To evaluate the cost-effectiveness of intravenous and subcutaneous vedolizumab compared to infliximab for moderately to severely active ulcerative colitis (UC) from an Iranian societal perspective.

A decision-analytic cost-utility model was developed using a decision tree and a Markov model. Direct and indirect costs were calculated. Treatment effectiveness and health state utility values were extracted from published literature. Effects were estimated using quality-adjusted life-years (QALYs). Costs and QALYs were projected over a lifetime and discounted at 3% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate uncertainties.

In base-case analysis, infliximab was associated with $28,888.5 costs and 15.17 QALYs. Vedolizumab was associated with 15.34 QALYs and costs of $27,916.90 for IV (induction and maintenance) and $28,200.40 for IV (induction) followed by SC (maintenance). The ICERs were estimated at -$5673.3/QALY and -$4,017.8/QALY, remaining negative across all sensitivity analyses. The cost of infliximab and vedolizumab and the probability of response to vedolizumab during maintenance were the key determinants of cost-effectiveness.

Vedolizumab (both IV and SC) resulted in reduced costs and improved QALYs compared to infliximab for moderate to severe UC in Iran. Therefore, we recommended including vedolizumab in the Iranian national formulary as a cost-effective treatment strategy.

Vedolizumab is approved for the treatment of moderately to severely active Crohn's disease (CD). Real-world evidence is essential for understanding the effectiveness and benefit-risk profile of vedolizumab outside clinical trial settings.

To identify, systematically review and assess the real-world effectiveness and treatment persistence of vedolizumab in patients with CD, particularly over long-term follow-up periods and among populations with differing treatment experience, and to compare with the treatment persistence of anti-tumour necrosis factor (TNF)-α treatment.

Literature searches were conducted to identify studies published from 2014 to 2022. Relevant congress searches were conducted (2015-2022) using Embase or by hand. Data on adults with CD treated with vedolizumab or anti-TNFα treatment in a real-world setting were extracted for meta-analysis.

Data from 73 studies, including 29,894 patients with CD, reported ≥ 1 outcome of interest for this analysis. Vedolizumab treatment persistence rate was 65.3% (95% confidence interval [CI] 60.2-70.1) at 1 year and 54.8% (95% CI 43.9-65.3) at 2 years. The treatment persistence rate with vedolizumab versus anti-TNFα treatment was 84.6% (95% CI 70.2-92.8) versus 75.3% (95% CI 69.7-80.2) at 1 year and 70.6% (95% CI 60.7-78.8) versus 64.6% (95% CI 56.7-71.8) at 2 years. The mucosal healing rate at 1 year was 40.6% (95% CI 34.2-47.3). Clinical remission rates were 39.4% (95% CI 33.9-45.1) at 1 year and 34.3% (95% CI 18.1-55.2) at 2 years. Corticosteroid-free clinical remission rates were 33.2% (95% CI 28.5-38.3) at 1 year and 20.4% (95% CI 12.5-31.5) at 2 years. All clinical outcome rates were higher in biologic-naive than in biologic-experienced patients.

Real-world use of vedolizumab was associated with favourable long-term effectiveness and treatment persistence. Vedolizumab is a suitable first-line biological option for biologic-naive patients with CD.

The heterogeneity and suboptimal efficacy of biological treatments and small molecule drugs necessitate their precise selection based on biomarkers that predict therapeutic responses in inflammatory bowel disease. Recent studies have identified numerous novel biomarkers predictive of responses to biologics and small molecule modulators, utilizing a variety of omics approaches in inflammatory bowel disease. In this review, we systematically examine baseline omics biomarkers that predict responses to biological therapies and small molecule drugs, drawing on literature from PubMed. Our analysis spans multiple omics disciplines, including genomics, transcriptomics (both bulk RNA and single-cell RNA sequencing), proteomics, microbiomics, and metabolomics, with particular emphasis on the impact of models integrating multiple omics datasets. Additionally, to further the field of precision medicine, we evaluated specific biomarkers that may exhibit distinct effects on responses to multiple therapeutic interventions.

Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.

Effectiveness and safety of advanced therapies for ulcerative colitis (UC) warrant assessment in the real world.

To perform a systematic review and summarize real-world evidence of advanced therapies approved for moderate-to-severe UC.

A systematic literature review was conducted using real-world studies of biologics or small molecules in UC using Embase, MEDLINE, and MEDLINE-In Process databases. Only products approved in any jurisdiction during the search were included. English-language full-papers (January 2005 to February 2022) and congress abstracts (January 2019 to February 2022) were included. Studies with less than 30 patients or only biologic-naive patients were excluded.

A total of 139 studies were included out of 3,930 identified articles (75%, published between 2019 and 2022; 64%, retrospective observational; 53%, from 5 countries [Italy, United States, Spain, United Kingdom, and Belgium]). Most studies were single agent (highest: vedolizumab = 50, tofacitinib = 24, and adalimumab = 18), and rates of clinical remission (CR) and adverse events varied widely. From the published comparative effectiveness studies (16), the rates of CR were numerically higher with vedolizumab vs anti-tumor necrosis factor (TNF)-α agents. Compared with vedolizumab, the effectiveness of tofacitinib was numerically greater in CR (occasionally significant). Rates of steroid-free CR were comparable between ustekinumab and tofacitinib. Infliximab was the most effective anti-TNFα agent, as reported by 2 studies. Remarkably, adverse events were similar across therapies in comparative studies.

Vedolizumab and tofacitinib were the most assessed therapies. In comparative studies, remission rates were numerically higher with tofacitinib vs vedolizumab and for vedolizumab vs anti-TNFα. Tofacitinib was comparable with ustekinumab for steroid-free CR. Safety was comparable across therapies. Future studies should explore the literature gaps identified, including limited comparative studies with small sample sizes, variations in study designs and patient characteristics, varied definitions of CR, and limited use of patient-reported outcome measures in real-world settings.

Granulocyte and monocyte apheresis (GMA) is a potential therapeutic option when combined with various drugs for treatment of ulcerative colitis (UC). In this study, we analyze the efficacy and safety of GMA combined with vedolizumab (VDZ) during induction in patients with moderate-severe UC and incomplete response to steroids.

Single-center retrospective review of patients receiving GMA+VDZ. Data on the disease and previous treatments were collected. Clinical response was classified as no response, response without remission, and remission. Available data on biochemical and endoscopic response were included. Adverse events (AEs) were recorded.

The study population comprised 6 patients with UC who had received GMA+VDZ during induction after failure of an anti-TNF agent. The median number of GMA sessions was 5 (IQR 4-5; 3-10). All the patients received VDZ 300mg iv at 0, 2, and 6 weeks, and 5 (83%) received an additional dose at week 10. During maintenance, all the patients continued VDZ iv every 8 weeks. The median follow-up was 57.6 months (IQR: 39-74). Four of the 6 patients achieved clinical remission after GMA+VDZ and continued in deep remission until the end of follow-up. A median, non-significant decrease of 1378μg/g (IQR: 924-5778μg/g) was observed for calprotectin and 42.2mg/l (IQR: 15.3-113.5) for CRP vs. baseline. No patient underwent colectomy. No treatment-related AEs were observed.

GMA+VDZ during induction can be effective and safe in selected patients with moderate-severe UC and partial response to steroids.

Alcohol use is the most important determinant of the development of alcohol-associated liver disease (ALD) and of predicting long-term outcomes in those with established liver disease. Worldwide, the amount, type, and pattern of use of alcohol vary. Alcohol use and consequent liver disease have been increasing in certain ethnic groups especially Hispanics and Native Americans, likely due to variations in genetics, cultural background, socio-economic status, and access to health care. Furthermore, the magnitude and burden of ALD have been increasing especially in the last few years among females and young adults who are at the prime of their productivity. It is critical to recognize the problem and care for these patients integrating cultural aspects in liver clinics. At the federal level, a societal approach is needed with the implementation of public health policies aiming to reduce alcohol consumption in the community. By addressing these challenges and promoting awareness, we can strive to reduce the burden of ALD, especially in high-risk demographic groups to improve their long-term health outcomes. Finally, we need studies and quality research examining these changing landscapes of demographics in ALD as a basis for developing therapeutic targets and interventions to reduce harmful drinking behaviours in these high-risk demographic groups.

Acute interstitial nephritis (AIN) is a complication of drugs that may cause permanent kidney injury. AIN has been reported in patients with inflammatory bowel disease (IBD) treated with the integrin inhibitor vedolizumab. Through systematic review of existing literature, we aimed to identify and describe cases of AIN in patients with IBD treated with vedolizumab.

We searched Medline, Embase, Cochrane, and Web of Science Core Collection between 1 January 2009 and 25 April 2023. The search yielded 1473 publications. Titles and abstracts were screened by two independent reviewers. Seventy publications were reviewed in full-text. Eight met the inclusion criteria. Clinical characteristics of AIN cases were extracted. Case causality assessment was performed according to two international adverse drug reaction probability assessment scales. Results were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Nine biopsy-confirmed cases of AIN were reported in six patients with ulcerative colitis and three with Crohn's disease. Mean age at AIN onset was 36 years (range = 19-58) and the majority of patients were females (n = 6/9). Time from vedolizumab treatment initiation to AIN onset spanned from hours to 12 months. Common symptoms were fever and malaise. Creatinine levels were elevated in all patients. Five patients sustained permanent kidney injury.

Our findings suggest that vedolizumab, although rarely, could cause AIN in patients with IBD. Awareness of laboratory findings and symptoms consistent with AIN, along with monitoring of the kidney function, could be warranted in patients with IBD treated with vedolizumab.

Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy.

To explores the issues of PNR and SLOR to non-TNFi therapies.

This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM).

In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response.

The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

Extraintestinal manifestations are frequent in patients with inflammatory bowel disease and have a negative impact on quality of life. Currently, however, there is no evidence available to determine which drug should be recommended for these patients beyond anti-tumour necrosis factor [anti-TNF] treatment. We aimed to analyse the frequency of new extraintestinal manifestations and the behaviour of pre-existing extraintestinal manifestations during advanced therapy.

We conducted a systematic search on November 15, 2022, and enrolled randomized controlled trials, cohorts, and case series reporting the occurrence and behaviour of extraintestinal manifestations in patients with inflammatory bowel disease receiving advanced therapy [non-TNF inhibitor biologicals and JAK inhibitors]. Proportions of new, recurring, worsening, and improving extraintestinal manifestations were calculated with 95% confidence intervals [CIs]. The risk of bias was assessed with the QUIPS tool.

Altogether, 61 studies comprising 13,806 patients reported eligible data on extraintestinal manifestations. The overall proportion of new extraintestinal manifestations was 8% [95% CI, 6-12%] during advanced therapy. There was no significant difference between the frequency of new extraintestinal manifestations during vedolizumab and ustekinumab therapy [11%, 95% CI, 8-15% vs 6%, 95% CI, 3-11%, p = 0.166]. The improvement of pre-existing manifestations was comparable between vedolizumab- and ustekinumab-treated patients, except for joint involvement [42%, 95% CI, 32-53% vs 54%, 95% CI, 42-65%, p = 0.029].

The proportion of new extraintestinal manifestations was low during advanced therapy. Furthermore, the improvement of pre-existing manifestations was comparable between advanced therapies, except for pre-existing joint manifestations.

Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better outcomes remains unclear.

We aimed to explore the associations between the timing of CR and therapeutic outcomes in UC.

This study included UC patients from the UNIFI trial. Week-2 CR and time to CR were the major variables of interest. Endoscopic remission (ER) at week 52 was the primary outcome. Multivariate logistic regression was performed to evaluate the association between variables and outcomes.

Week-2 CR was associated with ER (aOR: 2.37 [95% CI: 1.28, 4.37], p = 0.006) and Histological remission (HR) (aOR: 2.87 [95% CI: 1.42, 5.72], p = 0.003) at week 52. Moreover, C-reactive protein (CRP) remission could further stratify patients without CR and predict week-52 outcomes. Patients with clinical activity + CRP remission (aOR: 0.49 [95% CI: 0.26, 0.93], p = 0.039) and clinical activity + CRP activity (aOR: 0.24 [95% CI: 0.11, 0.52], p < 0.001) had gradually decreased likelihood of achieving ER, when compared to those with CR. For time to CR, we found that the earlier to CR, the better endoscopic and histological outcomes patients would attain. Patients achieving CR at weeks 2, 4/8, 12/16 and >16 had gradually reduced proportions of ER (51.9% vs. 40.8% vs. 31.6% vs. 8.8%, p < 0.001) and HR (37.0% vs. 19.8% vs. 17.1% vs. 6.1%, p < 0.001) at week 52. Compared with week 2, achieving CR at weeks 4/8, 12/16 and >16 had 39%, 55% and 92% lower likelihoods of week-52 ER, respectively.

Week-2 CR indicates better outcomes in UC patients receiving ustekinumab. Moreover, achieving CR more rapidly is associated with higher probability of ER and HR.

We explored the potential for differential efficacy of vedolizumab between early and late ulcerative colitis [UC] with evaluation of clinical, endoscopic, and histological endpoints.

This was a multicentre, multinational, open-label study in patients with moderately-to-severely active UC, defining early UC by a disease duration <4 years and bio-naïve and late UC by a disease duration > 4 years and additional exposure to tumour necrosis factor antagonists. Patients received standard treatment with intravenous vedolizumab for 52 weeks [300 mg Weeks 0, 2, 6, every 8 weeks thereafter without escalation]. The primary endpoint was corticosteroid-free clinical remission with endoscopic improvement [total Mayo score ≤2 with no subscore >1] at both Weeks 26 and 52.

A total of 121 patients were included: in the "early" group, 25/59 [42.4%] achieved the primary endpoint versus 19/62 [30.6%] in the "late" group [p = 0.18]. There were no significant differences between the two groups in endoscopic improvement [Week 26: "early" 32/59 [54.2%] versus "late" 29/62 [46.8%]; p = 0.412; Week 52: 27/59 [45.8%] versus 25/62 [40.3%]; p = 0.546] or in histological remission [Robarts Histopathology Index <3 without neutrophils in the epithelium and lamina propria] [Week 26: 24/59 [40.7%] versus 21/62 [33.9%]; p = 0.439; Week 52: 22/59 [37.3%] versus 22/62 [35.5%]; p = 0.837].

No significant differences in clinical, endoscopic, and histological outcomes were observed between "early" and "late" disease.

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.

Despite the growing therapeutic armamentarium, at least half of the patients with Crohn's disease will require surgery during their lifetime. Current evidence for the prevention and treatment of postoperative Crohn's disease supports the use of anti-tumor necrosis factor agents with limited data about the use of the newer biologics, vedolizumab and ustekinumab.

We performed a systematic review of available data to determine the efficacy of the newer biologics in the management of postoperative Crohn's disease. We included noncomparative and comparative studies. The main outcomes of interest were clinical and endoscopic postoperative recurrence rates.

The search strategy identified 1231 citations, with 32 eligible for review. Several studies showed that the postoperative Crohn's disease recurrence rates with the use of the newer biologics were comparable to previously published results with the use of anti-tumor necrosis factor agents, while other studies failed to show their efficacy. It is important to note that the studies were heterogeneous and included a relatively small sample size, making it difficult to draw a definite conclusion about the efficacy of the newer biologics in the management of postoperative Crohn's disease.

The newer biologics do play a role in the management of postoperative Crohn's disease. After our review, we proposed an updated algorithm on the role of newer biologics in the approach to patients with postoperative Crohn's disease. Yet, until we have better-designed studies, their definite positioning remains to be determined.

The therapeutic armamentarium for managing Crohn's disease (CD) has expanded significantly in recent decades. Several biologics with three different mechanisms of action [anti-tumor necrosis factor (TNF)-α, anti-integrin α4β7, and anti-IL 12/23] are currently available to manage CD.

This narrative review aims to summarize the most significant efficacy and safety data on the use of infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) and ustekinumab (UST) for the treatment of CD obtained from studies conducted in the real world (RW), compared to the results of randomized clinical trials (RCTs).

RW studies reported that biologic agents included in this analysis have higher remission rates and lower adverse event rates than findings from RCTs for treating patients with CD. All biological agents have proven effective and safe in RW studies, even when using biosimilars or switching to subcutaneous administration of the molecules for which they are available. Finally, anti-TNF-α agents, particularly IFX, have a higher rate of adverse events (AEs) than VDZ and UST. Therefore, patients at higher risk of AEs may benefit from other biologics than anti-TNF-α. However, further long-term RW studies are needed to confirm these findings.

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.

Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios.

Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening.

No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W.

Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

Real-world data on long-term outcomes of vedolizumab (VDZ) are scarce.

To assess long-term outcomes (up to 3 years) of VDZ in treating inflammatory bowel disease (IBD).

A nationwide, prospective multicentre extension of a Swedish observational study on VDZ assessing Effectiveness And Healthcare resource utilization in patients with IBD (SVEAH).

After re-consent, data of patients with Crohn's disease (CD) (n = 68) and ulcerative colitis (UC) (n = 46) treated with VDZ were prospectively recorded using an electronic case report form integrated with the Swedish IBD Register (SWIBREG). The primary outcome was clinical remission (defined as Harvey-Bradshaw Index ⩽4 in CD and partial Mayo score ⩽2 in UC) at 104 and 156 weeks in patients with a response and/or remission 12 weeks after starting VDZ. Secondary outcomes included health-related quality of life (HRQoL) and biochemical outcomes.

VDZ continuation rates were high at weeks 104 and 156, 88% and 84%, respectively, for CD and 87% and 78%, respectively, for UC. Of the 53 CD patients with a response/remission at 12 weeks, 40 (75%) patients were in remission at 104 weeks and 42 (79%) patients at 156 weeks. For UC, these numbers were 25/31 (81%) and 22/31 (71%), respectively. Improvements were seen in the Short Health Scale (p < 0.01 for each dimension; CD, n = 51; UC, n = 33) and the EuroQol 5-Dimensions, 5-levels index value (p < 0.01; CD, n = 39; UC, n = 30). Median plasma-C-reactive protein concentrations (mg/L) decreased from 5 at baseline to 4 in CD (p = 0.01, n = 53) and from 5 to 4 in UC (p = 0.03, n = 34) at 156 weeks. Correspondingly, median faecal-calprotectin (µg/g) decreased from 641 to 114 in CD patients (p < 0.01, n = 26) and from 387 to 37 in UC patients (p = 0.02, n = 17).

VDZ demonstrated high continuation rates and was associated with improvements in clinical outcomes, HRQoL measures and inflammatory markers at 2 and 3 years after treatment initiation in this prospective national SVEAH extension study.

ENCePP registration number: EUPAS22735.

Vedolizumab is a gut-selective anti-lymphocyte trafficking agent used to treat ulcerative colitis (UC) and Crohn's disease.

We aimed to evaluate the effectiveness, safety, and durability of the therapeutic effect of vedolizumab after treatment discontinuation in a real-world cohort of patients with UC treated in Poland.

This was a multicenter, prospective study involving patients with moderate to severely active UC from 12 centers in Poland who qualified for reimbursed treatment with vedolizumab between February and November 2019.

The primary endpoints were clinical response (⩾2-point improvement from baseline on partial Mayo score) and clinical remission (partial Mayo score 0-1), including steroid-free remission, at week 54. Other outcomes included response durability at 26 weeks after treatment discontinuation, identification of predictors of response and remission, and safety assessment.

In all, 100 patients with UC were enrolled (55 biologic naïve and 45 biologic exposed). At baseline, 68% of patients were on corticosteroids and 45% on immunomodulators. Clinical response was observed in 62% of patients, clinical remission in 50%, and steroid-free remission in 42.6% at week 54. Within 26 weeks after treatment discontinuation, 37% of patients who maintained response by week 54 relapsed. The decreased number of liquid stools and rectal bleeding and endoscopic response at week 14 were predictive factors for response at week 54. Time from diagnosis ranging 2-5 years, decreased stool frequency, and non-concomitant use of corticosteroids at baseline and at week 14 were predictive factors for remission at week 54. Partial Mayo score < 3 with no subscale score > 1 at week 54 was a predictive factor for durable response after treatment discontinuation. The rate of serious adverse events related to treatment was 3.63 per 100 patient-years.

Vedolizumab is effective and safe in UC treatment in Polish patients. However, the relapse rate after the treatment cessation was high.

ENCePP (EUPAS34119).

Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.

Clinicians face difficulty in when and in what order to position biologics and Janus kinase inhibitors in patients with anti-tumor necrosis factor-alpha (TNF) refractory ulcerative colitis (UC). We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF-exposed patients with UC in our prospective nationwide Initiative on Crohn and Colitis Registry.

Patients with UC who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment were identified in the Initiative on Crohn and Colitis Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (Simple Clinical Colitis Activity Index ≤2), biochemical remission (C-reactive protein ≤5 mg/L or fecal calprotectin ≤250 μg/g), and safety outcomes were compared after 52 weeks of treatment. Inverse propensity score-weighted comparison was used to adjust for confounding and selection bias.

Overall, 83 vedolizumab- and 65 tofacitinib-treated patients were included. Propensity score-weighted analysis showed that tofacitinib-treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at weeks 12, 24, and 52 compared with vedolizumab-treated patients (odds ratio [OR], 6.33; 95% confidence interval [CI], 3.81-10.50; P < .01; OR, 3.02; 95% CI, 1.89-4.84; P < .01; and OR, 1.86; 95% CI, 1.15-2.99; P = .01; and OR, 3.27; 95% CI, 1.96-5.45; P < .01; OR, 1.87; 95% CI, 1.14-3.07; P = .01; and OR, 1.81; 95% CI, 1.06-3.09; P = .03, respectively). There was no difference in infection rate or severe adverse events.

Tofacitinib was associated with superior effectiveness outcomes compared with vedolizumab in anti-TNF-experienced patients with UC along with comparable safety outcomes.

Post-marketing surveillance is essential to evaluate the risk/benefit profile of drugs; however, pharmacovigilance studies comparing persistence and safety of biologic therapies in patients with inflammatory bowel disease (IBD) are scant. The aim of this study was to prospectively investigate persistence together with safety profiles of biologics in a cohort of patients diagnosed with Crohn's Disease (CD) or ulcerative colitis (UC) followed by the IBD unit of Messina and treated with infliximab (IFX), adalimumab (ADA), golimumab (GOL), vedolizumab (VED), and ustekinumab (UST) from 2017 through 2021. Descriptive and treatment persistence analyses with predictors for discontinuation and occurrence of adverse drug reactions (ADRs) were performed. A total of 675 IBD patients were enrolled. A higher persistence rate was noted for UST and ADA in the first year (83.8% and 83.1%, respectively) and for IFX in the fifth year of treatment (58.1%). GOL, VED, and UST-all used as second/third-line therapies-seemed to have a higher risk of non-persistence than IFX (in order HR: 2.19; CI 95%: 1.33-3.61, 1.45; 1.04-2.04, 2.25; 1.25-4.07) as well as switchers and those who had at least one ADR (18.1; 13.22-24.68 and 1.55; 1.20-1.99, respectively). The reported ADRs, which were generally mild-moderate, were largely known. However, real-world data should be implemented to further study undetected safety concerns, including risk of malignancy.

Vedolizumab (VDZ) is an α4β7 integrin-antibody used to manage refractory ulcerative colitis (UC). This retrospective multicenter study aimed to identify predictors of efficacy or the time points when evaluation of VDZ therapy for UC would be most useful. We compiled data on 87 patients with moderate to severe active UC that was treated with VDZ. Overall clinical remission (CR) rates at 6 weeks and 52 weeks after VDZ administration were 44.4% (bio-naïve 44.2%, bio-failure 44.8%) and 52.8% (bio-naïve 53.5%, bio-failure 51.7%) respectively. Also, 83.3% (bio-naïve 81.3%, bio-failure 85.7%) of patients achieved mucosal healing at week 52. Among patients with a CR at week 52, 73.3% had a CR at week 6. In contrast, of patients who discontinued VDZ, 82.4% had not reached a CR at week 6. Our study demonstrated that VDZ was effective in a large percentage of UC patients, with a high mucosal healing rate even after prior biological exposures. This suggests that VDZ can be a treatment option even in bio-failure cases. Additionally, it was considered that early CR can predict long-term remission and that week 6 can be a helpful evaluation point for treatment decisions when using VDZ for UC.

The efficacy and safety of vedolizumab in bio-naïve patients with ulcerative colitis (UC) and Crohn's disease (CD) remain unknown.

To perform a meta-analysis regarding vedolizumab as first line of biological therapy for UC or CD.

A systematic review of Medline, EMBASE, and Cochrane databases per December 2020 was undertaken. Meta-analysis was conducted using random-effects models.

This systematic review identified 79 eligible studies with 4,520 and 3,494 bio-naïve patients with UC and CD, respectively, and 8,105 and 11,140 bio-exposed patients. Among bio-naïve patients with UC, a total of 40.0% (95%CI 27.0-54.0, I²=86%) and 63.9% (95%CI 47.0-79.2, I²=36%) achieved clinical remission at weeks 14 and 52, respectively. The corresponding rates in CD were 54.0% (95%CI 42.0-66.0, I²=23%), and 61.7% (95%CI 55.2-68.1, I²=0%). Bio-naïvety was associated with a higher probability of clinical remission at week 52 in UC (relative risk (RR)=1.32 (95%CI 1.14-1.53)), while this was only apparent until week 26 in CD (RR=1.60 (95%CI 1.30-1.95)). Finally, bio-naïve UC patients had a lower risk of serious adverse events (RR=0.29 (95%CI 0.09-0.95)).

Vedolizumab was found to have a favorable efficacy and safety profile in bio-naïve patients with UC and CD. The findings have implications in the management of IBD.

Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients with CD. We studied whether ECM biomarkers of neutrophil activity and mucosal damage could predict long-term response to VEDO in patients with CD. Serum levels of human neutrophil elastase (HNE)-derived fragments of calprotectin (CPa9-HNE), and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen, type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n = 32) before VEDO therapy. Long-term response was defined as VEDO treatment of at least 12 months. CPa9-HNE was significantly increased at baseline in non-responders compared with responders (p < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all p < 0.05). All biomarkers were associated with response to VEDO (all p < 0.05). To conclude, baseline levels of serum biomarkers for neutrophil activity and mucosal damage are linked to the pathology of CD, and are associated with long-term use of VEDO in patients with CD. Therefore, these biomarkers warrant further validation and could aid in therapeutic decision-making concerning vedolizumab therapy.

Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use.

Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy.

The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase.

Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX.

MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.

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.

With recent advances in machine learning, we demonstrated the use of supervised machine learning to optimize the prediction of treatment outcomes of vedolizumab through iterative optimization using VARSITY and VISIBLE 1 data in patients with moderate-to-severe ulcerative colitis. The analysis was carried out using elastic net regularized regression following a 2-stage training process. The model performance was assessed through AUROC, specificity, sensitivity, and accuracy. The generalizable predictive patterns suggest that easily obtained baseline and medical history variables may be able to predict therapeutic response to vedolizumab with clinically meaningful accuracy, implying a potential for individualized prescription of vedolizumab.

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.

We investigated the real-life effectiveness and safety of vedolizumab (VDZ) induction therapy among Korean patients with Crohn disease (CD) or ulcerative colitis (UC) for whom anti-tumor necrosis factor therapy previously failed.

Adult patients who started VDZ induction therapy at 16 centers were prospectively enrolled in the Korean VDZ nationwide registry. The coprimary outcomes were clinical remission, defined as a Crohn's Disease Activity Index score <150 points and a partial Mayo score ≤2 points with a combined rectal bleeding and stool frequency subscore ≤1 point at week 14 and endoscopic remission defined as a Mayo endoscopic subscore ≤1 point. We also analyzed predictors of clinical remission.

Between August 2017 and November 2019, a total of 158 patients (80 with CD and 78 with UC) received VDZ induction therapy. Clinical remission rates among patients with CD and patients with UC were 44.1% and 44.0%, respectively. Among patients with UC, the endoscopic remission rate was 32.4%. Clinical response and remission rates showed increasing trends during induction therapy. Multivariable analysis revealed that clinical response at week 6 was the only predictor of clinical remission at week 14 for both patients with CD and patients with UC. Among patients who experienced 1 or more adverse events (n = 71; 44.9%), disease exacerbation (n = 28; 17.7%) was the most common adverse event.

Among Korean patients with CD or UC for whom anti-tumor necrosis factor therapy failed, VDZ induction therapy was effective and safe. The early clinical response was associated with clinical remission after VDZ induction therapy.