Complex Perianal Crohn's Disease Research Articles

Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up

Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life. A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks. Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI-9.0 to-4.0, p=0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI-3.9 to-0.6, p=0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p=0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders. Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing. This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant2018.

Three-dimensional modelling as a novel interactive tool for preoperative planning for complex perianal fistulas in Crohn's disease.

The aim of this study is to demonstrate the added value of three-dimensional (3D) reconstruction models and artificial intelligence for preoperative planning in complex perianal Crohn's disease. MRI is the gold standard for diagnosis of complex perianal fistulas and abscess due to its high sensitivity, but it lacks high specificity values. This creates the need for better diagnostic models such as 3D image processing and reconstruction (3D-IPR) with artificial intelligence (AI) algorithms. This is a prospective study evaluating the utility of 3D reconstruction models from MRI in four patients with perineal Crohn's disease (pCD). Four pCD patients had 3D reconstruction models made from pelvic MRI. This provided a more visual representation of perianal disease and made possible location of the internal fistula orifice, seton placement in fistula tracts and abscess drainage. Three-dimensional reconstruction in CD-associated complex perianal fistulas can facilitate disease interpretation, anatomy and surgical strategy, potentially improving preoperative planning as well as intraoperative assistance. This could probably result in better surgical outcomes to control perianal sepsis and reduce the number of surgical procedures required in these patients.

P071 Fistula Healing After Fecal Diversion Surgery in Perianal Crohn's Disease; a Case Series.

BACKGROUND: Perianal fistula are seen in 25% of patients with Crohn's disease and are often refractory to medical therapy. Fecal diversion is used to treat perianal fistula, with 63% in clinical improvement, however data on fistula healing rates are often not reported. This case series aims to evaluate the response of complete fistula healing in complex perianal Crohn's disease after fecal diversion. METHODS: Patients with perianal Crohn's disease who underwent fecal diversion surgery from June 1, 2016 to June 1, 2020 with colorectal surgeons at UC Davis were selected through electronic medical record chart extraction using ICD-10 and CPT codes. RESULTS: Eleven patients with refractory perianal fistula underwent fecal diversion surgery from June 1, 2016 to June 1, 2020. Fistula healing was evaluated through imaging or exam under anesthesia. One patient was lost to follow up after surgery and not included in the outcomes. Time to follow up ranged from 4 to 24 months, with a mean of 11 months. Patient were aged 22–60 years. 5/11 were male. Ten of 11 patients were on biologic therapy at time of surgery, 4/10 (40%) had complete fistula healing, 6/10 (60%) had persistent fistula, and 3/10 (30%) were readmitted within 90 days for complications. Most frequent complications observed were peristomal wounds/skin infection (3/10), high ostomy output/dehydration (2/10), bowel obstruction (1/10). Two patients required proctectomy. CONCLUSION: Fistula healing rates after fecal diversion were low, at 40% and is accompanied by frequent complications such as output high ostomy.

Challenges in Crohn's disease: Complex perianal Crohn's disease

Perianal disease is a particularly morbid phenotype of Crohn's disease with significantly diminished quality of life, affecting up to a third of patients. Medical therapies achieve long term durable remission in only a third of patients. Thus, most undergo operative intervention, at the expense of a risk of incontinence. Mesenchymal stem cell therapy is an emerging therapy without risk of incontinence and improved efficacy as compared to conventional therapy. Additional manifestations of perianal Crohn's disease including hemorrhoids and skin tags are possible to manage operatively, only in the absence of proctitis and anal canal disease.

Tumor Necrosis Factor Inhibitors May Have Limited Efficacy for Complex Perianal Fistulas Without Luminal Crohn's Disease.

Complex perianal fistulas occurring in the absence of luminal inflammation (isolated perianal disease, IPD) may represent a specific phenotype of Crohn's disease (CD). We assessed the effectiveness of tumor necrosis factor (TNF)-antagonists in patients with IPD compared to those with perianal CD (PCD) with luminal inflammation. Patients were identified through our institutional radiology database and were classified as PCD or IPD based on the presence or absence of luminal inflammation by ileocolonoscopy and abdominal enterography. Consecutive adults (> 17years) with recurrent IPD who were treated with TNF antagonists were matched by age and gender to patients with complex PCD (1:2 ratio). Fistula remission was defined as an absence of fistula drainage. Surgery-free survival was assessed by Cox proportional hazard models. Twenty-two patients with IPD treated with a TNF antagonist were compared with 44 matched patients with PCD. A similar proportion of patients with IPD and PCD were treated with concomitant immunomodulators (55% vs. 66%) and underwent examinations under anesthesia prior to therapy (36% vs. 46%). Fistula remission at 3, 6, and 12months was lower for the IPD cohort: 9.5% versus 34%; 19% versus 39%; and 19% versus 43%. Surgical intervention after initiating anti-TNF therapy was more common for patients with IPD (HR 3.99: 95% CI, 1.62-9.83; p = 0.0026). Fewer patients with IPD achieved fistula remission, and more required surgical intervention after anti-TNF therapy, suggesting that TNF antagonists may not be as effective in these patients.

N802 Improving care for patients with perianal Crohn's disease; review of a perianal virtual clinic

Background: Effective communication within the inflammatory bowel disease (IBD) team is essential to the management of perianal Crohn's disease (PCD). We identified that medical, nursing and surgical care could be fragmented for patients with complex PCD. To address this we developed the perianal vi

Mesenchymal stem/stromal cell therapy for inflammatory bowel disease: an updated review with maintenance of remission.

There is a need for novel therapies for inflammatory bowel diseases (IBDs) that are well tolerated and effective. Currently, mesenchymal stem/stromal cells (MSCs) are being investigated in clinical trials for treatment of IBD. In this review, we update the recently published studies with an emphasis on the long-term efficacy of MSC therapy for IBD. A cumulative body of data, including a recent phase III randomized controlled trial demonstrated excellent fistula healing in patients with refractory Crohn's perianal fistulae treated via local injections of MSCs and with a good safety profile. Follow-up studies suggest long-term efficacy of MSC therapy for complex perianal Crohn's disease fistulae; however, the efficacy decreases over time and may necessitate repeat treatment. Systemic (intravenous) therapy for luminal IBD offers a relatively well tolerated alternative but its efficacy remains unclear. Recent studies demonstrate that MSCs are well tolerated and have an excellent short-term efficacy for the management of refractory fistulizing perianal Crohn's disease. The current data suggest that its influence may 'wear off' over time. More data on larger number of patients with longer duration of follow-up in the setting of a randomized placebo controlled trial are needed to confirm these promising results. For luminal IBD, there is a need for more mechanistic studies in representative preclinical murine models, and the results of an ongoing phase III randomized controlled trial are eagerly awaited.

The operative management of children with complex perianal Crohn's disease

Background/purposePerianal Crohn's disease (PCD) can affect both quality of life and psychological wellbeing. A subset of pediatric patients with complex PCD require surgical intervention, although appropriate timing and treatment regimens remain unclear. This study aimed to describe a large pediatric cohort in a tertiary center to determine the range of surgical management in children with complex PCD. MethodsA retrospective review of children requiring operative intervention for PCD over 13 years (2002–2014) was performed. PCD was divided into simple and complex based on the type of surgical procedure, and the two groups were compared. ResultsThe 57 children were divided into two groups: the simple group (N=43) underwent abscess drainage ± seton insertion alone, and the complex group (N=14) underwent loop ileostomy ± more extensive surgery. In the complex group, females were more predominant (57% of complex vs 30% of simple), and the average age at diagnosis was lower. Anti-TNF therapy was utilized in 79.1% of simple and 100% of complex PCD. All 14 complex patients underwent a defunctioning ileostomy, with 7 requiring further operations (subtotal colectomy=4, proctocolectomy ± anal sparing=5, plastic surgery reconstruction with perineal flap/graft=4). ConclusionComplex PCD represents a small but challenging subset of patients in which major surgical intervention may be necessary to alleviate the symptoms of this debilitating condition.Level of evidence: retrospective case study with no control group – level IV

Peristomal pyoderma gangrenosum after rectal adenocarcinoma in the context of colonic and complex perianal Crohn's disease

Peristomal pyoderma gangrenosum after rectal adenocarcinoma in the context of colonic and complex perianal Crohn's disease

Health Care Costs of Complex Perianal Fistula in Crohn’s Disease

To evaluate the use of health care resources and the associated costs of complex perianal Crohn's disease (CD) from the National Health System perspective. We conducted a multicenter, retrospective, observational study in which gastroenterologists from 11 hospitals in the Community of Madrid took part. Data was collected on the direct healthcare resources (pharmacological treatments, surgical procedures, laboratory/diagnostic tests, visits to specialists and emergency departments, and hospitalizations) consumed by 97 adult patients with complex perianal CD which was active at some point between January 1, 2005, and case history review. We recorded 527 treatments: 73.1% pharmacological (32.3% antibiotic, 20.5% immunomodulator, 20.3% biological) and 26.9% surgical. Mean annual global cost was €8,289/patient, 75.3% (€6,242) of which was accounted for by pharmacological treatments (€13.44 antibiotics; €1,136 immunomodulators; €5,093 biological agents), 12.4% (€1,027) by hospitalizations and surgery, 7.7% (€640) by medical visits, 4.2% (€350) by laboratory/diagnostic tests, and 0.4% (€30) by emergency department visits. Pharmacological therapies, and in particular biological agents, are the main cost driver in complex perianal CD; costs due to surgery and hospitalizations are much lower.

Combined modality treatment for complex fistulating perianal Crohn’s disease

Perianal disease affects 33% (range 8-90%) of patients with Crohn's disease. Fistulae are often complex and their management is often difficult and unsatisfactory. This study was a retrospective assessment of a combination of surgical treatment with a standardized protocol of infliximab (IFX) therapy. A consecutive series of patients with complex perianal Crohn's disease, presenting between January 2003 and June 2008, were included. Acute sepsis was initially treated with antibiotics and/or surgical drainage (MRI guided when appropriate) and loose seton insertion. IFX was given at 5 mg/kg, at 0, 2 and 6 weeks. End-points were complete, partial or no response. Setons were empirically removed after the second cycle of IFX. Forty-eight patients, average age 46 (range 24-82)years, with perianal Crohn's disease were identified. Three patients stopped IFX after the second infusion, either because of allergy (two patients) or for failure to respond (one patient). Fourteen patients were given maintenance IFX at 8-weekly intervals. Results were recorded for 48 patients, of whom 14 (29%) had a complete response, 20 (42%) had a partial response and 14 (29%) had no response to treatment. Outpatient follow-up was for a median of 20 months. Combining surgical procedures with IFX resulted in complete and partial remission in 29% and 42% of patients, respectively. No serious side effects occurred. Using a combined, intensive medico-surgical approach, good initial control of perianal disease was achieved safely.

Sa1898 Complex Perianal Crohn's Disease: Effectiveness of Combined Seton Placement and Anti-TNF Alpha Agents in Monotherapy or in Association With Immunosuppressants

Background and aim: IL-33, a new member of the IL-1 family, is linked to several immune and inflammatory disorders, such as IBD. Eosinophils (EOS) are found in active inflammatory lesions of IBD patients and can secrete proinflammatory molecules, alter epithelial barrier function and initiate mucosal immune responses leading to chronic gut inflammation. Recent evidence show that IL-33 can regulate EOS infiltration and function. The aim of this study is to determine IL-33-mediated EOS activation and ileal inflammation in the SAMP1/YitFc (SAMP) murine model of chronic enteritis. Material and methods: EOS were detected by IHC for major basic protein (MBP). IL-33 and EOS-associated cytokines, IL-5 and eotaxin-1,-2,-3, were measured by qPCR in a timecourse study of SAMP and AKR (parental control) ilea. Th2 cytokines were measured by ELISA in mesenteric lymph nodes (MLN) of SAMP treated daily with rIL-33 (33 ug/kg, ip for 1wk). EOS depletion and IL-33 neutralization studies were performed by ip administration (2X/wk for 6 wks) of Abs against IL-5/CCR3 and anti-ST2 (all 5mg/kg), respectively, on inflamed SAMP, and ileitis and cytokine expression evaluated. Results: Ileal IL-33, IL-5, and eotaxin-1 & -2 mRNA transcripts increased according to disease severity in SAMP (4vs. 20-wk-old, p<0.01) and were elevated vs. age-matched AKR controls (p<0.05). EOS infiltration showed a similar trend with more abundant and intense MBP staining in cells morphologically resembling EOS during disease progression in SAMP, and was virtually absent in AKR. Administration of rIL-33 induced an increase in the Th2 cytokines, IL-4, -5, &-10, levels in MLN of treated vs. vehicle-treated mice (p<0.05). Lastly, administration of either anti-IL-5/anti-CCR3 or antiST2 to inflamed SAMP resulted in a marked decrease in ileal inflammation (p<0.01), EOS infiltration, and Th2 cytokine/eotaxin-1&-2 mRNA expression (p<0.01) vs. IgG control-treated mice. Conclusions: Taken together, these data demonstrate a pathogenic role of IL33-mediated EOS infiltration and function in chronic intestinal inflammation, and that blockade of IL-33 and/or downstream EOS activation may represent a novel therapeutic modality to treat patients with IBD.

P393 Combination of surgical therapy and local injections of adalimumab in treatment of complex perianal Crohn's disease

In the emergency subgroup (3 patients), mean LoHS was 27.66 days (range: 15 47 days). Two patients were on steroid treatment at time of surgery and one encountered postoperative complications. Conclusions: LoHS and incidence of postoperative complications are significantly raised in those patients undergoing emergency procedures for UC. Multiple drug therapy and the use of a biological agent or steroids at time of surgery do not appear to affect LoHS significantly in this small sample. More extensive data is needed to identify potentially modifiable presurgical factors influencing LoHS and a larger data set would increase reliability of results.

Gracilis muscle transposition for complex fistula and persistent nonhealing sinus in perianal Crohnʼs disease

Complex fistulas and persistent perineal sinuses as a result of perianal Crohn's disease remain a major therapeutic challenge. A muscle transposition may promote wound healing by filling the perineal cavity and increasing tissue oxygenation. We aimed to evaluate the outcomes of the treatment at our institution over 8 years. A retrospective review was performed for patients who underwent gracilis muscle transposition for complex perianal Crohn's disease between 1999 and 2007. Data collected included patients' demographic data, previous treatments (medical and surgical), and outcome of the operation. A structured telephone interview was conducted to evaluate medium- to long-term outcomes of the treatment. Eighteen patients (8 men and 10 women, median age 33 years, range 17-59 years) underwent a gracilis muscle transposition between 1999 and 2007. Fourteen patients had a complex fistula, and 4 patients had a persistent nonhealing perineal sinus. Gracilis muscle transposition healed the perineum of 11 patients (61%) at a median follow-up of 10 months (range 1-88 months). The success rate for complex fistulas was 64% and that for persistent nonhealing perineal sinuses was 50%. Eight graft site infections and delayed healing were noted. There were no donor-site problems or major complication. Healing was maintained in 8 of 9 patients who were available for medium- to long-term follow-up (median 64 months, range 23-123 months), with high patient satisfaction. Gracilis transposition is a viable option as a treatment for complex perianal Crohn's disease. Efficacy was maintained in nearly 90% of patients in the medium to long term.

Adalimumab for Patientʼs with Crohnʼs Perianal Fistulas

Purpose: Infliximab (IFX) has been shown to be effective for treating perianal Crohn's disease (CD), but some patients develop intolerance or lack of response. Adalimumab (ADA) is a fully humanized anti-TNF antibody that has been shown to be safe and effective in patients (pts) with CD, including those pts who have lost response or are intolerant to IFX. Its utility in pts with perianal CD has not been proven. We report the outcomes of a series of perianal CD pts who were treated with ADA. Methods: Eight pts with complex fistulizing CD (3 – rectovaginal fistula, 1 – scrotal fistula, 2 – multiple perianal fistulas) who had either an adverse reaction or attenuated response to IFX were placed on ADA. Median pt age was 42, five (62.5%) were female. All pts received an 80mg loading dose of ADA. Seven were then placed on 40mg every other week (qow). One pt was placed on 40mg weekly at the onset of treatment. Immunomodulators were maximized [6MP/azathioprine −5 pts; methotrexate −2] and concomitant antibiotics [Cipro-5; Flagyl 1] were started in most pts. Two pts were on prednisone at time of presentation. Three pts were ultimately increased to weekly ADA dosing. Setons were placed in three patients (2 setons each). Therapy effectiveness was assessed by pt symptom report, physical examination, and endoscopic ultrasound (EUS). Results: Of the 8 pts evaluated, one was lost to follow-up. The median length of follow-up was 18 mns (12 – 24 mns). Four (57%) of the seven pts had complete cessation of drainage. Two (29%) pts had a significant decrease in fistula drainage. The median time for cessation of fistula drainage was six months. Of the four pts with cessation of drainage, three (75%) were on 40mg of ADA weekly while one (25%) was on 40mg qow. EUS was used in 7 of the pts at time of initiation of therapy to assess fistula activity. Five (71%) of seven pts had either complete or significant cessation of fistula drainage. In two (66%) of the 3 pts with seton placement, repeat EUS evaluations were used to evaluate healing and guide seton removal with complete cessation of drainage. Conclusions: ADA combined with seton placement may be effective in pts with complex perianal CD who have an attenuated response or intolerance to IFX. Prospective trials are warranted.

How should complex perianal Crohn's disease be treated in the Remicade era?

Perhaps one of the most difficult aspects of treat­ ing Crohn's disease (CD) is the management of complex perianal disease. Perianal fistulas occur in 17%-43% of patients with CD and are more com­ monly associated with colonic CD than small bowel CD. Almost 100% of patients with rectal CD have perianal fistulas at some point. Perianal fistulas in CD can be broken down into two categories: simple or low and complex or high fistulas. The treatment for the two categories is dif­ ferent, and this review will concentrate on complex or high fistulas. This group includes high trans­ sphincteric, suprasphincteric, and extrasphincteric fistulas; multiple fistulas; fistulas with multiple exter­ nal openings; rectovaginal fistulas; and any perianal fistula in the presence of active rectal disease. Remicade is a genetically constructed IgG1 mu­ rine-human chimeric molecule (75% human) that binds both soluble and bound TNFa. In 1999, Pres­ ent et al. I performed a randomized double-blinded placebo controlled trial of Remicade for fistulizing CD. Fifty-five percent of the fistulas (of which 90% were perianal) treated with 5 mg/kg Remicade at 0,2, and 6 weeks were reported as closed. Closure was defined as no drainage despite gentle compres­ sion. The median length of closure was 3 months. Sixty percent of patients reported adverse events, in­ cluding 11 % abscess formation. Based on this study and subsequent studies, the standard dosing regimen of Remicade for perianal fistulas is 5 mg/kg given at 0, 2, and 6 weeks. Maintenance therapy, when indi­ cated is 5 mg/kg every 8 weeks. Premedication with Tylenol, Benadryl, or corticosteroids is given as needed. Subsequent studies have shown a complete peria­ nal fistula closure rate between 25% and 67% and a rectovaginal fistula closure rate of 0%-13%. The Accent II trial randomized patients with fistulizing CD to initial therapy at 0, 2, and 6 weeks with either 5 mg/kg of Remicade or placebo. Sixty-nine percent of patients in the Remicade group responded. Those 69% were then randomized to maintenance therapy with either Remicade at 5 mg/kg or placebo every 8 weeks for 54 weeks. Of those patients on Remicade maintenance, 42% lost the effect of the medication by 54 weeks. Infusion reactions are seen in about 20%-30% of patients, and especially in those patients with subse­ quent doses. The majority of reactions are minor and include low-grade fever, rash, and tachycardia. Symptoms usually resolve with decreasing the infu­ sion rate or cessation of the infusion. Pretreatment with Tylenol and Benadryl, and sometimes cortico­ steroids, usually permits subsequent administration of Remicade. Approximately 2 % of patients have a severe infusion reaction consisting of anaphylaxis, dyspnea, and/or hypotension. In these patients, further treatment with Remicade is contraindicated. Infusion reactions are thought to occur due to the development of human antichimeric antibodies. Infectious complications are not uncommon with Remicade treatment. Abscesses develop in about 10%-35% of patients due to healing of the external opening prior to healing of the fistula tract. This can usually be prevented in perianal fistulas by the place­ ment of setons. Upper respiratory infections, includ­ ing bacterial pneumonia and Pneumocystis carinii, develop in up to 16% of patients. Tuberculosis has been reported in over 70 patients, as have other op­ portunistic infections. Also reported is the possible increased risk of lymphoma and development of lupuslike reactions. Resolution of clinical signs of the fistula such as drainage and closure of the external opening does not mean that the fistula tract has healed. Several studies using endoanal ultrasound and magnetic res­ onance imaging have shown that the fistula tract persists despite cessation of drainage and apparent

Local Injection of Infliximab for the Treatment of Perianal Crohn's Disease

Perianal disease is a serious complication of Crohn's disease and its surgical management is still controversial. It has been suggested that the local injection of infliximab has resulted in some potential benefit. This pilot study analyzed the feasibility and safety of such therapy in selected patients with severe perianal Crohn's disease. The study included 15 patients with complex perianal Crohn's disease in which sepsis was not controllable using surgical and medical therapy. Among them, four had previously undergone intravenous infusion of infliximab with no significant response, nine had contraindications for intravenous infusion, and two had associated stenosing ileitis and severe coloproctitis. The injection of 15 to 21 mg of infliximab, associated with surgical treatment, was performed at the internal and external orifices and along the fistula tract. Efficacy was measured by a complete morphologic evaluation using a personal score. No major adverse effects were reported. Ten of 15 patients healed after 3 to 12 infusions. Local injection of infliximab adjacent to the fistula tract of perianal Crohn's disease is safe and may help in fistula healing. A controlled, randomized trial is required to prove the value.