Assessment of perianal fistulizing Crohn’s disease activity with endoanal ultrasound: A retrospective cohort study

BACKGROUND Perianal fistulas pose dual challenges to Crohn's disease(CD)patients.Low patient compliance due to the complexity of existing examination methods plagues the treatment and follow-up management of perianal CD.AIM To determine the accuracy of endoanal ultrasound(EUS)and shear wave elastography(SWE)for evaluating perianal fistulizing CD(PFCD)activity.METHODS This was a retrospective cohort study.A total of 67 patients from August 2022 to December 2023 diagnosed with CD were divided into three groups:Non-anal fistula group(n=23),low-activity perianal fistulas[n=19,perianal disease activity index(PDAI)≤4],high-activity perianal fistulas(n=25,PDAI>4)based on the PDAI.All patients underwent assessments including EUS+SWE,pelvic magnetic resonance[pelvic magnetic resonance imaging(MRI)],C-reactive protein,fecal calprotectin,CD activity index,PDAI.RESULTS The percentage of fistulas indicated by pelvic MRI and EUS was consistent at 82%,and there was good consistency in the classification of perianal fistulas(Kappa=0.752,P<0.001).Significant differences were observed in the blood flow Limberg score(χ^(2)=8.903,P<0.05)and shear wave velocity(t=2.467,P<0.05)between group 2 and 3.Shear wave velocity showed a strong negative correlation with magnetic resonance novel index for fistula imaging in CD(Magnifi-CD)score(r=-0.676,P<0.001),a weak negative correlation with the PDAI score(r=-0.386,P<0.05),and a weak correlation between the Limberg score and the PDAI score(r=0.368,P<0.05).CONCLUSION EUS combined with SWE offers a superior method for detecting and quantitating the activity of perianal fistulas in CD patients.It may be the ideal tool to assess PFCD activity objectively for management strategies.

Perianal Crohn’s disease:Still more questions than answers

In this editorial we comment on the article by Pacheco et al published in a recent issue of the World Journal of Gastroenterology.We focus specifically on the burden of illness associated with perianal fistulizing Crohn’s disease(PFCD)and the diagnostic and therapeutic challenges in the management of this condition.Evol-ving evidence has shifted the diagnostic framework for PFCD from anatomical classification systems,to one that is more nuanced and patient-focused to drive ongoing decision making.This editorial aims to reflect on these aspects to help clinicians face the challenge of PFCD in day-to-day clinical practice.

Optimized timing of using infliximab in perianal fistulizing Crohn's disease

Infliximab(IFX),as a drug of first-line therapy,can alter the natural progression of Crohn’s disease(CD),promote mucosal healing and reduce complications,hospitalizations,and the incidence of surgery.Perianal fistulas are responsible for the refractoriness of CD and represent a more aggressive disease.IFX has been demonstrated as the most effective drug for the treatment of perianal fistulizing CD.Unfortunately,a significant proportion of patients only partially respond to IFX,and optimization of the therapeutic strategy may increase clinical remission.There is a significant association between serum drug concentrations and the rates of fistula healing.Higher IFX levels during induction are associated with a complete fistula response in these patients.Given the apparent relapse of perianal fistulizing CD,maintenance therapy with IFX over a longer period seems to be more beneficial.It appears that patients without deep remission are at an increased risk of relapse after stopping anti-tumor necrosis factor agents.Thus,only patients in prolonged clinical remission should be considered for withdrawal of IFX treatment when biomarker and endoscopic remission is demonstrated,especially when the hyperintense signals of fistulas on T2-weighed images have disappeared on magnetic resonance imaging.Fundamentally,the optimal timing of IFX use is highly individualized and should be determined by a multidisciplinary team.

Multidisciplinary and evidence-based management of fistulizing perianal Crohn's disease

Perianal symptoms are common in patients with Crohn's disease and cause considerable morbidity. The etiology of these symptoms include skin tags, ulcers, fissures, abscesses, fistulas or stenoses. Fistula is the most common perianal manifestation. Multiple treatment options exist although very few are evidence-based. The phases of treatment include: drainage of infection, assessment of Crohn's disease status and fistula tracts, medical therapy, and selective operative management. The impact of biological therapy on perianal Crohn's disease is uncertain given that outcomes are conflicting. Operative treatment to eradicate the fistula tract can be attempted once infection has resolved and Crohn's disease activity is controlled. The operative approach should be tailored according to the anatomy of the fistula tract. Definitive treatment is challenging with medical and operative treatment rarely leading to true healing with frequent complications and recurrence. Treatment success must be weighed against the risk of complications, specially anal sphincter injury. A full understanding of the etiology and all potential therapeutic options is critical for success. Multidisciplinary management of fistulizing perianal Crohn's disease is crucial toimprove outcomes.

Evaluating the effectiveness of infliximab on perianal fistulizing Crohn’s disease by magnetic resonance imaging

Background and aim:Data on the radiologic evaluation of perianal fistulizing Crohn’s disease(PFCD)naive to anti-tumor necrosis factor therapy are scarce,especially in Asian populations.We assessed the effectiveness of infliximab(IFX)on PFCD and explored predictors of‘deep remission’based on clinical and radiologic assessments.Methods:Patients with Crohn’s disease and active anal fistulas attending our care center for IFX therapy were prospectively enrolled.Each patient underwent clinical examination according to the Fistula Drainage Assessment Index,endoscopy for assessment of Crohn’s Disease Activity Index(CDAI)and Perianal Crohn’s Disease Activity Index(PCDAI),magnetic resonance imaging(MRI)to determine Van Assche score and Ng score,and laboratory tests up to 2 weeks prior to the start of and up to 2 weeks after the sixth IFX therapy(Week 32).Results:Among 38 patients treated with IFX,52.6%achieved clinical remission based on the Fistula Drainage Assessment Index and 42.1%achieved deep remission based on Ng score.Van Assche score(from 14.5±4.26 to 7.36±7.53),CDAI(from 170±92 to 71±69)and PCDAI(from 7.45±2.65 to 2.44±3.20)decreased significantly after six IFX treatments.The only predictor of deep remission was simple fistula(P=0.004,odds ratio=3.802,95%confidence interval:1.541–9.383).Conclusions:IFX has been shown to have appreciable effectiveness in Chinese patients with PFCD.MRI is the gold standard for evaluating PFCD,but Van Assche score has some limitations.

Establishing a rabbit model of perianal fistulizing Crohn's disease

BACKGROUND Crohn’s disease(CD)is a chronic nonspecific intestinal inflammatory disease.The aetiology and pathogenesis of CD are still unclear.Anal fistula is the main complication of CD and is a difficult problem to solve at present.The main limitation of developing new therapies is bound up with the short of preclinical security and effectiveness data.Therefore,an ideal animal model is needed to establish persistent anal fistula and an inflamed rectal mucosa.AIM To improve the induction method of colitis and establish a reliable and reproducible perianal fistulizing Crohn’s disease animal model to evaluate new treatment strategies.METHODS Twenty male New Zealand rabbits underwent rectal enema with different doses of 2,4,6-trinitrobenzene sulfonic acid to induce proctitis.Group A was treated with an improved equal interval small dose increasing method.The dosage of group B was constant.Seven days later,the rabbits underwent surgical creation of a transsphincteric fistula.Then,three rabbits were randomly selected from each group every 7 d to remove the seton from the fistula.The rabbits were examined by endoscopy every 7 days,and biopsy forceps were used to obtain tissue samples from the obvious colon lesions for histological analysis.The disease activity index(DAI),colonoscopy and histological scores were recorded.Perianal endoscopic ultrasonography(EUS)was used to evaluate the healing of fistulas.RESULTS Except for the DAI score,the colonoscopy and histological scores in group A were significantly higher than those in group B(P<0.05).In the ideal model rabbit group,on the 7 th day after the removal of the seton,all animals had persistent lumens on EUS imaging,showing continuous fullthickness high signals.Histological inspection of the fistula showed acute and chronic inflammation,fibrosis,epithelialization and peripheral proctitis of the adjoining rectum.CONCLUSION The improved method of CD colitis induction successfully established a rabbit perianal fistula CD preclinical model,which was confirmed by endoscopy and pathology.

Management of perianal fistulas in Crohn's disease:An upto-date review

Perianal disease is one of the most disabling manifestations of Crohn's disease.A multidisciplinary approach of gastroenterologist,colorectal surgeon and radiologist is necessary for its management.A correct diagnosis,based on endoscopy,magnetic resonance imaging,endoanal ultrasound and examination under anesthesia,is crucial for perianal fistula treatment.Available medical and surgical therapies are discussedin this review,including new local treatment modalities that are under investigation.

Emerging treatments for complex perianal fistula in Crohn's disease

Complex perianal fistulas have a negative impact on the quality of life of sufferers and should be treated.Correct diagnosis,characterization and classification of the fistulas are essential to optimize treatment.Nevertheless, in the case of patients whose fistulas are associated with Crohn's disease,complete closure is particularly difficult to achieve.Systemic medical treatments(antibiotics, thiopurines and other immunomodulatory agents,and, more recently,anti-tumor necrosis factor-αagents such as infliximab)have been tried with varying degrees of success.Combined medical(including infliximab)and less aggressive surgical therapy(drainage and seton placement)offer the best outcomes in complex Crohn's fistulas while more aggressive surgical procedures such as fistulotomy or fistulectomy may increase the risk of incontinence.This review will focus on emerging novel treatments for perianal disease in Crohn's patients. These include locally applied infliximab or tacrolimus, fistula plugs,instillation of fibrin glue and the use of adult expanded adipose-derived stem cell injection.More welldesigned controlled studies are required to confirm the effectiveness of these emerging treatments.

Burden and outcomes for complex perianal fistulas in Crohn's disease:Systematic review

AIM To systematically review the literature on epidemiology,disease burden, and treatment outcomes for Crohn's disease(CD) patients with complex perianal fistulas.METHODS PubMed, Embase, and Cochrane were searched for relevant articles(published 2000-November 2016) and congress abstracts(published 2011-November 2016).RESULTS Of 535 records reviewed, 62 relevant sources were identified(mostly small observational studies). The cumulative incidence of complex perianal fistulas in CD from two referral-centre studies was 12%-14%(follow-up time, 12 years in one study; not reported in the second study). Complex perianal fistulas result in greatly diminished quality of life; up to 59% of patients are at risk of faecal incontinence. Treatments include combinations of medical and surgical interventions and expanded allogeneic adipose-derived stem cells. High proportions of patients experience lack of or inadequate response to treatment(failure and relapse rates,respectively: medical, 12%-73% and 0%-41%; surgical:0%-100% and 11%.20%; combined medical/surgical:0%-80% and 0%-50%; stem cells: 29%-47% and not reported). Few studies(1 of infliximab; 3 of surgical interventions)have been conducted in treatment-refractory patients, a population with high unmet needs. Limited data exist on the clinical value of anti-tumour necrosis factor-α dose escalation in patients with complex perianal fistulas in CD.CONCLUSION Complex perianal fistulas in CD pose substantial clinical and humanistic burden. There is a need for effective treatments, especially for patients refractory to antitumour necrosis factor-α agents, as evidenced by high failure and relapse rates.

Higher infliximab and adalimumab trough levels are associated with fistula healing in patients with fistulising perianal Crohn’s disease

BACKGROUND Tumor necrosis factor-alpha inhibitors,including infliximab and adalimumab,are effective medical treatments for perianal fistulising Crohn’s disease(CD),but not all patients achieve fistula healing.AIM To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.METHODS In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia,we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment.Data collected included demographics,serum infliximab and adalimumab trough levels(mg/L)within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy.The primary outcome was fistula healing,defined as cessation in fistula drainage.The secondary outcome was fistula closure,defined as healing and closure of all external fistula openings.Differences between patients who did or did not achieve fistula healing were compared using the chi-square test,t test or Mann-Whitney U test.RESULTS One hundred and fourteen patients(66 infliximab,48 adalimumab)were included.Forty-eight(72.7%)patients on maintenance infliximab achieved fistula healing and 18(27.3%)achieved fistula closure.Thirty-seven(77%)patients on maintenance adalimumab achieved fistula healing and 17(35.4%)achieved fistula closure.Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not[infliximab:6.4(3.8-9.5)vs 3.0(0.3-6.2)mg/L,P=0.003;adalimumab:9.2(6.5-12.0)vs 5.4(2.5-8.3)mg/L,P=0.004].For patients on infliximab,fistula healing was associated with lower rates of detectable anti-infliximab antibodies and younger age.For patients on adalimumab,fistula healing was associated with higher rates of combination therapy with an immunomodulator.Serum trough levels for patients with and without fistula closure were not significantly different for infliximab[6.9(4.3-10.2)vs 5.5(2.5-8.3)mg/L,P=0.105]or adalimumab[10.0(6.6-12.0)vs 7.8(4.2-10.0)mg/L,P=0.083].CONCLUSION Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD.

Multi-national observational study to assess quality of life and treatment preferences in patients with Crohn’s perianal fistulas

BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling,and purulent perianal discharge,and METHODS This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries(April-August 2021).Patients were recruited into three cohorts:Cohort 1 included patients without perianal fistulas;cohort 2 included patients with perianal fistulas without fistula-related surgery;and cohort 3 included patients with perianal fistulas and fistula-related surgery.Validated patient-reported outcome measures were used to assess quality of life.Drivers of treatment preferences were measured using a discrete choice experiment(DCE).RESULTS In total,929 patients were recruited(cohort 1,n=620;cohort 2,n=174;cohort 3,n=135).Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF(cohorts 2 and 3)than for those with CD without CPF(cohort 1):Mean score 3.8 and 3.7 vs 4.1,respectively,(P<0.001).Similarly,mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF.Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery(cohorts 2 and 3):Mean score 41 and 42,respectively.In the DCE,postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice:Mean relative importance 35.7 and 24.7,respectively.CONCLUSION The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.

Indications and surgical options for small bowel, large bowel and perianal Crohn's disease

Despite advancements in medical therapy of Crohn's disease(CD), majority of patients with CD will eventually require surgical intervention, with at least a third of patients requiring multiple surgeries. It is important to understand the role and timing of surgery, with the goals of therapy to reduce the need for surgery without increasing the odds of emergency surgery and its associated morbidity, as well as to limit surgical recurrence and avoid intestinal failure. The profile of CD patients requiring surgical intervention has changed over the decades with improvements in medical therapy with immunomodulators and biological agents. The most common indication for surgery is obstruction from stricturing disease, followed by abscesses and fistulae. The risk of gastrointestinal bleeding in CD is high but the likelihood of needing surgery for bleeding is low. Most major gastrointestinal bleeding episodes resolve spontaneously, albeit the risk of re-bleeding is high. The risk of colorectal cancer associated with CD is low. While current surgical guidelines recommend a total proctocolectomy for colorectal cancer associated with CD, subtotal colectomy or segmental colectomy with endoscopic surveillance may be a reasonable option. Approximately 20%-40% of CD patients will need perianal surgery during their lifetime. This review assesses the practice parameters and guidelines in the surgical management of CD, with a focus on the indications for surgery in CD(and when not to operate), and a critical evaluation of the timing and surgical options available to improve outcomes and reduce recurrence rates.

Does capsule endoscopy have an added value in patients with perianal disease and a negative work up for Crohn's disease?

AIM:To investigate the role of capsule endoscopy in patients with persistent perianal disease and negative conventional work up for Crohn's disease(CD).METHODS:Patients with perianal disease(abscesses,fistulas,recurrent fissures) were evaluated for underlying CD.Patients who had a negative work up,defined as a negative colonoscopy with a normal ileoscopy or a normal small bowel series or a normal CT/MR enterography,underwent a Pillcam study of the small bowel after signing informed consent.Patients using nonsteroidal anti-inflammatory drugs or who had a history of inflammatory bowel disease or rheumatic disease were excluded.RESULTS:We recruited 26 patients aged 21-61 years(average 35.6 years),17 males and 9 females.One case could not be evaluated since the capsule did not leave the stomach.In 6 of 25(24%) patients with a negative standard work up for Crohn's disease,capsuleendoscopy(CE) findings were consistent with Crohn's disease of the small bowel.Family history of CD,white blood cell,hemoglobin,erythrocyte sedimentation rate or C-reactive protein did not predict a diagnosis of CD.Capsule endoscopy findings led to a change in treatment.CONCLUSION:In patients with perianal disease and a negative conventional work up to exclude CD,CE leads to incremental diagnostic yield of 24%.

Modern surgical strategies for perianal Crohn's disease

One of the most challenging phenotypes of Crohn’s disease is perianal fistulizing disease(PFCD).It occurs in up to 50%of the patients who also have symptoms in other parts of the gastrointestinal tract,and in 5%of the cases it occurs as the first manifestation.It is associated with severe symptoms,such as pain,fecal incontinence,and a significant reduction in quality of life.The presence of perianal disease in conjunction with Crohn’s disease portends a significantly worse disease course.These patients require close monitoring to identify those at risk of worsening disease,suboptimal biological drug levels,and signs of developing neoplasm.The last 2 decades have seen significant advancements in the management of PFCD.More recently,newer biologics,cell-based therapies,and novel surgical techniques have been introduced in the hope of improved outcomes.However,in refractory cases,many patients face the decision of having a stoma made and/or a proctectomy performed.In this review,we describe modern surgical management and the most recent advances in the management of complex PFCD,which will likely impact clinical practice.

Long-term efficacy of infliximab maintenance therapy for perianal Crohn’s disease

AIM:To assess the long-term efficacy of seton drainage with infliximab maintenance therapy in treatment of stricture for perianal Crohn’s disease(CD). METHODS:Sixty-two patients with perianal CD who required surgical treatment with or without infliximab between September 2000 and April 2010 were identified from our clinic’s database.The activities of the perianal lesions were evaluated using the modified perianal CD activity index(mPDAI)score.The primary endpoint was a clinical response at 12-15 wk after surgery as a shortterm efficacy.Secondary endpoints were recurrence as reflected in the mPDAI score,defined as increased points in every major element.The clinical responses were classified as completely healed(mPDAI=0),partially improved(mPDAI score decreased more than 4 points),and failure or recurrence(mPDAI score increased or decreased less than 3 points). RESULTS:There were 43 males and 19 females,of whom 26 were consecutively treated with infliximab after surgery as maintenance therapy.Complete healing was not seen.Failure was seen in 10/36(27.8%) patients without infliximab and 4/26(15.4%)patients with infliximab(P=0.25).Partial improvement was seen in 26/36(72.2%)patients without infliximab and 22/26(88.5%)patients with infliximab(P=0.25). Short-term improvement was achieved in 48/62(77.4%) patients.Although the mPDAI score improved significantly with surgery regardless of infliximab,it decreased more from baseline in patients with infliximab(50.0%) than in those without infliximab(28.6%),(P=0.003). In the long-term,recurrence rates were low regardless of infliximab in patients without anorectal stricture.In patients with anorectal stricture,cumulative recurrence incidences increased gradually and exceeded 40%at 5 years regardless of infliximab.No efficacy of infliximab treatment was found(P=0.97).Although the cumulative rate of ostomy creation was also low in patients without stricture and high in patients with stricture,no protective efficacy was found with infliximab treatment(P =0.6 without stricture,P=0.22 with stricture). CONCLUSION:Infliximab treatment was demonstrated to have short-term efficacy for perianal lesions.Longterm benefit with infliximab was not proven,at least in patients with anorectal stricture.

Review of stem cells as promising therapy for perianal disease in inflammatory bowel disease

Those patients with perianal Crohn's disease or ul-cerative colitis experience a difficult to treat disease process with a delayed state and often inability to heal despite current therapies. The approaches currently used to treat these patients with corticosteroids,antibiotics,immunomodulators, anti-tumor necrosis factor-α drug, and surgical repair are limited in their healing ability. This review presents all current literature since emergence in the early 2000s of stem cell therapy for patients with perianal inflammatory bowel disease and analyzes the efficacy, outcomes and safety within these studies.

An unusual presentation of fistulating Crohn's disease:Ascites

Whilst ascites is a common presenting complaint in patients with decompensated chronic liver disease and disseminated malignancy,in Crohn's disease however,it is exceptionally rare.We describe a patient with no prior history of inflammatory bowel or liver disease,presenting with rapid onset gross ascites and scrotal swelling.Further investigations revealed severe hypoalbuminemia and transudative ascitic fluid with normal other liver function tests and a negative liver screen.Computed tomography revealed widespread ascites and pleural effusions with no features of malignancy or portal hypertension,and a small bowel barium series showed features of fistulating small bowel Crohn's disease.An ileo-colonoscopy confirmed the presence of terminal ileal inflammatory stricture.The patient's clinical condition and serum albumin improved with a combination of diuretics,elemental diet,antibiotics and oral 5-aminosalicylic acid therapy.

One more chance of fistula healing in inflammatory bowel disease:Stem cell therapy

Patients with fistulizing inflammatory bowel disease are traditionally difficult to treat. This patient population often experiences delayed or insufficient healing of fistulas using current standard regimens including anti-biotics, immunomodulators, anti-tumor necrosis factor--α drug, placement of setons, and surgical repair. Several studies over the last ten to fifteen years have been conducted using stem cell therapies with promising results in this patient population. These studies show stem cell therapy in fistulizing disease to be successful in healing between 60%--88% compared to currently 50% with infliximab. Moreover, remission was seen 24 wk to 52 wk in these studies. Further research with a multi--approach treatment using medications, stem cell therapy, and surgical interventions will likely be the future of this innovative treatment approach.

Stem cell therapy:light in the tunnel for penetrating Crohn’s disease

Patients with Crohn’s disease frequently suffer from fistula resulting from adverse sequelae of persistent complicated active disease or surgical intervention.Fistula affects a patient’s quality of life and is directly associated with the need for surgical intervention.Diagnosis of fistula can be made through CT enterography,MR enterography,gastrograffin-based imaging,and transanal ultrasound.Treatment for fistula mainly consists of medication,endoscopic procedures,and surgery.There are emerging approaches under current investigation,such as stem cell therapy.The results showed a decent response in patients with perianal and rectovaginal fistula with minimal side effects.Further investigation is still needed for other internal fistula.

儿童肛周瘘管型克罗恩病的临床特征及预后

目的分析儿童肛周瘘管型克罗恩病(perianal fistulizing Crohn's disease,pfCD)患儿的临床特征、治疗及预后。方法回顾性选择2015年4月—2023年4月间诊断为克罗恩病(Crohn's disease,CD)的6~17岁患儿142例为研究对象,根据是否存在肛周瘘管型病变,分为pfCD组(60例)和非pfCD组(82例),比较两组患儿的临床特征、治疗及预后。结果pfCD发生率为42.3%(60/142)。pfCD组男性比例,病变范围累及结肠、小肠结肠比例,以及合并上消化道病变的比例高于非pfCD组(P<0.05)。pfCD组英夫利西单抗诱导缓解及维持缓解治疗比例高于非pfCD组(P<0.05)。pfCD组中,复杂性肛瘘患儿占62%(37/60),肛瘘非切割性挂线引流术治疗在复杂性肛瘘患儿中比例为62%(23/37),显著高于简单性肛瘘患儿(4%,1/23)(P<0.05)。两组患儿治疗54周黏膜愈合率和临床缓解率差异均无统计学意义(P>0.05)。pfCD组治疗54周瘘管愈合率为57%(34/60),其中简单性肛瘘患儿瘘管愈合率高于复杂性肛瘘患儿(P<0.05)。结论儿童CD患者中pfCD发生率高,pfCD患儿生物制剂使用比例高,复杂性肛瘘非切割性挂线引流术比例高,CD患儿随访中需要密切关注pfCD的发生。