Crohn's disease (CD) is a chronic, inflammatory bowel disease with a wide range of presentations, including perianal disease. Presentation is variable, ranging from skin tags to complex fistulas, strictures, and nonhealing wounds. Symptoms of perianal CD can be devastating and may impact quality of life. Optimal management requires coordinated medical and surgical therapy. When possible, conservative treatment of perianal disease should be attempted. However, surgical treatment is often required, and some patients may ultimately require total proctocolectomy with permanent diversion due to the severity of disease. Even with close attention and treatment, disease can be recurrent, and complications of treatment are sometimes worse than the initial presentation. Novel treatments, including use of mesenchymal stem cells and autologous fat grafting, hold some promise, but are not yet widely available. Thorough knowledge of treatment options, careful patient selection, coordination between medical and surgical providers, and setting realistic expectations are important in the successful treatment of difficult perineal CD.

To share the experience of a US national reference laboratory, offering genotyping for TPMT and NUDT15, TPMT enzyme phenotyping and detection of thiopurine metabolites.

Retrospective review of archived datasets related to thiopurines drug therapy including patients' data that underwent TPMT and NUDT15 genotyping, and smaller data sets where genotyping was performed with TPMT enzyme levels (phenotyping) +/- therapeutic drug monitoring (TDM).

Thirteen percent of patients had variants in one or both genes tested. Testing for NUDT15 revealed 3.9% additional patients requiring thiopurines dosing recommendations. A correlation between TPMT enzyme activity and TPMT polymorphisms (odds ratio OD = 71.41, p-value <0.001) and between older age and higher enzyme levels (OD = 0.98, p-value = 0.002) was identified. No correlation between sex and TPMT enzyme levels, nor between TPMT genotyping and the level of thiopurine metabolites was found.

Adding NUDT15 to TPMT genotyping, identified additional 3.9% patients to benefit from thiopurine dose modifications. A significant correlation between genetic variants in TPMT and TPMT enzyme levels and between age and enzyme levels was established, while no correlation was identified between sex and enzyme levels nor between TPMT variation and thiopurine metabolites. Providers rely more significantly on genotyping only approach, rather than genotyping and phenotyping.

Crohn's disease (CD) causes gastrointestinal symptoms (i.e., diarrhea and abdominal pain), systemic symptoms (i.e., fatigue, anemia, weight loss, and fever), and perianal fistulas that produce anal pain. Because of the frequent occurrence of diarrhea and ulcers in the rectum, CD is often exacerbated by perianal abscesses and/or fistulas. Perianal fistulizing CD (PFCD) has an unknown etiology and recurring symptoms such as pain and discharge, which seriously affects the patient's quality of life (QOL). In the past, radical surgery was performed for PFCD, but due to the risk of anal sphincter impairment, conservative therapy using antibiotics and immunosuppressive medications is currently the first treatment option. PFCD management has greatly improved with the use of biologics such as the antitumor necrosis factor alpha (TNF-α) antibodies infliximab and adalimumab. In this review, the results of the administration of anti-TNF-α (certolizumab pegol), anti-interleukin-12/23 (ustekinumab), and anti-α4β7 integrin antibodies (vedolizumab) were evaluated. Our investigation showed that these medications may be effective for maintenance therapy to prevent the recurrence of anal fistulas. In addition to biologics, molecular target drugs and even regenerative medicine using mesenchymal stem cells have been introduced to further expand the treatment options for consideration by medical personnel. We herein discuss the management of PFCD by focusing on studies conducted in the United States and Europe where researchers used recommended guidelines and consensus statements to evaluate the efficacy of each medication and published their findings in peer-reviewed journals.

The long-term remission rates achieved with current treatment options for Crohn's disease with perianal fistula (CD-PAF)-including antibiotics, biologics, immunomodulators, and Janus kinase inhibitors, often combined with advanced surgical interventions-remain unsatisfactory. This chapter explores several innovative biomaterials-based solutions, such as plugs, adhesives, fillers, and stem cell-based therapies. The key approaches and treatment outcomes of these advanced therapies are examined, focusing on their ability to modulate the immune response, promote tissue healing, and improve patient outcomes. Additionally, the chapter discusses future directions, including the optimization of biomaterial designs, enhancement of delivery and retention of regenerative therapies, and a deeper understanding of the underlying mechanisms of healing.

Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences.

This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation.

Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.

The perianal disease affects up to one-third of individuals with Crohn's disease (CD), causing disabling symptoms and significant impairment in quality of life, particularly for those with perianal fistulising CD (PFCD). The collaborative effort between gastroenterologists and surgeons is essential for addressing PFCD to achieve fistula closure and promote luminal healing. Limited fistula healing rates with conventional therapies have prompted the emergence of new biological agents, endoscopic procedures and surgical techniques that show promising results. Among these, mesenchymal stem cells injection is a particularly hopeful therapy. In addition to the burden of fistulas, individuals with perianal CD may face an increased risk of developing anal cancer. This underscores the importance of surveillance programmes and timely interventions to prevent late diagnoses and poor outcomes. Currently, there is no established formal anal screening programme. In this review, we provide an overview of the current state of the art in managing PFCD, including novel medical, endoscopic and surgical approaches. The discussion also focuses on the relevance of establishing an anal cancer screening programme in CD, intending to propose a risk-based surveillance algorithm. The validation of this surveillance programme would be a significant step forward in improving patient care and outcomes.

Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated.

To assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP.

A prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP.

Thirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA.

Up to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge-rechallenge-switch) achieved an overall GI tolerance to thiopurines in most of the patients.

The use of mesenchymal stem cells is considered a novel and promising therapeutic option for patients with perianal fistulizing Crohn's disease; however, data on its clinical application remain scarce. This multicenter nationwide study aimed to assess the clinical efficacy of mesenchymal stem cells in closing complex anal fistulas.

In this study 14 Crohn's disease patients (3 males, 11 females) with complex anal fistulas treated in 3 tertiary hospitals in Austria were included between October 2018 and April 2021. Injection of 120 million allogeneic expanded adipose-derived mesenchymal stem cells (Cx601-darvadstrocel) was performed in each patient. Closure of the external fistula opening without secretion by external manual compression was defined as treatment success.

The median age of the patient population at the time of surgery was 32 years (range 26-53 years) with a median body mass index of 21.7 kg/m2 (range 16.7-26.6 kg/m2). Of the patients 12 (86%) received monoclonal antibodies (infliximab, adalimumab, ustekinumab, vedolizumab) at the time of surgery. The median number of complex fistulas was 1.4 (range 1-2), The median operative time was 20 min (range 6-50 min) with no perioperative complications. After a median follow-up of 92 weeks, we found successful fistula closure in 57.1% (n = 8) of treated patients. The perianal disease activity index did not improve significantly from initially 7 to a median of 6 after 52 weeks (p = 0.495).

Darvadstrocel is a safe, minimally invasive surgical technique without significant perioperative complications. Clinical success can be expected in about half of the treated patients.

Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. In addition, there may be a link between the use of thiopurines or anti-tumor necrosis factor drugs (anti-TNF) and these pathologies. The treatment of patients with Crohn's disease who have previously been diagnosed with lymphoma is a challenge for gastroenterologists. In this report, we examine important clinical issues related to the treatment of patients with inflammatory bowel disease with active lymphoma, as well as of patients with hematological cancer history. In this discussion, we take into account most of the available treatments for inflammatory bowel disease, as well as the impact of chronic inflammation and viral infections. In addition, we try to find common ground for the development of lymphoproliferative disorders and autoimmune diseases. Patients with inflammatory bowel disease may be at higher risk of developing lymphomas and other cancers of the gastrointestinal tract. Chronic inflammatory processes and viral infections play an important role in carcinogenesis. In addition, there may be a link between the use of thiopurines or anti-TNF drugs and these pathologies. A significant risk of the development of lymphoma in people undergoing each therapy should be considered, and it should be estimated how much greater this risk will be in patients with a history of lymphoproliferative disorders. The following review is an attempt to answer which therapy would be the most appropriate for patients with Crohn's disease and a history of lymphoma treatment. A lack of clear guidelines creates great challenges for doctors.

Stem cell transplantation is a promising therapeutic option for curing perianal fistula in Crohn's disease (CD). Anti-tumor necrotic factor (TNF) therapy combined with drainage procedure is effective as well. However, previous studies are limited to proving whether the combination treatment of biologics and stem cell transplantation improves the effect of fistula closure.

This study aimed to evaluate the long-term outcomes of stem cell transplantation and compare Crohn's perianal fistula (CPF) closure rates after stem cell transplantation with and without anti-TNF therapy, and to identify the factors affecting CPF closure and recurrence.

The patients with CD who underwent stem cell transplantation for treating perianal fistula in our institution between Jun 2014 and December 2022 were enrolled. Clinical data were compared according to anti-TNF therapy and CPF closure.

A total of 65 patients were included. The median age of females was 26 years (range: 21-31) and that of males was 29 (44.6%). The mean follow-up duration was 65.88 ± 32.65 months, and complete closure was observed in 50 (76.9%) patients. The closure rates were similar after stem cell transplantation with and without anti-TNF therapy (66.7% vs 81.6% at 3 year, P = 0.098). The patients with fistula closure had short fistulous tract and infrequent proctitis and anorectal stricture (P = 0.027, 0.002, and 0.008, respectively). Clinical factors such as complexity, number of fistulas, presence of concurrent abscess, and medication were not significant for closure. The cumulative 1-, 2-, and 3-year closure rates were 66.2%, 73.8%, and 75.4%, respectively.

Anti-TNF therapy does not increase CPF closure rates in patients with stem cell transplantation. However, both refractory and non-refractory CPF have similar closure rates after additional anti-TNF therapy. Fistulous tract length, proctitis, and anal stricture are risk factors for non-closure in patients with CPF after stem cell transplantation.

Crohn's disease (CD), a chronic inflammatory bowel disorder, manifests in various phenotypes, with fistulizing perianal CD (CD-PAF) being one of its most severe phenotypes. Characterized by fistula formation and abscesses, CD-PAF impacts 17% to 34% of all CD cases and with a significantly deleterious impact on patient's quality of life, while increasing the risk for anorectal cancers. The pathogenesis involves a complex interplay of genetic, immunological and environmental factors, with cytokines such as tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) playing pivotal roles. Diagnostic protocols require a multi-disciplinary approach including colonoscopy, examination under anesthesia and magnetic resonance imaging. In terms of treatment, biologics alone often prove inadequate, making surgical interventions such as setons and fistula surgeries essential. Emerging therapies such as mesenchymal stem cells are under study. The South Asian context adds layers of complexity, including diagnostic ambiguities related to high tuberculosis prevalence, healthcare access limitations and cultural stigma toward perianal Crohn's disease and ostomy surgery. Effective management necessitates an integrated, multi-disciplinary approach, especially in resource-constrained settings. Despite advances, there remain significant gaps in understanding the disease's pathophysiology and a dearth of standardized outcome measures, underscoring the urgent need for comprehensive research.

Inflammatory bowel diseases (IBDs) are chronic, recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis and Crohn's disease, is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations.

During the last decades, therapeutic goals in IBD evolved toward endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMAs). DMAs include conventional immunosuppressants (thiopurines, methotrexate), biologic drugs (anti-TNF, anti-integrin, and anti-IL-12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with aggressive course of disease and risk factors for poor prognosis should be treated with biologic therapy early, while conventional immunomodulators should be used in those with milder course of disease in the absence of risk factors.

Challenges in the treatment of IBD patients include the choice of effective yet safe drug and prevention or overcoming loss of response.

Perianal Crohn's disease affects 25%-35% of patients with Crohn's disease and has proven to be one of the most difficult complications of the disease to treat. Patients with perianal Crohn's disease have lower health-related quality of life scores typically related to pain and fecal incontinence. In addition, patients with perianal Crohn's disease have higher rates of hospitalizations, surgeries, and overall healthcare costs. A multidisciplinary approach is necessary for the successful management of Crohn's disease with perianal fistula. Medical management is required to treat the underlying immune dysregulation to heal the luminal inflammation and the inflammation within the fistula tracts. Current options for medical therapy include biologics, dual therapy with thiopurines, therapeutic drug monitoring, and a close follow-up. Surgical management is critical to drain abscesses before immunosuppressive therapy and place setons when appropriate. Once the patient's inflammatory burden is well managed, definitive surgical therapies including fistulotomies, advancement flaps, and ligation of intersphincteric fistula tract procedures can be considered. Most recently, the use of stem cell therapy in the treatment of perianal fistula has given new hope to the cure of perianal fistula in Crohn's disease. This review will outline the most current data in the medical and surgical management of perianal Crohn's disease.

Perianal fistula is a common inflammatory condition in the general population and affects the area around the anal canal. Although most cases are benign, they cause serious morbidity and require surgical treatment due to a high risk of recurrence. MR imaging is a gold standard technique for the evaluation of perianal fistulas and provides accurate information on the anatomy of the anal canal, its relationship to the anal sphincter complex, accurate identification of secondary tracts or abscesses, and reporting associated complications. MR imaging can help monitor treatment effects and determine treatment methods. Crohn's disease-related fistulas often require medical rather than surgical treatment. The radiologist is required to know the anatomy and MR imaging findings of the perianal fistula to present an accurate diagnosis to the clinician.

Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that mimics human perianal disease is needed to test innovative therapies.

This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease.

This was an animal preclinical study.

The experiments were performed at the animal laboratory at the Johns Hopkins University.

Four sus scrufus female pigs were included in the study.

Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease.

An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology.

Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining.

The fistulas were surgically induced and did not occur naturally.

A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 .

La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).

We aimed to develop criteria for treatment intensification in patients with (1) luminal Crohn's disease (CD), (2) CD with perianal disease and/or fistula, (3) CD with small bowel stenosis, (4) in the postoperative setting, and (5) for discontinuing or reducing the dose of treatment in patients with CD.

PubMed and Embase were searched for studies published since 1998 which may be relevant to the five defined topics. Results were assessed for relevant studies, with preference given to data from randomized, controlled studies. For each question, a core panel of 12 gastroenterologists defined the treatment target and developed statements, based on the literature, current guidelines, and relevant additional studies. The evidence supporting each statement was graded using the Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). A modified Delphi process was used to refine statements and gain agreement from 54 Japanese specialists at in-person and online meetings conducted between October 2020 and April 2021.

Seventeen statements were developed for treatment intensification in luminal CD (targeting endoscopic remission), six statements for treatment intensification in perianal/fistulizing CD (targeting healing of perianal lesions and complete closure of the fistula), six statements for treatment intensification in CD with small bowel stenosis (targeting resolution of obstructive symptoms), seven statements for treatment intensification after surgery (targeting endoscopic remission), and five statements for discontinuing or reducing the dose of treatment in patients with CD.

These statements provide guidance on how and when to intensify or de-intensify treatment for a broad spectrum of patients with CD.

Perianal fistulas (PAFs) represent a severe complication of Crohn's disease (CD). Despite the advent of biologic and small-molecule therapeutics for luminal disease, PAFs in CD (CD-PAF) are relatively resistant to treatment, with less than 50% responding to any therapy. We report an injectable, biodegradable, mechanically fragmented nanofiber-hydrogel composite (mfNHC) loaded with adipose-derived stem cells (ADSCs) for the treatment of fistulas in a rat model of CD-PAF. The ADSC-loaded mfNHC results in a higher degree of healing when compared to surgical treatment of fistulas, which is a standard treatment. The volume of fistulas treated with mfNHC is decreased sixfold compared to the surgical treatment control. Molecular studies reveal that utilization of mfNHC reduced local inflammation and improved tissue regeneration. This study demonstrates that ADSC-loaded mfNHC is a promising therapy for CD-PAF, and warrants further studies to advance mfNHC toward clinical translation.

As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8l showed potent inhibitory activities against interferon-stimulated genes (IC₅₀: 3.3 nM) and NF-κB pathways (IC₅₀: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1β, TNF-α, IL-12, and IFN-γ. In vivo, 8l produced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.

Perianal fistulizing Crohn's disease (PFCD) represents a challenging and complex disease phenotype. Patients typically suffer a more severe disease course than those without perianal complications and are often managing debilitating symptoms. Etiology is understood to be multifactorial, with genetic predisposition, microbiological insult, aberrant immunity, and mechanical factors all implicated. As a result, multimodal treatment strategies must be employed to achieve disease control and fistula closure. This requires the complimentary involvement of medical and surgical disciplines in order to ensure thorough assessment and treatment tailored to the individual scenario and patient goals. The aim of this article is to describe an overview of the various treatment strategies available for PFCD, focusing on how a synergistic approach is required to ensure maximal chances of success.

Nodular regenerative hyperplasia (NRH) has been associated with thiopurine therapy in patients with inflammatory bowel disease (IBD), but prevalence and prognosis of NRH remain unclear. This study is a cross-sectional search for NRH in IBD patients with long-term azathioprine or 6-mercaptopurine treatment.

Thirty-three IBD patients with continuous azathioprine/6-mercaptopurine treatment for at least 5 years were included. Laboratory tests, thiopurine metabolite levels, liver histology, MRI were examined for NRH and signs of portal hypertension.

NRH was not observed in this cohort of 33 patients. Nevertheless, some possibly related signs of vascular changes were found by MRI in three patients. Also, splenomegaly, which may be associated with portal hypertension, was found in one patient. No high thiopurine dose neither high metabolite levels were found in these patients.

No NRH was found in this group of IBD patients with long-term azathioprine/6-mercaptopurine treatment. Larger multicenter studies are needed to determine the prevalence of NRH in thiopurine-treated IBD patients.

In this study, we investigated the effects of radish sprout ethanol extract (RSE) on inflammatory responses in the macrophages and a mouse model of colitis. RSE administration was found to effectively inhibit the phosphorylation of IκB and, in turn, the production of pro-inflammatory enzymes and cytokines in lipopolysaccharide-stimulated macrophages. In dextran sulfate sodium (DSS)-colitis mice, RSE administration prevented body weight and colon length reduction, while decreasing inflammation and mucosal necrosis. The diversity of the fecal microbiota was significantly increased in the group treated with RSE. In addition, RSE administration decreased the relative abundance of the phylum Proteobacteria, which includes many pathogens, and increased the abundance of the genus Akkermansia. Beta diversity analyses showed that RSE administration restored the gut microbiota composition close to that of healthy mice. For the first time, we identified glycosides of sinapic acid as part of hydroxycinnamic acids in RSE with colitis-alleviating effects. Notably, 1,2-O-disinapoyl glucoside substantially decreased nitric oxide generation in LPS-stimulated macrophages.

Perianal fistula is one of the most common complications in Crohn's disease, and various medical and surgical treatments are being tried. The aim of this study was to compare the perianal fistula closure rates following treatment with anti-tumor necrosis factor (TNF) agents or autologous adipose tissue-derived stem cell (auto-ASC) transplantation with Crohn's disease (CD).

CD patients who underwent seton placement for perianal fistula from January 2015 to December 2019 at a tertiary referral center were retrospectively reviewed. Patients were divided into two groups, one that received sequential treatments with anti-TNF agents (anti-TNF group) and the other that underwent auto-ASC transplantation (stem cell group). Clinical variables and fistula closure rates were compared in the two groups.

Of the 69 patients analyzed, 39 were treated with anti-TNF agents and 30 underwent auto-ASC transplantation. Compared with the stem cell group, patients in the anti-TNF group were older (p=0.028), were more frequently male (p=0.019), had fistulas with more penetrating behavior (p=0.002), had undergone surgery more frequently (p=0.010), and had a shorter interval from seton placement to intended treatment (p<0.001). During a median follow-up of 46 months (range, 30-52.5 months), fistula closure rates were significantly faster (83.3% vs. 23.1%, p<0.001), and the mean interval from seton placement to fistula closure significantly shorter (14 vs. 37 months, p<0.001) in the stem cell than in the anti-TNF group. Three patients experienced fistula recurrence, all in the stem cell group.

Medical treatment using anti-TNF agents and auto-ASC transplantation are feasible treatment options after seton placement for Crohn's perianal fistula. However, the closure rate was significantly faster and the time to closure significantly shorter in patients who underwent auto-ASC transplantation than medical treatment.

This study was retrospectively registered and approved by the Institutional Review Board of Asan Medical Center, number 2020-1059 .

Immunomodulator monotherapy is an important component in the treatment of inflammatory bowel disease (IBD). However, there is conflicting literature about thiopurines maintaining long-term remission in patients with active IBD.

To determine the durable clinical remission rate in adults with Crohn's disease (CD) or ulcerative colitis (UC) on thiopurine monotherapy over 5 years.

We performed a retrospective analysis of adult patients identified at McGill University Health Centre from 2009 to 2012. We included IBD patients who initiated thiopurine monotherapy and were in remission for at least 3 months (Harvey-Bradshaw Index (HBI) < 5 points for CD and partial Mayo Score (pMS) < 2 points in UC). The primary endpoint was sustained clinical remission on thiopurines during a 5-year follow-up. This included patients who had not relapsed or discontinued the drug due to side effects. The secondary endpoint was clinical relapse over the follow-up period, which was defined as HBI > 5 in CD and pMS > 2 in UC.

There were 148 patients included in the study (100 CD; 48 UC). At 5 years, 23% (34/148) patients remained in clinical remission on thiopurine monotherapy (25 CD and 9 UC patients). Thirty-three percent (33/100) of CD and 46% (22/48) of UC patients relapsed while on thiopurines. There was no difference in relapse rates between CD and UC patients. Eighty-four percent (42/50) of patients with CD with side effects and all UC (17/17) patients who experienced side effects discontinued the drug.

This analysis demonstrates that there is poor sustainability of clinical remission in IBD patients on thiopurine monotherapy given that a high proportion of patients discontinue thiopurines due to either relapse or side effects.

Objectives: The incidence of Crohn's disease and the number of associated surgeries are increasing in Korea. This study investigated the effect of azathioprine/6-mercaptopurine (6-MP) and TNF-α antagonists on abdominal and perianal surgery in Korean patients with Crohn's disease. Design: A retrospective cohort study. Setting: Data from the Crohn's Disease Clinical Network and Cohort (CONNECT) were used. Patients with confirmed Crohn's disease between 1982 and 2008 from 32 hospitals in the Republic of Korea were enrolled. The effect of azathioprine/6-MP on abdominal and perianal surgery was analysed using logistic regression analysis adjusting for age and sex. Participants: In total, 1161 Crohn's disease patients were included in the Republic of Korea in the surgery (n = 462, male = 339, female = 123) and control groups (n = 699, male = 484, female = 215). Results: In total, 1161 patients were selected, with 462 patients who underwent abdominal (n = 245) or perianal surgery (n = 217). The preoperative usage rates of azathioprine/6-MP were 18.8% and 65.1% (p < 0.0001) in the surgery and control groups, respectively. The preoperative usage rates of TNF-α antagonists were 7.1% and 23.3% (p < 0.0001) in the surgery and control groups, respectively. A multivariate analysis revealed that the preoperative use of azathioprine/6-MP had an odds ratio of 0.094 for all surgeries (95% confidence interval [CI]: 0.070-0.127, p < 0.0001), 0.131 for abdominal surgery (95% CI: 397-1.599, p < 0.0001), and 0.059 for perianal surgery (95% CI: 0.038-0.091, p < 0.0001). The preoperative use of TNF-α antagonists had an odds ratio of 0.225 for all surgeries (95% CI: 0.151-0.335, p < 0.0001), 0.403 for abdominal surgery (95% CI: 0.261-0.623, p < 0.0001), and 0.064 for perianal surgery (95% CI: 0.026-0.160, p < 0.001). Strengths of this study: The study presents new evidence of the reduced risk of surgery following azathioprine use in Crohn's disease patients. Limitations of this study (1) This was not a controlled prospective study. (2) There was a selection bias specific to the CONNECT cohort. (3) The combination or sequential use of azathioprine/6-MP and TNF-α antagonists was not excluded. Conclusion: Azathioprine/6-MP is significantly associated with a reduced risk of abdominal and perianal surgery in Korean patients with Crohn's disease.

Many Crohn's disease (CD) patients will undergo surgery over the course of their life. It is thought that with the introduction of disease-modifying agents like anti-TNF therapy, there would be a population-level decrease in the need for surgery. This time-trend study aimed to assess the changes in surgical rates following the induction of anti-TNF therapy.

Adult CD patients who underwent abdominal surgery (identified by administrative coding) between January of 1996 and December of 2013 at 1 of the 4 Edmonton-area hospitals were included. Patient charts were manually reviewed to confirm diagnosis and gather demographic and disease-related data. Population-adjusted annual incidence rates for IBD surgery were calculated by dividing the number of surgeries by estimates for total population of CD patients in Edmonton. Time-trend analysis was conducted to identify change points, calculate annual percent change (APC), and associated 95% confidence intervals (CIs).

A total of 1410 patients with Crohn's disease underwent surgery for their disease. The surgical rate decreased by 8.4% each year (95% CI, -9.6% to -7.3%). There was a 36.2% increase in the use of anti-TNF therapy per year (95% CI, 31.3% to 41.5%). Changes in modifiable risk factors for surgery were also seen, including the proportion of active smokers decreasing by 2.2% per year (95% CI, -3.7% to -0.6%).

Although anti-TNF therapy seems to play a role, the decrease in surgical trends is likely multifactorial, owing to a decline in smoking trends, earlier diagnosis, earlier treatment, improved patient education, and changes in clinical practice.

Perianal fistula is one of the most challenging complications of Crohn's disease (CD). We aimed to describe treatment response with surgical and medical therapies, and long-term complications.

We retrospectively analyzed records of patients with perianal fistulizing CD who were prospectively followed from January 2005 to December 2018.

Among 807 patients, 81 (10%) had perianal fistula and 65 were included in the final analysis. The mean age of presentation was 27.4 ± 10.3 years, and 78.5% were males with a median duration of follow-up of 45 (IQR, 24-66) months. 75.4% (n = 49) had complex fistulae. 55.4% (n = 36) of patients received multiple courses (> 5 courses) of antibiotics. Complete response rates with immunomodulators, fistula surgery, biologicals, and diversion were 25%, 42.8%, 39.5%, and 45.4%, respectively. The relapse rate was highest after fistula surgery (52.6%). 44.6% of patients received medical (immunomodulators-21 and biologicals-8) whereas 46.1% received surgery as the first-line therapy. The absence of perianal abscess was associated with complete fistula closure. One patient developed malignancy and 4 (6.1%) died at the end of follow-up. Among the patients (n = 28) who received biologicals, TB reactivation occurred in one patient (3.5%).

Medical therapy should be offered as first-line therapy, and immunomodulators can be considered when patients cannot afford biologicals. Surgery offers temporary improvement and is associated with high relapse rates. Absence of perianal abscess predicts long-term complete fistula closure.

Thiopurine methyltransferase (TPMT) activity influences azathioprine conversion into active metabolite 6-thioguanine nucleotide (6-TGN). Low TPMT activity correlates with high 6-TGN and risk for myelosuppression. Conversely, normal-to-high TPMT activity may be associated with low 6-TGN and drug resistance, the so-called hypermetabolizers. Our aim was to identify the effect of normal-to-high TPMT activity on 6-TGN concentrations in an inflammatory bowel disease population.

A retrospective chart review of patients aged ≥18 with inflammatory bowel disease, on azathioprine, with documented TPMT activity and 6-TGN concentration was performed. Correlations were evaluated via the Spearman rho correlation coefficient. Linear regression was used to determine the effect of TPMT activity on 6-TGN accounting for confounders. Relationships between TPMT activity, drug dose, and 6-TGN levels were defined via average causal mediation effects.

One hundred patients were included. No correlation was observed between TPMT activity, azathioprine dosing, and metabolite concentrations. Overall, 39% of the cohort had a therapeutic 6-TGN level of >230 pmol/8 × 10⁸ red blood cells (RBCs). No patient under 1 mg/kg achieved a therapeutic 6-TGN level, whereas 42% of patients taking 2.5 mg/kg did. The median 6-TGN concentration was higher for those in remission (254 pmol/8 × 10⁸ RBCs, interquartile range: 174, 309) versus those not in remission (177 pmol/8 × 10⁸ RBCs, interquartile range: 94.3, 287.8), though not significantly (P = 0.08). Smoking was the only clinical factor associated with 6-TGN level. On multivariate linear regression, only age, azathioprine dose, and obese body mass index were predictive of metabolite concentration.

Variations within the normal range of TPMT activity do not affect 6-TGN concentration.

Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use.

To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.

English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed.

Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance.

The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

Perianal fistulizing Crohn's disease is associated with a poor quality of life and current medical and surgical treatment options are limited. Darvadstrocel, composed of mesenchymal stem (stromal) cells (MSC), has recently been approved by the European Medicines Agency (EMA) for the treatment for perianal disease. This drug profile educates the reader with this novel treatment approach.

A literature search was performed on PubMed with focus on perianal fistulizing Crohn's disease and mesenchymal stem (stromal) cells. This review summarizes evidence of the current standard of care and discusses the mechanism of action, manufacturing, and application and safety of darvadstrocel.

Darvadstrocel is a safe and effective therapy for complex perianal fistulizing Crohn's disease.

Perianal fistulizing Crohn's disease (PFCD) is a common, disabling and aggressive phenotype that negatively impacts on the quality of life of affected patients. Its successful treatment is still a struggle for both physicians and patients. Significant advances in the management of this condition have occurred in the last two decades holding promise for a better future. This culminated into the concept of a collaborative multidisciplinary approach using the latest medical therapies combined with modern surgical and endoscopic techniques. Despite this, PFCD management and treatment have not been standardized yet. Thus the gastroenterologist and surgeon have to be familiar with several approaches and/or techniques. The positioning of each therapeutic option will certainly evolve with new data, but for the time being it should be driven by patient's characteristics, physician's preference and/or experience, costs and availability in local practice. Additionally, patient's perception of benefits and risks of treatment may differ from those of physicians and recognition of this difference is a starting point for difficult clinical decision-making. In this paper, a multidisciplinary group of Italian IBD experts explore and discuss current medical and surgical therapeutic options, highlighting areas of unmet needs in PFCD, with particular focus on the optimal patient flow within the Italian clinical reality.

Recommendations are advice that is given and considered to be beneficial; however, they are still suggestions and are therefore open to different interpretations. In this sense, the final objective of the review has been to try to homogenize, with the evidence available, the approach to the diagnosis and medical/surgical treatment of one of the most complex manifestations of Crohn's disease, such as simple and complex perianal fistulas.

Little is known of the outcome of patients with perianal Crohn's disease after stopping anti-tumour necrosis factor (TNF) therapy.

To evaluate the rate of relapse in perianal Crohn's disease (CD) after stopping anti-TNF therapy.

Consecutive perianal CD patients treated with anti-TNF therapy with subsequent discontinuation were retrieved from prospective inflammatory bowel disease database of institutes in Hong Kong, Shanghai, Taiwan, Malaysia, Thailand and Singapore from 1997 to June 2019. Cumulative probability of perianal CD relapse was estimated using Kaplan-Meier method.

After a median follow-up of 89 months (interquartile range [IQR]: 65-173 months), 44 of the 78 perianal CD patients (56.4%) relapsed after stopping anti-TNF, defined as increased fistula drainage or recurrence of previously healed fistula, after stopping anti-TNF therapy. Cumulative probabilities of perianal CD relapse were 50.8%, 72.6% and 78.0% at 12, 36 and 60 months, respectively. Younger age at diagnosis of CD [adjusted hazard ratio (HR): 1.04; 95% CI 1.01-1.09; P = .04] was associated with a higher chance of perianal CD relapse. Among those with perianal CD relapse (n = 44), retreatment with anti-TNF induced remission in 24 of 29 patients (82.8%). Twelve (27.3%) patients required defunctioning surgery and one (2.3%) required proctectomy. Maintenance with thiopurine was not associated with a reduced likelihood of relapse [HR = 1.10; 95% CI: 0.58-2.12; P = .77]. Among the 17 patients who achieved radiological remission of perianal CD, five (35.3%) developed relapse after stopping anti-TNF therapy after a median of 6 months.

More than half of the perianal CD patients developed relapse after stopping anti-TNF therapy. Most regained response after resuming anti-TNF. However, more than one-fourth of the perianal CD patients with relapse required defunctioning surgery. Radiological assessment before stopping anti-TNF is crucial in perianal CD.

According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.

Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.

Crohn's colitis carries a risk for permanent stoma with extirpation of the rectum. We aimed to estimate the proctectomy rate and identify risk factors for proctectomy in patients with Crohn's colitis.

For this study, we retrospectively reviewed data from consecutive patients with Crohn's disease (CD) affecting the colon or anorectal region undergoing bowel resection in a reference colorectal centre between 2006 and 2016. The cumulative risk for proctectomy was calculated using the Kaplan-Meier curve. We used univariate and multivariate logistic regression analyses to determine independent risk factors for proctectomy. Outcomes after proctectomy concerning reoperation frequency and perineal wound healing are also described.

In total, this study included 125 patients. Proctectomy was performed in 36 patients (28.8%), of whom 14 patients (38.9%) experienced perineal wound healing problems. The rates of proctectomy were 5.6% and 32.0% 10 and 20 years after CD diagnosis, respectively. Female gender (odds ratio (OR) 3.375, 95% confidence interval (CI) 1.304-8.733, P = 0.012), disease duration (OR 1.067, 95% CI 1.011-1.126, P = 0.018) and history of perianal disease (OR 3.160, 95% CI 1.215-8.219, P = 0.018) were independent risk factors for a proctectomy procedure, whereas thiopurine medication (OR 0.170, 95% CI 0.060-0.486, P = 0.001) was an independent protective factor for proctectomy.

The duration of Crohn's disease, female gender and a history of perianal disease were significant risk factors for a proctectomy procedure. Future research should examine whether immunosuppressive and biological medications reduce the risk for proctectomy.

Four novel ligands, namely N-benzhydryl benzamide, N, N-diphenethyl benzamide, N, N-dihexyl benzamide, and N, N-dioctyl benzamide (L1, L2, L3, and L4, respectively), based on the benzamide unit were designed and computed for their different properties, such as absorption spectrum, dipole moment, theoretically expected biological properties, and frontier molecular orbitals, by evaluating the HOMO/LUMO energy orbitals strength with DFT approaches and comparing these properties with the R benzamide properties available in literature. All molecules have a suitable frontier molecular orbital diagram and L1 exhibits maximum absorption at 246.8 nm due to the strong electron donating effect of the diphenylmethane ligand group. Moreover, strongly extended conjugated groups caused a redshift in absorption spectra. Newly designed molecules may show strong biological activities against cancer, bacterial diseases, and harmful fungal disorders. Graphical abstract Orbital energy, electron density and frontier molecular orbitals view of four designed novel benzamide derivates.