Perianal fistulising Crohn's disease: utilising the TOpClass classification in clinical practice to provide targeted individualised care.

BACKGROUND AND AIMS: Perianal fistulation is a challenging phenotype of Crohn's disease with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalised, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulising Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS: An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, IBD surgeons, and radiologists specialised in PFCD. The process was informed by the multi-disciplinary team management of eight high-volume fistula centres in North America, Europe, and Australia. RESULTS: The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimisation of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION: This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient-goal centred approach to medical and surgical management options for individual patients with PFCD.

The aetiology of pouchitis in patients with inflammatory bowel disease.

Restorative proctocolectomy with ileal pouch-anal anastomosis is a treatment option for patients with refractory ulcerative colitis. Pouchitis is the most common complication, representing a spectrum of diseases ranging from acute antibiotic-responsive type to chronic antibiotic-refractory. Early accurate diagnosis using a combined assessment of symptoms, endoscopy and histology is important for both treatment and prognostication. Most patients respond well to antibiotic therapy; however, management of chronic antibiotic-refractory pouchitis remains a challenge, and treatment options are based on small studies. Pouchitis is thought to be driven by the interaction between genetics, the immune system and the environment but as yet a causal relationship has yet to be identified. Further longitudinal assessment of the pouch integrating new technologies may help us understand the factors driving pouchitis. This review outlines the currently understood risk factors and aetiology of pouchitis.

Systematic review and meta-analysis of endoscopic versus medical management of peptic ulcers with adherent clots.

Peptic ulcer disease is an important cause of upper gastrointestinal bleeding. Current guidelines recommend endoscopic treatment for ulcers with active bleeding or non-bleeding visible vessels, but the optimal management of ulcers with adherent clots is unclear. We performed a systematic review of the efficacy of endoscopic versus medical management of peptic ulcers with adherent clots. A systematic literature search was performed through September 2022 (MEDLINE, Embase, and CENTRAL). Randomized controlled trials (RCTs) comparing the effect of endoscopic versus medical management alone for peptic ulcers with adherent clots on the outcome of recurrent bleeding were incuded. A random-effects meta-analysis was performed to estimate the overall treatment effect. We included seven RCTs reporting on the endoscopic versus medical management of peptic ulcers with adherent clots. The pooled cohort comprised 268 patients with a mean age of 62.8 years and a mean follow up of 20 days. There was a significant reduction in the risk of recurrent bleeding with endoscopic hemostatic treatment for peptic ulcers with adherent clots, compared with medical management alone (risk ratio [RR] = 0.40, 95% confidence interval [CI] 0.16-0.95, 268 participants). However, there was no difference in mortality (RR = 0.90, 95% CI 0.23-3.59, 52 participants) or need for ulcer surgery (RR = 0.48, 95% CI 0.10-2.28, 52 participants) between endoscopic and medical management groups. In summary, there was evidence for a reduction in recurrent bleeding from peptic ulcers with adherent clots treated with endoscopic hemostatic techniques compared with medical management alone but no difference in rates of mortality or need for surgery.

Update for surgeons on novel induction treatments for acute severe inflammatory bowel disease associated colitis.

BACKGROUND: The landscape of biologic agents for the treatment of inflammatory bowel disease (IBD) associated colitis is rapidly evolving, requiring surgeons to be up-to-date as part of multi-disciplinary, evidence-based care. An update on novel therapies used to induce remission in IBD-associated colitis is presented. METHODS: A systematic search through Ovid MEDLINE and CENTRAL using a combination of MeSH terms and Boolean operators was conducted. RESULTS: One thousand and twenty articles from which 38 articles were selected for inclusion in this review. Novel agents were trialled as 4th or 5th line treatment following conventional treatment failure. Rates of serious adverse effects were low. Janus kinase (JAK) inhibitors (upadacitinib and tofacitinib) were efficacious in inducing remission in ulcerative colitis, and IL-23p19 inhibitors (mirikizumab, guselkumab, and risankizumab) in Crohn's colitis. Evidence was limited for other drug classes. CONCLUSION: JAK-inhibitors and IL-23p19 inhibitors were found to be the most effective agents for inducting remission following failure of standard of care treatment. A significant proportion of patients did not respond, highlighting the inherent challenge in optimizing treatment for moderate to severe IBD-associated colitis. More robust study designs and comparator trials are required.

Risk factors for malignancy and serious infection in patients with inflammatory bowel disease: a retrospective analysis.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of malignancy and infection compared to the general population. AIMS: We aim to identify risk factors for malignancy or serious infection in our IBD cohort. METHODS: Patients with IBD from a single tertiary referral centre were included. Demographic and clinical details, including immunosuppressant exposure, were collected and medical records retrospectively screened for adverse events, including malignancy or infection requiring hospitalisation. Logistic regression was used to evaluate risk factors for adverse events. RESULTS: Five hundred and forty-nine patients with IBD (340 Crohn disease (CD) and 209 ulcerative colitis (UC)) were studied. Forty-eight malignancies, including 39 (81.3%) non-melanoma skin cancers, 3 (6.3%) haematologic malignancies and 6 (15.4%) solid-organ malignancies, were identified, and 92 cases of serious infection were detected. IBD duration (odds ratio (OR) = 1.08; 95% confidence interval (CI) = 1.03-1.13) and ileocolonic CD (OR = 4.96; 95% CI = 1.13-21.71) were associated with increased odds of overall cancer. Compared with patients not previously exposed to the given class of immunosuppression assessed, the development of overall malignancy was not higher with thiopurine exposure (OR = 1.00; 95% CI = 0.50-2.24) or anti-tumour necrosis factor-alpha (TNF-α) exposure (OR = 0.78; 95% CI = 0.37-1.64). Similarly, compared with patients not exposed, infection risk was not affected by thiopurine (OR = 0.74; 95% CI = 0.46-1.20) or anti-TNF exposure (OR = 0.60; 95% CI = 0.38-0.95). CONCLUSIONS: Factors including ileocolonic CD and increasing IBD duration were associated with higher malignancy risk in this cohort. Compared with non-exposure, patients exposed to thiopurines were not at increased risk of malignancy or serious infection. Similarly, patients exposed to anti-TNF treatment did not experience increased rates of malignancy or serious infection compared to patients not exposed to this treatment.

Outcomes of a Comprehensive Specialist Inflammatory Bowel Disease Nursing Service.

BACKGROUND: Inflammatory bowel disease (IBD) is best managed by a multidisciplinary team within a dedicated IBD service. IBD nurses play an important role within this team. We aimed to evaluate the contribution of our comprehensive outpatient IBD nursing service on patient outcomes, quality of care, and healthcare costs. METHODS: We performed a retrospective review of all IBD nurse encounters with patients over a 12-month period from October 2020 to September 2021 at a tertiary IBD referral center. Each nurse encounter was classified with respect to its clinical context, activities, and outcomes. Descriptive statistics were used to characterize these encounters and an economic analysis was performed to estimate the cost savings to the hospital. RESULTS: A total of 2537 nurse encounters occurred with 682 patients; 41% of encounters were nurse-initiated contacts with patients and 34% were patient-initiated contacts with the nurse helpline (26% via email, 8% via telephone). Most encounters involved clinical assessments (66%), providing education, counseling or updates (47%), and reviewing investigation results (38%). A gastroenterologist was consulted for advice in 35% of contacts. An estimated 29 emergency department visits, 1925 outpatient clinic visits, and 137 general practitioner visits were avoided. After deducting costs incurred, a net estimated annual saving of up to AUD $570 838 was achieved. Nurses commonly facilitated faster access to investigations (29%), education provision (28%), delivery of biologic services (25%), and medication changes (19%). CONCLUSIONS: A comprehensive IBD nursing service is associated with improved patient outcomes and quality of care, and reduced healthcare costs. This study supports the expanding role of IBD nurses in a modern multidisciplinary IBD service and the need for greater funding and integration of IBD nurses into IBD services.

Vedolizumab for induction and maintenance of remission in Crohn's disease.

BACKGROUND: Vedolizumab blocks inflammatory activity within the gastrointestinal tract. Systematic reviews have demonstrated the efficacy of vedolizumab in ulcerative colitis and inflammatory bowel disease in general. This systematic review and meta-analysis summarises the current evidence of vedolizumab in the induction and maintenance of remission in Crohn's disease. OBJECTIVES: To evaluate the benefits and harms of vedolizumab versus placebo for the induction and maintenance of remission in people with Crohn's disease. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 30 November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing vedolizumab to placebo for the induction or maintenance of remission in people with Crohn's disease. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. For induction studies, the primary outcome was 1. clinical remission, and secondary outcomes were rates of 2. clinical response, 3. adverse events, 4. serious adverse events, 5. surgery, 6. endoscopic remission and 7. endoscopic response. For maintenance studies, the primary outcome was 1. maintenance of clinical remission, and secondary outcomes were rates of 2. adverse events, 3. serious adverse events, 4. surgery, 5. endoscopic remission and 6. endoscopic response. We used GRADE to assess certainty of evidence. MAIN RESULTS: We analysed induction (4 trials, 1126 participants) and maintenance (3 trials, 894 participants) studies representing people across North America, Europe, Asia and Australasia separately. One maintenance trial administered subcutaneous vedolizumab whilst the other studies used the intravenous form. The mean age ranged between 32.6 and 38.6 years. Vedolizumab was superior to placebo for the induction of clinical remission (71 more per 1000 with clinical remission with vedolizumab; risk ratio (RR) 1.61, 95% confidence interval (CI) 1.20 to 2.17; number needed to treat for an additional beneficial outcome (NNTB) 13; 4 studies; high-certainty evidence) and superior to placebo for inducing clinical response (105 more per 1000 with clinical response with vedolizumab; RR 1.43, 95% CI 1.19 to 1.71; NNTB 8; 4 studies; high-certainty evidence). For the induction phase, vedolizumab may be equivalent to placebo for the development of serious adverse events (9 fewer serious adverse events per 1000 with vedolizumab; RR 0.91, 95% CI 0.62 to 1.33; 4 studies; low-certainty evidence) and probably equivalent to placebo for overall adverse events (6 fewer adverse events per 1000 with vedolizumab; RR 1.01, 95% CI 0.93 to 1.11; 4 studies; moderate-certainty evidence). Vedolizumab was superior to placebo for the maintenance of clinical remission (141 more per 1000 with maintenance of clinical remission with vedolizumab; RR 1.52, 95% CI 1.24 to 1.87; NNTB 7; 3 studies; high-certainty evidence). During the maintenance phase, vedolizumab may be equivalent to placebo for the development of serious adverse events (3 fewer serious adverse events per 1000 with vedolizumab; RR 0.98, 95% CI 0.68 to 1.39; 3 studies; low-certainty evidence) and probably equivalent to placebo for the development of overall adverse events (0 difference in adverse events per 1000; RR 1.00, 95% CI 0.94 to 1.07; 3 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS: High-certainty data across four induction and three maintenance trials demonstrate that vedolizumab is superior to placebo in the induction and maintenance of remission in Crohn's disease. Overall adverse events are probably similar and serious adverse events may be similar between vedolizumab and placebo during both induction and maintenance phases of treatment. Head-to-head research comparing the efficacy and safety of vedolizumab to other biological therapies is required.

Prevalence of NUDT15 Genetic Variants and Incidence of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Nudix hydrolase 15 [NUDT15] genetic variants confer an increased risk of thiopurine-induced leukopenia [TIL]; however, their global prevalence in inflammatory bowel disease [IBD] patients is unknown. We aimed to evaluate the global prevalence of NUDT15 variants in IBD patients and incidence of TIL in these patients. METHODS: Six databases were searched from inception until July 2022. Studies reporting the frequency of any NUDT15 variant and/or frequency of leukopenia in adult IBD patients with these variants were included. A random effects model was performed to estimate the pooled prevalence of variants, incidence of early [≤8 weeks] and late [>8 weeks] leukopenia, and relative risk of developing leukopenia. RESULTS: Twenty studies comprising 5232 patients were included. The pooled prevalence of the *1/*3 c.415C > T C/T diplotype was 13% (95% confidence interval [CI]: 10-18%), *3/*3 c.415C > T T/T diplotype was 2% [95% CI: 1-2%], *1/*5 c.52G > A G/A diplotype was 2% [95% CI: 1-3%], and *1/*6 c.36_37insGGAGTC ins/- diplotype was 7% [95% CI: 4-12%]. The pooled prevalence of *1/*3 was high in Japanese [20%, 95% CI: 16-24%] and Chinese patients [18%, 95% CI: 12-27%]. The incidence of early leukopenia was 20% [95% CI: 16-26%] in *1/*3 patients, 99% [95% CI: 7-100%] in *3/*3 patients, and 49% [95% CI: 29-69%] in *1/*6 patients. The incidence of late leukopenia was 36% [95% CI: 26-49%] in *1/*3 patients. CONCLUSIONS: NUDT15 variants are common and strongly predict TIL in IBD patients. Pre-treatment NUDT15 genotyping should be considered particularly in Asian populations, to guide thiopurine dosing and prevent myelotoxicity.

Relationship Between Serum Ustekinumab Trough Concentration and Clinical and Biochemical Disease Activity: A Real-World Study in Adult Patients with Crohn's Disease.

BACKGROUND AND OBJECTIVES: The role of therapeutic drug monitoring for ustekinumab in the treatment of Crohn's disease has not been defined. This study aimed to explore the relationship of serum ustekinumab trough concentration (UTC) with clinical and biochemical disease outcomes in a real-world setting. METHODS: We performed a retrospective analysis of Crohn's disease patients treated at a single tertiary centre. Ustekinumab was given as a single intravenous induction dose, followed by maintenance subcutaneous injections every 4 to 8 weeks. Rates of clinical remission (Harvey-Bradshaw Index ≤ 4), biochemical remission (C-reactive protein < 5 mg/l and faecal calprotectin < 150 µg/g) and complete remission were assessed at baseline and at the time of UTC testing during maintenance therapy. The association between baseline variables and UTC was tested using linear regression. We also performed an external validation analysis of UTC cut-offs established in four previously published studies. RESULTS: This study included 43 patients. Compared to 8-weekly dosing, a 2.49- and 2.65-fold increase in UTC was associated with 6-weekly and 4-weekly dosing respectively. However, there was no significant difference in clinical, biochemical or complete remission among the dosing groups. An external validation of previously published optimal UTC cut-offs found low predictive value for our patient population. CONCLUSIONS: In this study, dosing interval was the only determinant significantly associated with a higher UTC for patients on maintenance ustekinumab therapy. While a higher UTC may be achieved with dose escalation, it was not associated with improved rates of clinical or biochemical response in our cohort.

Autologous fat graft injections for the treatment of perianal fistulas in Crohn's disease: a systematic review and single-arm meta-analysis.

BACKGROUND: Crohn's perianal fistulas are often refractory to standard management. Fat graft injections are hypothesised to improve fistula healing rates. We evaluated the treatment efficacy of fat graft injections for Crohn's perianal fistulas in a systematic review (PRISMA). METHODS: We completed database searches of MEDLINE (Ovid), Embase, and PubMed. All studies published in English in full text or abstract, from January 2001 to August 2021, evaluating fat graft injections for Crohn's perianal fistulas were selected. Included randomized controlled trials, single-arm intervention trials, cohort studies, and case series; excluded single case reports. Primary outcome was pooled clinical healing, defined as non-draining treated fistulas, or closure, defined as closure of treated fistulas. Secondary outcomes were clinical healing, clinical closure, radiologic response, and adverse events. RESULTS: Of 1258 publications identified, 891 articles were assessed for eligibility, and 107 relevant for manuscript review. Forty-nine patients received fat graft injections for Crohn's perianal fistulas across four single-arm intervention trials. Clinical healing or closure was achieved in 74% in a pooled single-arm meta-analysis (95% confidence interval: 57%, 85%), with moderate heterogeneity between studies. Clinical healing was achieved in 20% and 60% at 3 and 12 months, respectively. Clinical closure was achieved in 83% at 6 months. Variable parameters were used to define radiologic response, with success rates from 20% to 67%. Minimal adverse events were reported. CONCLUSION: Fat graft injections show promise as a novel treatment for Crohn's perianal fistulas in this systematic review and meta-analysis. Assessment in controlled matched studies is warranted.

ECCO Topical Review on Biological Treatment Cycles in Crohn's Disease.

There are now a growing number of licensed biological therapies for patients with Crohn's disease. However, there can be significant costs associated with long-term maintenance treatment, as well as some concerns about potential side-effects. As a result, there has been increasing interest in elective biological treatment discontinuation in selected patients, after a sustained period of remission. Following discontinuation, in cases of relapse, evidence to date has suggested that remission may often be regained by re-treatment with the same biological agent. Therefore, a concept has emerged in which cycles of biological therapy might be used. If this treatment strategy were to be applied in a subgroup of patients at low risk of relapse, cycling might allow a substantial number of patients to have a lower, overall therapeutic burden-ensuring decreased exposure to biological therapy but still enabling appropriate disease control. Currently, there remains uncertainty about the benefit-risk balance for using cycles of biological treatment for patients with Crohn's disease. Accordingly, an expert panel was convened by the European Crohn's and Colitis Organisation [ECCO] to review the published literature and agree a series of consensus practice points. The panel aimed to provide evidence-based guidance on multiple aspects of biological treatment discontinuation and cycling, including the risk of relapse after elective treatment discontinuation, predictors of probable relapse or remission, safety, patient preferences, and pharmacoeconomic aspects. Crucially, discussions about biological treatment discontinuation and cycling should be individualized, to enable shared decision-making by patients with their clinicians.

Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020.