This meta-analysis directly compares the efficacy and safety of vedolizumab and tumor necrosis factor-α (TNF-α) inhibitors for patients with inflammatory bowel disease (IBD), contrary to the previous one which provided an indirect comparison. In this meta-analysis, only the studies that directly compared two treatments (vedolizumab and TNF-α inhibitors) to each other (head-to-head approach) were considered. A comprehensive literature search was conducted using the following databases: PubMed, Embase, the Cochrane Library, and Web of Science. The pooled estimates of efficacies and safety were calculated as relative risk (RR) and 95 % confidence interval (CI). The presence of bias in the published material was evaluated using Begg's test. Sensitivity analysis was used to evaluate the pooled results' robustness. In total, 32 eligible studies were finally included. Results showed that the efficacy of vedolizumab was superior to TNF-α inhibitors in clinical remission [1.26, 95 % CI: 1.15-1.39]. Moreover, the vedolizumab group showed a reduced incidence of severe adverse events (RR = 0.63, 95 % CI: 0.42-0.94) compared to TNF-α inhibitors. Our results revealed superior efficacy and safety of vedolizumab compared to TNF-α inhibitors, which provided direct evidence for the use of vedolizumab in IBD treatment. Future studies are needed to confirm our findings.

We aimed to assess the risk of serious infection in patients with inflammatory bowel disease (IBD) treated with vedolizumab compared with those treated with anti-tumor necrosis factors (TNF) and the general population.

In this Swedish cohort study, treatment episodes were identified from nationwide health registers. We used Cox regression with propensity score-matched cohorts to estimate hazard ratios (HRs) for incident serious infections, defined as infections requiring hospital admission.

During 1,376 treatment episodes in Crohn's disease, the rate of serious infections per 100 person-years (PY) was 5.18 (95% CI = 3.98-6.63) with vedolizumab vs 3.54 (95% CI = 2.50-4.85) with anti-TNF; HR = 1.72 (95% CI = 1.12-2.65), partly explained by more gastrointestinal infections. Compared with the rate of 0.75/100 PY (95% CI = 0.59-0.92) in a matched general population cohort, vedolizumab demonstrated higher risk (HR = 7.00; 95% CI = 5.04-9.72). During 1,294 treatment episodes in ulcerative colitis, the corresponding rates were 3.74/100 PY (95% CI = 2.66-5.11) with vedolizumab vs 3.42/100 PY (95% CI = 2.31-4.89) with anti-TNF; HR = 0.80 (95% CI = 0.47-1.36) during the initial 1.1 years and HR = 2.03 (95% CI = 0.65-6.32) after 1.1 years (truncated due to nonproportional hazards). Pneumonia accounted for 40% of all infections among anti-TNF, whereas no case was observed among vedolizumab episodes. Compared with the rate of 0.69/100 PYs (95% CI = 0.53-0.87) in a matched general population cohort, vedolizumab showed an HR of 5.45 (95% CI = 3.67-8.11).

Vedolizumab was associated with increased risks of serious infections compared with anti-TNF in Crohn's disease but not in ulcerative colitis. Nonetheless, the panorama of serious infections seemed to differ between the drugs. Our findings underscore the importance of clinical awareness of infections and the safety profile of the 2 therapies.

Ulcerative Colitis (UC) is an inflammatory disorder characterized by chronic intestinal inflammation and immune dysregulation. Despite a clear association between cellular senescence and chronic inflammation and immune dysregulation, the mechanisms underlying cellular senescence in UC remain unclear. We screened differentially expressed genes (DEGs) associated with cellular senescence in multiple UC datasets, performed immune infiltration analysis, and constructed clinical diagnostic models. Additionally, we investigated the relationship between key genes related to cellular senescence and disease remission in UC patients undergoing biologic therapy, validating their expression in a single-cell dataset. We identified six DEGs associated with cellular senescence (TWIST1, IGFBP5, MME, IFNG, ME1, FOS). Immune infiltration results indicated strong correlations of four of these genes with immune cells and pathways. Through WGCNA, GO, and KEGG analyses, we found that gene modules strongly associated with the expression of hub genes in cellular senescence were enriched in inflammation-related pathways. In the single-cell dataset, the expression of these six key genes exhibited similarities with Immune infiltration results. Additionally, we constructed a nomogram using these six genes for diagnosing UC, demonstrating good diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant association between changes in the expression levels of these cell genes and disease remission in UC patients undergoing biologic therapy. This study utilizes bioinformatic analysis and machine learning to identify and analyze features associated with cellular senescence in multiple UC datasets. It provides insights into the role of cellular senescence in the premature onset of intestinal aging in UC and offers new perspectives for exploring novel therapeutic targets.

Inflammatory bowel disease (IBD) is a chronic, relapsing condition wherein biologics have improved disease prognosis but introduced elevated infection susceptibility. Vedolizumab (VDZ) demonstrates unique safety advantages; however, a comprehensive systematic comparison regarding the risk of Clostridioides difficile infection (CDI) between vedolizumab and alternative medications remains absent.

Medline, Embase, Cochrane, and clinicaltrials.gov registry were comprehensively searched. Pooled estimates of CDI proportion, incidence, pooled risk ratio between ulcerative colitis (UC) and Crohn's disease (CD), vedolizumab and other medications were calculated. Data synthesis was completed in R using the package "meta".

Of the 338 studies initially identified, 30 met the inclusion/exclusion criteria. For CDI risk, the pooled proportion was 0.013 (95% CI 0.010-0.017), as well as the pooled proportion of serious CDI was 0.004 (95% CI 0.002-0.008). The comparative pooled risk ratios revealed: UC versus CD at 2.25 (95% CI 1.73-2.92), vedolizumab versus anti-TNF agents at 0.15 (95% CI 0.04-0.63) for UC and 1.29 (95% CI 0.41-4.04) for CD.

The overall CDI risk in IBD patients exposed to vedolizumab was estimated to be 0.013. An increased risk of CDI was noted in UC patients receiving vedolizumab compared to those with CD. Vedolizumab potentially offers an advantage over anti-TNF agents for UC regarding CDI risk, but not for CD.

The study was registered on the PROSPERO registry (CRD42023465986).

No head-to-head trial directly compares the effectiveness of vedolizumab (VDZ) and infliximab (IFX) in patients with ulcerative colitis (UC) who were naïve to biologic therapy.

We aimed to compare the clinical and endoscopic effectiveness of VDZ and IFX in biologic-naïve patients with UC in real-world settings.

It was a multicenter, observational, real-world cohort study conducted at five centers.

Patients diagnosed with UC and treated with either IFX or VDZ as their first-line biologic therapy were retrospectively enrolled. Steroid-free remission, clinical response, clinical remission, and endoscopic healing at week 14 and week 52 were compared between the two groups after propensity score weighting.

A total of 199 patients (117 VDZ and 82 IFX) were included in the study. There were no significant differences in steroid-free remission (64.6% vs 56.1%, p = 0.224), clinical response (83.4% vs 73.4%, p = 0.086), or clinical remission (69.4% vs 60.1%, p = 0.174) at week 14. However, VDZ showed better results in steroid-free remission (67.5% vs 44.4%, p = 0.004), clinical response (69.7% vs 47.1%, p = 0.005), and clinical remission (67.5% vs 44.4%, p = 0.004) at week 52. In terms of endoscopic healing, VDZ was similar to IFX at week 14 (25.7% vs 17.4%, p = 0.185), but VDZ had a significantly higher rate at week 52 (29.5% vs 11.8%, p = 0.027). VDZ was found to be superior to IFX in therapeutic continuation (hazard ratio = 0.339, 95% CI: 0.187-0.614, p < 0.001). The rate of adverse events was similar between the two groups (6.8% vs 8.5%, p = 0.655).

VDZ demonstrated similar clinical and endoscopic effectiveness to IFX at week 14 in biologic-naïve patients with UC, but appeared to be superior at week 52. The safety outcomes were comparable between the groups.

Data on infliximab efficacy in bio-exposed patients with ulcerative colitis (UC) are limited.

To evaluate infliximab effectiveness and its predictors in UC patients with prior exposure to subcutaneous (SC) anti-TNF agent.

In this multicenter retrospective study (8 centers), we included all consecutive UC patients with prior exposure to subcutaneous anti-TNF, starting infliximab for symptomatic UC, excluding acute severe colitis. Corticosteroid-free clinical remission (CFREM) was assessed at week 14 (W14) and W52 while endoscopic improvement (CFREM + endoscopic Mayo score≤1) was evaluated at W14.

Overall, 104 patients were included (pancolitis=54.8%, primary failure to subcutaneous anti-TNF=57.4%, concomitant immunosuppressant=53.8%, median partial Mayo score at baseline=7[5-8]). The rate of CFREM was 33.6% (35/104) at W14 and 40.4% (42/104) at W52. At W14, endoscopic improvement was achieved in 29.8%(31/104). In multivariable analysis, concomitant immunosuppressant was associated with higher rate of CFREM at W14(OR=2.83[1.06-7.54], p = 0.037) and W52(OR=2.68[1.16-6.22];p = 0.021), while primary failure to a previous subcutaneous anti-TNF agent led to lower rate of CFREM at W14 (OR=0.37[0.14-0.98], p = 0.046). After a median follow-up of 20.9 months[11.7-33.7]), 50.0%(52/104) patients had discontinued infliximab.

Infliximab is an effective option in UC patients previously exposed to prior subcutaneous anti-TNF agent and should be used with concomitant immunosuppressant.

Ulcerative Colitis (UC) manifests as a chronic inflammatory condition of the intestines, marked by ongoing immune system dysregulation. Disulfidptosis, a newly identified cell death mechanism, is intimately linked to the onset and advancement of inflammation. However, the role of disulfidptosis in UC remains unclear.

We screened differentially expressed genes (DEGs) associated with disulfidptosis in multiple UC datasets, narrowed down the target gene number using lasso regression, and conducted immune infiltration analysis and constructed a clinical diagnostic model. Additionally, we explored the association between disulfidptosis-related key genes and disease remission in UC patients receiving biologic therapy. Finally, we confirmed the expression of key genes in FHC cells and UC tissue samples.

In the differential analysis, we identified 20 DEGs associated with disulfidptosis. Immune infiltration results revealed that five genes (PDLIM1, SLC7A11, MYH10, NUBPL, OXSM) exhibited strong correlations with immune cells and pathways. Using GO, KEGG and WGCNA analyses, we discovered that gene modules highly correlated with disulfidptosis-related gene expression were significantly enriched in inflammation-related pathways. Additionally, we developed a nomogram based on these five immune-related disulfidptosis genes for UC diagnosis, showing robust diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant link between changes in the expression levels of these cell genes and disease remission in UC patients receiving biologic therapy. In line with previous studies, similar expression changes of the target gene were seen in both UC cell models and tissue samples.

This study utilized bioinformatic analysis and machine learning to identify and analyze features associated with disulfidptosis in multiple UC datasets. This enhances our comprehension of the role disulfidptosis plays in intestinal immunity and inflammation in UC, providing new perspectives for developing innovative treatments for UC.

Biologic agents have demonstrated efficacy in treating ulcerative colitis (UC); however, treatment failure to tumor necrosis factor inhibitors (TNFi) is common in the real world. Data on preferential sequencing in clinical practice after failure remain limited.

This study aimed to evaluate real-world outcomes of patients cycling to TNFis or switching to non-TNFi biologics following first-line failure with TNFis.

Retrospective cohort study in Germany.

Adult patients with UC were identified using administrative claims data from 1 May 2014 to 30 June 2022 provided by a statutory sickness fund. Patients newly initiating first-line therapy with TNFis and then switching to another agent were identified. Patients were defined as within-class switched (WCS), if they cycled to another TNFi, or outside-class switchers (OCS), if they switched to a non-TNFi biologic [ustekinumab (UST) or vedolizumab (VDZ)] and followed from index (switch date) to death, insurance end, or study end on 30 June 2022. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline characteristics between groups, and weighted Cox regression models were used to compare primary (time to discontinuation and second treatment switch) and secondary outcomes (corticosteroid-free drug survival).

We identified 166 patients initiating TNFis and switching to a subsequent treatment (mean age: 42.9 years, 49.4% female). Following IPTW, there were 71 and 76 patients in the WCS and OCS groups, respectively. Compared to OCS, WCS were more likely to discontinue the new therapy [hazard ratio (HR), 1.82, 95% confidence interval (CI), 1.14-2.89, p = 0.012], and switch a second time (HR, 3.46, 95% CI, 1.89-6.36, p < 0.001). Moreover, WCS showed an increased likelihood of initiating prolonged corticosteroid therapy (HR, 1.42, 95% CI, 0.77-2.59, p = 0.260); however, the results were not significant.

Following first-line TNFi failure, this study suggests that real-world outcomes among patients with UC are less favorable when cycling to another TNFi, compared to switching to a non-TNFi such as UST or VDZ.

This study compares the effectiveness of different biologic therapies and sequences in patients with inflammatory bowel disease [IBD] using real-world data from a large cohort with long exposure.

Demographic, disease, treatment, and outcome data were retrieved for patients in the UK IBD BioResource. Effectiveness of treatment was based on persistence free of discontinuation or failure, analysed by Kaplan-Meier survival analysis with inverse probability of treatment weighting to adjust for differences between groups.

In total, 13 222 evaluable patients received at least one biologic. In ulcerative colitis [UC] first-line vedolizumab [VDZ] demonstrated superior effectiveness over 5 years compared to anti-tumour necrosis factor [anti-TNF] agents [p = 0.006]. VDZ was superior to both infliximab [IFX] and adalimumab [ADA] after ADA and IFX failure respectively [p < 0.001 and p < 0.001]. Anti-TNF therapy showed similar effectiveness when used as first-line treatment, or after failure of VDZ. In Crohn's disease [CD] we found significant differences between first-line treatments over 10 years [p = 0.045], with superior effectiveness of IFX compared to ADA in perianal CD. Non-anti-TNF biologics were superior to a second anti-TNF after first-line anti-TNF failure in CD [p = 0.035]. Patients with UC or CD experiencing TNF failure due to delayed loss of response or intolerance had superior outcomes when switching to a non-anti-TNF biologic, rather than a second anti-TNF.

We provide real-world evidence to guide biologic selection and sequencing in a range of common scenarios. Our findings challenge current guidelines regarding drug selection after loss of response to first anti-TNF treatment.

Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential.

Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure.

A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates.

Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6-14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52-54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE.

For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

We conducted this multicenter, retrospective cohort study aiming to evaluate the effectiveness and safety of vedolizumab (VDZ) and infliximab (IFX) in biologic-naïve patients with moderate-to-severe ulcerative colitis (UC).

Biologic-naïve patients with moderate-to-severe UC who were treated with IFX or VDZ for at least 14 weeks at three tertiary hospitals in southwest China between January 2021 and January 2023 were retrospectively included. Efficacy of the biologics was evaluated based on the steroid-free clinical remission rate, clinical remission rate, and mucosal healing rate at Weeks 14 and 52. Adverse events related to biologic use were recorded.

Altogether 122 biologic-naïve patients with moderate-to-severe UC were included. No marked differences in the steroid-free clinical remission rate and clinical remission rate were observed between the two groups at Week 14 or Week 52 (P > 0.05). The VDZ group exhibited a higher mucosal healing rate at Week 14 compared to the IFX group (33.3% vs 16.9%, P = 0.036), while that at Week 52 did not differ between the two groups (65.6% vs 47.1%, P = 0.098). There was no statistically significant difference in the rate of adverse events between the two groups (P = 0.071).

VDZ and IFX showed comparable clinical efficacy and safety profiles and can be used as viable first-line therapeutic options for biologic-naïve patients with moderate-to-severe UC.

Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC) but little is known when it is used as the second anti-TNF.

To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients.

Retrospective observational study.

Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially).

Overall, 473 UC patients were included (330 IVi and 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4% in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission.

The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy.

Ulcerative colitis (UC) is an inflammatory disease characterized by recurrent episodes of chronic intestinal inflammation. It is closely associated with immune dysregulation in the intestines. However, the mechanisms underlying the role of immune-related N7-methylguanosine (m7G) internal modification in UC remain unclear.

We conducted a screening of differentially expressed genes (DEGs) associated with m7G and performed immune infiltration analysis. We then investigated the correlation between m7G-related DEGs and immune cells or pathways. To further explore the functional implications, we conducted functional enrichment analysis to identify gene modules that strongly correlated with hub gene expression. In addition, we constructed a miRNA regulatory network for the hub genes in UC. Furthermore, we examined the association between hub genes and disease remission in UC patients undergoing biologic therapy.

We obtained 13 m7G-related DEGs and conducted an in-depth analysis of immune infiltration. Among them, we identified five hub genes (NUDT7, NUDT12, POLR2H, QKI, and PRKCB) that showed diagnostic potential for UC. Through WGCNA and KEGG analysis, we found that gene modules strongly correlated with m7G hub gene expression were enriched in inflammation-related pathways. Furthermore, Kaplan-Meier survival analysis revealed a significant association between changes in hub gene expression levels and disease remission in UC patients undergoing biologic therapy.

The findings of this study demonstrate that five m7G-related DEGs, including the m7G-modified recognition protein QKI, play a key role in the occurrence and progression of UC intestinal inflammation, which is closely related to intestinal immunity. These results provide valuable insights into the mechanisms of m7G modification in UC development and offer new perspectives for exploring novel therapeutic targets for UC.

Background: About a third of patients with inflammatory bowel disease (IBD) do not respond to anti-tumor necrosis factor (anti-TNF) therapy. In our study, we evaluated the effectiveness of vedolizumab and ustekinumab in achieving clinical and endoscopic outcomes in anti-TNF-experienced patients with IBD. Methods: We conducted a retrospective cohort study. Electronic medical records of patients with moderate to severe IBD, who were previously received anti-TNF therapies, were reviewed and evaluated retrospectively in a gastroenterology center. Outcomes of patients treated with ustekinumab or vedolizumab after failing one anti-TNF agent were evaluated. The primary outcomes were the percentage of hospitalization, surgery, mucosal healing and steroid-free remission. Mucosal healing was defined as a Mayo endoscopic score of 0 or 1 in ulcerative colitis (UC) and an SES-CD score of less than 3 in Crohn's disease (CD). Outcomes were quantified using descriptive analysis. Results: A total of 207 (130 CD: 77 UC) patients with IBD who had previously received one anti-TNF agent were included in the study. Of the total cohort, 62 (30.0%) patients were receiving vedolizumab, and 145 (70.0%) patients were on ustekinumab. 101 (77.6%) patients with CD who failed one anti-TNF therapy were on ustekinumab. Of these patients, 26 (19.7%) patients were hospitalized, and 12 (11.9%) patients had IBD-related surgery. 16 (16.1%) patients had at least one corticosteroid course. 60 (59.0%) patients with CD on ustekinumab achieved mucosal healing. 29 (22.3%) patients with CD who failed one anti-TNF therapy were receiving vedolizumab. Of those, 7 (25%) patients were hospitalized, and 11 (37.9%) patients had IBD-related surgery. 15 (51.0%) patients achieved mucosal healing. 44 (57.1%) patients with UC who failed one anti-TNF therapy were on ustekinumab. Of these 6 (14.1%) patients were hospitalized, 3 (7.0%) patients had IBD-related surgery and 13 (30%) patients had at least 1 corticosteroid course. 25 (57.0%) patients achieved mucosal healing. 33 (42.8%) patients with UC who failed one anti-TNF therapy were receiving vedolizumab. Of those, 6 (18.6%) patients were hospitalized, and 16 (49.6%) patients had at least 1 corticosteroid course. 17 (53.2%) patients achieved mucosal healing. Conclusion: Ustekinumab and vedolizumab were both effective in achieving clinical outcomes in patients with IBD after failing an anti-TNF agent. However, patients receiving ustekinumab had numerically higher percentages of reaching target outcomes than patients receiving vedolizumab. A prospective head-to-head trial is warranted to confirm these findings.

Despite a growing number of available therapeutic options for ulcerative colitis (UC), up to 50% of patients do not respond to initial treatment or lose response over time, highlighting the need for novel therapies. The IL-23 pathway has emerged as an important therapeutic target for UC. Mirikizumab is a humanized IgG4 monoclonal antibody against the p19 subunit of IL-23, dosed intravenously during induction and subcutaneously during maintenance. It is effective for the induction and maintenance of remission in moderately to severely active UC, including patients with prior failure of biological or tofacitinib therapy. Like other IL-23 antagonists, mirikizumab has a favorable safety profile. It is the first agent of its class to receive regulatory approval for moderately to severely active UC in Europe.

Many observational studies on the use of vedolizumab [VDZ] in patients with Crohn's disease [CD] and ulcerative colitis [UC] have been published in the past few years. We aimed to comprehensively summarise its effectiveness and safety by pooling data only from observational studies.

PubMed/Medline and Embase were systematically searched for observational studies on patients with CD and UC treated with VDZ through December 2021. The rates of clinical remission and overall adverse events were the primary outcomes. The rates of steroid-free clinical remission, clinical response, mucosal healing, C-reactive protein normalisation, loss of response, VDZ dose escalation, colectomy, serious adverse events, infections, and malignancies were considered as secondary outcomes.

In all, 88 studies comprising 25 678 patients [13 663 with CD and 12 015 with UC] met the inclusion criteria. In patients with CD, the pooled estimate rates of clinical remission were 36% at induction and 39% at maintenance. In patients with UC, the pooled estimate rates of clinical remission were 40% at induction and 45% at maintenance. The pooled estimate of incidence rate of adverse events was 34.6 per 100 person-years. At multivariable meta-regression analysis, studies with increased male proportion were independently associated with higher rates of clinical remission and steroid-free clinical remission at both induction and maintenance, and clinical response at maintenance in patients with CD. Studies with increased disease duration were independently associated with higher mucosal healing rates at maintenance in patients with UC.

Observational studies demonstrated extensively the effectiveness of VDZ, with a reassuring safety profile.

Safety is a key consideration when choosing advanced therapies (biologic agents and oral small-molecule inhibitors/modulators) in patients with inflammatory bowel diseases (IBDs). We performed a systematic review and meta-analysis comparing the risk of serious infections with advanced therapies in active comparator studies.

Through a systematic search until February 28, 2022, we included 20 head-to-head studies comparing risk of serious infections with tumor necrosis factor α (TNFα) antagonists, vedolizumab, ustekinumab, tofacitinib, filgotinib, and ozanimod in patients with IBD. We performed random-effects meta-analysis comparing different advanced therapies.

No significant difference was observed in the risk of serious infections between vedolizumab vs TNFα antagonists in all patients with IBD (17 cohorts: odds ratio [OR], 0.84; 95% CI, 0.68-1.04), with moderate heterogeneity (I2 = 37%); on subgroup analysis, vedolizumab was associated with a lower risk of serious infections in patients with ulcerative colitis (11 cohorts: OR, 0.68; 95% CI, 0.56-0.83; I2 = 0%), but not in Crohn's disease (CD) (9 cohorts: OR, 1.03; 95% CI, 0.78-1.35; I2 = 42%). Age, sex, prior biologic exposure, and use of biologic monotherapy did not influence this association. In patients with CD, ustekinumab was associated with a lower risk of serious infections vs TNFα antagonists (3 cohorts: OR, 0.49; 95% CI, 0.25-0.93; I2 = 16%) and vs vedolizumab (3 cohorts: OR, 0.40; 95% CI, 0.17-0.93; I2 = 67%). Few studies compared other advanced therapies.

Vedolizumab may offer net benefit over TNFα antagonists in patients with ulcerative colitis, but not in CD. Ustekinumab may offer net benefit over TNFα antagonists and vedolizumab in patients with CD.

Comparative trials among biological drugs for the treatment of ulcerative colitis (UC) provided conflicting results. After patent expire of infliximab originator, adalimumab, infliximab biosimilar, golimumab and vedolizumab have been approved in Italy.We compared the efficacy of these four biologics in UC according to the concept of continuous clinical remission (CCR).

In a retrospective, multicentre study, all UC patients treated with adalimumab, infliximab biosimilar, golimumab or vedolizumab between 2014 and 2019 were included. All drugs were compared to each other according to the 1-year CCR rate, defined as Mayo partial score ≤2, with bleeding subscore = 0, without any relapse or optimization with dose escalation, topical treatments or steroid use after first clinical remission.

Four-hundred sixteen patients (adalimumab = 90, infliximab biosimilar = 105, golimumab = 79, vedolizumab = 142) were included. CCR was achieved in similar percentages among the groups (33%, 37%, 28%, 37%, respectively). All drugs were equivalent in biologic-naive patients, while vedolizumab was better than a second anti-TNFα in prior anti-TNFα agent failures. No differences were found according to type of adverse events or severe adverse events.

Based on a strict definition of clinical remission, all biologics appear equally effective at 1 year. Changing to vedolizumab is more effective than switching to another anti-TNFα in TNFα failures.

The positioning of new biologic agents for the treatment of Crohn's disease (CD) following failure of initial anti-tumor necrosis factor (anti-TNF) therapy remains a challenge in the real world.

This study aims to investigate the real-world outcomes associated with the sequential use of biologics in CD patients that newly initiate anti-TNFs, specifically comparing those that switch to another anti-TNF versus biologics with other modes of action.

Retrospective cohort study.

We identified CD patients who newly began anti-TNF therapy between 1 October 2014 and 31 December 2018 using two German claims databases. Patients were classified as within-class switchers (WCS) if they switched to another anti-TNF or outside-class switchers (OCS) if they switched to vedolizumab (VDZ) or ustekinumab (UST). To compare WCS and OCS, baseline covariates were adjusted through inverse probability of treatment weighting (IPTW), and time-to-event analyses were performed using Cox Proportional Hazard regressions. Results from both databases were meta-analyzed using an inverse variance model.

Overall, 376 prevalent adult CD patients who initiated anti-TNFs and switched to another biologic were identified. After IPTW, there were 152 and 177 patients in the WCS and OCS group, respectively. WCS were more likely to receive prolonged corticosteroid therapy [hazard ratio (HR): 1.63, 95% confidence interval (CI): 1.17-2.27, p = 0.004], switch a second time to a different biologic (HR: 2.44, 95% CI: 1.63-3.66, p < 0.001), and discontinue treatment (HR: 1.71, 95% CI: 1.25-2.34, p = 0.001) than OCS.

This study suggests that CD patients exhibit more favorable outcomes when switching outside the anti-TNF class to VDZ or UST after initial anti-TNF failure than switching to a second anti-TNF. With loss of response to anti-TNFs as a concern in the real world, comparative evidence from claims data assessing sequential use of biologics can help optimize treatment algorithms of patients after anti-TNF failure.

Vedolizumab is a monoclonal antibody used to treat inflammatory bowel disease (IBD). There is little known about the safety and comparative efficacy of this agent in the elderly population.

Here, we present data on the safety and comparative efficacy of vedolizumab versus tumor necrosis factor α antagonists (anti-TNF) in elderly patients with IBD.

This retrospective cohort study included IBD patients started on vedolizumab or anti-TNF at age 60 or older at a single tertiary IBD center. Safety was evaluated by assessing for the development of serious infection. The comparative needs for IBD-related surgery, IBD-related hospitalization, and drug discontinuation for any reason were obtained. Efficacy was assessed by comparing changes in endoscopic, histologic, and patient-report outcomes.

212 cases were identified-108 patients treated with vedolizumab and 104 patients treated with anti-TNF. There were no significant differences between cohorts in serious infection, surgical intervention, or IBD-hospitalization-free survival (p = NS). Drug discontinuation survival was different between anti-TNF and vedolizumab (p = 0.02) with more patients remaining on vedolizumab at the time of last follow-up (51.9% vs. 25.9%). Endoscopic remission and response rates were higher in the vedolizumab versus anti-TNF group (65.7% vs. 45.2%, p = 0.02; 80.0% vs. 59.3%, p < 0.001).

In a cohort of IBD patients over age 60, vedolizumab showed no statistically significant differences in infection, hospitalization, or surgical intervention-free survival as compared to anti-TNF. Vedolizumab was discontinued less frequently than anti-TNF. Patients on vedolizumab had higher rates of endoscopic remission and response.

Anti-tumor necrosis factor (TNF)α antibody (ATA) and biologics/molecular targeted agents with other mechanisms (non-ATA) are currently available for refractory ulcerative colitis (UC). However, the knowledge about optimal drug selection after the initial treatment with ATA failure is lacking. This study assessed whether the response to the initial ATA could be a basis for selecting subsequent agents in UC patients.

Ulcerative colitis patients treated with ATA or non-ATA as the subsequent biologic after the failure of initial ATA were retrospectively analyzed. The efficacy at 14 weeks was examined according to the response to initial ATA.

Of 163 patients treated with the first ATA, the efficacy of subsequent ATA and non-ATA was evaluated in 63 and 36, respectively. Remission and response to subsequent-line therapy, regardless of ATA or non-ATA, were lower in patients with primary nonresponse (PNR) to initial ATA than in patients with efficacy to initial ATA (33.3% vs 69.2%, P < 0.01). In patients with PNR to initial ATA, the remission rate with subsequent ATA was significantly lower than with subsequent non-ATA (4.3% vs 26.3%, P = 0.04). In patients who showed efficacy to initial ATA, the remission rate with subsequent ATA was also lower than that with subsequent non-ATA (30.6% vs 56.3%, P = 0.08). PNR with initial ATA was the predictor of PNR to subsequent ATA (odds ratio: 5.62, 95% confidence interval: 1.50-21.7).

Non-ATA may be suitable in UC patients as the subsequent biologics regardless of the outcome of the first ATA.

Despite advances in the medical management of ulcerative colitis (UC), a subgroup of patients does not respond to currently available therapies. A number of novel drugs are in late stages of clinical development or have recently received regulatory approval for UC.

This review focuses on three drug classes that have recently been approved or are awaiting approval for UC: antibodies against interleukin (IL)-23, sphingosine-1-phosphate receptor (S1PR) modulators, and selective inhibitors of Janus kinases (JAK). We provide an overview of their mechanism of action and summarize available evidence for their efficacy and safety. Finally, we discuss expected future challenges in UC management.

The evaluated drugs have demonstrated efficacy with an acceptable safety profile. IL-23 antagonists appear to be safest with very few (serious) adverse events, while the use of S1PR modulators or JAK inhibitors has been associated with infectious and cardiovascular/thromboembolic events, albeit in low numbers. Although advances in drug development are promising, there is an urgent need for (validated) biomarkers to guide rational treatment selection. The scarcity of head-to-head trials also complicates comparisons between available drugs. Breaking the therapeutic ceiling of efficacy in UC will require marked advances in management extending well beyond drug development.

The management of moderate to severe ulcerative colitis has undergone significant changes over the past 15 years due to the regulatory approval of several new drugs. In particular, following the approval of the first biological, i.e. infliximab, a number of further biological drugs, such as adalimumab, golimumab, vedolizumab and ustekinumab, and small molecules, such as tofacitinib, have been approved, thus enriching the therapeutic armamentarium for ulcerative colitis. Choice of therapy must take into consideration not only the need to induce and maintain disease remission according to the patient's profile, but also age, co-morbidities, and prior treatments. To guide these decisions, the Italian Group for the Study of Inflammatory Bowel Disease has developed clinical guidelines that supersede its earlier document from 2011. These new guidelines were developed following the GRADE methodology for rating the quality of the evidence and for determining the strength of the recommendations. This article presents the methodology and results, in the form of 20 statements with commentary on the use of the five biologics and tofacitinib for managing the intestinal manifestations of active ulcerative colitis and for maintaining remission. A separate technical review reports the analyses of the evidence upon which the present recommendations are based.

Sequential drug treatment with biological agents in ulcerative colitis (UC) is becoming increasingly complex. There are few studies comparing head-to-head outcomes in second-line treatments. The study assesses whether using anti-tumour necrosis factor (anti-TNF)-α therapy following the α4β7 integrin blocker vedolizumab (VDZ) or VDZ after an anti-TNF has more favourable clinical outcomes in UC in a real-world outpatient setting.

Patients with UC who were exposed to first-line anti-TNF (adalimumab or infliximab) or VDZ who subsequently switched to the alternate class between May 2013 and August 2020 were identified by reviewing patient databases at 10 hospitals. Data were collected retrospectively using patient records. Baseline demographics, disease activity indices, biochemical markers, endoscopic Mayo score, colectomy rates, treatment persistence and urgent hospital utilisation composite endpoint (UHUC) rates were examined over a 52-week period.

Second-line week 52 treatment persistence was higher in the VDZ group (71/81, 89%) versus the anti-TNF group (15/34, 44%; p=0.0001), as were week 52 colectomy-free survival (VDZ: 77/80, 96%, vs anti-TNF: 26/32, 81%; p=0.009), week 52 UHUC survival (VDZ: 68/84, 81%, vs anti-TNF: 20/34, 59%; p=0.002) and week 52 corticosteroid-free clinical remission (CFCR) rates (VDZ: 22/34, 65%, vs anti-TNF: 4/20, 20%; p=0.001).

Compared with second-line anti TNF usage, the VDZ second-line cohort had significantly higher 52-week treatment persistence, UHUC survival, higher colectomy-free survival rates and higher week 52 CFCR. These data suggest that VDZ is an effective biologic in UC as a second-line therapy after anti-TNF exposure. It highlights the effect of biological order on clinically important outcomes.

About a third of patients with inflammatory bowel disease do not respond to anti-tumour necrosis factor (anti-TNF) therapy, which is challenging.

To review the current data on the two main strategies when facing primary non-response to an anti-TNF agent in inflammatory bowel disease: changing to a second anti-TNF (switching) or to a drug with another mechanisms of action (swapping).

We performed a bibliographic search to identify studies reporting on efficacy of any biologic treatment after primary anti-TNF non-response.

The efficacy of a second anti-TNF is lower when the reason to withdraw the first one is primary failure. Nevertheless, switching to another anti-TNF even after primary failure may still be effective in some patients. Both vedolizumab and ustekinumab have generally been shown to be less effective in anti-TNF exposed patients. However, despite primary anti-TNF failure, patients may respond to vedolizumab or ustekinumab in a limited but considerable number of cases. The cause for swapping (primary vs. secondary anti-TNF failure) seems to have limited effect on vedolizumab efficacy. Primary anti-TNF non-response seems to be a clearer predictor of treatment failure for ustekinumab. Unfortunately, the two main strategies to treat specifically a patient with primary non-response to an anti-TNF agent-switching to a second anti-TNF or swapping for vedolizumab/ustekinumab-have not been properly compared.

The data reviewed in the present study clearly emphasise the imperative need to carry out head-to-head randomised trials in patients exposed to anti-TNF agents in general, and specifically in those with primary non-response to these agents.

The development of biological treatments has transformed the management of a broad spectrum of autoimmune/inflammatory diseases. However, little is known about their use in solid-organ transplant recipients. This study aimed to evaluate complications occurring with biologic treatments in solid-organ transplant recipients.

A systematic review of the literature was performed in the Medline, Embase and Cochrane databases, up to 01/10/2020, to identify published case reports or series reporting the use of biologic treatments in solid organ transplant recipients with chronic inflammatory diseases. We collected data on patient characteristics and reported complications.

In total, 57 articles were included, totalling 187 patients (141 liver, 42 kidney, 3 heart, and 1 liver-kidney transplant recipients). Inflammatory bowel diseases represented the most common indication for biologic treatment initiation (80.7%), followed by rheumatic diseases (7.5%), hereditary periodic fever syndromes (5.9%) and psoriasis (4.8%). Anti-TNFα were mainly used (77.5%; mainly monoclonal antibodies (70%) compared to soluble receptor etanercept (7.5%)), followed by the anti-α4β7 integrin, vedolizumab (27.3%) and the anti-IL-1R, anakinra (6.9%). Median treatment duration was 12 months. Infections occurred in 54 patients (28.9%) through 88 recorded events. No therapeutic or demographic factors were associated with occurrence of infection. Sixteen patients (8.6%) developed malignancies, and acute graft rejections occurred in 5 patients (2.7%). Among the 187 patients, 9 deaths were reported (4.8%).

This review assembles the largest number of published reports regarding the use of biological treatments in solid organ transplant recipients, providing data about their safety. Further comparative studies are needed to assess the safety of biological treatments in transplanted patients.

This review addresses the selection of biologic and small molecule therapy for patients with moderate to severe ulcerative colitis (UC). With several new treatment options approved within the past few years, an update in positioning is timely and relevant.

Updates on the safety and comparative efficacy of approved therapeutic agents for UC are presented. Newly approved therapies including tofacitinib and ustekinumab, as well as where to position these treatments are discussed. Data on the first-ever head-to-head trial of biologic therapy in UC are examined. This review provides an evidence-based overview of the optimal management strategies of patients in both the inpatient and outpatient settings.

As we move closer towards the goal of personalized therapy for our patients with UC, we hope to better select appropriate and effective treatment options. Newly approved therapies provide us with additional options for management. Future advancements in predictive serologic, mucosal, genetic, and fecal markers can enable us to tailor therapy to an individual patient.

Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.

Inflammatory bowel disease (IBD) management has changed dramatically over the past 20 years, after the introduction of targeted biological therapies. However, the impact of these new drugs in changing the natural history of disease is still under debate. Recent evidence seems to suggest that the extent of their efficacy might be, at least partially, dependent on the timing of their introduction and on the subsequent management strategy. In this complex landscape, the potential role for a more dynamic approach with treatments based on sequencing and combining targeted therapies has been explored only minimally so far. In this review, we aim to explore the potential biological rationale behind the use of sequential and combination therapies in IBD, to summarise the current knowledge on this topic and to propose a management algorithm that combines these notions.