Maintenance Of Clinical Remission Research Articles

Efficacy and safety of etrolizumab in treatment of moderate to severe ulcerative colitis: A systematic review and meta-analysis.

Etrolizumab is a promising drug for treating moderate to severe ulcerative colitis. The aim of this study was to assess the efficacy and safety of etrolizumab for induction and maintenance of remission in moderate to severe ulcerative colitis. We searched the following databases: PUBMED, Web of Science, OVID, and SCOPUS from inception to January 15. Inclusion criteria were any phase 2 and 3 clinical trials that compared etrolizumab with a placebo in treating moderate to severe ulcerative colitis, excluding case reports, animal studies, phase 1 trials, and conference abstracts due to duplication. We used RevMan software (5.4) for the meta-analysis. Five clinical trials were included in our meta-analysis. The total number of patients included in the study is 1248 patients, 860 patients in the etrolizumab group and 388 patients in the placebo group. In the induction phase, the pooled analyses showed a statistically significant association between etrolizumab and increased clinical remission, and endoscopic remission compared with placebo (risk ratio [RR] = 2.66, 95% confidence interval [CI] = 1.69-4.19, p < 0.0001), and (RR = 2.35, 95% CI = 1.52-3.65, p = 0.0001), respectively. In the maintenance phase, the pooled analyses showed a statistically significant association between etrolizumab and increased histologic remission and endoscopic remission (RR = 2.04, 95% CI = 1.40-2.98, p = 0.0002) and (RR = 1.92, 95% CI = 1.29-2.85, p = 0.001), respectively. No statistically significant difference was observed in adverse events between etrolizumab and placebo in the induction and maintenance phases. Our results show that etrolizumab is an effective and safe drug for the induction and maintenance of clinical remission in moderate to severe ulcerative colitis patients, as proved by histologic and endoscopic findings. Future randomized trials are still needed to compare etrolizumab to the other agents and further establish its value for the practice.

Additive efficacy and safety of probiotics in the treatment of ulcerative colitis: a systematic review and meta-analysis.

We aim to report the latest pooled analyses to evaluate the additive efficacy and safety of probiotics in the treatment of ulcerative colitis (UC). We systematically searched the relevant literature investigating the efficacy and/or safety of probiotics in patients with UC from PubMed, Embase and Web of Science up to January 2023. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included studies according to the inclusion and exclusion criteria. Any discrepancies throughout these processes were solved by consensus. All statistical analyses were performed by Review Manager version 5.4 and Stata version 15.0. A total of 13 articles were included in the pooled analyses, and the studies were all randomized controlled trials with a total of 930 patients. There were no significant differences between the probiotics and placebo groups concerning demographic and baseline characteristics. For patients with active UC, the probiotic group boosted the remission rate by 87% compared to the placebo group, but failed to reach a statistical difference (OR: 1.87; 95% CI 0.98, 3.57; P = 0.06, I2 = 67%); furthermore, there were no statistical differences in maintenance of clinical remission, clinical response, change in UCDAI scores, or mucosal healing outcomes in the probiotic group compared to the placebo group. For patients in clinical remission, the clinical relapse rates were significantly lower in the probiotic group than in the placebo group (OR: 0.34; 95% CI 0.14, 0.79; P = 0.01). Moreover, this study did not observe a significant difference between the two groups for general adverse events rate (OR: 1.98; 95% CI 0.69, 5.68; P = 0.20). Probiotic-assisted therapy may be effective in inhibiting UC recurrence in patients in clinical remission without increasing the risk of treatment-related adverse events; furthermore, probiotics may increase the rate of clinical remission in patients with active UC. However, caution is needed when interpreting the clinical efficacy of probiotics in improving the clinical outcome of patients with active UC.

Mirikizumab: A New Therapeutic Option for the Treatment of Ulcerative Colitis.

To review the pharmacologic and clinical profile of mirikizumab in the treatment of moderate to severe ulcerative colitis (UC). A PubMed search was performed from inception to December 2023 using keywords mirikizumab, interleukin-23 inhibitor, and UC. Information was also obtained from package inserts as well as published abstracts. Phase 3 studies plus relevant literature on mirikizumab pharmacologic and clinical profile were reviewed. Mirikizumab approval was based on LUCENT-1 and LUCENT-2. In the phase 3 studies involving patients with moderate to severe UC, mirikizumab, when compared to placebo, resulted in clinical remission in a significantly higher proportion of patients in both the induction and maintenance phase. In addition, mirikizumab met the secondary endpoints of alternate definition of clinical remission, endoscopic remission, glucocorticoid-free clinical remission, histologic-endoscopic mucosal remission, and improvement in bowel urgency status, bowel-urgency remission, and maintenance of clinical remission. Common adverse events noted include infection (15.1%), injection-site reaction (8.7%), nasopharyngitis (7.2%), and headache (3.3%). Mirikizumab is the first selective interleukin 23 (IL-23) inhibitor approved for UC. Additional studies are required to determine how to position mirikizumab in both biologic-naïve and biologic-experienced patients with moderate to severe UC. Mirikizumab provides a novel mechanism of action for the treatment of moderate to severe UC and is another welcomed treatment advance in the treatment arsenal, providing a more selective mechanism of action while maintaining a comparable safety profile.

OP06 Risankizumab Maintenance Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Efficacy and Safety in the Randomised Phase 3 COMMAND Study

Abstract Background Risankizumab (RZB), a monoclonal antibody targeting interleukin-23 p19, was evaluated for maintenance therapy in patients with moderately to severely active ulcerative colitis (UC) and clinical response to RZB intravenous (IV) induction treatment in a phase 3 double-blind, placebo (PBO)-controlled withdrawal (WD) maintenance study, COMMAND (NCT03398135). Methods Patients with moderately to severely active UC who achieved a clinical response per Adapted Mayo score after 12 or 24 weeks (wks) of RZB IV treatment in the phase 2b and phase 3 INSPIRE induction studies (NCT03398148)1 were randomized 1:1:1 in COMMAND to RZB 180 mg (RZB180), 360 mg (RZB360), or PBO (RZB withdrawal) subcutaneous (SC) treatment every 8 wks for 52 wks. The efficacy analysis included responders to 12 wk of RZB IV, while the safety analysis included responders to 12 or 24 wk of RZB IV. The primary endpoint was clinical remission per Adapted Mayo score at wk 52. Key secondary endpoints included endoscopic improvement, HEMI, endoscopic remission, steroid-free clinical remission, maintenance of clinical remission, no bowel urgency, and no abdominal pain at wk 52. Results At baseline of induction, demographics and disease characteristics were similar between treatment groups; 75% of 548 patients had history of inadequate response or intolerance to ≥ 1 advanced therapy (AT). Patients receiving RZB180 (40.2%) and RZB360 (37.6%) achieved significantly higher rates of clinical remission vs WD (25.1%) (adjusted treatment difference vs WD: 16.3% and 14.2%, respectively; P ≤ .01) (Fig. 1A). Greater proportions of patients achieved endoscopic improvement, HEMI, endoscopic remission, steroid-free clinical remission, maintenance of clinical remission, no bowel urgency, and no abdominal pain with RZB180 and RZB360 vs WD (Fig. 1B). The overall rates of adverse events (AEs), and serious infections were similar among treatment groups (Table 1). Serious (presented as events/100 patient-years [E/100 PY]) (RZB180: 5.9; RZB360: 6.3; WD: 11.4) and severe AEs (RZB180: 1.6; RZB360: 4.0; WD: 8.0) were lower in the RZB arms vs WD. No active tuberculosis, adjudicated anaphylaxis, serious hypersensitivity, or adjudicated major adverse cardiovascular events were reported in any treatment group. Conclusion In patients with moderately to severely active UC responding to 12-week RZB induction therapy, RZB maintenance dosing with 180 mg and 360 mg SC was superior to placebo in achieving clinical remission as well as other key clinical, endoscopic, and histological-endoscopic endpoints. RZB was well-tolerated, with no new safety concerns observed.

Reduction of Fecal Calprotectin Levels Induced by a Short Course of Escherichia Coli Nissle is Associated with a Lower Likelihood of Disease Flares in Patients with Ulcerative Colitis in Clinical Remission.

Fecal calprotectin (FC) is a biomarker of gut inflammation, and Escherichia coli Nissle 1917 (EcN) is a probiotic strain able to reduce gut inflammation and maintain disease remission in patients with inflammatory bowel disease (IBD). The aim is to assess the effects of EcN administration in patients with IBD in clinical remission and altered FC values. We prospectively included 82 patients with ulcerative colitis (UC) (n=49) and Crohn's disease (CD) (n=33) in clinical remission and with FC values above 250 mcg/g (T0) who were treated with EcN alone for 2 months. FC values were assessed at the end of EcN treatment (T1) and clinical disease activity at 3 months (T2). At T1 median FC values were significantly lower compared to T0 both in patients with CD (312 mcg/g vs 626 mcg/g, p<0.0001) and UC (100 mcg/g vs 584 mcg/g; p<0.0001). Patients with UC who experienced disease relapse at T2 had lesser reduction in median FC values at T1 (-229 mcg/g, vs -397 mcg/g, p=0.049), while in patients with CD we observed no statistically significant difference (-358 mcg/g, vs -427; p=0.568). In patients with UC, a reduction of at least 532 mcg/g in FC had an accuracy of 69.7% and a positive predictive value of 65.7% in predicting maintenance of remission. A short course of EcN was associated with a reduction of FC values in patients with IBD in clinical remission and baseline altered FC values, and in patients with UC this decrease was associated with maintenance of clinical remission.

Systematic review with meta-analysis: Medical therapies for treatment of ulcerative proctitis.

Ulcerative proctitis (UP) is a common highly symptomatic form of ulcerative colitis that can be difficult to treat. To assess the efficacy of medical treatments for UP. We searched MEDLINE, EMBASE, and CENTRAL on 23 November 2022 for randomised controlled trials (RCTs) of medical therapy for adults with UP. Primary outcomes included induction and maintenance of clinical remission. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for each outcome. We included 53 RCTs (n = 4096) including 46 induction studies (n = 3731) and seven maintenance studies (n = 365). First-line therapies included topical 5-aminosalicylic acid (5-ASA), conventional corticosteroids, budesonide, and oral 5-ASA. Therapy for refractory UP included topical tacrolimus and small molecules. Topical 5-ASA was superior to placebo for induction (RR 2.72, 95% CI 1.94-3.82) and maintenance of remission (RR 2.09, 95% CI 1.26-3.46). Topical corticosteroids were superior to placebo for induction of remission (RR 2.83, 95% CI 1.62-4.92). Topical budesonide was superior to placebo for induction of remission (RR 2.34, 95% CI 1.44-3.81). Combination therapy with topical 5-ASA and topical corticosteroids was superior to topical monotherapy with either agent. Topical tacrolimus was superior to placebo. Etrasimod was superior to placebo for induction (RR 4.71, 95% CI 1.2-18.49) and maintenance of remission (RR 2.08, 95% CI 1.31-3.32). Topical 5-ASA and corticosteroids are effective for active UP. Topical 5-ASA may be effective for maintenance of remission. Tacrolimus may be effective for induction of remission. Etrasimod may be effective for induction and for maintenance of remission. Trials should include UP to expand the evidence base for this under-represented population.

Identification of crucial genes of pediatric inflammatory bowel disease in remission by protein-protein interaction network and module analyses.

Although the main treatments of inflammatory bowel disease (IBD) aim at the induction and maintenance of clinical remission, several studies have demonstrated inflammation still present in clinical remission. The goal of this study was to analyze the gene expression profiles between the pediatric IBD and control samples, aiming to further investigate the underlying therapeutic target in remission. Gene expression profiles data of GSE33943 were downloaded from Gene Expression Omnibus, which included 45 pediatric IBD samples and 13 control samples. The differentially expressed genes (DEGs) between IBD and control samples were identified by LIMMA package in R and the function of DEGs were predicted by Gene Ontology and KEGG pathway enrichment analyses using GeneAnswer package. Furthermore, a protein-protein interaction (PPI) network was constructed through the STRING database and functional module was obtained using ClusterONE. A total of 224 DEGs were screened between IBD and control samples. These DEGs (e.g. up-regulated FAS and down-regulated CCL5) were mainly enriched in cytokine‒cytokine receptor interaction and chemokine signaling pathway. In addition, some hub genes (e.g. up-regulated PSMA2 and PSMA6) were obtained through PPI network and functional module. These two genes were involved in Proteasome alpha-subunit and conserved site by functional module analysis. The immune and Proteasome mechanisms are still active during remission and FAS, PMSF6 and PMSF2 may be underlying targets for therapy of this disease.

A Mediterranean Diet Pattern Improves Intestinal Inflammation Concomitant with Reshaping of the Bacteriome in Ulcerative Colitis: A Randomised Controlled Trial.

Dietary patterns are important in managing ulcerative colitis [UC], given their influence on gut microbiome-host symbiosis and inflammation. We investigated whether the Mediterranean Diet Pattern [MDP] vs the Canadian Habitual Diet Pattern [CHD] would affect disease activity, inflammation, and the gut microbiome in patients with quiescent UC. We performed a prospective, randomised, controlled trial in adults [65% female; median age 47 years] with quiescent UC in an outpatient setting from 2017 to 2021. Participants were randomised to an MDP [n = 15] or CHD [n = 13] for 12 weeks. Disease activity [Simple Clinical Colitis Activity Index] and faecal calprotectin [FC] were measured at baseline and week 12. Stool samples were analysed by 16S rRNA gene amplicon sequencing. The diet was well tolerated by the MDP group. At week 12, 75% [9/12] of participants in the CHD had an FC >100 μg/g, vs 20% [3/15] of participants in the MDP group. The MDP group had higher levels of total faecal short chain fatty acids [SCFAs] [p = 0.01], acetic acid [p = 0.03], and butyric acid [p = 0.03] compared with the CHD. Furthermore, the MDP induced alterations in microbial species associated with a protective role in colitis [Alistipes finegoldii and Flavonifractor plautii], as well as the production of SCFAs [Ruminococcus bromii]. An MDP induces gut microbiome alterations associated with the maintenance of clinical remission and reduced FC in patients with quiescent UC. The data support that the MDP is a sustainable diet pattern that could be recommended as a maintenance diet and adjunctive therapy for UC patients in clinical remission. ClinicalTrials.gov no: NCT0305371.

Comparative efficacy and safety of combination therapy with infliximab for Crohn's disease: a systematic review and network meta-analysis.

There is not enough information to position medications for the treatment of Crohn's disease (CD). Therefore, using a network meta-analysis and systematic review, we evaluated the efficacy and safety of combination therapy and infliximab (IFX) monotherapy in CD patients. We identified randomized controlled trials (RCTs) in CD patients who were given IFX-containing combination therapy versus IFX monotherapy. Induction and maintenance of clinical remission were the efficacy outcomes, while adverse events were the safety outcomes. The surface under cumulative ranking (SUCRA) probabilities was used to assess ranking in the network meta-analysis. In total, 15 RCTs with 1586 CD patients were included in this study. There was no statistical difference between different combination therapies in induction and maintenance of remission. In terms of inducing clinical remission, IFX + EN (SUCRA: 0.91) ranked highest; in terms of maintaining clinical remission, IFX + AZA (SUCRA: 0.85) ranked highest. There was no treatment that was significantly safer than the others. In terms of any adverse events, serious adverse events, serious infections, and infusion/injection-site reactions, IFX + AZA (SUCRA: 0.36, 0.12, 0.19, and 0.24) was ranked lowest for all risks; while IFX + MTX (SUCRA: 0.34, 0.06, 0.13, 0.08, 0.34, and 0.08) was rated lowest for risk of abdominal pain, arthralgia, headache, nausea, pyrexia, and upper respiratory tract infection. Indirect comparisons suggested that efficacy and safety of different combination treatments are comparable in CD patients. For maintenance therapies, IFX + AZA was ranked highest for clinical remission and lowest for adverse events. Further head-to-head trials are required.

Real-world efficacy and safety of vedolizumab in managing ulcerative colitis versus Crohn’s disease: results from an Italian multicenter study

ABSTRACT Background Vedolizumab (VDZ) can be used to treat refractory ulcerative colitis (UC) and Crohn’s disease (CD). We assessed whether there are differences in treating UC vs CD with VDZ. Research design and methods Mayo score in UC and the Harvey-Bradshaw Index (HBI) in CD scored the clinical activity. Achievement and maintenance of clinical remission during the follow-up, and safety were the primary endpoints. Results 729 patients (475 with UC and 254 with CD), median follow-up of 18 (IQR 6-36) months, were enrolled. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients (74.4% in CD vs 62.9% in UC, p<0.002) while, during the follow-up, no difference was found (81.5% in the UC group and 81.5% pts in the CD group; p=0.537). The clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics (p<0.0001) were significantly associated with prolonged clinical remission. The clinical response was significantly higher in UC (90.1%) vs CD (84.3%) (p=0.023), and surgery occurred more frequently in CD (1.9% in UC vs 5.1% in CD, p=0.016). Conclusion We found differences when using VDZ in UC vs CD in real life. These parameters can help the physician predict this drug’s longterm efficacy.

P630 Upadacitinib Improves Clinical Outcomes in Patients with Moderate to Severely Active Crohn’s Disease Irrespective of Previous Failure to Respond to Biologics or Conventional Therapies

Abstract Background Upadacitinib (UPA), an oral, selective Janus kinase inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) in patients (pts) with moderately to severely active Crohn’s disease (CD) in phase 3 multicentre, double-blind, PBO-controlled induction U-EXCEL and U-EXCEED, and maintenance U-ENDURE trials.1-3 This analysis compared clinical outcomes in pts treated with UPA vs PBO once daily (QD) among pts without or with a history of biologic failure. Methods Eligible pts with an average daily very soft/liquid stool frequency (SF) ≥4 and/or abdominal pain score (APS) ≥2, plus a Simple Endoscopic Score for CD (excluding the narrowing component) ≥6 (≥4 for pts with isolated ileal disease) were randomized (2:1) to UPA 45 mg (UPA45) or PBO in U-EXCEL and U-EXCEED. Induction responders (≥30% decrease in average daily very soft/liquid SF and/or APS, neither worse than baseline) to 12-week (wk) UPA45 were re-randomized 1:1:1 for maintenance to UPA 15 mg (UPA15), UPA 30 mg (UPA30) or PBO QD in U-ENDURE. Clinical remission, response (CR-100), and maintenance of clinical remission, along with adverse events (AEs) were assessed through maintenance wk 52. Results Baseline demographics/characteristics were similar for all treatment groups; pts with prior biologic failure were 71.5% PBO and 72.0% UPA45 in induction and 76.4% PBO, 73.4% UPA15 and 75.6% UPA30 in maintenance. Among pts without/with biologic failure history, those treated with UPA45 exhibited higher rates for clinical remission at wk 12 (CDAI: UPA45 54.1%/40.5% vs PBO 39.4%/19.4%; SF/APS: UPA45 54.0%/42.2% vs PBO 28.3%/14.1%, Fig. 1A). Similar results were observed at wk 52 with UPA15 and UPA30 vs PBO (Fig. 1B). Irrespective of biologic failure status, a higher proportion of patients on either UPA dose maintained clinical remission from maintenance wk 0 to wk 52 (Fig. 1C). Higher proportions of pts with prior biologic failure achieved CR-100 with UPA45 vs PBO at wk 12 (53.2% vs 26. 9%); at wk 52 differences from PBO were found for either UPA dose in pts without or with prior biologic failure (Fig. 1D). Serious AEs and serious infections were similar across treatment groups (Tables 1-2). No tuberculosis or adjudicated cardiovascular events were reported. Malignancy, opportunistic infections, thrombotic events, and gastrointestinal perforations were infrequent (&amp;lt;1.0% or 10 E/100PY). Conclusion All upadacitinib doses achieved greater clinical efficacy than placebo during induction and maintenance periods, irrespective of patient prior exposure to biologic therapy, with an acceptable safety profile.

OP37 Is the withdrawal of anti-tumour necrosis factor in inflammatory bowel disease patients in remission feasible without increasing the risk of relapse? Results from the randomised clinical trial of GETECCU (EXIT)

Abstract Background Background: The feasibility of anti-TNF discontinuation in inflammatory bowel disease (IBD) must be proven in clinical trials including patients in clinical, endoscopic, and radiologic remission at the time of anti-TNF withdrawal to make recommendations for clinical practice. Aims Primary: to compare the rates of clinical remission at 1 year in patients who discontinue anti-TNF treatment vs. those who continue treatment. Secondary objectives: to know the effect of anti-TNF withdrawal on relapse-free time, mucosal healing and safety; and to identify predictive factors for relapse. Methods Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis (UC) or Crohn’s disease (CD) in clinical remission for &amp;gt; 6 months were randomised to maintain anti-TNF treatment [maintenance arm (MA)] or to withdraw it [withdrawal arm (WA)]. Patients who were on infliximab (IFX) received IFX 5 mg/kg or an intravenous placebo every 8 weeks, while patients on adalimumab (ADA) received subcutaneous ADA 40 mg or placebo every other week. Patients were followed-up until month 12 or up to the time of clinical relapse, whichever came first. Inclusion and exclusion criteria, trial scheme and definitions are summarized in figures 1a, 1b and 1c. Results were analysed by intention-to-treat (ITT) and by per-protocol (PP). Local investigators were blinded to faecal calprotectin (FC) and IFX and ADA trough levels. On-site monitoring was performed to assess data quality. Results 159 patients were screened, from whom 140 were randomised and comprised the ITT cohort: 70 allocated to the MA and 70 to the WA. Fifteen patients dropped out before the end of follow-up (12 months or relapse), leaving 63 patients in the MA and 62 patients in the WA for the PP analysis. The characteristics of patients in the MA and WA were similar (figure 2). The proportions of patients who maintained clinical remission -59/70 (84%), 95% confidence interval (CI)=74-92% in the MA vs. 53/70 (76%), 95%CI=64-85% in the WA- and who remained without significant endoscopic lesions at the end of follow-up were similar between groups (figures 3a, 3b, 3c). Only the proportion of patients with FC &amp;gt;250 mg/g was higher in the WA at the end of follow-up (figure 3d). Maintenance of clinical remission was no different between groups (figure 4). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar between groups (4% in MA vs. 7% in WA). Conclusion Anti-TNF withdrawal in selected IBD patients in clinical, endoscopic, and radiologic remission could be feasible without an increase in the risk of clinical relapse. Long-term follow-up of these patients is warranted.

P505 Real word long-term efficacy and safety of vedolizumab in managing ulcerative colitis versus crohn’s disease: results from “long vedo” italian multicenter study

Abstract Background Current data about long-term use of vedolizumab (VDZ) in ulcerative colitis (UC) versus Crohn’s disease (CD) patients are limited. We aimed to assess whether there are differences in term of long-term efficacy and safety of VDZ in UC vs. CD patients. Methods Clinical activity was scored according to the Mayo score in UC and to the Harvey-Bradshaw Index (HBI) in CD. The primary endpoints were the achievement of clinical remission within 6 month of treatment, maintenance of clinical remission during a long follow-up, and safety. Secondary endpoints were clinical response to treatment, achievement of mucosal healing (MH), steroid discontinuation, and treatment optimization during the follow-up. Results The study group consisted of 729 patients (475 patients with UC and 254 CD patients with CD) with a median follow-up of 18 (interquartile range 6-36) months. Clinical remission at the 6th month of treatment was achieved in 488 (66.9%) patients, higher in CD patients (74.4 vs. 62.9, p&amp;lt;0.000) while, at the maximal follow-up, it was achieved and maintained in 81.5% of patients (UC vs. CD, p=0.667). At uni- and multivariate analysis, reaching clinical remission at the 6th month of treatment (p=0.001) and being naïve to biologics were significantly associated with longer clinical remission (p&amp;lt;0.0001). Long-term follow up clinical response was significantly higher in UC vs. CD (p=0.023) and surgery occurred more frequently in CD (p=0.04), while no difference were found between UC and CD about the other secondary endpoints Conclusion Overall, no significant differences were found about the long-term use of VDZ in UC vs. CD. However, we identified some parameters the can help the physician to predict the long-term efficacy of this drug.

P698 Role of an exclusion diet (reduced disaccharides, saturated fats, emulsifiers, red and ultraprocessed meats) in maintaining the remission of chronic inflammatory bowel diseases in adults

Abstract Background Inflammatory bowel diseases (IBD) are a main focus in current research with diet being an emerging therapeutic line due to its links both in onset and progression. A Western-style diet high in processed foods, food additives, red meat, and animal fat has been linked to a higher risk of developing IBD. The aim of this study was to establish an association between an anti-inflammatory exclusion diet and maintenance of remission in IBD. Also, we assessed the efficacy and safety of this diet compared to a non-dietary group and the possible therapeutic effect of this diet in the maintenance of IBD remission. Methods One hundred seventeen adult IBD patients in remission (64 patients with Crohn’s disease- CD and 53 patients with ulcerative colitis- UC) were randomized at their own will to a 6-months exclusion diet (n=32) or a habitual diet (n=85). Dietary patterns, clinical activity of the disease and inflammatory markers were assessed at baseline and at the end of dietary intervention. Results The acceptance rate of the exclusion diet in our cohort was 27.35% (30% in UC and 20% in CD). The exclusion diet and control populations were similar, except for immunosuppressive treatment (only 30% of patients in the exclusion diet group had an immunomodullator compared to 70% in the control group (p-value &amp;lt;0.001)). The clinical remission after six months was maintained in the exclusion diet arm (100%). In the control arm, 3 patients had clinically active disease (1 patient with UC and 2 patients with CD) and 80 patients maintained the clinical remission state (96.4%) (p-value = 0.278). Figure 1 is depicting the remission rates in different patient groups. Regarding biochemical markers, erythrocyte sedimentation rate (ESR) at baseline was higher in the exclusion diet arm: 31 (5-62) than in the control arm 14.5 (4-48) (p-value=0.011), but six months after, the groups were similar (p-value = 0.440). Fecal calprotectin at baseline was higher than 300 micrograms/gram in 30% of cases in the exclusion diet arm and in 25.8% of cases in the control arm (p-value = 0.774). Six months after, 50% of cases had a higher fecal calprotectin (&amp;gt;300 micrograms/gram) in the intervention arm and only 20.5% in the control arm (p-value = 0.033). Figure 1. Maintenance of clinical remission 6 months after intervention Conclusion We found a better trend of sustained clinical remission in patients who follow an exclusion diet. However, the threshold for statistical significance was not achieved. The clinical study continues, these are preliminary data. There is also a trend of improvement in ESR in the intervention group, but the levels of fecal calprotectin did not improved.

VEDOLIZUMAB, USTEKINUMAB AND TOFACITINIB AS TRIPLE THERAPY FOR ULCERATIVE COLITIS

Abstract BACKGROUND Therapies for ulcerative colitis include mesalamine, immunomodulators, biologics, and small molecules. Unfortunately, patient response is not universal, and efficacy can diminish with time, postulated to be from increased drug clearance, anti-drug antibodies with biologics, and immune mediated pathogenesis changes. Biologic combinations have been investigated for producing synergistic drug effects and extending targeted therapy in patients lacking monotherapy response, with promise shown in two drug combinations (1), but not investigated using three. CASE A 20-year-old Caucasian male with UC presented in August 2015 following 1 month hospitalization for Clostridium difficile infection. He had 2 infusions of infliximab 10 mg/kg continued post-discharge, and started mesalamine 4.8gm qd, 6-mercaptopurpine (6MP) 100mg qd, and prednisone taper. By November 2015, colonoscopy showed severe Mayo 3 pancolitis. Due to insufficient response 6MP and infliximab were discontinued and he started vedolizumab. August 2016 colonoscopy had chronic colitis with Mayo 2 inflammation of the ascending, transverse, descending and rectosigmoid colon so prednisone 40mg was initiated and vedolizumab increased to vedolizumab q4 weeks. He responded well clinically and was tapered off prednisone by October 2016. November 2016 colonoscopy had right sided colitis resolution with residual proctosigmoiditis (Mayo 2); May 2017 colonoscopy still had rectosigmoid inflammation (Mayo 2) with chronic active colitis, so ustekinumab q8 weeks was added. December 2017 colonoscopy was unimproved so ustekinumab increased to q4 weeks, prednisone was increased, and he requested addition of budesonide and mesalamine. With clinical improvement, prednisone was tapered by February 2020. However, December 2020 colonoscopy showed severe (Mayo 3) recto-sigmoiditis with mild colitis in the descending to transverse colon, so tofacitinib XR 22 mg qd was added. He improved clinically, so budesonide was discontinued in February 2021. November 2021 colonoscopy showed complete endoscopic remission (Mayo 0) so he initiated de-escalation with initially discontinuing mesalamine and increasing ustekinumab initially to q8 week intervals and later vedolizumab to q8 weeks with maintenance of clinical remission. Given marginal effect, ustekinumab was discontinued initially and later, tofacitinib was discontinued. He remains in remission on vedolizumab q8 weeks monotherapy. CONCLUSION Combination therapies may be considered for suitable patients experiencing severe, refractory disease. Although patients with multiple comorbidities, frailty, immunosuppression or certain contraindications may not be well suited, this patient presents as an ideal candidate with no comorbidities and few other therapeutic options. REFERENCES (1) Privitera G et al. Combination therapy in IBD. Autoimmunity Reviews. 2021 Jun 1;20(6):102832.

Efficacy and safety of medical therapies in microscopic colitis: a systematic review and network meta-analysis.

The mainstay of treatment for microscopic colitis (MC) is budesonide. However, the optimal formulation and dosage of budesonide to induce and maintain remission has not yet been clearly demonstrated. To compare the data for efficacy and safety of treatments to induce and maintain remission for MC. We conducted a meta-analysis of randomised controlled trials (RCTs) comparing treatment with each other or placebo for induction and maintenance of clinical and histological remission in MC. We searched MEDLINE (1946 to May 2021), EMBASE and EMBASE Classis (1947 to May 2021), the Cochrane central register of controlled trials (Issue 2, May 2021) and conference proceedings between 2006 and 2020. Results were reported as pooled relative risks (RRs) with 95% confidence intervals (CIs) to summarise the effect of each comparison tested, with treatments ranked according to p score. We identified 15 RCTs in total for the treatment of MC. Entocort 9 mg ranked first for clinical (RR: 4.89, CI: 2.43-9.83; p score: 0.86) and histological (RR: 13.39, CI: 1.92-93.44; p score 0.94) induction of remission, whilst VSL#3 ranked second for clinical induction (RR: 5.30, CI: 0.68-41.39; p score 0.81). Budenofalk 6 mg/3 mg alternate day dosing ranked first for clinical maintenance of remission (RR: 3.68, CI: 0.08-159.92, p-score 0.65). Entocort and Budenofalk were associated with the greatest adverse events for induction and maintenance of clinical remission, respectively, although the overall withdrawal numbers for treatment versus placebo groups were 10.9% (22/201) and 10.5% (20/190), respectively. Entocort 9 mg/day ranked first among the treatment options in inducing remission and Budenofalk 6 mg/3 mg alternate day dosing for maintaining remission in the treatment of MC. Moving forward, mechanistic studies exploring the differences between Entocort and Budenofalk would be valuable whilst future RCT studies are needed in non-corticosteroidal maintenance, particularly looking into immunomodulators, biologics and probiotics.

Replacement of Adalimumab Originator to Adalimumab Biosimilar for a Non-Medical Reason in Patients with Inflammatory Bowel Disease: A Real-life Comparison of Adalimumab Biosimilars Currently Available in Italy

Adalimumab (ADA) biosimilars have been included into the therapeutic armamentarium of inflammatory bowel disease (IBD); however, comparative data on the efficacy and safety of the different ADA biosimilars after replacing the ADA originator for a non-medical reason remains scarce. We aimed to compare in a real-life setting the efficacy and safety of four ADA biosimilars SB5, APB501, GP2017, and MSB11022 in IBD patients after replacing the originator for a non-medical reason. A multicenter retrospective study was performed on consecutive IBD patients, analyzing clinical, laboratory, and endoscopic data. The primary endpoints of the study were maintenance of clinical remission and safety of the different biosimilars. 153 patients were enrolled, 26 with UC and 127 with CD. Clinical remission was maintained in 124 out of 153 (81%) patients after a median (IQR) follow-up of 12 (6-24) months, without any significant difference between the four ADA biosimilars. ADA biosimilars dosage was optimized in five patients (3.3%). Loss of remission was significantly higher in UC patients (10/26 patients, 38.5%) than in CD patients (19/127 patients, 14.9%, p<0.025). Adverse events occurred in 12 (7.9%) patients; the large majority were mild. No difference in efficacy and safety was found between ADA biosimilars when used to replace the ADA originator for a non-medical reason. However, in UC patients the replacement of ADA originator for this reason should be carefully assessed.

Pharmacological Management of Inflammatory Bowel Disease: a Century of Expert Opinions in Cecil Textbook of Medicine.

Advances in drug therapy for inflammatory bowel disease (IBD) [Crohn disease and ulcerative colitis (UC)] have contributed to a decrease in the severity of these chronic and disabling conditions. What are the milestones of the changes in the expert approach to the pharmacological management of IBD in the past century? To determine the changes in the experts' approach to the management of regional ileitis and UC, as presented in a widely used textbook in the United States. The chapters presenting the management of IBD in the 26 editions of Cecil Textbook of Medicine published from 1927 through 2020. No specific interventions existed from 1927 through 1942. The pharmacological management of IBD has had 3 slightly overlapping eras starting in 1943. During the first period (1943-1951), the medical management relied on antibiotics, primarily sulfonamides and chloramphenicol. In the second (1955-75), experts recommended the use of adrenocorticotropic hormone or corticosteroids and 5-aminosalicylate. In the third era, which commenced in 1979 and is continuing to date, the pharmacological interventions have been expanded and refined to include 5 main drug classes, 5-aminosalicylates (sulfasalazine, mesalamine, and olsalazine), corticosteroids (prednisone and budesonide), immunomodulators (azathioprine, 6-mercaptopurine, cyclosporine, and tofacitinib), biologics (infliximab adalimumab certolizumab pegol, and natalizumab), and antibiotics (metronidazole and ciprofloxacin). A consensus exists that the monoclonal antibodies again tumor necrosis factor alpha are cost-effective for induction and maintenance of clinical remission in both UC (golimumab) and Crohn disease (certolizumab pegol). The newer agents ustekinumab (a monoclonal antibody to the interleukin p40 subunit) and vedolizumab (a monoclonal antibody to the homing receptor integrin complex) have also performed well. The pharmacological management of IBD has been the focus of intense research and development in the past 60 years. The pillars of drug treatment have been 5-aminosalicylates and corticosteroids. Recent pharmacological innovations (immunomodulators and biologicals) constitute an encouraging paradigm shift in the treatment of UC and Crohn disease.

Efficacy of biological therapies and small molecules in induction and maintenance of remission in luminal Crohn’s disease: systematic review and network meta-analysis

ObjectiveThere are numerous biological therapies and small molecules licensed for luminal Crohn’s disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this...

A145 EFFICACY AND SAFETY OF UPADACITINIB MAINTENANCE THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM A RANDOMIZED PHASE 3 STUDY

BackgroundUpadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials.AimsEvaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials.MethodsThe primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI).ResultsBaseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%).ConclusionsIn patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed.Funding AgenciesAbbVie