adding immunomodulators to non-TNF antagonist biologics, particularly in patients who are naïve to immunomodulators, may possibly be beneficial. Besides efficacy, the guideline panel also reviewed that there is an increase in risk of infections and malignancy (lymphoma and nonmelanoma skin cancers) with thiopurine use. In view of the limited and conflicting data, the guideline panel identified this area as a knowledge gap to be informed by further studies. Question 7: In patients in steroid-free remission on combination therapy of TNF-antagonist þ immunomodulator, is (1) discontinuation of immunomodulator or (2) discontinuation of TNF antagonist, superior to continuation of combination therapy? Recommendations: In patients with UC who are in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA makes no recommendation in favor of withdrawing immunomodulators or continuing combination therapy. [No recommendation, knowledge gap] In patients with UC who are in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA suggests AGAINST withdrawal of TNF antagonists. [Conditional recommendation, very low certainty of evidence] Summary and Certainty of Evidence Several RCTs and observational studies have examined the impact of withdrawal of thiopurine therapy in patients on combination immunomodulator and biologic therapy. A systematic review by Katibian et al90 summarized the impact of withdrawal of immunomodulators in patients with IBD receiving combination therapy. A total of 8 RCTs comprising 733 patients were identified; three-quarters of the patients in the studies had CD. Most studies required patients to be in sustained corticosteroid-free remission for 1334 Singh et al Gastroenterology Vol. 167, Iss. 7 GUIDELINES at least 6 months before attempting drug withdrawal. Compared with patients continuing combination therapy, there was no increase in risk of relapse among patients stopping combination therapy (16.8% vs 14.8%; RR, 1.15; 95% CI, 0.75–1.76) (Supplementary Figure 16). The overall certainty of evidence was rated as very low, due to serious risk of bias, indirectness because most patients in these trials had CD, and very serious imprecision (Table 15). In contrast to immunomodulator cessation, cessation of TNF antagonists in patients on combination therapy is associated with a 2-fold increase in risk of relapse compared with continuing combination therapy (31.5% vs 11.2%; RR, 2.35; 95% CI, 1.38–4.01) (Supplementary Figure 17). The overall certainty of evidence was rated as very low, due to serious risk of bias, indirectness because most patients in these trials had CD, and serious imprecision due to low number of events (Table 15). In the STORI trial in CD, nearly 80% of patients ceasing TNF antagonist therapy experienced a disease relapse requiring re-initiation of the biologic within 7 years after treatment cessation.91 Benefits and Harms As outlined in the section above, combination therapy with an immunomodulator and TNF antagonist is associated with an increase in risk of infections and lymphoma compared with monotherapy with either agent alone. Any benefit of combination therapy should be weighed against a potential increase in risk of treatment-related adverse outcomes. Rationale and Implementation Considerations The guideline panel used data from both CD and UC to inform this recommendation, as it was felt that the likely expected outcomes are similar across diseases and conclusions can be extrapolated. Most clinical trials of therapy discontinuation examined outcomes with <2 years of follow-up; the panel recognized that the clinical impact of treatment discontinuation may need to be viewed over a longer time horizon. In 3 trials, infliximab trough concentrations at the end of trial were lower and proportion of patients with antibodies to infliximab was higher in patients who underwent immunomodulator withdrawal vs those who continued combination therapy. Whether the lower trough level on withdrawal would result in increased rates of clinical relapse with longer follow-up is unknown. In contrast, in the DIAMOND2 trial, mean adalimumab trough concentration and anti-adalimumab antibody positivity rate were not different between patients who had immunomodulator withdrawal compared with those who continued combination therapy.82 Recognizing the gaps in data and the need for longer follow-up, the panel made no recommendation in favor of or against withdrawal of immunomodulators in patients on a combination of TNF antagonist and immunomodulators. In patients with moderate (as opposed to severe) disease, on their first biologic, long-duration of remission, or at higher risk for treatment-related adverse effects of infection or malignancy (such as older adults), it may be reasonable to consider discontinuation of immunomodulator therapy after 12–18 months while continuing TNF antagonist use. It is important to measure TNF antagonist trough levels before immunomodulator withdrawal. Patients with higher trough levels are more likely to maintain clinical remission after immunomodulator withdrawal than patients with borderline or low TNF antagonist levels.92 It is also important to closely monitor for disease relapse using clinical symptoms, biomarkers, and endoscopic assessment (12–24 months after therapy withdrawal). Question 8: In adult outpatients with moderate-to-severe UC, is upfront use of advanced therapies and/or immunomodulator therapy superior to step-up therapy (acceleration to advanced therapies and/or immunomodulator therapy only after failure of 5-ASA) for inducing and maintaining remission? Recommendation: In adult outpatients with moderate-to-severe UC, the AGA suggests early use of advanced therapies with or without immunomodulator therapy, rather than gradual step up after failure of 5-ASAs. [Conditional recommendation, very low certainty of evidence] Comment: Patients, particularly those with less severe disease, who place higher value on the safety of 5-ASA therapy, and lower value on the efficacy of immunosuppressive therapies, may reasonably choose gradual step therapy with 5-ASA therapy. Summary and Certainty of Evidence Since the last guideline published in 2020, we did not identify any new RCTs comparing a strategy of upfront use of advanced therapies and/or immunomodulator therapy vs step-up therapy in patients with moderate-to-severe UC. We also did not identify any trials comparing the efficacy of advanced therapies vs 5-ASA for patients with moderateto-severe UC. There are 3 trials that compared thiopurines in this population.93–95 Based on a meta-analysis of these studies, patients treated with thiopurines achieved higher rates of corticosteroid-free clinical remission compared with patients treated with 5-ASAs. In the UCSUCCESS trial, although infliximab was not more efficacious than immunomodulator monotherapy for achieving clinical remission, it was more effective for achieving endoscopic improvement.80 By extension, advanced therapies would be more effective than 5-ASA for induction of remission in patients with moderate-to-severe UC. It is important to note that 5-ASAs are not indicated for the treatment of moderate-to-severe UC and have been approved for mild-to-moderate UC. Based on this indirect evidence, it follows that delaying treatment of moderateto-severe UC with advanced therapies or immunomodulators to treat with 5-ASA drugs may be detrimental, both because 5-ASAs may not work as primary therapy and because use of these drugs will introduce a treatment delay impairing quality of life and increasing risk of December 2024 AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis 1335 GUIDELINES Table 15.GRADE Evidence Profile Comparing Withdrawal of Immunomodulators or Withdrawal of Biologics Compared With Continuing Combination Therapy for Risk of Relapse in Patients With Moderate-to-Severe Ulcerative Colitis in Steroid-Free Remission on Combination Therapy Outcomes Study event rates [n/N (%)] Relative effect, RR (95% CI) Absolute effecta No. of participants (studies) Quality of the evidence (GRADE)b Risk with continuing combination therapy Risk with IMM withdrawal Withdrawal of IMMs (while continuing biologic therapy) compared with continuing combination therapy in adult outpatients with moderate-to-severe UC in steroid-free remission Risk of relapse at 12 mo (CRITICAL) 30/202 (14.9%) 34/202 (16.8%) 1.15 (0.75–1.76) 22 more per 1000 (from 37 fewer to 113 more) 404 (5 RCTs) ⨁c,d,e VERY LOW Outcomes Study event rates [n/N (%)] Relative effect, RR (95% CI) Absolute effecta No. of participants (studies) Quality of the evidence (GRADE)b Risk with continuing combination therapy Risk with biologic withdrawal Withdrawal of biologics (while continuing IMM monotherapy) compared with continuing combination therapy in adult outpatients with moderate-to-severe UC in steroid-free remission Risk of relapse at 12 mo (CRITICAL) 22/196 (11.2%) 63/200 (31.5%) 2.35 (1.38–4.01) 152 more per 1000 (from 43 more to 338 more) 396 (4 RCTs) ⨁c,d,f VERY LOW IMM, immunomodulator. a Absolute effects estimated based on the following placebo rates across trials: induction of clinical remission w10%; maintenance of clinical remission w15%. b GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. c Rated down for serious risk of bias (open-level trials with subjective end points). d Rated down for indirectness because most patients in these trials had CD. e Rated down for very serious imprecision due to very wide CIs crossing unity. f Rated down for imprecision because optimal information size not met (<200 events). 1336 Singh et al Gastroenterology Vol. 167, Iss. 7 GUIDELINES complications. Based on serious indirectness of the evidence with unclear estimates of magnitude of benefit, we rated the certainty of evidence as very low. Benefits and Harms Risks associated with advanced therapies or immunomodulator therapy have been outlined earlier and may be greater than those associated with 5-ASA therapy. However, these risks should be interpreted in the context of risks of UC-related complications, including colectomy, hospitalization, and persistent disease activity resulting in inferior quality of life, if step-up therapy is used. Rationale and Implementation Considerations Inadequately controlled UC is associated with an increased risk of colectomy, hospitalization, corticosteroid use, and long-term risk of colorectal cancer. UC is a progressive disease that can result in bowel damage.96 Hence, risk-congruent therapy is warranted to minimize risk of short- and long-term complications. Unfortunately, prediction models to identify patients at high risk of complications or disease severity indices have not been well-validated. Ideally, evidence regarding top-down vs step-up therapy would be best informed by a pragmatic RCT comparing outcomes in patients assigned to risk-congruent therapy vs conventional management. In the absence of these data, based on indirect evidence, it is likely that step-up therapy using 5-ASAs first, particularly in patients on the more severe side of the disease spectrum with more severe disease, may be detrimental. Question 9: In adult outpatients with moderate-to-severe ulcerative colitis failing 5-ASAs, who are now to be treated with immunomodulators or advanced therapies, is continuing 5-ASAs superior to stopping the 5-ASAs for inducing and maintaining remission? Recommendation: In adult outpatients with moderate-to-severe UC, who have failed 5-ASAs, and have escalated to therapy with immunomodulators or advanced therapies, the AGA suggests stopping 5-ASAs. [Conditional recommendation, low certainty of evidence] Implementation Considerations 1. A subset of patients who have significant but not complete response with advanced therapies or immunomodulators may benefit from ongoing 5-ASAs to achieve remission. This may be particularly important for patients with residual proctitis who may benefit from adding rectal 5-ASA. 2. The independent benefit of long-term 5-ASAs in preventing colorectal cancer in patients with IBD has not been robustly demonstrated. Summary and Certainty of Evidence Since the last guideline published in 2020, we did not identify any new RCTs directly addressing withdrawal of 5- ASA therapy in patients with moderate-to-severe UC being treated with immunomodulators or advanced therapies. Mantzaris et al97 randomized patients with moderate-tosevere UC, in corticosteroid-free clinical, endoscopic, and histologic remission on azathioprine and olsalazine, to either continuing azathioprine and olsalazine (0.5 mg 3 times daily) or azathioprine alone. Over the course of 2 years, there were no observed differences in risk of relapse severe enough to merit corticosteroid use (RR, 1.02; 95% CI, 0.77–1.34). To examine whether concomitant 5-ASA impacts treatment response with advanced therapies, we updated our prior approach, conducting a pooled analysis of individual patient-level data of RCTs of advanced therapies in patients with moderate-to-severe UC. By design, all patients in these trials had moderate-to-severely active disease, despite prior or concomitant 5-ASA exposure. The patients in these trials had to maintain their baseline medications, so they could not stop or start 5-ASA during the trial. Across 10 RCTs with 6044 patients, 4134 patients received concomitant 5-ASA at baseline and maintained stable dose throughout the induction period. Compared with patients not receiving 5-ASA, patients receiving concomitant 5-ASA were slightly older, more likely to be non-White, more likely to have moderate endoscopic activity, have shorter disease duration, slightly lower C-reactive protein, and more likely to be biologicnaïve. Subsequently, we compared the RR of active intervention vs placebo in patients who were vs not on concomitant 5-ASA during the trial, using extended modified Poisson regression model with studies being considered as clusters. The model contained main effects of drug, exposure, or nonexposure to concomitant 5-ASA, their product term, and confounders, including prior biologic exposure, endoscopic severity at baseline, race, disease extent, baseline C-reactive protein, fecal calprotectin, hemoglobin, albumin, concomitant corticosteroids, and smoking status. After adjusting for confounding variables, the ratio of RR for inducing clinical remission in those on concomitant 5-ASA vs no concomitant 5-ASA was 1.04 (95% CI, 0.78–1.39), suggesting no treatment effect modification. The overall certainty of evidence supporting lack of benefit of continuing vs stopping 5-ASAs in patients with moderate-tosevere UC being treated with advanced therapies, after prior exposure to and failure of 5-ASA, was rated as low. Evidence was rated down due to imprecision and indirectness (Table 16). Benefits and Harms 5-ASAs are generally safe medications, with very low rates of idiosyncratic serious or life-threatening complications.98 There are rare reports of allergic interstitial nephritis, pancreatitis, pericarditis, myocarditis, and pneumonitis. Continuing 5-ASA may add pill burden and contribute to high cost of care. December 2024 AGA Living Guideline for Moderate-to-Severe Ulcerative Colitis 1337 GUIDELINES Rationale and Implementation Considerations We relied on a combination of direct evidence in patients on thiopurines, and indirect evidence in patients treated with advanced therapies, to determine the efficacy of continuing vs stopping 5-ASA in patients who escalate therapy after failing 5-ASA. Due to the short duration of follow-up in clinical trials, we were not able to study the impact of concomitant 5-ASAs on longer-term risk of disease-related complications, including surgery and development of colorectal neoplasia. Large observational studies have suggested no difference in the risk of adverse clinical outcomes between patients who continue vs stop 5-ASA after starting advanced therapies or immunomodulators.99–101 The guideline panel acknowledged that there may be a subset of patients with UC who have improved, but not achieved remission, with advanced therapies and who continue to experience mild to moderate symptoms due to residual proctitis—these patients may benefit from continuing or adding rectal 5-ASA. The guideline panel also acknowledged that one proposed benefit of long-term 5-ASA use is potential chemoprevention effect against colorectal cancer, but this remains unproven. Although large observational studies and meta-analyses have variably suggested that patients with UC treated with 5-ASA have lower risk of developing colorectal cancer, recent evidence suggests that chronically active disease is a strong risk factor for developing neoplasia, and sustained remission is a protective factor against colorectal cancer regardless of the therapy used that achieves this outcome.102 Knowledge Gaps The guideline panel identified several knowledge gaps that need to be addressed in future studies. There was a paucity of head-to-head comparison trials in moderate-to-severe UC. As more treatment options become available, it is important, in addition to comparison against placebo, that these trials include a range of active comparators to accurately inform positioning of different treatments and therapeutic mechanisms. With the availability of multiple therapeutic options, it is likely that many treatment-exposed patients may have received treatments other than TNF antagonists. There is a gap in the literature regarding the efficacy of different therapies in the setting of failure or intolerance to non–TNF-antagonist advanced therapy. This may be particularly relevant to drugs that may have a greater overlap in their therapeutic mechanisms (eg, anti-trafficking agents). In addition, it is important that efficacy based on prior exposure from RCTs should report out separate strata of prior exposure (both single and multiple biologics, as well as type of prior advanced therapy). Observational studies are also important to address this gap in a real-world setting. The panel recognized the importance of treatment outcomes beyond clinical remission in the management of moderate-to-severe UC. However, there was Table 16.GRADE Evidence Profile Comparing Continuing vs Stopping 5-Aminosalicylates in Patients With Moderate-toSevere Ulcerative Colitis Being Treated With Advanced Therapies Who Have Failed 5-Aminosalicylates Outcomes Study event rates [n/N (%)] Relative effect, RR (95% CI) Absolute effecta No. of participants (studies) Quality of the evidence (GRADE)b Risk without concomitant 5-ASA Risk with concomitant 5-ASA Continuing 5-ASA compared with stopping 5-ASA in patients with moderate-to-severe UC being treated with advanced therapies who have failed 5-ASA Induction of clinical remission (CRITICAL) 413/1910 (21.6%) 1149/4134 (27.8%) 1.04 (0.78–1.39) 9 more per 1000 (from 48 fewer to 84 more) 6044 (10 RCTs) ⨁⨁c,d LOW a Absolute effects estimated based on the following placebo rates across trials: induction of clinical remission w10%; maintenance of clinical remission w15%. b GRADE Working Group grades of evidence. High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. c Rated down for indirectness (not trials of continuing vs stopping 5-ASA, but rather concomitant 5-ASA vs no concomitant 5- ASA at trial entry) d Rated down for serious imprecision with wide CIs. 1338 Singh et al Gastroenterology Vol. 167, Iss. 7 GUIDELINES significant heterogeneity in the time point and end point ascertained between the different clinical trials. As end points begin to incorporate endoscopic and histologic healing, consistency in reporting outcomes across trials will be important to inform relative positioning. However, it will remain a challenge to compare older trials that may not have assessed this outcome or differed in their study design. The panel recognized that future selection of therapy may be based on predictive clinical and biomarker-based models. At this time, there is a paucity of data on how such models can inform treatment selection in the realworld setting. There is clearly a need for identifying biomarkers predictive of response to individual therapies, to facilitate optimal choice of therapies. Ongoing research efforts using multi-omic platforms using serum, stool, and tissue specimens have potential to inform biomarkers predictive of response to specific therapies. Once these are available, clinical trials or prospective comparative effectiveness studies using integrated clinical-, pharmacokinetic- and biomarker-based treatment positioning strategies vs usual care could provide guidance on appropriate management strategies. Shared decision making is an important process in selecting the management strategy for management of moderate-to-severe UC. Different therapies have distinctive risk–benefit profiles with varying balance of treatment efficacy vs risk of treatment-related side effects. In addition, different patients based on age, clinical phenotype, and disease status, have different risks of disease- vs treatment-related complications. Accurate and validated risk prediction models to accurately identify patients at high risk of disease- vs treatmentrelated complications, and how different treatments modify these risks, is vital to know and communicate effectively to patients. Pairing this information with patients’ values and preferences would facilitate shared decision making, as the treatment landscape rapidly evolves in this field. The panel also recognized that there may be several novel therapeutic strategies that may be applied in the coming years, including combination advanced therapy or episodic use of nonimmunogenic advanced therapies, such as small molecules. Further primary data are required to accurately inform the positioning of such strategies. Living Guidelines Updating Plan Recognizing the rapid evolution of drug development and transforming treatment strategies, the AGA will update relevant recommendations from these guidelines by periodic review of evidence every 6 months. The evidence reviewed will include availability of phase 3 or phase 4 efficacy data for new treatments, treatment strategies, or existing treatments, as well as significant new safety concerns informing treatment positioning. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Gastroenterology at www.gastrojournal.org, and at https://doi.org/10.1