Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: A multicenter international study.

BACKGROUND: Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. METHODS: This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. RESULTS: One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6 months (q1 -q3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p = 0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p < 0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p = 0.11). CONCLUSIONS: Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.

Patients With Inflammatory Bowel Diseases Have Impaired Antibody Production After Anti-SARS-CoV-2 Vaccination: Results From a Panhellenic Registry.

BACKGROUND: Four EMA-approved vaccines against SARS-CoV-2 are currently available. Data regarding antibody responses to initial vaccination regimens in patients with inflammatory bowel diseases (IBD) are limited. METHODS: We conducted a prospective, controlled, multicenter study in tertiary Greek IBD centers. Participating patients had completed the initial vaccination regimens (1 or 2 doses, depending on the type of COVID-19 vaccine) at least 2 weeks before study enrolment. Anti-S1 IgG antibody levels were measured. Demographic and adverse events data were collected. RESULTS: We tested 403 patients (Crohn's disease, 58.9%; male, 53.4%; median age, 45 years) and 124 healthy controls (HCs). Following full vaccination, 98% of patients seroconverted, with mRNA vaccines inducing higher seroconversion rates than viral vector vaccines (P = .021). In total, IBD patients had lower anti-S1 levels than HCs (P < .001). In the multivariate analysis, viral vector vaccines (P < .001), longer time to antibody testing (P < .001), anti-TNFα treatment (P = .013), and age (P = .016) were independently associated with lower anti-S1 titers. Vedolizumab monotherapy was associated with higher antibody levels than anti-TNFα or anti-interleukin-12/IL-23 monotherapy (P = .023 and P = .032). All anti- SARS-CoV-2 vaccines were safe. CONCLUSIONS: Patients with IBD have impaired antibody responses to anti-SARS-CoV-2 vaccination, particularly those receiving viral vector vaccines and those on anti-TNFα treatment. Older age also hampers antibody production after vaccination. For those low-response groups, administration of accelerated or prioritized booster vaccination may be considered.

Thisis a multicenter study on IBD patients after COVID-19 vaccination and anti-S1 IgG antibody levels measurement. Patients with IBD have lower antibody responses than healthy controls, particularly those receiving viral vector vaccines and those on anti-TNFα or combination treatment.

Poor performance of predictive equations to estimate resting energy expenditure in patients with Crohn's disease.

Studies exploring the accuracy of equations calculating Resting Energy Expenditure (REE) in patients with Crohn's disease are lacking. The aim of this study was to investigate the accuracy of REE predictive equations against indirect calorimetry in Crohn's disease patients. REE was measured using indirect calorimetry (mREE) after an overnight fasting. Fourteen predictive equations, with and without body composition analysis parameters, were compared with mREE using different body weight approaches. Body composition analysis was performed using dual X-ray absorptiometry. 186 Crohn's disease outpatients (102 males) with mean age 41.3±14.1 years and 37.6% with active disease were evaluated. Mean mREE in the total sample was 1734±443 kcal/day. All equations under-predicted REE and showed moderate correlations with mREE (Pearson's r or Spearman's rho 0.600-0.680 for current weight, all p-values<0.001). Accuracy was low for all equations at the individual level (28-42% and 25-40% for current and adjusted body weight, respectively, 19-33% for equations including body composition parameters). At the group level, accuracy showed wide limits of agreement and proportional biases. Accuracy remained low when sample was studied according to disease activity, sex, body mass index and medication use. All predictive equations underestimated REE and showed low accuracy. Indirect calorimetry remains the best method for estimating REE of patients with Crohn's disease.

Real-World Use and Adverse Events of SARS-CoV-2 Vaccination in Greek Patients with Inflammatory Bowel Disease.

Since inflammatory bowel disease (IBD) patients were excluded from vaccine authorization studies, limited knowledge exists regarding perceptions and unfavorable effects of COVID-19 vaccination in this group. We aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines in Greek IBD patients. Fully vaccinated IBD patients followed in Greek centers were invited to participate. All patients filled out an anonymous online survey concerning the vaccination program, which included information regarding demographics, clinical characteristics, treatment, vaccination perceptions and potential AEs. Overall, 1007 IBD patients were included. Vaccine hesitancy was reported by 49%. Total AEs to vaccination were reported by 81% after dose 1 (D1) and 76% after dose 2 (D2), including isolated injection site reactions (36% and 24% respectively). Systemic AEs were more common after D2 (51%, D2 vs. 44%, D1, p < 0.0001). Very few patients reported new onset abdominal symptoms (abdominal pain 4% (D1), 6% (D2) and diarrhea 5% (D1), 7% (D2)). There were no serious AEs leading to emergency room visit or hospitalization. In multivariate analysis, AEs occurrence was positively associated with young age and female gender (p < 0.0005 for both doses), whereas inactive disease was negatively associated with AE in D1 (p = 0.044). SARS-CoV-2 vaccination in Greek IBD patients demonstrated a favorable and reassuring safety profile.

Response to Anti-α4ß7 Blockade in Patients With Ulcerative Colitis Is Associated With Distinct Mucosal Gene Expression Profiles at Baseline.

BACKGROUND: Improving treatment outcomes with biological therapy is a demanding current need for patients with inflammatory bowel disease. Discovery of pretreatment prognostic indicators of response may facilitate patient selection and increase long-term remission rates. We aimed to identify baseline mucosal gene expression profiles with predictive value for subsequent response to or failure of treatment with the monoclonal antibody against integrin α4ß7, vedolizumab, in patients with active ulcerative colitis (UC). METHODS: Mucosal expression of 84 immunological and inflammatory genes was quantified in RNA extracted from colonic biopsies before vedolizumab commencement and compared between patients with or without response to treatment. Significantly differentiated genes were further validated in a larger patient cohort and within available public data sets, and their functional profiles were studied accordingly. RESULTS: In the discovery cohort, we identified 21 genes with a statistically significant differential expression between 54-week responders and nonresponders to vedolizumab. Our validation study allowed us to recognize a "core" mucosal profile that was preserved in both discovery and validation cohorts and in the public database. The applied functional annotation and analysis revealed candidate dysregulated pathways in nonresponders to vedolizumab, including immune cell trafficking, TNF receptor superfamily members mediating noncanonical NF-kB pathway, in addition to interleukin signaling, MyD88 signaling, and toll-like receptors (TLRs) cascade. CONCLUSIONS: Nonresponse to vedolizumab in UC is associated with specific pretreatment gene-expression mucosal signatures and dysregulation of particular immunological and inflammatory pathways. Baseline mucosal and/or systemic molecular profiling may help in the optimal stratification of patients to receive vedolizumab for active UC.

Predictors of Response to Vedolizumab in Patients with Ulcerative Colitis: Results from the Greek VEDO-IBD Cohort.

BACKGROUND: Optimization of treatment with biologics is currently an unmet need for patients with ulcerative colitis (UC). Real-world studies provide neutral estimates of drug efficacy and safety within unselected patient populations and allow for the recognition of specific characteristics that affect response to therapy. AIMS: We aimed to depict the efficacy of vedolizumab in patients with UC in a real-world setting and identify prognosticators of improved outcomes. METHODS: Patients with active UC who commenced treatment with vedolizumab were prospectively followed up. Patient-reported outcomes (PROs) and clinical/endoscopic-reported outcomes were recorded at baseline and at weeks 14 and 54. Predefined endpoints of early and persistent efficacy were analyzed against clinical characteristics to identify prognostic factors for response. RESULTS: We included 96 patients (anti-TNF-exposed = 38.5%). At week 14, 73 patients (76%) had clinical response and 54 (56.3%) clinical remission. At week 54, the primary endpoint of vedolizumab persistence was met by 72 patients (75%), whereas steroid-free clinical remission by 59.4%. Among patients who had endoscopy, rates for mucosal healing (Mayo endoscopic score of 0) were 29.8% at week 14 and 44.6% at week 54, respectively. Vedolizumab treatment led to significant improvements in quality of life. Corticosteroid-refractory or anti-TNF-refractory disease, articular manifestations, and high baseline UC-PRO2 were associated with decreased efficacy of vedolizumab in the primary and secondary outcomes. CONCLUSIONS: Vedolizumab is characterized by high efficacy and long-term treatment persistence in UC. More aggressive disease, as indicated by refractoriness to steroids or anti-TNFs and elevated baseline PROs, may predict suboptimal response and help pre-treatment prognostic stratification of patients.

A rare case of duodenal-type follicular lymphoma in rectum appearing as hyperplastic polyp with metachronous appearance in duodenum and stomach.

Hyperplastic polyps consist a very frequent finding in colonoscopy having a very low potential to malignancy. According to the international guidelines, it is recommended that all polyps should be resected except for diminutive (≤ 5 mm) rectal and rectosigmoid polyps which are predicted with confidence to be hyperplastic. Therefore, in departments where optical diagnosis can be ensured, a "resect and discard" strategy may be implemented for diminutive polyps. In our case, a duodenal-type follicular lymphoma was detected in a 5 mm rectum polyp with hyperplastic appearance. After 4 months, the lymphoma was detected also in stomach and duodenum. Under therapy with Rituximab, she is in remission. To our knowledge, there has never been reported such a case in the literature. Furthermore, it alerts us that we should be very cautious with the optical diagnosis and the "resect and discard strategy".

The natural history of COVID-19 in patients with inflammatory bowel disease: a nationwide study by the Hellenic Society for the study of IBD.

OBJECTIVES: COVID-19 has evolved into a global health crisis, variably affecting the management of patients with chronic illnesses. Patients with inflammatory bowel disease (IBD) may represent a vulnerable population due to frequent administration of immune-modifying treatments. We aimed to depict the natural history of COVID-19 infection in Greek patients with IBD at a nationwide level via unbiased reporting of all cases that were registered during the sequential waves of the pandemic. METHODS: Following a national call from the Hellenic Society for the study of IBD, we enrolled all IBD patients with established diagnoses of COVID-19. Clinical and epidemiological data, including COVID-19 modifying factors and IBD-associated therapies, were analyzed against adverse outcomes (hospitalization, ICU admission and death). RESULTS: We identified 154 IBD patients who were diagnosed with COVID-19 (men: 58.4%; mean age=41.7 years [SD = 14.9]; CD: 64.3%). Adverse outcomes were reported in 34 patients (22.1%), including 3 ICU admissions (1.9%) and two deaths (1.3%). Multivariate logistic regression analysis showed that age (OR = 1.04, 95% CI, 1-1.08) and dyspnea at presentation (OR = 7.36, 95% CI, 1.84-29.46) were associated with worse outcomes of COVID-19 infection. In contrast, treatment with biologics, in particular anti-TNF agents, exerted a protective effect against an unfavorable COVID-19 disease course (OR = 0.4, 95% CI, 0.16-0.99). Patients on subcutaneous biologics were more likely to halt treatment due to the infection as compared to those on intravenous biologics. CONCLUSIONS: IBD patients who developed COVID-19 had a benign course with adverse outcomes being infrequent. Treatment with anti-TNF biologics had a protective effect, thus, supporting continuation of therapy during the pandemic.

TL1A: A New Potential Target in the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. In the last few years, the development of biological agents targeting cytokines and receptors involved in IBD pathogenesis has led to better outcomes and has improved the course of the disease. Despite their effectiveness, drugs such as tumor necrosis factor (TNF) inhibitors, anti-Interleukin-12/23 and anti-integrins, do not induce a response in about one-third of patients, and 40% of patients lose response over time. Therefore, more efficient therapies are required. Recent studies showed that TL1A (Tumor necrosis factor-like cytokine 1A) acts as a regulator of mucosal immunity and participates in immunological pathways involved in the IBD pathogenesis. In this review article, we analyze the role of TL1A as a new potential target therapy in IBD patients.

Application of Ultrasound Elastography for Assessing Intestinal Fibrosis in Inflammatory Bowel Disease: Fiction or Reality?

BACKGROUND: Intestinal fibrosis and subsequent strictures represent an important burden in inflammatory bowel disease (IBD). Both the detection and evaluation of the degree of fibrosis in stricturing Crohn's disease (CD) are important when deciding the best therapeutic strategy (medical anti-inflammatory therapy, endoscopic dilation, surgery). Ultrasound elastography (USE) is a non-invasive technique that has been proposed in the field of IBD for evaluating intestinal stiffness as a biomarker of intestinal fibrosis. OBJECTIVE: The aim of this review is to discuss the ability and current role of ultrasound elastography in the assessment of intestinal fibrosis. RESULTS AND CONCLUSION: Data on USE in IBD are provided by pilot and proof-of-concept studies with small sample size. The first type of USE investigated was strain elastography, while shear wave elastography has been introduced recently. Despite the heterogeneity of the methods of the studies, USE has been proven to be able to assess intestinal fibrosis in patients with stricturing CD. However, before introducing this technique in current practice, further studies with larger sample sizes are needed. In addition, the use of homogeneous parameters, the assessment of reproducibility, and the identification of validated cut-off values are essential.

Patients with Inflammatory Bowel Disease Are Not at Increased Risk of COVID-19: A Large Multinational Cohort Study.

The impact of COVID-19 on inflammatory bowel disease (IBD) patients under pharmacological immunosuppression is still not clearly understood. We investigated the incidence of COVID-19 and the impact of immunosuppression and containment measures on the risk of SARS-CoV-2 infection in a large IBD cohort, from a multicenter cohort from 21st of February to 30th of June, 2020. Ninety-seven patients with IBD (43 UC, 53 CD, one unclassified IBD) and concomitant COVID-19 over a total of 23,879 patients with IBD were enrolled in the study. The cumulative incidence of SARS-CoV-2 infection in patients with IBD vs. the general population was 0.406% and 0.402% cases, respectively. Twenty-three patients (24%) were hospitalized, 21 (22%) had pneumonia, four (4%) were admitted to the Intensive Care Unit, and one patient died. Lethality in our cohort was 1% compared to 9% in the general population. At multivariable analysis, age > 65 years was associated with increased risk of pneumonia and hospitalization (OR 11.6, 95% CI 2.18-62.60; OR 5.1, 95% CI 1.10-23.86, respectively), treatment with corticosteroids increased the risk of hospitalization (OR 7.6, 95% CI 1.48-40.05), whereas monoclonal antibodies were associated with reduced risk of pneumonia and hospitalization (OR 0.1, 95% CI 0.04-0.52; OR 0.3, 95% CI 0.10-0.90, respectively). The risk of COVID-19 in patients with IBD is similar to the general population. National lockdown was effective in preventing infection in our cohort. Advanced age and treatment with corticosteroids impacted negatively on the outcome of COVID-19, whereas monoclonal antibodies did not seem to have a detrimental effect.

Endoscopy after surgery in inflammatory bowel disease: Crohn's disease recurrence and pouch surveillance.

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are immune-mediated disorders characterized by a chronic inflammation, with intermittent exacerbations of symptoms and inflammation. In both diseases, medical treatment has made revolutionary steps forward. Nevertheless, surgery is still required in many cases due to inefficacy of multiple medical therapies. It is not clear whether surgery rates in inflammatory bowel diseases (IBD) are currently decreasing despite all improvements. AREAS COVERED: Multidisciplinary management is critical in surgical patients to improve long-term outcomes. Endoscopy plays a crucial role, both before and after surgery, in planning therapeutic strategies and stratifying risk of recurrence. Aim of this review is to provide a deeper insight into the central role of endoscopy in the postoperative management of IBD patients, focusing on recent research advances, future challenges and unresolved questions. EXPERT OPINION: Both UC and CD surgical patients need endoscopy to define the correct therapeutic choice, predict subsequent disease course and adopt the correct surveillance strategy. In the next future, newer endoscopic techniques could be systematically applied in IBD patients after surgery, to assess early postoperative inflammation, response to treatment, or, regarding UC, to provide enhanced pouch surveillance, allowing for early detection of inflammation and dysplasia.

Treat to target or 'treat to clear' in inflammatory bowel diseases: one step further?

INTRODUCTION: Inflammatory bowel diseases (IBD) are chronic and progressive diseases. Long-term complications are demolitive surgery and colon-rectal cancer. A 'treat to target' strategy, in which the treatment aims to achieve objective outcomes, has already been introduced in the management of chronic conditions as rheumatic diseases. This approach is emerging as suitable for ulcerative colitis and Crohn's disease. Targets are predefined therapeutic goals demonstrated to prevent end-organ dysfunction. An optimization or switch of therapy is considered depending on the target's achievement, with regular monitoring. AREAS COVERED: According to the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) indications, mucosal healing and clinical remission are the main targets in IBDs. Histological remission is increasingly being considered as a novel target and has given rise to the new concept of 'disease clearance' which includes clinical, endoscopic and microscopic remission. We aim to review current evidence on the treat-to-target strategy in comparison to a stricter treat-to-clear in the IBD field. EXPERT OPINION: Prospective studies on treat-to-target algorithm are sparse; a treat-to-clear approach is desirable but far from adoption in the daily practice and clinical trials. The ultimate goals of a treat-to-clear strategy differ in UC and in CD, including histological healing and transmural healing, respectively.

Early Intervention in Ulcerative Colitis: Ready for Prime Time?

Growing evidence shows that ulcerative colitis (UC) is a progressive disease similar to Crohn's disease (CD). The UC-related burden is often underestimated by physicians and a standard step-up therapeutic approach is preferred. However, in many patients with UC the disease activity is not adequately controlled by current management, leading to poor long-term prognosis. Data from both randomized controlled trials and real-world studies support early intervention in CD in order to prevent disease progression and irreversible bowel damage. Similarly, an early disease intervention during the so-called "window of opportunity" could lead to better outcomes in UC. Here, we summarize the literature evidence on early intervention in patients with UC, highlighting strengths and limitations of this approach.

Targeting the gut layers in Crohn's disease: mucosal or transmural healing?

INTRODUCTION: Although the landmark of Crohn's Disease (CD) is the transmural inflammation, mucosal healing (MH), which is assessed by colonoscopy, is currently the gold standard of CD management. Transmural healing (TH) is a new concept evaluated by cross-sectional imaging (CSI) techniques, such as bowel ultrasound (US), computed tomography enterography (CTE), and magnetic resonance enterography (MRE). Little is known about the clinical significance of persisting mural disease and the predictive value of complete TH. AREAS COVERED: The authors reviewed the available literature on TH and its meaning as predictor of long-term outcomes in CD, to explore if TH may be a better target compared to MH in CD patients, in terms of disease outcome, such as medication changes, hospitalization, or surgery. EXPERT OPINION: Some evidence suggests that achieving TH has a predictive value in CD management and correlates with better disease outcome than MH, although existing studies are few and with limitations. A definitive definition of TH is not yet established and the frequency or the preferred modality of TH evaluation remains unclear. Implementing TH in treat-to-target approach may enable stricter disease monitoring with noninvasive methods and finally change the disease course, preventing irreversible bowel damage.

Genetic analysis and clinical description of Greek patients with Peutz-Jeghers syndrome: Creation of a National Registry.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder caused by germline mutations in the STK11 tumor suppressor gene. PJS patients face a cumulative cancer risk as high as 93% for all sites combined. The present study reports the spectrum of STK11 mutations in eight families with clinical diagnosis of PJS, summarizes the clinical characteristics of sixteen mutation carriers and launches a National Registry for PJS in Greece. STK11 loss-of-function (LoF) mutations were detected in 87.5% of index patients. Carriers presented with their first manifestation at a median age of 24.9 years, while early-onset breast cancer was the most frequent malignancy observed, highlighting the need for breast surveillance. Out of the deleterious STK11 mutations identified, two were novel: c.375_376delGT and c.676_679dupAACG, with 57.2% of these potentially occurring de novo. Using all available clinical and genetic data, the National Registry for Greek PJS was established in an attempt to better characterize the syndrome and raise awareness among patients and clinicians (available at https://www.peutzjeghersgreece.org). This is the first comprehensive genetic analysis and clinical characterization of Greek PJS patients, where a high incidence of breast cancer was observed and the first attempt to centralize all data in a National Registry.

The contribution of long non-coding RNAs in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) are multifactorial autoimmune diseases with growing prevalence but the interaction between genetic, environmental and immunologic factors in their development is complex and remains obscure. There is great need to understand their pathogenetic mechanisms and evolve diagnostic and therapeutic tools. Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that are known to interfere in gene regulation but their roles and functions have not yet been fully understood. While they are widely investigated in cancers, little is known about their contribution in other diseases. There is growing evidence that lncRNAs play critical role in regulation of immune system and that they interfere in the pathogenetic mechanisms of autoimmune diseases, like IBDs. Recent studies have identified lncRNAs in the proximity of IBD-associated genes and single nucleotide polymorphisms within IBD-associated lncRNAs as well. Furthermore, blood samples and pinch biopsies were also analyzed and a plethora of lncRNAs are found to be deregulated in Crohn's disease (CD), Ulcerative colitis (UC) or both. (Especially in UC samples the lncRNAs INFG-AS1 and BC012900 were found to be significantly up-regulated. Similarly, ANRIL, a lncRNA that nest different disease associated SNPs, is significantly down-regulated in inflamed IBD tissue.) This review aims at recording for the first time recent data about lncRNAs found to be deregulated in IBDs and discussing suggestive pathogenetic mechanisms and future use of lncRNAs as biomarkers.