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).
Revista»Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
BACKGROUND: Several observational studies on Tofacitinib (TOFA) in ulcerative colitis (UC) have been published over the last 2 years.
AIMS: To estimate effectiveness and safety of TOFA arising from real-world experience.
METHODS: PubMed Central/Medline and Embase were systematically searched for real-world observational studies on TOFA for the treatment of UC through November 2020.
RESULTS: Seven studies comprising 759 patients met the inclusion criteria. The pooled estimate rates were 49% for clinical response, 40% for clinical remission, and 34% for corticosteroid-free clinical remission at induction, while the rates of endoscopic response and endoscopic remission were 37% and 19%, respectively. At maintenance, the pooled estimate rates of clinical response, clinical remission, and corticosteroid-free clinical remission were 36%, 35%, and 24%, respectively. The pooled estimate of incidence rate of adverse events was 53.0 per 100 person-years (PY), while the pooled estimate of incidence rate of withdrawal of TOFA due to adverse events was 9.3 per 100 PY, with a pooled rate of infections of 17.6 per 100 PY.
CONCLUSIONS: Cumulative analysis of data from real-world studies confirmed the good efficacy of TOFA in UC shown by randomized controlled trials for both induction and maintenance, while the safety profile was consistent with previous reports.
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.
WHAT IS KNOWN AND OBJECTIVE: In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of Janus kinase (JAK) inhibitors for ulcerative colitis (UC).
METHODS: We searched PubMed, EMBASE, Web of Science and Cochrane Library from the database inception until 13 August 2021. No randomized controlled trials (RCTs) that directly compared these interventions were identified. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. Ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.
RESULTS AND DISCUSSION: Seven RCTs including 3190 patients met the inclusion criteria. Filgotinib 100 mg was ranked highest for induction of endoscopic remission (SUCRA, 0.67) whereas peficitinib 75 mg BID was ranked highest for induction of clinical response (SUCRA, 0.72). Peficitinib 75 mg was ranked highest for induction of mucosal healing (SUCRA, 0.71), whereas peficitinib 150 mg was ranked highest for clinical remission (SUCRA, 0.74). Tofacitinib 3 mg had the highest probability of being the best treatment in terms of change from baseline in Mayo score (SUCRA, 0.78). Adverse events (AEs) and treatment discontinuations or withdrawals from the study due to AEs did not differ between JAK inhibitors and placebo groups.
WHAT IS NEW AND CONCLUSION: Based on indirect comparisons, peficitinib 75 mg/75 mg BID/150 mg, tofacitinib 3 mg and filgotinib 100mg were the most efficacious JAK inhibitor interventions in patients with UC. However, head-to-head trials are warranted to inform clinical decision-making with greater confidence.
BACKGROUND: Biological agents are commonly used for the treatment of ulcerative colitis (UC). As new treatments, tofacitinib, and fecal microbiota transplantation (FMT) have demonstrated efficacy in treating UC. This network meta-analysis aims to determine the efficacy and safety of biological agents, tofacitinib, and FMT.
METHODS: A network meta-analysis was conducted by systematically searching the PubMed, Embase, and Cochrane Libraries. According to strict inclusion and exclusion criteria, we included randomized controlled trials (RCTs) of biological agents, tofacitinib, and FMT in UC. A random-effect model was chosen by the network meta-analysis and sensitivity analysis. Heterogeneity test and publication bias test were performed to determine the efficacy of treatments.
RESULTS: Data were extracted from 16 RCTs and we found that all treatments were more effective than the placebos. A total of 21 comparisons were made to determine efficiency. We found that infliximab, vedolizumab, and FMT performed better curative effect in terms of absolute effects and relative ranks. Furthermore, there was no statistical difference in the efficacy of biological agents, tofacitinib, and FMT. Moreover, no treatments were found to increase the occurrence of adverse events when compared with placebos, except infliximab. However, vedolizumab seemed to reduce the occurrence of adverse events compared with infliximab.
CONCLUSION: Of the biological agents, vedolizumab and infliximab were the most effective, suggesting that biological agents are still a better choice. Nevertheless, tofacitinib and FMT may be promising alternatives with high efficacies. However, more safety and maintenance studies need to be conducted in future for the acquisition of more accurate results.Abbreviations: FMT: Fecal microbiota transplantation; UC: Ulcerative colitis; RCTs: Randomized controlled trials; IBD: Inflammatory bowel disease; CD: Crohn's disease; IBS: Irritable bowel syndrome; CDI: Clostridium difficile infections; ITT: Intention-to-treat; RR: Relative risk; CI: Confidence interval; CrI: Credible intervals; IFX: Infliximab; ADA: Adalimumab; TFB: Tofacitinib; GLM: Golimumab; VDZ: Vedolizumab; PBO: Placebo; wk: week; F: Female; M: Male; AEs: Adverse events; SAEs: Serious adverse events; anti-TNF: Anti-tumor necrosis factors.
BACKGROUND: Knowledge of the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC) is relevant to confirm the benefit observed in clinical trials.
METHODS: This systematic review and meta-analysis evaluated the real-world effectiveness of tofacitinib for moderate to severely active UC. The primary outcome was clinical remission evaluated at week 8, weeks 12 to 16, and month 6. Secondary outcomes were response, corticosteroid-free remission, mucosal healing, colectomy, and safety.
RESULTS: Seventeen studies with a total of 1162 patients with UC were included. Remission (11 studies) was achieved in 34.7% of patients at week 8 (95% confidence interval [CI], 24.4%-45.1%), 47% at weeks 12 to 16 (95% CI, 40.3%-53.6%), and 38.3% at month 6 (95% CI, 29.2%-47.5%) at month 6 duplicated. Response was achieved in 62.1%, 64.2%, 50.8%, and 41.8% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Corticosteroid-free remission (5 studies) was achieved in 38.4%, 44.3%, 33.6%, and 31% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Mucosal healing was achieved in 48.3% and 45.3% of patients at week 8 and weeks 12 to 16, respectively. Patients who were biologic-naïve (11.6%) had a significantly higher rate of response at week 8 (1.38; 95% CI, 1.03-1.84). The incidence rates of serious adverse events and herpes zoster was 8.9 and 6.9 per 100 patient-years, respectively.
CONCLUSIONS: This meta-analysis of real-world studies confirms the effectiveness of tofacitinib in a highly refractory population of patients with moderate to severely active UC. Tofacitinib showed an acceptable safety profile. These findings were consistent with clinical trials and further support the use of tofacitinib in UC.
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.
OBJECTIVES: Review of efficacy and safety of Janus kinase (JAK) inhibition in immune-mediated inflammatory diseases (IMIDs).
METHODS: A systematic literature research (SLR) of all publications on JAK inhibitors (JAKi) treatment published until March 2019 using MEDLINE, EMBASE and the Cochrane Library. Efficacy and safety were assessed in randomised controlled trials (RCTs), integrating long-term extension periods additionally for safety evaluation.
RESULTS: 3454 abstracts were screened with 85 included in the final analysis (efficacy and RCT safety: n=72; safety only: n=13). Efficacy of RCTs investigating tofacitinib (TOFA, n=27), baricitinib (BARI, n=9), upadacitinib (UPA, n=14), filgotinib (FILGO, n=7), decernotinib (DEC, n=3) and peficitinib (PEF, n=7) was evaluated. Six head-to-head trials comparing JAKi with tumour necrosis factor inhibitors (TNFi) were included. Efficacy of JAKi was shown in rheumatoid arthritis (RA) for all agents, psoriatic arthritis (TOFA, FILGO), ankylosing spondylitis (TOFA, FILGO), systemic lupus erythematosus (BARI), chronic plaque psoriasis (TOFA, BARI, PEF), ulcerative colitis (TOFA, UPA), Crohn's disease (UPA, FILGO) and atopic dermatitis (TOFA, BARI, UPA). Safety analysis of 72 RCTs, one cohort study and 12 articles on long-term extension studies showed increased risks for infections, especially herpes zoster, serious infections and numerically higher rates of venous thromboembolic events. No increased malignancy rates or major adverse cardiac events were observed.
CONCLUSION: JAKi provide good efficacy compared to placebo (and to TNFi in RA and Pso) across various IMIDs with an acceptable safety profile. This SLR informed the task force on points to consider for the treatment of IMIDs with JAKi with the available evidence.
Objective : To compare the relative efficacy of ustekinumab (UST) versus other therapies for 1-year response and remission rates in patients with moderate-severe UC. Methods : Randomised controlled trials reporting induction and maintenance efficacy of anti-TNFs (infliximab [IFX], adalimumab [ADA], golimumab [GOL]), vedolizumab (VDZ), tofacitinib (TOF) or UST were identified through a systematic literature review. Analyses were conducted for clinical response, clinical remission and endoscopic-mucosal healing for populations with and without failure of prior biologics (non-biologic failure, NBF; biologic failure, BF). Maintenance data from trials with re-randomised response designs were re-calculated to correspond to treat-through arms. Bayesian network meta-analyses (NMA) were conducted to obtain posterior distribution probabilities for UST to perform better than comparators. Results : Six trials included NBF patients and four included BF patients. In NBF patients, UST as a 1-year regimen showed higher probabilities of clinical response, remission and endoscopic-mucosal healing versus all treatments: Bayesian probabilities of UST being better than active therapies ranged from 91% (VDZ) to 100% (ADA) for response; 82% (VDZ) to 99% (ADA) for remission and 82% (IFX) to 100% (ADA and GOL) for endoscopic-mucosal healing. In BF patients, UST was the most effective treatment (Q8W dose); however, effect sizes were smaller than in the NBF population. Conclusions : Results indicate a higher likelihood of response, remission and endoscopic-mucosal healing at 1 year with UST versus comparators in the NBF population. In BF patients, a higher likelihood of response to UST versus most comparators was also observed, although results were more uncertain.
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.
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).
