BACKGROUND: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC). AIM: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes. METHODS: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation. RESULTS: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals. CONCLUSION: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation.

• MeSH
• biologické markery analýza   MeSH
• Crohnova nemoc * farmakoterapie   MeSH
• dospělí MeSH
• gastrointestinální endoskopie MeSH
• indukce remise MeSH
• lidé MeSH
• ustekinumab * terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.

• MeSH
• Crohnova nemoc * metabolismus   patologie   imunologie   MeSH
• dospělí MeSH
• endopeptidasy metabolismus   genetika   MeSH
• extracelulární matrix metabolismus   patologie   MeSH
• fibroblasty * metabolismus   patologie   MeSH
• fibróza * MeSH
• ileum patologie   metabolismus   imunologie   MeSH
• jaderné proteiny metabolismus   genetika   MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• monocyty * metabolismus   patologie   imunologie   MeSH
• myši MeSH
• receptory buněčného povrchu metabolismus   genetika   MeSH
• transkripční faktor Twist * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The cost of caring for patients with inflammatory bowel disease (IBD) continues to increase worldwide. The cause is not only a steady increase in the prevalence of Crohn's disease and ulcerative colitis in both developed and newly industrialised countries, but also the chronic nature of the diseases, the need for long-term, often expensive treatments, the use of more intensive disease monitoring strategies, and the effect of the diseases on economic productivity. This Commission draws together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, and how to deliver affordable care for IBD in the future. The key conclusions are that (1) increases in health-care costs must be evaluated against improved disease management and reductions in indirect costs, and (2) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and the cost-effectiveness of care. International collaborations should be sought out to evaluate novel models of care (eg, value-based health care, including integrated health care, and participatory health-care models), as well as to improve the education and training of clinicians, patients, and policy makers.

• MeSH
• Crohnova nemoc * epidemiologie   MeSH
• gastroenterologie * MeSH
• idiopatické střevní záněty * epidemiologie   terapie   MeSH
• lidé MeSH
• náklady na zdravotní péči MeSH
• ulcerózní kolitida * epidemiologie   terapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

BACKGROUND: A treat-to-target strategy, in which strictly defined treatment targets facilitate decision making in clinical practice, is advocated as an optimised management approach for some chronic disorders. The aim of the STARDUST trial was to assess whether a treat-to-target strategy with early endoscopy, regular biomarker and clinical symptom monitoring, and dose intensification for persistent inflammatory activity, was more successful in achieving endoscopic improvement at week 48 than a clinically driven maintenance strategy in patients with moderate-to-severe active Crohn's disease receiving ustekinumab. METHODS: This open-label, multicentre, randomised phase 3b trial included adults with active, moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450 and Simple Endoscopic Score in Crohn's Disease [SES-CD] ≥3) for whom conventional therapy or one biologic therapy, or both, had failed. Patients received intravenous ustekinumab approximating 6 mg/kg at baseline and subcutaneous ustekinumab 90 mg at week 8. At week 16, patients with a CDAI improvement of 70 or more points from baseline were randomly assigned (1:1) to receive standard-of-care or treat-to-target maintenance treatment through week 48. Randomisation was balanced by using randomly permuted blocks and was stratified by biologic history status and baseline SES-CD score. All patients who signed informed consent, who were not screening failures, and who received at least one dose of study treatment were included in week 16 analyses. All patients included in week 16 analyses and randomly assigned to one of the maintenance treatment regimens were included in the week 48 efficacy and safety analyses (ie, on an intention-to-treat basis). Patients assigned to the treat-to-target arm received ustekinumab every 12 weeks or every 8 weeks based on SES-CD improvement from baseline and could escalate to every 4 weeks through week 48 if prespecified targets were missed. Patients assigned to the standard-of-care arm received ustekinumab every 12 weeks or every 8 weeks; those receiving treatment every 12 weeks could escalate per European labelling. The primary efficacy endpoint was endoscopic response at week 48 (SES-CD score ≥50% decrease from baseline), analysed by non-responder imputation. This trial is registered at ClinicalTrials.gov, NCT03107793, and is active but not recruiting. FINDINGS: 498 patients received standard induction treatment, of whom 440 were randomly assigned to the treat-to-target group (n=219) or the standard-of-care group (n=221). At week 48, there was no significant difference in endoscopic response (83 [38%] of 219 patients vs 66 [30%] of 221 patients; p=0·087), endoscopic remission (25 [11%] vs 32 [15%]; p=0·334), mucosal healing (31 [14%] vs 37 [17%]; p=0·449), and clinical remission (135 [62%] vs 154 [70%]; p=0·072) between the two groups; clinical response was significantly lower in the treat-to-target group than in the standard-of-care group (149 [68%] vs 172 [78%]; p=0·020). Other endoscopic, clinical, and biomarker outcomes were generally not significantly different between groups. The most commonly reported treatment-emergent adverse events were nasopharyngitis (29 [13%] of 219 patients in the treat-to-target group vs 29 [13%] of 221 patients in the standard-of-care group), abdominal pain (23 [11%] vs 19 [9%]), arthralgia (24 [11%] vs 19 [9%]), and headache (24 [11%] vs 21 [10%]). INTERPRETATION: Timely escalation of ustekinumab therapy for patients with Crohn's disease, based on early endoscopic response, clinical symptoms, and biomarkers, did not result in significantly better endoscopic outcomes at week 48 than symptom-driven decisions alone. Future studies need to confirm if some subgroups of patient might benefit from a treat-to-target strategy with ustekinumab. FUNDING: Janssen-Cilag.

• MeSH
• Crohnova nemoc * terapie   MeSH
• dospělí MeSH
• indukce remise MeSH
• intravenózní podání MeSH
• lidé MeSH
• standardní péče MeSH
• ustekinumab * škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

Background: Faecal microbiota transplantation (FMT) is an emerging treatment modality, but its current clinical use and organisation are unknown. We aimed to describe the clinical use, conduct, and potential for FMT in Europe. Methods: We invited all hospital-based FMT centres within the European Council member states to answer a web-based questionnaire covering their clinical activities, organisation, and regulation of FMT in 2019. Responders were identified from trials registered at clinicaltrials.gov and from the United European Gastroenterology (UEG) working group for stool banking and FMT. Findings: In 2019, 31 FMT centres from 17 countries reported a total of 1,874 (median 25, quartile 10-64) FMT procedures; 1,077 (57%) with Clostridioides difficile infection (CDI) as indication, 791 (42%) with experimental indications, and 6 (0•3%) unaccounted for. Adjusted to population size, 0•257 per 100,000 population received FMT for CDI and 0•189 per 100,000 population for experimental indications. With estimated 12,400 (6,100-28,500) annual cases of multiple, recurrent CDI and indication for FMT in Europe, the current European FMT activity covers approximately 10% of the patients with indication. The participating centres demonstrated high safety standards and adherence to international consensus guidelines. Formal or informal regulation from health authorities was present at 21 (68%) centres. Interpretation: FMT is a widespread routine treatment for multiple, recurrent CDI and an experimental treatment. Embedded within hospital settings, FMT centres operate with high standards across Europe to provide safe FMT. A significant gap in FMT coverage suggests the need to raise clinical awareness and increase the FMT activity in Europe by at least 10-fold to meet the true, indicated need. Funding: NordForsk under the Nordic Council and Innovation Fund Denmark (j.no. 8056-00006B).

• Publikační typ
• časopisecké články MeSH

BACKGROUND AND AIMS: Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM-1, induced remission in patients with moderate-to-severe ulcerative colitis [UC] in the TURANDOT study. We aimed to assess long-term safety, tolerability, and efficacy of ontamalimab in TURANDOT II. METHODS: TURANDOT II was a phase 2, multicentre, open-label [OL] study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab (NCT01771809). Patients were randomised to 75 mg or 225 mg ontamalimab every 4 weeks for 72 weeks [OL1]. The dosage could be increased to 225 mg from Week 8 at the investigator's discretion. All patients then received 75 mg every 4 weeks for 72 weeks [OL2], followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events [AEs], serious AEs [SAEs], and AEs leading to withdrawal. Mucosal healing [MH; centrally read endoscopy] was assessed. RESULTS: Of 330 patients, 180 completed OL1; 94 escalated to 225 mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE [10.0%] was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis [0.9%]. One death and four cancers [all unrelated to ontamalimab] occurred. No PML [progressive multifocal leukoencephalopathy]/lymphoproliferative disorders occurred. Geometric mean high-sensitivity C-reactive protein [hsCRP] and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned to placebo in TURANDOT achieving MH increased from 8.8% [6/68] at baseline to 35.3% at Week 16 [24/68; non-responder imputation]. The corresponding increase in the ontamalimab group was from 23.3% [61/262] to 26.7% [70/262]. CONCLUSIONS: Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

• MeSH
• C-reaktivní protein analýza   MeSH
• dospělí MeSH
• gastrointestinální endoskopie metody   statistika a číselné údaje   MeSH
• gastrointestinální látky aplikace a dávkování   škodlivé účinky   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   MeSH
• imunologická odpověď na dávku MeSH
• leukocytární L1-antigenní komplex analýza   MeSH
• lidé MeSH
• molekuly buněčné adheze antagonisté a inhibitory   MeSH
• monitorování léčiv * metody   statistika a číselné údaje   MeSH
• mukoproteiny antagonisté a inhibitory   MeSH
• ulcerózní kolitida * diagnóza   farmakoterapie   imunologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND AND AIMS: Vedolizumab was shown to be safe and effective for the treatment of Crohn's disease [CD] and ulcerative colitis [UC] in the GEMINI Long-Term Safety [LTS] study. The vedolizumab Extended Access Program [XAP] provides patients with continued treatment. This XAP pharmacokinetics [PK] sub-study investigated vedolizumab efficacy, safety, and PK. METHODS: Vedolizumab dosing frequency was reduced from every 4 weeks [Q4W] to every 8 weeks [Q8W] at XAP enrolment, and patients were followed for 56 weeks. Outcomes included: efficacy, loss of clinical benefit, and re-escalation to Q4W dosing; and vedolizumab PK, immunogenicity, and adverse events. RESULTS: Among 167 enrolled patients [CD = 88, UC = 79], 80 [91%] with CD and 73 [92%] with UC completed 56 weeks; 76 [86%] and 71 [90%] with CD and UC, respectively, remained on Q8W dosing for 56 weeks. Clinical remission, corticosteroid-free clinical remission, and C-reactive protein levels were stable among patients remaining on Q8W through Week 56. Four patients with CD and two with UC resumed Q4W dosing [three with CD regained clinical response]. Patients with CD who completed Week 56 on Q8W dosing had median trough vedolizumab concentrations of 43.6 µg/mL at enrolment and 10.4 µg/mL at Week 56; concentrations were 42.4 µg/mL and 13.3 µg/mL, respectively, in patients with UC. Treatment-related adverse events were infrequent; no new or serious adverse events related to vedolizumab were reported. CONCLUSIONS: In the XAP-PK sub-study, adherence to Q8W dosing was high, with no loss of efficacy; very few patients required re-escalation to Q4W. There were no new safety signals.

• MeSH
• Crohnova nemoc * diagnóza   farmakoterapie   imunologie   MeSH
• dospělí MeSH
• gastrointestinální látky aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• imunologická odpověď na dávku MeSH
• integriny antagonisté a inhibitory   MeSH
• intravenózní infuze MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• ulcerózní kolitida * diagnóza   farmakoterapie   imunologie   MeSH
• vysazování léků metody   MeSH
• výsledky a postupy - zhodnocení (zdravotní péče) MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• klinické zkoušky MeSH
• multicentrická studie MeSH

BACKGROUND: PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. METHODS: This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. FINDINGS: Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (-1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. INTERPRETATION: PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. FUNDING: Pfizer.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• gastrointestinální látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• indukce remise MeSH
• injekce subkutánní MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• ulcerózní kolitida farmakoterapie   patologie   MeSH
• výsledek terapie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

• MeSH
• celogenomová asociační studie MeSH
• epigenomika metody   trendy   MeSH
• genetická predispozice k nemoci MeSH
• idiopatické střevní záněty diagnóza   genetika   MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND AND AIMS: Prophylactic azathioprine (AZA) is efficacious in preventing postoperative Crohn's disease (CD) recurrence. However, it is unknown whether AZA should be started immediately after surgery. We compared the efficacy of systematic vs endoscopy-driven AZA in preventing CD recurrence at week 102. METHODS: This prospective, multicentre trial included CD patients undergoing curative resection with ileocolonic anastomosis and at higher risk of recurrence. Patients were randomized to systematic AZA initiated ≤2 weeks from surgery, or endoscopy-driven AZA in which therapy was only initiated in case of endoscopic recurrence (Rutgeerts' score ≥i2) at weeks 26 or 52 following surgery. The primary endpoint was endoscopic remission (i0-i1) at week 102. Secondary endpoints included complete endoscopic remission (i0) and clinical remission. RESULTS: The study was prematurely stopped due to slow recruitment. Between 2005 and 2011, 63 patients (28 male, median age 36 years) were randomized to systematic (n = 32) or endoscopy-driven AZA (n = 31). Twenty-one patients withdrew prematurely (8 clinical recurrence, 6 adverse reactions to AZA, 7 patient's preference). In the endoscopy-driven AZA group, 14 patients had to initiate AZA (11 at week 26, 3 at week 52). Endoscopic remission was achieved by 50% in the systematic and 42% in the endoscopy-driven AZA group (p = 0.521). No difference in secondary endpoints was found. CONCLUSIONS: Systematic AZA therapy in patients at higher risk of postoperative CD recurrence is not superior to endoscopy-driven treatment. Early postoperative endoscopic evaluation between weeks 26 and 52 seems most appropriate to guide further therapy, but larger studies are warranted. (ClinicalTrials.gov NCT02247258.).

• MeSH
• analýza podle původního léčebného záměru MeSH
• anastomóza chirurgická MeSH
• azathioprin terapeutické užití   MeSH
• Crohnova nemoc diagnóza   prevence a kontrola   chirurgie   MeSH
• dospělí MeSH
• ileum chirurgie   MeSH
• imunosupresiva terapeutické užití   MeSH
• indukční chemoterapie MeSH
• klinické rozhodování MeSH
• kolon chirurgie   MeSH
• kolonoskopie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• předčasné ukončení klinických zkoušek MeSH
• prospektivní studie MeSH
• recidiva MeSH
• rozvrh dávkování léků MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH