Symptom burden, management and treatment goals of people with MS spasticity: Results from SEEN-MSS, a large-scale, self-reported survey.

BACKGROUND: Spasticity occurs frequently in people with multiple sclerosis (PwMS) and may affect non-physical aspects of life. However, there is a paucity of data assessing the full impact of spasticity in PwMS. OBJECTIVE: This survey of PwMS and spasticity (PwMSS) was undertaken to understand the impact of spasticity in physical, functional, emotional, and social domains. METHODS: SEEN-MSS (Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity), an online survey, was developed in collaboration with three US-based MS organizations (conducted February-April 2021). RESULTS: Survey was completed by 1,177 PwMSS, 78% female, mean age 56.8yrs, 16.8yrs from MS diagnosis, 11.5yrs with spasticity. Considering day-to-day goals of treatment, respondents reported that managing symptoms(46%) was nearly as important as slowing disease progression(54%). Most reported spasticity was a constant reminder of their MS. Participants reported that spasticity limited daily activities (92%), caused pain (92%), impaired sleep (89%) and negatively impacted emotional well-being (87%). Spasticity fostered a sense of dependence (61%), isolation (40%), decline in self-confidence (75%), self-image (70%), and social connection (62%). CONCLUSIONS: Spasticity has wide-reaching negative impacts on multiple aspects of life, causing substantial burden for PwMSS. Results emphasize the need to fully understand the burden of spasticity and addressing individual needs of PwMSS.

ECCO Position on Harmonisation of Crohn's Disease Mucosal Histopathology.

In inflammatory bowel disease [IBD], mucosal healing is a major therapeutic target and a reliable predictor of clinical course. However, endoscopic mucosal healing is not synonymous with histological healing, and the additional benefits of including histological remission as a target are unclear. In Crohn´s disease [CD], there are few studies highlighting the value of histological remission as a therapeutic target. Histological activity can persist in CD patients who are in endoscopic remission, and the absence of histological activity may be associated with lower relapse rates. Therefore, standardisation of procedures to evaluate CD histological activity is desirable. Topics that would benefit from standardisation and harmonisation include biopsy procedures, biopsy processing techniques, the content of histological scores, and the definitions of histological remission, histological response, and histological activity. In line with these needs, the European Crohn's and Colitis Organisation [ECCO] assembled a consensus group with the objective of developing position statements on CD histology based on published evidence and expert consensus. There was agreement that definitions of histological remission should include absence of erosion, ulceration, and mucosal neutrophils; that the absence of neutrophilic inflammation is an appropriate histological target in CD; that CD histological scores, such as the Global Histological Disease Activity Score, lack formal validation; and that histological scoring systems for ulcerative colitis, including the Geboes Score, Robarts Histopathology Index, and Nancy Histological Index, can be used for scoring intestinal biopsies in CD patients.

Obstructed defecation syndrome associated with paradoxical puborectalis contraction: osteopathic treatment versus anal biofeedback. Results of a pilot study.

BACKGROUND: Biofeedback is the most widespread rehabilitative therapy for the treatment of anismus after failed conservative treatment. Osteopathy represents an alternative therapy for constipation. The aim of this study was to evaluate short- and long-term results of osteopathic treatment as compared to biofeedback in patients with dyssynergic defecation. METHODS: This was a prospective cohort pilot study on 30 patients with dyssynergic defecation enrolled at the Colorectal Clinic of the University Hospital of Ferrara, Italy, from May 2015 to May 2016 and followed until May 2020. Dyssynergic defecation was defined as the inappropriate contraction of the pelvic floor or less than 20% relaxation of basal resting sphincter pressure (on anal manometry) with adequate propulsive forces during attempted defecation. Dyssynergic patients were divide into 2 treatment groups: 15 patients had osteopathy and 15 patients had biofeedback. Before and 3 months after rehabilitation treatment, all patients had anorectal manometry, defecography, and ultrasound, and were evaluated with the Cleveland Clinic Florida (CCF) constipation score, obstructed defecation syndrome (ODS) score, Colo-rectal-anal Distress Inventory (CRADI-8), Colo-rectal-anal Impact Questionnaire (CRAIQ-7), and the Brusciano Score (BS). To evaluate the efficacy of osteopathy and biofeedback in the long-term, all patients completed the above-mentioned questionnaires 5 years later via a telephone interview. RESULTS: The two treatments were similarly effective in the short term with reduction in questionnaires scores, and increase in the percentage of anal sphincter release at straining at anorectal manometry in both groups. The ODS score was significantly reduced in biofeedback group (p = 0.021). The 3-month post-treatment BS was lower in the osteopathy group, but this just failed to reach statistical significance (p = 0.050). Periodic rehabilitation reinforcements were provided. The CCF constipation score decreased significantly in the osteopathy group (p = 0.023) after 5 years. CONCLUSIONS: Osteopathy is a promising treatment for dyssynergic defecation, and it can be associated with biofeedback.

Inflammatory Bowel Disease Management During the COVID-19 Outbreak: The Ten Do's and Don'ts from the ECCO-COVID Taskforce.

Our knowledge of COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and on appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as inflammatory bowel disease [IBD]. In this review, we have compiled existing evidence on the impact of COVID-19 in IBD patients and provide guidance on the most appropriate care to adopt during the pandemic. Our review highlights that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management should be carefully adapted: [i] in SARS-CoV-2-positive IBD patients, medical treatments should be re-evaluated [with a particular focus on corticosteroids] always with the purpose of treating active disease and maintaining remission; [ii] non-urgent surgeries and endoscopic procedures should be postponed for all patients; [iii] online consultancy should be implemented; and [iv] hospitalization and surgery should be limited to life-threatening situations.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Correction to: Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication. The complete correct affiliation should read as follows.

Segmental Colectomy for Ulcerative Colitis: Is There a Place in Selected Patients Without Active Colitis? An International Multicentric Retrospective Study in 72 Patients.

BACKGROUND AND AIMS: The aim of this study was to report a multicentric experience of segmental colectomy [SC] in ulcerative colitis [UC] patients without active colitis, in order to assess if SC can or cannot represent an alternative to ileal pouch-anal anastomosis [IPAA]. METHODS: All UC patients undergoing SC were included. Postoperative complications according to ClavienDindo's classification, long term results, and risk factors for postoperative colitis and reoperation for colitis on the remnant colon, were assessed. RESULTS: A TOTAL OF: 72 UC patients underwent: sigmoidectomy [n = 28], right colectomy [n = 24], proctectomy [n = 11], or left colectomy [n = 9] for colonic cancer [n = 27], 'diverticulitis' [n = 17], colonic stenosis [n = 5], dysplasia or polyps [n = 8], and miscellaneous [n = 15]. Three patients died postoperatively and 5/69 patients [7%] developed early flare of UC within 3 months after SC. After a median followup of 40 months, 24/69 patients [35%] were reoperated after a median delay after SC of 19 months [range, 2-158 months]: 22/24 [92%] underwent total colectomy and ileorectal anastomosis [n = 9] or total coloproctectomy [TCP] [n = 13] and 2/24 [8%] an additional SC. Reasons for reoperation were: colitis [n = 14; 20%], cancer [n = 3] or dysplasia [n = 3], colonic stenosis [n = 1], and unknown reasons [n = 3]. Endoscopic score of colitis before SC was Mayo 23 in 5/5 [100%] patients with early flare vs 15/42 without early flare [36%; p = 0.0101] and in 9/12 [75%] patients with reoperation for colitis vs 11/35 without reoperation [31%; p = 0.016]. CONCLUSIONS: After segmental colectomy in UC patients, postoperative early colitis is rare [7%]. Segmental colectomy could possibly represent an alternative to IPAA in selected UC patients without active colitis.

Correction to: Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): ulcerative colitis.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of ulcerative colitis management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of ulcerative colitis. The committee was able to identify some points of major disagreement and suggested strategies to improve the quality of available data and acceptance of guidelines.

Inflammatory bowel disease position statement of the Italian Society of Colorectal Surgery (SICCR): Crohn's disease.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a position statement of Italian colorectal surgeons to address the surgical aspects of Crohn's disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the surgical treatment of Crohn's disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of inflammatory bowel disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the general principles of surgical treatment of inflammatory bowel disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Darvadstrocel for the treatment of patients with perianal fistulas in Crohn's disease.

Despite significant advances in medical and surgical therapy for perianal fistulas in Crohn's disease (CD), treatment results are still modest, and a specific need for more effective therapies is a reality. Darvadstrocel is composed of expanded human allogeneic mesenchymal adult stem cells extracted from adipose tissue and constitutes the first stem cell therapy for perianal fistulizing CD to receive approval from the European Medicines Agency (EMA). This therapy is injected in both internal and external openings, as well as inside the fistula tracks, to induce fistula healing. In this monograph, the authors review the preclinical pharmacology of darvadstrocel, as well as pharmacokinetics and metabolism, and cover the main indications and detailed information on the efficacy and safety profile of the agent. Possible interactions with other agents used to treat CD are also explored. Darvadstrocel is a safe and effective therapy for perianal complex fistulas in CD, and represents the beginning of a new era of mesenchymal stem cell therapy in this difficult phenotype of the disease.

Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study‡.

Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.

Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition.

AIM: To test the cross-immunogenicity of anti-CT-P13 IBD patients' sera to CT-P13/infliximab originator and the comparative antigenicity evoked by CT-P13/infliximab originator sera. METHODS: Sera of patients with IBD with measurable anti-CT-P13 antibodies were tested for their cross-reactivity to 5 batches of infliximab originator and CT-P13. Anti-drug antibody positive sera from treated patients were used to compare antigenic epitopes. RESULTS: All 42 anti-CT-P13 and 37 anti-infliximab originator IBD sera were cross-reactive with infliximab originator and CT-P13 respectively. Concentration of anti-drug antibodies against infliximab originator or CT-P13 were strongly correlated both for IgG1 and IgG4 (P < 0.001). Anti-CT-P13 sera of patients with IBD (n = 32) exerted similar functional inhibition on CT-P13 or infliximab originator TNF binding capacity and showed reduced binding to CT-P13 in the presence of five different batches of CT-P13 and infliximab originator. Anti-CT-P13 and anti-infliximab originator IBD sera selectively enriched phage-peptides from the VH (CDR1 and CDR3) and VL domains (CDR2 and CDR3) of infliximab. Sera reactivity detected major infliximab epitopes in these regions of infliximab in 60%-79% of patients, and no significant differences were identified between CT-P13 and infliximab originator immunogenic sera. Minor epitopes were localised in framework regions of infliximab with reduced antibody reactivity shown, in 30%-50% of patients. Monoclonal antibodies derived from naïve individuals and ADA-positive IBD patients treated with CT-P13 provided comparable epitope specificity to five different batches of CT-P13 and infliximab originator. CONCLUSIONS: These results strongly support a similar antigenic profile for infliximab originator and CT-P13, and point toward a safe switching between the two drugs in anti-drug antibody negative patients.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

BACKGROUND: Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. AIM: To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. METHODS: We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. RESULTS: Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. CONCLUSIONS: This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis.

BACKGROUND: Biological therapies have improved the care of patients with ulcerative colitis (UC). Tofacitinib, an oral small-molecule Janus kinase inhibitor, is potentially a new treatment option. AIM: To comparatively assess efficacy and harm of tofacitinib and biologics (infliximab, adalimumab, golimumab and vedolizumab) in adult patients not previously exposed to TNF antagonists. METHODS: We performed a comprehensive search of PubMed, Embase, Scopus, clinical trial registries, regulatory authorities' websites and major conference proceedings, through August 2017, to identify randomised, placebo-controlled or head-to-head trials assessing tofacitinib or biologics as induction and/or maintenance therapy in moderate-to-severe UC. Two reviewers independently extracted study data and outcomes, and investigated each trial's risk-of-bias. We used conventional meta-analysis to synthesise direct evidence, and network meta-analysis for adjusted indirect treatment comparisons. RESULTS: Fifteen randomised, double-blind, placebo-controlled trials (n = 3130) contributed data for induction: All treatments are superior to placebo. Indirect treatment comparisons showed that infliximab is better than adalimumab (OR: 2.01, 95% CI: 1.36-2.98) and golimumab (1.67, 1.08-2.59) in clinical response, better than adalimumab (2.10, 1.21-3.64) in clinical remission, and better than adalimumab (1.87, 1.26-2.79) and golimumab (1.75, 1.13-2.73) in mucosal healing. No indirect comparisons between tofacitinib and biologics reached statistical significance. Nine studies (n = 1776) contributed maintenance data showing that all treatments have higher clinical efficacy than placebo. Safety analyses indicated no increased rates of adverse events for the treatments under evaluation (except for infliximab), while vedolizumab may have an advantage regarding the occurrence of serious adverse events. CONCLUSIONS: Tofacitinib and biologics are efficacious and safe for UC. Further high-quality research is warranted to establish the best therapeutic option.