Perianal Crohn's Disease Research Articles

P642 Network meta-analysis: efficacy and safety of treatments for fistulising Crohn’s disease

Abstract Background Fistulas are a debilitating complication of Crohn’s disease (CD) and treatment options remain limited, with sub-optimal efficacy. It is essential that other treatment options are considered, and there is a lack of head-to-head comparisons between them making positioning treatments challenging. To our knowledge this is the first network meta-analysis to help position all treatments for fistulising CD. Methods MEDLINE, EMBASE, EMBASE classic, the Cochrane central registry and Cochrane Specialised Trial Register were searched between 1978 and 2022 for randomised controlled trials (RCTs) reporting on treatments for fistulising CD. The primary outcomes were the efficacy of medical therapies at achieving fistula remission and maintenance of fistula closure. A network meta-analysis was performed using the frequentist model with pooled relative risks and P scores used to rank treatments, in accordance to PRISMA guidelines [Figure 1]. Results 964 studies were identified with the search criteria, with 28 RCTs after screening included for analysis with a total of 2,239 patients. At the 8 – 12 week end-point, none of the interventions were statistically significant, with tacrolimus ranked first at 4 times better than placebo (RR, 4.56; 95% CI, 0.76 – 27.30) at inducing remission of fistulas [Figure 2]. At the 16 – 24 week time point, infliximab produced the only statistically significant result with the 5mg/kg dose proving most effective (RR, 2.30; 95% CI, 1.40 – 3.77) [Figure 3]. At 44 weeks ustekinumab was found to be most superior with it being 2.38 times (RR, 2.38; 95% CI, 1.24 – 4.56) more superior to placebo, with adalimumab (RR, 2.06; 95% CI, 1.06 – 3.99) and infliximab 5mg/kg (RR, 1.68; 95% CI, 1.03 – 2.75) also producing a statistically significant result [Figure 4]. A limitation of this network meta-analysis is the significant heterogeneity between studies and variations in end-point definition, with certain small numbers in certain intervention groups limiting generalisability. Conclusion Despite infliximab being favoured in international guidelines for the treatment of perianal fistulising CD, other biologics such as ustekinumab and adalimumab may have a role. Future RCTs with standardised end-points are needed to further investigate biologics, especially ustekinumab and adalimumab, head-to-head against infliximab in the treatment of fistulising CD.

P155 Natural history of anal stricture in pediatric-onset Crohn’s disease: a two-decades population-based study

Abstract Background The natural history of anal stricture complicating pediatric-onset Crohn’s disease (CD) is poorly known. The aims of this study were: to determine in a population-based study the risk of anal stricture in pediatric-onset CD; to identify risk factors for anal stricture; and to evaluate the natural history of anal stricture at the population level. Methods All patients with a diagnosis of CD made before the age of 17 years between 1988 and 2011 in a population-based registry were followed retrospectively until 2013. A specific collection of additional data was performed in patients with anal stricture at diagnosis or during follow-up. Variables collected included: proctological examination, diagnostic management and treatment. Multivariate Cox models were used to identify factors associated with anal stricture. Results Among the 1,007 included CD patients (females, 451 (44.8%); median age at diagnosis 14.4 years (IQR, 12.0-16.1), median follow-up 8.8 years (IQR, 4.6-14.2)), only one (0.1%) had anal stricture at diagnosis while 26 (2.6%) presented anal stricture during follow-up. Cumulative incidence of anal stricture at 5 and 10 years after diagnosis was 0.6% (CI95%, 0.1-1.1) and 1.4% (CI95%, 0.5-2.3), respectively. Among the 27 patients with anal stricture, 25 (92.6%) had already at least one episode of anal ulceration or fistulizing perianal CD (pCD). In multivariable analysis, the presence of extra-intestinal manifestations (Hazard Ratio (HR) 2.2, CI95% 1.0-4.8, p=0.027), colonic location (L1 vs L3 HR 0.0 (-); L2 vs L3 HR 1.2, CI95% 0.6-2.7, p=0.006) and history of fistulizing pCD (HR 9.9, CI95% 4.3-22.8, p<0.0001) were significantly associated with anal stricture. Eleven (41%) patients needed at least one dilation. After a median follow-up of 16.9 years (IQR, 11.5-20.2), healing of anal stricture was observed only once. One patient (3.7%) presented an anal cancer 7 years after the diagnosis of anal stricture. Nine (33.3%) patients needed a stoma. Among them, 8 already had a fistulizing pCD and 4 needed an abdominoperineal amputation. Anal stricture was significantly associated with an increased risk of stoma (HR 5.8, CI95% 2.3-14.3), p=0.0002). Conclusion Anal stricture is a rare event in pediatric onset CD, occurring in 1.5% of patients over a 10 year-period after diagnosis. However, anal stricture had a negative impact on disease prognosis with a five-fold increase of the risk of stoma.

OP11 Ileocecal resection for recently diagnosed ileocecal Crohn’s disease is associated with improved long-term outcomes compared to anti-tumor necrosis factor therapy: a population-based study

Abstract Background Early treatment of Crohn’s disease (CD) often involves biologics such as anti-tumor necrosis factor (anti-TNF) agents. Ileocecal resection (ICR), while a therapeutic option in early CD, is generally reserved for complicated CD or when medical treatment fails. We aimed to compare long-term outcomes of ICR and anti-TNF therapy as index treatment for ileocecal CD, initiated within one year of diagnosis, in the Danish nationwide cohort. Methods Using cross-linked nationwide registers, we identified all individuals who lived in Denmark and were diagnosed with ileal CD between 2003 and 2018. We included individuals who underwent ICR or received anti-TNF drugs as index treatment for ileocecal CD within one year of diagnosis. We excluded patients who did not have pathology information confirming disease in the ileocecal region. The primary outcome was a composite of CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD diagnosis. We conducted Cox proportional hazards regression analyses to compare outcomes in the two groups after adjusting for potential confounders. We also determined the proportion of individuals initiated on immunomodulator (IMM), anti-TNF, or no therapy at 5 years after ICR. Results Of the 16,443 individuals diagnosed with ileocecal CD between 2003 and 2018, 581 (3.5%) and 698 (4.2%) individuals with confirmed disease in the ileocecal region underwent ICR and received anti-TNF as the index treatment, respectively. The composite outcome occurred in 273 individuals (IR 110.3/100,0 person years (PY)) in the ICR group and in 318 individuals (IR 201.9/100,0 PY) in the anti-TNF group. The risk of the composite outcome was 33% lower in the ICR group compared to the anti-TNF group (aHR 0.67; 95% CI 0.54, 0.83), after adjusting for demographic and clinical variables. On analysis of individual outcomes, ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not CD-related hospitalization or perianal CD diagnosis. Of individuals who underwent ICR, the proportion that was initiated on IMM, anti-TNF treatment or no treatment at 5 years of follow up was 47.5%, 17.1%, and 50.3%, respectively. Conclusion These data support the role of ICR as an index treatment for ileocecal CD and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Further studies will help identify characteristics of individuals who needed no treatment after ICR.

P494 Impact of early optimization of ustekinumab on mid-term targets in severe Crohn’s disease: THE MUST study

Abstract Background As a substantial proportion of patients with Crohn’s disease (CD) experiences a refractory disease course, immediate drug intensification may be an option to optimize the effectiveness of current biotherapies. Aim : to compare the one-year efficacy of immediate dose escalation of ustekinumab 90 mg to 4-weekly with that of 8-weekly dosing after intravenous (iv) induction in severe active CD patients. Methods The MUST (meta-optimization of Ustekinumab) study is a real-life multicenter observational French retrospective cohort study including patients with severe active CD. All patients from three academic IBD centers who received induction therapy with IV ustekinumab followed with subcutaneous (sc) UST 90 mg, either 4-weekly (MUST group) or 8-weekly (STD group) were included from Jan 2019 to Dec 2020. The choice of treatment regimen was left at the physician’s discretion. Severe active CD was defined by HBI > 16 and stool frequency (SF) ≥ 4 and abdominal pain (AP) ≥ 2 over one week and at least one objective evidence of inflammation (CRP ≥ 5 mg/L and/or FCal ≥ 250 μg/g and/or radiologic and/or endoscopic signs of disease activity). The primary endpoint was PRO-2 based clinical remission defined by SF≤2-8 and AP ≤1, and either FCal <250 μg/g and/or CRP <5 mg/L at week 52. Key secondary endpoints were PRO-2 remission, endoscopic improvement and steroid-free clinical remission at week 52. Results 203 adult patients were included, either in the MUST group (n = 59) or in the STD group (n = 144). Baseline patient demographics and disease characteristics were similar between groups. Median disease duration was 9 years (IQR: 5 – 14 yrs), 66% were females. Disease location according to the Montreal classification was L1 and L3 in 36% and 44 % of patients. All had previously been exposed to more than one biotherapy, 27% experienced perianal CD, and 35% had undergone previous CD-related surgery. At week 52, the adjusted difference between the two groups for the primary endpoint was 15.8% (95% confidence interval (CI) 0.21 – 0.94; p = 0.029) with significantly higher clinical remission in the MUST group. The adjusted difference for PRO-2 remission was 3.7% (CI 0.45 - 1.66; p = 0.64). All patients, except one in the STD group, were weaned off steroids at week 52. Endoscopic improvement was similar in both groups (61.9% vs. 61.5%, p=0.98). Adverse events were not significantly different in both arms (42.4% vs 34.7%, p=0.338). Conclusion In the treat-to-target era, our real-life study shows that immediate escalation of ustekinumab therapy to 4-weekly dosing could achieve higher clinical remission at one year than 8-weekly dosing in severe CD. These findings should be confirmed in a dedicated prospective randomized trial.

Ustekinumab Promotes Radiological Fistula Healing in Perianal Fistulizing Crohn's Disease: A Retrospective Real-World Analysis.

There is insufficient evidence to confirm the efficacy of ustekinumab (UST) in promoting fistula closure in perianal fistulizing Crohn's disease (CD) patients. We aimed to evaluate the efficacy of UST in a real-world setting. The data were retrospectively analyzed. Intestinal clinical and endoscopic changes were evaluated. Fistula radiological outcomes were determined using the Van Assche score. A total of 108 patients were included, 43.5% of whom had complex perianal fistulas. Intestinal clinical and endoscopic remission was achieved in 65.7% and 31.5% of patients, respectively. The fistula clinical remission and response rates were 40.7% and 63.0%, respectively, with a significant reduction in Perianal Crohn's disease Activity Index [5.0(3.0, 8.0) vs. 7.5(5.0, 10.0), p < 0.001] and Crohn's Anal Fistula Quality of Life [23.5(9.3, 38.8) vs. 49.0(32.3, 60.0), p < 0.001]. Radiological healing, partial response, no change, and deterioration were observed in 44.8%, 31.4%, 13.4%, and 10.4% of patients, respectively. The cut-off UST trough concentration for predicting fistula clinical remission was 2.11 μg/mL with an area under the curve of 0.795, a sensitivity of 93.3%, and a specificity of 67.6%. UST is efficacious in promoting radiological fistula closure in patients with perianal fistulizing CD. A UST trough concentration over 2.11 μg/mL was correlated with a higher likelihood of perianal fistula clinical remission.

Perianal fistulizing Crohn's disease is associated with a higher prevalence of HPV in the anorectal fistula tract. A comparative study

Background & AimsPerianal fistulizing Crohn's disease is the main risk factor for anal cancer in patients with inflammatory bowel disease. Whether this occurs due to a higher frequency of human papillomavirus remains unclear. The authors aimed to evaluate the prevalence of HPV and high-risk HPV in patients with perianal Crohn's disease, compared with a control group. MethodsThe authors conducted a two-center cross-sectional study in which perianal fistulizing Crohn's disease patients were matched for age and sex with patients with anorectal fistula without Crohn's disease. Biopsy specimens were obtained from fistulous tracts during examination under anesthesia for both groups. The samples were sent for HPV detection and genotyping using the INNO-LiPA test. ResultsA total of 108 subjects (54 in each group) were recruited. The perianal fistulizing Crohn's disease group showed a statistically higher frequency of HPV in the fistulous tract than the control group (33.3% vs. 16.7%; p = 0.046). Separate analyses on high-risk types demonstrated that there was a numerically higher frequency of HPV in the perianal fistulizing Crohn's disease group. In multiple logistic regression, patients with perianal fistulizing Crohn's disease were found to have a chance of HPV 3.29 times higher than patients without Crohn's disease (OR = 3.29; 95% CI 1.20‒9.01), regardless of other variables. The types most frequently identified in the perianal fistulizing Crohn's disease group were HPV 11 (12.96%) and HPV 16 (9.26%). ConclusionPerianal fistulizing Crohn's disease is associated with a higher prevalence of HPV than in patients with anorectal fistula without Crohn's disease.

Pediatric perianal Crohn's disease behavior in the era of biologic therapy.

To describe perianal Crohn's disease behavior and the role of biological therapy in a sample of pediatric patients. A retrospective study of pediatric patients with Crohn's disease (CD) treated in our institution from 2017 to 2021, with a minimum follow up period of 6 months, was conducted. Patients were divided whether they had perianal disease (PD) or not. Baseline characteristics, extension of disease, growth failure rate, aggressive pattern rate, use of biological therapy and need for surgery, among other variables, were compared between both groups. Clinical and/or radiological improvement in the last 6 months of follow up was considered good control of PD. Seventy eight pediatric patients with CD were included. Median age at diagnosis was 10.5 years, and median follow up time was 3.8 years. 64.1% patients were male. Of all, 15 (19.2%) had perianal disease, of which 10 had fistulizing findings and 5 had non fistulizing findings. PD was presented at diagnosis in 8 patients, and the rest developed it in a median time of 1 year from diagnosis. PD was associated with growth failure (p=0.003), use of biological therapies (p=0.005), and need for second line of biologics (p=0.005). Most patients (12/15, 80%) had good control of PD with the treatment received. CD patients with PD seem to need a more aggressive treatment, with biological therapies playing a key role for its handling nowadays. These patients require close nutritional evaluation that ensures proper development and growth.

Effectiveness and safety of darvadstrocel in patients with complex perianal fistulizing Crohn's disease: a systematic review.

Managing complex perianal fistulizing Crohn's disease (CD) remains challenging, despite current medical and surgical treatment approaches. Darvadstrocel, a therapy utilizing adipose-derived stem cells, shows promise in promoting tissue regeneration and healing, offering a novel and effective treatment for fistula management. A systematic literature search was conducted on PubMed and Scopus to identify studies involving patients with complex perianal fistulizing CD treated with darvadstrocel. In total, 2 randomized controlled trials (RCT), 5 observational studies with retrospective data collection and 2 observational studies with prospective design were included in the final review. Data from the European ADMIRE-CD RCT demonstrated that darvadstrocel is superior to placebo in terms of clinical and imaging improvement over both the short and long term. These findings align with the prospective studies analyzed in this systematic review. The rate of treatment-emergent adverse events in the ADMIRE-CD trial's RCTs was similar in both the darvadstrocel and control groups, with perianal abscess being the most common adverse event up to 52 weeks after drug administration. Retrospective studies indicated no side-effects beyond 52 weeks. Darvadstrocel appears to be a new, potentially effective and safe treatment option for the management of complex perianal fistulas. However, more randomized clinical trials are needed to evaluate the efficacy and safety profile of the drug.

Efficacy and safety of mesenchymal stem cells in the treatment of perianal fistulas in Crohn's disease: a meta-analysis of randomized controlled trials.

Local mesenchymal stem cell (MSC) therapy for perianal fistulas in Crohn's disease (CD) has yielded promising results, but it still remains controversial. In this study, we aimed to conduct a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of MSC therapy for perianal CD (pCD). RCTs reporting MSC therapy for perianal fistulas in CD were searched and included. The effectiveness and safety data were analyzed using RevMan 5.3. A total of 7 RCTs were included in this meta-analysis. The analysis showed that patients receiving MSC therapy presented a higher healing rate (HR) of pCD than those in the control group (odds ratio (OR)=1.42; 95% confidence interval (CI) 1.18, 1.71; P=0.0002). Compared with placebo (saline solution), MSC therapy improved the HR of pCD (OR=1.85; 95% CI 1.32, 2.60; P=0.0004). MSC therapy showed significant long-term efficacy (OR=1.36; P=0.009; 95% CI 1.08, 1.71). When MRI was used to evaluate fistula healing, a pooled analysis showed that the MSC group achieved a higher HR than the control group (OR=1.95; 95% CI 1.33, 2.87; P=0.0007). Allogeneic MSC therapy was superior to the control treatment in improving HR (OR = 1.97; 95% CI 1.40, 2.75; P<0.001). Furthermore, no significant differences were observed between MSC therapy and placebo in terms of adverse events (AEs) (OR = 1.16; 95% CI 0.76, 1.76; P = 0.48). None of the AEs were judged to be related to MSC treatment. This meta-analysis of RCTs provided evidence that local MSC injection is safe and efficacious for perianal fistulas in CD. In addition, this treatment has favorable long-term efficacy and safety profiles.

Biallelic TLR4 deficiency in humans

Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). Athird individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.

Temporal and Sequential Relationships Between Perianal and Severe Ileal Crohn’s, Both as Strong Representations of Crohn’s Fistulizing Phenotypes

Abstract Introduction/Objective Most cases of inflammatory bowel disease can be categorized as ulcerative colitis(UC) or Crohn’s disease(CD) on the basis of clinical profile, disease distribution, imaging and endoscopic findings, and pathological abnormalities. Ileal CD with deep fissuring ulcers and imminent or overt fistulae represents a specific phenotype. A similar fistulizing phenotype is indicated by complex perianal CD which shows fistulous tracts between rectum and perineum. We followed CD patients with either disease to discover if both fistulizing phenotypes occurred concurrently or with any predictable sequence. Methods/Case Report From our databases, we collected 21 patients with complex perianal CD(M:F=7:14, ages 23-80) and 19 patients with fistulizing ileal CD(M:F=11:8, ages 10-67) and followed them for a period of up to 16 years(2005-2021). Our purpose was to discover if both fistulizing phenotypes occurred in the same patients, and if so, was it concurrent or in any sequence, and to find the strength of the clinical diagnosis of CD when one or both phenotypes presented in a patient. Results (if a Case Study enter NA) Concurrent occurrence of perianal and ileal CD was the most common(6/21 perianal &amp; 8/19 ileal cases: total 35%). When patients first presented with perianal CD, they had an equal chance of not manifesting ileal phenotype(5/21) or manifesting it earlier(5/21: average of 5 years earlier) or later(5/21: average of 2.5 years later). However, when patients first presented with ileal CD, they had a strong possibility of having manifested perianal disease in the past(10/21 or 48%: average of 5 years), when it was overlooked as a strong indicator of Crohn’s. Perianal CD was considered a strong clinical diagnosis of Crohn’s but only when it occurred concurrently or was preceded by ileal CD. Fistulizing Ileal CD was considered a strong clinical diagnosis of Crohn’s and most cases had prior perianal CD. Conclusion Both perianal and severe ileal CDs are fistulizing phenotypes that are strong indicators of Crohn’s and occur concurrently in 35% of cases. When followed for a long period, both phenotypes manifest in most patients when they have severe fistulizing disease. Perianal CD appears to precede ileal CD by an average of 5 years. While fistulizing ileal CD is clinically unequivocally diagnosed as Crohn’s, perianal CD may be overlooked as Crohn’s, unless there is concurrent or prior ileal CD.

Knowledge of perianal Crohn's disease among nurses in an Italian tertiary centre

Background: Patients with Crohn's disease can develop anal and perianal lesions, such as fistulas, ulcers, skin tags, perianal abscesses and strictures. Perianal Crohn's disease (PCD) is a condition that has a major impact on patients' quality of life. The multidisciplinary team includes a nurse who manages the patient according to evidence-based medicine. Clinical practice and post-registration training are the way forward for nurses to acquire the skills needed to deliver quality care. Aims: This study explored the assessment of nurses' knowledge of PCD. A cross-sectional survey was used to look at the nurses' knowledge. Methods: The questionnaire was administered over 2 months, between September and October 2019. The questionnaire was anonymous, validated by a panel of experts in the field and consisted of 30 questions to assess knowledge and two questions to assess the need for training. It was directed to 120 clinical nurses in the departments of medicine and abdominal surgery. Results: There were 120 nurses enrolled, and 64.2% of nurses had cared for patients with PCD at least once. The survey showed a fairly low level of knowledge of the diagnostic and therapeutic care pathways for patients affected by PCD. On the other hand, a high need for training and in-depth study of the subject emerged. Conclusion: The nurse, an integral part of the multidisciplinary team, plays an important role in the education of these patients. Nurses' present level of knowledge can certainly be improved thanks to their willingness to undertake training courses or to use information tools.

Placebo Response Rates in Randomized Controlled Trials for Perianal Crohn's Disease: A Systematic Review and Meta-Analysis.

Perianal fistulizing disease is a common complication of Crohn's disease [CD], for which new therapies are urgently needed. To assist the design of clinical trials for novel therapeutics, we conducted a systematic review and meta-analysis of randomised controlled trials [RCTs] to quantify placebo rates and identify factors influencing them in perianal CD [pCD]. We searched MEDLINE, Embase and CENTRAL from inception to June 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for pCD. Placebo fistula response and remission rates for induction and maintenance trials were extracted and pooled using a random-effects model. Mixed-effects meta-regression was used to evaluate the impact of patient and study-level characteristics on point estimates. In 17 RCTs [13 induction, five maintenance] the pooled placebo fistula response and remission rate for induction trials was 25% (95% confidence interval [CI] 17-36%) and 17% [95% CI 11-25%], respectively. For maintenance trials, the pooled placebo fistula response and remission rate was 23% [95% CI 17-32%] and 19% [95% CI 14-25%], respectively. Trials enrolling patients with less disease activity and a higher proportion with ileal predominant disease were associated with significantly higher placebo response rates. Trials originating in Europe [compared to North America], therapies requiring perianal injection and a longer timepoint to measure remission were associated with higher placebo remission rates. Placebo response and remission rates in pCD trials are influenced by patient and disease-related factors, as well as the type of intervention being studied. These contemporary rates will inform trial design for novel therapeutics.

S2711 Biologic Therapies for Isolated Recurrent, Persistent Complex Perianal Fistulas Without Luminal Crohn's Disease

Introduction: Isolated complex perianal fistulas are abnormal connections between the epithelial surfaces of the anal canal and the perianal skin, meeting criteria for complex perianal fistula but without evidence of inflammatory bowel disease (IBD). While over half of patients with Crohn’s disease (CD) have perianal fistulas, isolated perianal CD is rare. Here we discuss five cases of patients presenting with isolated recurrent complex perianal fistula, and we describe their diagnostic evaluation, attempted therapies, and outcomes. Case Description/Methods: Five adults (3 women, 2 men; mean age 38 years old) with no prior GI symptoms/diseases initially presented with perianal pain (3/5), perirectal mass (2/5), diarrhea (1/5), and abdominal pain (1/5) (Table). All patents underwent exam under anesthesia (EUA) with incision and drainage (I&D) of perirectal abscesses, and setons were placed in perianal/rectal fistulas in 4/5 cases. Each patient had colonoscopy without evidence of inflammation on endoscopy or histology. Radiographic imaging (MRIs, MREs, and CT) revealed fistulas and abscesses but no evidence of luminal inflammation. All patients were treated with antibiotics and 4/5 received biologic therapy (Adalimumab, Infliximab, or Ustekinumab). Despite surgical and medical management, complex perianal fistulas were persistent in all patients at follow-up after an average of 45 months. Discussion: For patients who develop recurrent complex fistulas, a presumptive diagnosis of CD is often made. However, patients who present with complex perianal fistulas in the absence of the luminal inflammation characteristically found in CD are said to have isolated perianal disease (IPD). It is unclear whether IPD represents truly isolated severe cryptoglandular fistulas or early presentation of undiagnosed CD, which renders the best treatment approach a clinical dilemma. IPD is classically treated with antibiotics and local surgical intervention, whereas perianal CD treatment is more complex, incorporating the use of immunosuppressive therapy. The cases described in our cohort reveal the importance of a multimodal approach when treating IPD in the absence of luminal findings of CD. While classic medications for CD are unlikely to succeed when used alone for IPD, their incorporation into the treatment regimen may be critical in achieving eventual resolution of perianal disease. Given the similarity in management, it is important to consider CD in the differential for IPD patients even in the absence of luminal findings. Table 1. - Patient Summary PT # Initial Presentation Diagnostic Evaluations Subsequent Diagnosis Medical Therapies Attempted Surgical Procedures Ultimate Diagnosis and Plan (1) 39F Painful perianal mass, presumed to be an abscess or hemorrhoids Flexible sigmoidoscopyColonoscopy with bxMRIEUA Refractory perirectal and rectovaginal fistula with abscess IBD medications: AdalimumabMethotrexate Non-IBD medical therapies: CiprofloxacinMetronidazoleAmoxicillin-Clavulanic acidPrednisone I&DSeton placementFistulectomy with sphincterotomyDiverting sigmoid colostomyFistulotomy Non-healing cryptoglandular anal fistula complicated by surgery Discontinue IBD therapySurgical f/u with consideration for clinical trial of stem cell injection or transperitoneal repair (2) 34M Abdominal pain, diagnosed with sigmoid diverticulitis Colonoscopy with bxMRIMRECT scanEUA Refractory perianal fistula with abscess IBD medications: InfliximabUstekinumabTacrolimusAzathioprine Non-IBD medical therapies: MetronidazoleCiprofloxacin I&DSeton placement Isolated perianal disease in the setting of presumed CD Chronic treatment with chronic, cyclical abx (Ciprofloxacin or Amoxicillin-Clavulanic acidIBD-directed therapy (Azathioprine + Infliximab; will consider Upadacitinib once approved by the FDA)Planning for surgical f/u (3) 43M Painful perianal mass, presumed to be a rectal abscess Colonoscopy with bxMRIEUA Refractory perianal abscess Non-IBD medical therapies: Amoxicillin-Clavulanic acid I&D Isolated cryptoglandular abscess with potential hemorrhoids No need for chronic antibioticsSitz baths and PrepH as neededIf symptoms worsen will plan for EUA and surgical f/u (4) 24F Perianal pain, diagnosed as perianal abscess with fistula Colonoscopy with bxMRIEUA Refractory perianal abscess, inflammatory arthropathy IBD medications: AdalimumabInfliximabAzathioprine Non-IBD medical therapies: CiprofloxacinMetronidazole I&DSeton placement Presumed CD with perianal disease and inflammatory arthropathy IBD-directed therapy (Azathioprine + Infliximab)Planning for surgical f/u (5) 50F Diarrhea and rectal ulcers, presumed to have CD Colonoscopy with bxMRICTEUA Refractory perianal fistula with abscess IBD medications: Infliximab Non-IBD medical therapies: ColchicinePrednisone I&DSeton placementPerineal debridementLay open fistulotomy Presumed CD with perianal disease IBD-directed therapy (Infliximab) Abbreviations: Bx = biopsies. CD = Crohn’s disease. EUA = exam under anesthesia. F = female. F/U = follow up. I&D = incision and drainage. IBD = inflammatory bowel disease. M = male. MRE = magnetic resonance elastography. MRI = magnetic resonance imaging

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

The relationship between perianal fistula activity and abdominal adipose tissue in Crohn’s disease: an observational study

ObjectiveThe aim of this study was to analyze the relationship between abdominal adipose tissue and perianal fistula activity in patients with Crohn's disease (CD) using cross-sectional imaging.MethodsPatients with perianal fistulizing CD who underwent pelvic magnetic resonance imaging (MRI) and abdominal computed tomography (CT) were retrospectively enrolled. We scored the fistulas in each patient's MRI images based on Van Assche's classification. The area and density of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (at the third, fourth, and fifth lumbar (L3, L4, and L5) levels were measured by averaging five slices of measurements at each vertebral level in CT images, and areas were further standardized by the lumbar height2 (heightL1-5). The VAT/SAT ratio (VSR) and VAT/Total adipose tissue (VA/TA) index were calculated. Based on MRI scores, patients were divided into two groups with low and high activity, and their clinical, MRI features, and CT parameters were compared. We evaluated patients with follow-up MRI and compared the differences in clinical and radiological indicators among patients with different outcomes.ResultsOverall, 136 patients were included, 77 in the low-activity group and 59 in the high-activity group. Patients in the high activity group had lower subcutaneous adipose index (all levels, p < 0.05) and visceral adipose index (L3 level, p < 0.01), but higher SAT and VAT density (all levels, p < 0.01), VSR (L5 level, p = 0.07) and VA/TA index (L5 level, p < 0.05).ConclusionThere were differences in adipose tissue composition among CD patients with different active perianal fistulas.

Identification of the optimal medical and surgical management for patients with perianal fistulising Crohn's disease.

The aim of our study was to assess the best medical and surgical approaches for perianal Crohn's disease (PCD) in order to identify an optimal combined medical and surgical treatment. Medical records of all patients with PCD treated with TNFα antagonists in two referral centres between 1998 and 2018 were reviewed. Predictors of long-term outcomes were identified using a Cox proportional hazard model. A total of 200 patients were included. Fifty-three patients (26.5%) were treated with adalimumab and 147 (73.5%) with infliximab. A combination of TNFα antagonist with an immunosuppressant and the presence of proctitis were independently associated with fistula closure. Seton was placed in 127 patients (63.5%) before starting biological therapy. Eighty patients (40%) underwent additional perineal surgery. Prior PCD surgery, seton positioning, additional perineal surgery, and additional surgery within 52 weeks of anti-TNFα treatment were associated with an increased rate of fistula closure. Finally, medical combination therapy (anti-TNFα plus immunosuppressant) along with seton placement and additional surgery within 1 year was the best management for PCD patients (p= 0.02). Combined medical and surgical management is required for the treatment of PCD patients. Medical combination therapy associated with seton placement and additional surgery within 1 year is the best management for PCD patients.

A Preclinical Validation of Iron Oxide Nanoparticles for Treatment of Perianal Fistulizing Crohn's Disease.

Fistulizing anoperineal lesions are severe complications of Crohn’s disease (CD) that affect quality of life with a long-term risk of anal sphincter destruction, incontinence, permanent stoma, and anal cancer. Despite several surgical procedures, they relapse in about two-thirds of patients, mandating innovative treatments. Ultrasmall particles of iron oxide (USPIO) have been described to achieve in vivo rapid healing of deep wounds in the skin and liver of rats thanks to their nanobridging capability that could be adapted to fistula treatment. Our main purpose was to highlight preclinical data with USPIO for the treatment of perianal fistulizing CD. Twenty male Sprague Dawley rats with severe 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced proctitis were operated to generate two perianal fistulas per rat. At day 35, two inflammatory fistulas were obtained per rat and perineal magnetic resonance imaging (MRI) was performed. After a baseline MRI, a fistula tract was randomly drawn and topically treated either with saline or with USPIO for 1 min (n = 17 for each). The rats underwent a perineal MRI on postoperative days (POD) 1, 4, and 7 and were sacrificed for pathological examination. The primary outcome was the filling or closure of the fistula tract, including the external or internal openings. USPIO treatment allowed the closure and/or filling of all the treated fistulas from its application until POD 7 in comparison with the control fistulas (23%). The treatment with USPIO was safe, permanently closed the fistula along its entire length, including internal and external orifices, and paved new avenues for the treatment of perianal fistulizing Crohn’s disease.

Transperineal ultrasonography for treatment response evaluation in children with perianal Crohn's disease.

PurposeThis study assessed the performance of transperineal ultrasonography (TPUS) in evaluating the treatment response in children with perianal Crohn’s disease (PACD) compared with pelvic magnetic resonance imaging (MRI).MethodsThis retrospective study was approved by the Institutional Review Board of our institution, which waived the requirement for informed consent. Twenty-nine patients (19 boys and 10 girls; median age, 14 years [range, 8 to 18 years]) with 56 fistulas were examined. Each fistula’s thickness and abscess size were measured using both modalities, and treatment response was classified as positive or negative based on each modality. The concordance of the classifications was compared between TPUS and pelvic MRI. A receiver operating characteristic curve (ROC) was used to evaluate the performance of TPUS.ResultsTPUS found 80.4% (45/56) of the fistulas. On MRI, 39 fistulas (70%) were classified as having positive treatment responses, and the remaining 17 as having no response. The agreement of the classifications between TPUS and MRI was moderate (κ=0.486; P<0.001; Spearman ρ=0.573; P<0.001). Based on the ROC analysis with the MRI findings as a reference to distinguish positive from negative treatment responses, TPUS exhibited sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 63.3%, 93.3%, 95.0%, 56.0%, and 73.3%, respectively.ConclusionTPUS can be an appropriate adjuvant imaging modality for pelvic MRI to evaluate the treatment response of PACD in children when initial TPUS detects PACD with a location and imaging features comparable to those visualized on MRI.

Therapeutic Drug Monitoring of Biologics in Crohn's Disease.

Reactive therapeutic drug monitoring (TDM) is considered the standard of care for optimizing biologics in inflammatory bowel disease (IBD) including Crohn's disease (CD). Preliminary data show that proactive TDM is associated with positive outcomes in IBD and can be also used to efficiently guide therapeutic decisions in specific clinical scenarios. Higher biological drug concentrations are associated with favorable therapeutic outcomes in specific IBD populations or phenotypes including pediatric CD, perianal fistulizing CD, small bowel CD, and following an ileocolonic resection for CD. Future perspectives of TDM include the use of rapid testing, pharmacogenomics, and pharmacokinetic dashboards toward individualized therapy.