Purpose: Previous reviews produced weak evidence regarding the responsiveness of the Inflammatory Bowel Disease Questionnaire (IBDQ-32) to changes in ulcerative colitis (UC) health indicators. This systematic review and meta-analysis provide an updated synthesis on IBDQ-32 responsiveness. Methods: A systematic literature review identified 11 articles reporting IBDQ-32 responder analyses in randomized control trials, which were included in a random effects meta-analysis, and 15 articles linking IBDQ-32 change to change in UC health indicators, which were summarized narratively. Meta-analysis compared differences between IBDQ-32 responder proportions in efficacious and nonefficacious treatment arms relative to placebo. Linear meta-regression examined the association of treatment efficacy and proportions of IBDQ-32 responders in active treatment compared with placebo. Results: Meta-analysis showed larger differences in IBDQ-32 response proportions between active treatment and placebo for efficacious treatments (pooled OR, 2.19; 95% CI, 1.83-2.63) than nonefficacious treatments (pooled OR, 1.21; 95% CI, 0.84-1.74; Cochran’s Q[df = 1] = 8.26, P = .004). Meta-regression showed that the magnitude of treatment efficacy positively predicted IBDQ-32 response in active treatments relative to placebo (β = 0.21, P < .001). Moderate to strong correlations were found between change in IBDQ-32 and change in health indicators (eg, patient-reported measures, disease activity, endoscopic indices; correlations, 0.37-0.64 in absolute values). Patients achieving clinical response or remission showed greater change in IBDQ-32 total scores (range, 22.3-50.1 points) and more frequently met clinically meaningful thresholds on the IBDQ-32 than those not achieving clinical response or remission (all P < .05). Conclusions: The IBDQ-32 is responsive to changes in UC health indicators and disease activity, including in response to efficacious treatment (relative to placebo).
BACKGROUND: There is a growing armamentarium for the treatment of moderate-to-severe ulcerative colitis. We aimed to compare the relative efficacy and safety of biologics and small molecule drugs for the treatment of patients with moderate-to-severe ulcerative colitis.
METHODS: In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials without language restrictions for articles published between Jan 1, 1990, and July 1, 2021. Major congresses' databases from Jan 1, 2018, to July 3, 2021, were reviewed manually. Phase 3, placebo-controlled or head-to-head randomised controlled trials (RCTs) assessing the efficacy and safety of biologics or small molecule drugs as induction or maintenance therapies for patients with moderate-to-severe ulcerative colitis were included. Phase 2 RCTs were excluded because of their small sample sizes and inclusion of doses not further explored in phase 3 RCTs. Summary data from intention-to-treat analyses were extracted from included reports by JSL and PAO. The primary outcome was the induction of clinical remission. A network meta-analysis was done under the frequentist framework, obtaining pairwise odds ratios (ORs) and 95% CIs. The surface under the cumulative ranking (SUCRA) was used to rank the included agents for each outcome. Higher SUCRA scores correlate with better efficacy, whereas lower SUCRA scores correlate with better safety. Maintenance data on efficacy for treat-straight-through and randomised responder trials are also presented. This study is registered with PROSPERO, CRD42021225329.
FINDINGS: Our search yielded 5904 results, from which 29 studies (four being head-to-head RCTs) fulfilled our inclusion criteria and were included. Of these, 23 studies assessed induction therapy with either a biologic or small molecule drug, comprising 10 061 patients with ulcerative colitis. A risk of bias assessment showed a low risk of bias for most of the included studies. Upadacitinib was significantly superior to all other interventions for the induction of clinical remission (infliximab [OR 2·70, 95% CI 1·18-6·20], adalimumab [4·64, 2·47-8·71], golimumab [3·00, 1·32-6·82], vedolizumab [3·56, 1·84-6·91], ustekinumab [2·92, 1·31-6·51], etrolizumab [4·91, 2·59-9·31], tofacitinib [2·84, 1·28-6·31], filgotinib 100 mg [6·15, 2·98-12·72], filgotinib 200 mg [4·49, 2·18-9·24], and ozanimod (2·70, 1·18-6·20), and ranked highest for the induction of clinical remission (SUCRA 0·996). No differences between active interventions were observed when assessing adverse events and serious adverse events. Vedolizumab ranked lowest for both adverse events (SUCRA 0·184) and serious adverse events (0·139), whereas upadacitinib ranked highest for adverse events (0·843) and ozanimod ranked highest for serious adverse events (0·831).
INTERPRETATION: Upadacitinib was the best performing agent for the induction of clinical remission (the primary outcome) but the worst performing agent in terms of adverse events in patients with moderate-to-severe ulcerative colitis. Vedolizumab was the best performing agent for safety outcomes. With the paucity of direct comparisons in the published literature, our results might help clinicians to position drugs in treatment algorithms.
FUNDING: None.
Objectives: Because only one head-to-head randomized trial of biologics for moderate-to-severe ulcerative colitis (UC) has been performed, indirect treatment comparisons remain important. This systematic review and network meta-analysis examined efficacy and safety of biologics and tofacitinib for moderate-to-severe UC, using values for vedolizumab as a reference. Methods: Relevant studies (N=19) of vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, and tofacitinib were identified. Study design differences were addressed by assessing efficacy outcomes conditional on response at maintenance initiation. Primary analysis used fixed-effect models to estimate odds ratios for efficacy and safety endpoints. Results: Compared with vedolizumab 300 mg, adalimumab 160/80 mg was associated with less clinical remission (odds ratio, 0.69 [95% credible interval, 0.54-0.88]), and infliximab 5 mg/kg was associated with more clinical remission (1.67 [1.16-2.42]) and response (1.63 [1.15-2.30]). Adalimumab 40 mg, golimumab 50 mg, and ustekinumab 90 mg Q12W had significantly lower clinical remission rates during maintenance (0.62 [0.45-0.86], 0.55 [0.32-0.95], and 0.59 [0.35-0.99]) versus vedolizumab 300 mg Q8W. Response results were similar. Tofacitinib 10 mg had the highest maintenance treatment efficacy estimates and highest infection risk. Conclusion: Network meta-analysis and novel integrated benefit-risk analysis suggest a potentially favorable efficacy-safety balance for vedolizumab compared with adalimumab and other advanced UC therapies.
Background: Current management of ulcerative colitis (UC) is aimed to treat active disease and to maintain remission. For patients in whom conventional treatment is no longer effective, biological or small molecule therapy may be an option. The aim was to assess the cost-effectiveness of induction and maintenance treatment up to 1 year of UC with infliximab (IFX), adalimumab (ADA), golimumab, vedolizumab (VDZ) and tofacitinib (TFB) compared with standard of care (SoC) in Poland. Methods: A hybrid decision tree/Markov model was used to estimate the expected costs and effects of four biologics, TFB and placebo in patients with the diagnosis of moderate to severe UC who had an inadequate response, lost response, or were intolerant to a conventional therapy. Prior exposure to anti-TNF was considered. At the beginning of the maintenance phase, the decision to continue biological therapy was determined by the achievement of response at the end of induction. Efficacy data were obtained from a network meta-analysis using placebo as the common comparator. Costs were presented in 2018 Polish zloty (PLN) and outcomes included quality-adjusted life-years (QALYs). The analysis was performed from the Polish public payer’s perspective and lifetime horizon was set. Results: In anti-TNF naïve, IFX and VDZ were characterized by the most favourable incremental cost-effectiveness ratios (ICURs) compared with SoC, PLN211,250.78 and PLN361,694.61/QALY (€49,589.38 and €84,904.84/QALY), respectively. In anti-TNF-exposed population the most effective treatment was TFB. Both ADA and VDZ were more effective than SoC; however, ICUR values were much above the cost-effectiveness threshold. The incorporation of biosimilars reversed the ranking of treatments in relation to the growing ICUR. Conclusion: Although ICUR values for all biological therapies exceeded the acceptability threshold in Poland, for anti-TNF-naïve UC patients IFX and for anti-TNF-exposed UC patients VDZ are currently the most cost-effective alternatives.
BACKGROUND & AIMS: We compared the efficacy and safety of different first-line (biologic-naïve) and second-line (prior exposure to tumor necrosis factor [TNF] antagonists) agents for treatment of moderate to severely active ulcerative colitis in a systematic review and network meta-analysis.
METHODS: We searched publication databases through September 30, 2019 for randomized trials of adults with moderate to severe ulcerative colitis treated with TNF antagonists, vedolizumab, tofacitinib, or ustekinumab, as first-line or second-line agents, compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of remission and endoscopic improvement; safety outcomes were serious adverse events and infections. We performed fixed-effects network meta-analysis using frequentist approach, and calculated odds ratios (ORs) and 95% CI values. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities.
RESULTS: In biologic-naïve patients, infliximab was ranked highest for induction of clinical remission (OR vs placebo, 4.07; 95% CI, 2.67-6.21; SUCRA,0.95) and endoscopic improvement (SUCRA, 0.95) (moderate confidence in estimates [CE]). In patients with prior exposure to TNF antagonists, ustekinumab (SUCRA,0.87) and tofacitinib (SUCRA,0.87) were ranked highest for induction of clinical remission and were superior to vedolizumab (OR vs ustekinumab, 5.99; 95% CI, 1.13-31.76 and OR vs tofacitinib, 6.18; 95% CI, 1.003-8.00; moderate CE) and adalimumab (OR vs ustekinumab, 10.71; 95% CI, 2.01-57.20 and OR vs tofacitinib, 11.05; 95% CI, 1.79-68.41; moderate CE). Vedolizumab had lowest risk of infections (SUCRA, 0.81), followed by ustekinumab (SUCRA, 0.63) in maintenance trials.
CONCLUSIONS: In a systematic review and network meta-analysis, we found infliximab to be ranked highest in biologic-naïve patients, and ustekinumab and tofacitinib were ranked highest in patients with prior exposure to TNF antagonists, for induction of remission and endoscopic improvement in patients with moderate to severe ulcerative colitis. More trials of direct comparisons are needed to inform clinical decision-making with greater confidence.
BACKGROUND: Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option.
AIM: To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists.
METHODS: We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC. Two reviewers independently extracted study data and outcomes, and investigated each trial's risk-of-bias. We used conventional meta-analysis to synthesise direct evidence, and network meta-analysis for adjusted indirect treatment comparisons.
RESULTS: Fifteen randomised, double-blind, placebo-controlled trials (n = 3130) contributed data for induction: All treatments are superior to placebo. Indirect treatment comparisons showed that infliximab is better than adalimumab (OR: 2.01, 95% CI: 1.36-2.98) and golimumab (1.67, 1.08-2.59) in clinical response, better than adalimumab (2.10, 1.21-3.64) in clinical remission, and better than adalimumab (1.87, 1.26-2.79) and golimumab (1.75, 1.13-2.73) in mucosal healing. No indirect comparisons between tofacitinib and biologics reached statistical significance. Nine studies (n = 1776) contributed maintenance data showing that all treatments have higher clinical efficacy than placebo. Safety analyses indicated no increased rates of adverse events for the treatments under evaluation (except for infliximab), while vedolizumab may have an advantage regarding the occurrence of serious adverse events.
CONCLUSIONS: Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.
Purpose: Previous reviews produced weak evidence regarding the responsiveness of the Inflammatory Bowel Disease Questionnaire (IBDQ-32) to changes in ulcerative colitis (UC) health indicators. This systematic review and meta-analysis provide an updated synthesis on IBDQ-32 responsiveness. Methods: A systematic literature review identified 11 articles reporting IBDQ-32 responder analyses in randomized control trials, which were included in a random effects meta-analysis, and 15 articles linking IBDQ-32 change to change in UC health indicators, which were summarized narratively. Meta-analysis compared differences between IBDQ-32 responder proportions in efficacious and nonefficacious treatment arms relative to placebo. Linear meta-regression examined the association of treatment efficacy and proportions of IBDQ-32 responders in active treatment compared with placebo. Results: Meta-analysis showed larger differences in IBDQ-32 response proportions between active treatment and placebo for efficacious treatments (pooled OR, 2.19; 95% CI, 1.83-2.63) than nonefficacious treatments (pooled OR, 1.21; 95% CI, 0.84-1.74; Cochran’s Q[df = 1] = 8.26, P = .004). Meta-regression showed that the magnitude of treatment efficacy positively predicted IBDQ-32 response in active treatments relative to placebo (β = 0.21, P < .001). Moderate to strong correlations were found between change in IBDQ-32 and change in health indicators (eg, patient-reported measures, disease activity, endoscopic indices; correlations, 0.37-0.64 in absolute values). Patients achieving clinical response or remission showed greater change in IBDQ-32 total scores (range, 22.3-50.1 points) and more frequently met clinically meaningful thresholds on the IBDQ-32 than those not achieving clinical response or remission (all P < .05). Conclusions: The IBDQ-32 is responsive to changes in UC health indicators and disease activity, including in response to efficacious treatment (relative to placebo).
