The management of patients with inflammatory bowel disease-associated spondyloarthritis: Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Society of Rheumatology (SIR) recommendations based on a pseudo-Delphi consensus.

Spondyloarthritis (SpA) is the most frequent extraintestinal manifestation in patients with inflammatory bowel diseases (IBD). When IBD and spondyloarthritis coexist, musculoskeletal and intestinal disease features should be considered when planning a therapeutic strategy. Treatment options for IBD and SpA have expanded enormously over the last few years, but randomized controlled trials with specific endpoints focused on SpA are not available in the IBD setting. To address this important clinical topic, the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and the Italian Society of Rheumatology (SIR) jointly planned to draw updated therapeutic recommendations for IBD-associated SpA using a pseudo-Delphi method. This document presents the official recommendations of IG-IBD and SIR on the management of IBD-associated SpA in the form of 34 statements and 4 therapeutic algorithms. It is intended to be a reference guide for gastroenterologists and rheumatologists dealing with IBD-associated SpA.

Pragmatic trial design to compare real-world effectiveness of different treatments for inflammatory bowel diseases: the PRACTICE-IBD European consensus.

BACKGROUND AND AIMS: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid comparative pragmatic studies in inflammatory bowel diseases (IBDs). METHODS: Statements were issued by a panel of 11 European experts in IBD management and trial methodology on four main topics: (I) study design; (II) eligibility, recruitment and organization, flexibility; (III) outcomes; (IV) analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement (1 to 9; cut-off ≥7 for approval) with the statements by 18 additional European experts in IBD. RESULTS: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: 7 for study design, 6 for eligibility, recruitment and organization, flexibility, 8 for outcomes, and 4 for analysis. CONCLUSIONS: Pragmatic randomized clinical trials can address important questions in IBD clinical practice, and may provide complementary high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality pragmatic clinical trials that can aid decision making in choosing a management strategy for IBDs.

Current Approaches for Monitoring of Patients with Inflammatory Bowel Diseases: A Narrative Review.

BACKGROUND: Patients with inflammatory bowel diseases (IBD) require proactive monitoring both during the active phase to evaluate therapeutic response and during the remission phase to evaluate relapse or colorectal cancer surveillance. However, monitoring may vary between patients with ulcerative colitis (UC) and Crohn's disease (CD), with distinct tools and intervals. METHODS: This narrative review aims to focus on modern approaches to IBD monitoring, considering international guidelines and expert consensus. RESULTS: The most recent European diagnostic guidelines advocate a combination of clinical, laboratory, endoscopic, and radiological parameters to evaluate the disease course of patients with IBD. Unfortunately, the conventional symptom-based therapeutic approach does not improve long-term outcomes and there is no single ideal biomarker available. Endoscopy plays a key role in evaluating response to therapy as well as monitoring disease activity. Recently, bedside intestinal ultrasound (IUS) has gained increasing interest and diffusion as it appears to offer several advantages including the monitoring of therapeutic response. CONCLUSION: In light of growing clinical advances, we present a schematic evidence-based monitoring algorithm that can be easily applied in clinical practice which combines all major monitoring modalities, including noninvasive tools such as IUS and video-capsule endoscopy.

Safety and effectiveness of tofacitinib in ulcerative colitis: Data from TOFA-UC, a SN-IBD study.

BACKGROUND: Real-world evidence is needed to determine the value of tofacitinib (TOFA) for the treatment of ulcerative colitis (UC). AIM: To assess the safety and effectiveness of TOFA in clinical practice. METHODS: TOFA-UC is a multicenter, observational study performed among the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). All consecutive patients with UC starting TOFA from its introduction in Sicily (July 2021) to July 2022 were included. RESULTS: 111 patients were included (mean follow-up: 31.7 ± 14.9 weeks; biologic-experienced: 92.8%). Nineteen adverse events were reported (17.1%; incidence rate: 28.2 per 100 patient years), including 11 cases of hypercholesterolemia and 3 infections (no cases of herpes zoster reactivation. At week 8, the rates of clinical response, steroid free clinical remission, and CRP normalization were 74.8%, 45.0%, and 56.9%, respectively, and 68.5%, 51.4%, and 65.2%, respectively, at the end of follow-up. Eighteen patients experienced a loss of response after successful induction (21.7%; incidence rate: 33.2 per 100 patient years). Twenty-six patients (23.4%) discontinued TOFA over time, of whom 3 due to AEs, and 23 to non response or loss of response. CONCLUSIONS: TOFA is safe and effective in patients with UC, including those with history of multiple failures to biological therapies.

Role of ustekinumab in treatment of ulcerative colitis: a narrative review.

The therapeutic armamentarium for gastroenterologists in treating ulcerative colitis (UC) has been rapidly growing since the introduction of monoclonal antibodies directed against anti-TNFs. Ustekinumab is a monoclonal antibody binding the shared p40 subunit of IL-12 and IL-23, and the inhibition of these two cytokines, implicated in host response to microbial pathogens, has demonstrated clinical efficacy in different immune-mediated diseases, including moderate-to-severe UC. This narrative review summarizes the newest clinical evidence regarding the efficacy, effectiveness and safety of ustekinumab in moderate-to-severe UC, including specific situations (pregnancy, breastfeeding, elderly/pediatric populations, extraintestinal manifestations, acute severe UC, pouchitis and dual biological therapy). Finally, positioning is discussed in light of the existing evidence.

Ustekinumab (UST) is a biological drug that has been recently licensed as a novel therapy for ulcerative colitis, one of the two main conditions that constitute inflammatory bowel diseases. UST has been previously successfully used in psoriasis and psoriatic arthritis, two conditions in which dysregulation of the immune system causes inflammation in the skin and joints, and Crohn's disease, a type of inflammatory bowel disease. This led to great interest in the use of UST for treating patients with moderate and severe ulcerative colitis. UST is administered with a weight-based intravenous infusion followed by subcutaneous administration every 8 weeks, which can be performed at home and is effective in reducing symptoms of the disease with a particularly favorable safety profile. These features make UST a suitable option for treating especially elderly and frail patients, as well as patients who did not benefit or had side effects with other biological therapies and patients who also suffer from psoriasis or psoriatic arthritis.

Attitudes towards Vaccinations in a National Italian Cohort of Patients with Inflammatory Bowel Disease.

BACKGROUND: The vaccination status of patients with inflammatory bowel disease (IBD) should be investigated before starting any treatment, and patients should eventually be vaccinated against vaccine-preventable diseases (VPDs). Patients with IBD may have suboptimal vaccination rates. The aim of this study was to evaluate the vaccination coverage, attitude towards vaccinations, and determinants among an Italian cohort of patients with IBD. METHODS: AMICI, the Italian IBD patients' association, sent an anonymous web-based questionnaire in February 2021. Previous vaccination status and patients' attitudes towards vaccinations were recorded. We examined the factors influencing their attitudes using crude and adjusted odds ratios (adjORs) with 95% confidence intervals (CIs). RESULTS: Among the 4039 patients invited, 1252 patients (including 729 women, median age 47.7 [37-58]) completed the questionnaire, with a response rate of 25.3%. Respondents declared being vaccinated against tetanus (74.1%), flu (67.7%; last season), MMR (43.3%), HBV (37.1%), pneumococcus (29.1%), meningitis (20%), HAV (16%), VZV (15.3%), and HPV (7.6%). Complete vaccination history was not remembered by 20.7% of the patients. One thousand one hundred and twelve (88.8%) expressed a positive attitude towards vaccination, 91 (7.3%) were indifferent, and 49 (3.9%) reported being opposed to vaccinations. The belief of a possible return of VPDs with a decline in vaccination coverage rates was the factor most strongly related to a positive attitude towards vaccinations (adjOR 5.67, 95% CI 3.45-9.30, p-value < 0.001). CONCLUSIONS: A low vaccination rate against some VPDs was found among a national cohort of patients with IBD, despite a generally positive attitude towards vaccinations.

Nutritional care at centres managing patients with inflammatory bowel disease: A nationwide survey in Italy.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at risk of malnutrition, but little is known about how IBD centres provide nutritional care. AIM: To assess how nutritional care is delivered at IBD centres across Italy. METHODS: 120 IBD centres were invited to answer a web-based questionnaire. RESULTS: 76 questionnaires (63.3%) were completed. An IBD-dedicated nutritionist is present in 27 centres (35.5%). Fifty-two centres (68.4%) have an IBD multidisciplinary team, and 22 of these include a nutritionist. In the outpatient setting, malnutrition risk is evaluated at each visit in 23 centres (30.3%), while nutritional status is assessed at each visit in 21 centres (27.6%). These assessments are performed by a gastroenterologist in almost all centres (93.4% and 88.2%, respectively) and more rarely by a nutritionist (32.9% and 36.9%), dietician (7.9% and 2.6%) or nurse (3.9% and 9.2%). The decision to offer oral nutritional support is made by a gastroenterologist alone (35.5%), a nutritionist alone (23.7%), or a team of the two (38.2%). CONCLUSIONS: Nutritional care for IBD patients appears quite far from satisfactory in the Italian reality. Educational and structural interventions are urgently needed to improve assessment and treatment of malnutrition in everyday clinical practice.

Ustekinumab is a promising option for the treatment of postoperative recurrence of Crohn's disease.

BACKGROUND AND AIM: Postoperative recurrence (POR) following ileocolonic resection is a major concern in patients with Crohn's disease (CD). The role of ustekinumab (UST) in this setting is poorly known. METHODS: All consecutive CD patients with a baseline colonoscopy at 6-12 months from ileocolonic resection showing POR (Rutgeerts score ≥ i2) who were treated with UST after the baseline colonoscopy and with an available post-treatment endoscopy, were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). The primary outcome was endoscopic success, defined as reduction of at least one point of Rutgeerts score. The secondary outcome was clinical success, assessed at the end of follow-up. Reasons for clinical failure included mild clinical relapse (Harvey-Bradshaw index 5-7), clinically relevant relapse (Harvey-Bradshaw index > 7), and need for new resection. RESULTS: Forty-four patients were included (mean follow-up: 17.8 ± 8.4 months). The baseline postoperative colonoscopy showed severe POR (Rutgeerts score i3 or i4) in 75.0% of patients. The post-treatment colonoscopy was performed after a mean of 14.5 ± 5.5 months following initiation of UST. Endoscopic success was reported in 22 out of 44 (50.0%) patients, of whom 12 (27.3%) achieved a Rutgeerts score i0 or i1. Clinical success at the end of follow-up was reported in 32 out of 44 patients (72.7%); none of the 12 patients with clinical failure had achieved endoscopic success at post-treatment colonoscopy. CONCLUSIONS: Ustekinumab could be a promising option for the treatment of POR of CD.

Safety, hesitancy of coronavirus disease 2019 vaccination and pandemic burden in patients with inflammatory bowel disease: data of a national study (ESCAPE-IBD).

BACKGROUND AND AIMS: The purpose of this study was to present data on the safety of anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of inflammatory bowel disease (IBD) patients of an ongoing multicenter study (ESCAPE-IBD) sponsored by the Italian Group for the study of Inflammatory Bowel Disease (ClinicalTrials.gov Identifier: NCT04769258). METHODS: Anti-SARS-CoV-2 vaccination was administrated to 809 IBD patients. Interviews were conducted to report adverse events related to vaccination. Of these 809, 346 patients were surveyed on the pandemic burden and the main reason for hesitancy in coronavirus disease 2019 vaccination. The chi-square test was used to compare categorical variables. Logistic regression was used to assess the relationship between disease-related characteristics and the onset of adverse events. RESULTS: About 45% of patients had at least one side effect, following the first dose (10%), the second (15%), and both doses (19%). All the adverse events were mild and lasted only a few days. Logistic regression analysis revealed that female sex ( P  < 0.001), younger age ( P  = 0.001), seroconversion ( P  = 0.002), and comorbidity ( P  < 0.001) were significantly associated with adverse events. The survey showed that the main concerns were the possibility of adverse event (33%). Almost all patients (99%) felt safer having been vaccinated at their IBD reference center. CONCLUSION: The vaccine reactions experienced in IBD patients were mostly self-limited. We found high acceptance and good safety of SARS-CoV-2 vaccination in our cohort.

Use of biologics for the management of Crohn's disease: IG-IBD technical review based on the GRADE methodology.

The therapeutic armamentarium for the management of Crohn's disease (CD) is rapidly expanding. Several biologic therapies (e.g. infliximab, adalimumab, vedolizumab, and ustekinumab) have been regulatory approved, and there is considerable practice variability in the treatment of patients with CD. This technical review systematically searched and identified the current evidence, synthesized it using meta-analytic methodology, appraised its quality, and concisely presented it, thus forming the basis for developing clinical practice recommendations on the use of biologic treatments in adult patients with CD.

Sarcopenia is a negative predictive factor for endoscopic remission in patients with Crohn's disease treated with biologics.

BACKGROUND: Sarcopenia has been associated with poor prognosis in chronic diseases. AIMS: To investigate the role of sarcopenia in predicting clinical and endoscopic outcomes in patients with Crohn's disease (CD). METHODS: Consecutive CD patients who started biologics between 2014 and 2020 and underwent abdominal magnetic resonance or computed tomography within 6 months from the beginning of the biological therapy were enroled. Sarcopenia was defined as Psoas Muscle Index (PMI) lower than 5.4 cm²/m² (men) and 3.56 cm²/m² (women). Univariate and multivariate analyses were used to evaluate whether sarcopenia could predict steroid-free clinical remission (SFCR), endoscopic remission (ER), hospitalisation and surgery after 12 months of therapy. RESULTS: 358 patients were included. Sarcopenia was found in 18.2% of patients, and it was associated with a lower rate of ER (14.8% vs 47.7%; p = 0.002) after 12 months of therapy, while it was not associated with SFCR (65.1% vs 70.1%; p = 0.435), hospitalisation (9.2% vs 7.8%; p = 0.801) and surgery (3.1% vs 6.1%; p = 0.549). Sarcopenia was identified as a predictor of lack of ER (odds ratio [OR]=5.2; p = 0.006), as well as smoking (OR=2.5; p = 0.028) and perianal disease (OR=2.6; p = 0.020). CONCLUSION: Sarcopenia is a negative prognostic factor for ER in CD patients treated with biologics.

Effectiveness and Safety of Vedolizumab in Inflammatory Bowel Disease: A Comprehensive Meta-analysis of Observational Studies.

BACKGROUND AND AIMS: Many observational studies on the use of vedolizumab [VDZ] in patients with Crohn's disease [CD] and ulcerative colitis [UC] have been published in the past few years. We aimed to comprehensively summarise its effectiveness and safety by pooling data only from observational studies. METHODS: PubMed/Medline and Embase were systematically searched for observational studies on patients with CD and UC treated with VDZ through December 2021. The rates of clinical remission and overall adverse events were the primary outcomes. The rates of steroid-free clinical remission, clinical response, mucosal healing, C-reactive protein normalisation, loss of response, VDZ dose escalation, colectomy, serious adverse events, infections, and malignancies were considered as secondary outcomes. RESULTS: In all, 88 studies comprising 25 678 patients [13 663 with CD and 12 015 with UC] met the inclusion criteria. In patients with CD, the pooled estimate rates of clinical remission were 36% at induction and 39% at maintenance. In patients with UC, the pooled estimate rates of clinical remission were 40% at induction and 45% at maintenance. The pooled estimate of incidence rate of adverse events was 34.6 per 100 person-years. At multivariable meta-regression analysis, studies with increased male proportion were independently associated with higher rates of clinical remission and steroid-free clinical remission at both induction and maintenance, and clinical response at maintenance in patients with CD. Studies with increased disease duration were independently associated with higher mucosal healing rates at maintenance in patients with UC. CONCLUSIONS: Observational studies demonstrated extensively the effectiveness of VDZ, with a reassuring safety profile.

Use of biologics for the management of Crohn's disease: IG-IBD clinical guidelines based on the GRADE methodology.

A cure for Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract of unknown etiology, is not available, so patients require lifelong management to keep inflammation under control. The therapeutic armamentarium has expanded with approval of several biological drugs, including infliximab, adalimumab, vedolizumab and ustekinumab - monoclonal antibodies that target different inflammatory pathways - and darvadstrocel, a suspension of expanded human allogeneic, adipose-derived, mesenchymal stromal cells for the treatment of refractory complex perianal fistula. Notwithstanding existing practice guidelines on medical therapy for CD, the Italian Group for the Study of Inflammatory Bowel Disease felt the need to issue new guidelines focused on the use of biologics for managing the intestinal manifestations of CD and based on the GRADE methodology. This document presents recommendations regarding six clinical settings, from the induction to the maintenance of clinical remission, and from optimization and de-escalation of treatments to dealing with perianal CD and post-operative recurrence. The 19 evidence-based statements are supported by information on the quality of the evidence, agreement rate among panel members, and panel comments mainly based on evidence from real world studies.

Severe Activity of Inflammatory Bowel Disease is a Risk Factor for Severe COVID-19.

BACKGROUND: Data from the first wave of the coronavirus disease 2019 (COVID-19) pandemic suggested that patients with inflammatory bowel disease (IBD) are not at higher risk of being infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) than the general population and that a worse prognosis is not associated with immunomodulatory drugs, with the possible exception of systemic steroids. METHODS: This retrospective, observational study included consecutive IBD patients from the Sicilian Network for Inflammatory Bowel Disease (SN-IBD) cohort who had a SARS-CoV-2 infection diagnosis (polymerase chain reaction-confirmed presence of the viral genome in a nasopharyngeal swab) during the second COVID-19 pandemic wave (September 2020 to December 2020). Data regarding demographics, IBD features and treatments, and comorbidities were analyzed in correlation with COVID-19 clinical outcomes. RESULTS: Data on 122 patients (mean age, 43.9 ±â€…16.7 years; males, 50.0%; Crohn's disease, 62.3%; ulcerative colitis, 37.7%) were reported. Twelve patients developed COVID-19-related pneumonia (9.8%), 4 (3.3%) required respiratory assistance (nonmechanical ventilation or orotracheal intubation), and 4 died (case fatality rate, 3.3%). In a multivariable analysis, age (odds ratio [OR], 1.034; 95% CI, 1.006-1.147; P = .032) and severe IBD activity (OR, 13.465; 95% CI, 1.104-164.182; P = .042) were independent predictors of COVID-19-related pneumonia, while severe IBD activity (OR, 15.359; 95% CI, 1.320-178.677; P = .030) was the only independent predictor of severe COVID-19, a composite endpoint defined as the need for respiratory assistance or death. A trend towards a protective role of tumor necrosis factor α inhibitors on pneumonia development was reported (P = .076). CONCLUSIONS: In this cohort of patients with IBD and SARS-CoV-2 infection, severe IBD activity was the only independent risk factor for severe COVID-19.

This retrospective, observational study on patients with inflammatory bowel disease and severe acute respiratory syndrome coronavirus 2 infection showed that severe inflammatory bowel disease activity was the only independent risk factor for severe coronavirus disease 2019.

Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study.

BACKGROUND: Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. AIMS: To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) METHODS: Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). RESULTS: 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0-4.1]; p<0.001). CONCLUSIONS: Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258).