Managing metastatic Crohn's disease: a single center experience, review of the current evidence, and treatment algorithm.

BACKGROUND: Crohn's disease (CD) is an inflammatory bowel disease (IBD) that, besides gastrointestinal symptoms, may encompass extra-intestinal symptoms, such as dermatological manifestations. Of those, metastatic CD (MCD) is a rare extra-intestinal manifestation for which the management is uncertain. METHODS: We conducted a retrospective case series of patients with MCD seen at the University hospital Leuven, Belgium, combined with an overview of the recent literature. Electronic medical records were searched from January 2003 till April 2022. For the literature search, Medline, Embase, Trip Database, and The Cochrane Library were searched from inception to April 1, 2022. RESULTS: A total of 11 patients with MCD were retrieved. In all cases noncaseating granulomatous inflammation was found on skin biopsies. Two adults and one child were diagnosed with MCD prior to their diagnosis of CD. Seven patients were treated with steroids (intralesional, topical or systemic). Six patients needed a biological therapy to treat MCD. Surgical excision was performed in three patients. All patients reported a successful outcome and most cases achieved remission. The literature search yielded 53 articles, including three reviews, three systematic reviews, 30 case reports and six case series. A treatment algorithm was generated based on literature and multidisciplinary discussion. CONCLUSION: MCD remains a rare entity and diagnosis is often difficult. A multidisciplinary approach including skin biopsy is necessary to diagnose and treat MCD efficiently. Outcome is generally favorable, and lesions respond well to steroids and biologicals. We propose a treatment algorithm based on the available evidence and multidisciplinary discussion.

Hydrated Nucleus Pulposus Extrusion in Dogs: Thoracolumbar Compared to Cervical Cases.

OBJECTIVE: The aim of this study was to review and describe cases of thoracolumbar (TL) hydrated nucleus pulposus extrusion (HNPE) diagnosed with magnetic resonance imaging and surgery, and compare them to cases of cervical (C) HNPE. STUDY DESIGN: Retrospective, single-center study. RESULTS: Thirty-six dogs met the inclusion criteria. Fifteen cases were C and 21 TL. Thirteen dogs were chondrodystrophic breeds, mean body weight was 13 kg, median age was 7.5 years, and 30/36 were male. Fewer dogs were chondrodystrophic in the C group compared with the TL group (p = 0.022). More than 90% had an acute onset, and strong activity was more often reported in the TL group. TL HNPE was more often painful, and extruded disc material more often lateralized (p = 0.017). Median Modified Frankel Score at presentation was 3 and 72.2% were non-ambulatory. More TL HNPE (11/21) were treated surgically compared with C HNPE (4/15). Treatment choice was correlated with spinal cord compression (p = 0.0075). Median Modified Frankel Score improved during hospitalization (p = 0.002) and there was no difference in outcome between C and TL HNPE or conservative and surgical treatment. Mean follow-up time was 33 days. All patients were ambulatory at follow-up. CONCLUSION: This study suggests that the HNPE is not limited to the C vertebral column of dogs and can occur in the TL vertebral column as well. Dogs with TL HNPE show spinal hyperesthesia more often and extruded nucleus material is more often lateralized. Outcome is similar to what has previously been described for C HNPE.

Non-conventional Versus Conventional Strictureplasties for Crohn's Disease. A Systematic Review and Meta-analysis of Treatment Outcomes.

BACKGROUND: Strictureplasties [SXP] represent an alternative to bowel resection in Crohn's disease [CD]. Over the years, there has been growing interest in the role of non-conventional SXP for the treatment of extensive CD. A systematic review was performed on complications and recurrence following conventional and non-conventional SXP. METHODS: The available literature was screened according to the PRISMA statement, until June 2020. Results were categorised into three groups: studies reporting on conventional SXPs; studies with a mixed cohort of conventional and non-conventional SXPs [% non-conventional SXPs ≤15%]; and studies reporting on non-conventional SXPs. Considered endpoints were postoperative complications and overall and SXP site-specific surgical recurrence. Random-effect meta-analysis and meta-regression were used to obtain and compare combined estimates between groups. RESULTS: A total of 26 studies for a total of 1839 patients with CD were included. The pooled postoperative complication rates were was 15.5% (95% confidence interval [CI] 11.2%-20.3%), 7.4% [95% CI 0.2%-22.9%], and 19.2% [95% CI 5-39.6%] for the three groups, respectively. The rates of septic complications were 4% [95% CI 2.2%-6.2%], 1.9% [95% CI 0.4%-4.3%], and 4.2% [95% CI 0.9%-9.8%], respectively. Cumulative overall surgical recurrence rates were 27.5% [95% CI 18.5%-37.6%], 13.2% [95% CI 8.6%-18.7%], and 18.1% [95% CI 6.8%-33.3%]; and SXP site-specific surgical recurrence rates were 13.2% [95% CI 6.9%-21.2%], 8.3% [95% CI 1.6-19.3%], and 8.8% [95% CI 2.2%-19%], respectively. Formal comparison between the groups revealed no differences. CONCLUSIONS: Non-conventional SXP did not differ from conventional SXP with respect to safety and long-term recurrence. Consistent heterogeneity was observed and partially limits the conclusions of this study.

Long-term clinical outcome after thiopurine discontinuation in elderly IBD patients.

INTRODUCTION AND AIM: Thiopurines - although used frequently in inflammatory bowel diseases (IBD) - carry a significant safety risk, particularly with prolonged use and/or in elderly patients. Stopping therapy, however, may trigger relapses. We assessed the long-term outcome of elderly IBD patients after discontinuation of thiopurine while in clinical remission. METHODS: Electronic medical records from IBD patients >60 years whoever received thiopurine treatment were reviewed. Patients who stopped thiopurine after 60 years of age while in clinical and/or endoscopic remission were included. Long-term outcomes included duration of clinical remission, time to clinical relapse, and development of malignancy. RESULTS: In total, 142 patients receiving thiopurines while they were >60 years were identified. Ninety-one patients stopped thiopurines at >60years while in clinical and/or endoscopic remission. After a median follow-up of 66 months, 28 (30.8%) developed a clinical relapse. The median duration of TP therapy in relapses was significantly shorter than in patients who remained in remission (median 45 vs. 103 months, respectively; p = .005). After relapse, 10 patients started a biological (36%) and seven received steroids (25%). Surgery was needed in 36% of patients (10/28). Overall, 26 malignancies developed. CONCLUSION: Discontinuation of TP in elderly IBD patients in clinical and/or endoscopic remission results in sustained clinical remission in two-thirds of patients. Patients who flare can mostly be rescued with biologicals although one-third necessitate surgery. A significant proportion of patients developed malignancies under but also after thiopurines discontinuation, indicating that these patients necessitate a continued close follow-up. Decision-making in this vulnerable subgroup of patients remains difficult.

Therapeutic outcome of diverticular associated colitis - a retrospective single centre experience.

BACKGROUND: Diverticular associated colitis (DAC) has become increasingly appreciated as a form of inflammatory disease, localized mainly in the sigmoid, and defined as chronic inflammation of the interdiverticular mucosa with sparing of rectum, right colon and diverticula themselves. METHODS: A retrospective case identification from January 2005 to December 2016 was performed. Patients with a diagnosis of DAC based on clinical, endoscopic and histological findings were enrolled. We analyzed their characteristics and response to therapy, and performed a review of literature. RESULTS: Out of 377 pathology reports, 37 cases of DAC were identified, with a median age of 73 years and followed during 1-13 years. Six patients (16.22%) were refractory to conservative treatment and required surgery. In three patients (8.11%) evolution to ulcerative colitis (UC) was observed. Patients were divided into four endoscopic patterns, with a more benign course for type A "crescentic fold disease" compared to the other subtypes. Patients with type B "mild to moderate ulcerative colitis-like" were at significantly higher risk of persistent disease activity or relapse (p < 0.01). CONCLUSION: DAC is a multifaceted disease and considered to be a relatively benign condition. However, a subset of patients requires surgery and/or may progress to develop UC.

Fungal and Bacterial Loads: Noninvasive Inflammatory Bowel Disease Biomarkers for the Clinical Setting.

Microbiome sequence data have been used to characterize Crohn's disease (CD) and ulcerative colitis (UC). Based on these data, we have previously identified microbiomarkers at the genus level to predict CD and CD relapse. However, microbial load was underexplored as a potential biomarker in inflammatory bowel disease (IBD). Here, we sought to study the use of fungal and bacterial loads as biomarkers to detect both CD and UC and CD and UC relapse. We analyzed the fecal fungal and bacterial loads of 294 stool samples obtained from 206 participants using real-time PCR amplification of the ITS2 region and the 16S rRNA gene, respectively. We combined the microbial data with demographic and standard laboratory data to diagnose ileal or ileocolonic CD and UC and predict disease relapse using the random forest algorithm. Fungal and bacterial loads were significantly different between healthy relatives of IBD patients and nonrelated healthy controls, between CD and UC patients in endoscopic remission, and between UC patients in relapse and non-UC individuals. Microbial load data combined with demographic and standard laboratory data improved the performance of the random forest models by 18%, reaching an average area under the receiver operating characteristic curve (AUC) of 0.842 (95% confidence interval [CI], 0.65 to 0.98), for IBD diagnosis and enhanced CD and UC discrimination and CD and UC relapse prediction. Our findings show that fecal fungal and bacterial loads could provide physicians with a noninvasive tool to discriminate disease subtypes or to predict disease flare in the clinical setting.IMPORTANCE Next-generation sequence data analysis has allowed a better understanding of the pathophysiology of IBD, relating microbiome composition and functions to the disease. Microbiome composition profiling may provide efficient diagnosis and prognosis tools in IBD. However, the bacterial and fungal loads of the fecal microbiota are underexplored as potential biomarkers of IBD. Ulcerative colitis (UC) patients have higher fecal fungal and bacterial loads than patients with ileal or ileocolonic CD. CD patients who relapsed harbor more-unstable fungal and bacterial loads than those of relapsed UC patients. Fecal fungal and bacterial load data improved prediction performance by 18% for IBD diagnosis based solely on clinical data and enhanced CD and UC discrimination and prediction of CD and UC relapse. Combined with existing laboratory biomarkers such as fecal calprotectin and C-reactive protein (CRP), microbial loads may improve the diagnostic accuracy of IBD and of ileal CD and UC disease activity and prediction of UC and ileal CD clinical relapse.

Mesenteric panniculitis as a presentation of Whipple's disease: case report and review of the literature.

BACKGROUND: Whipple's disease is a rare, multi-organ disease caused by Tropheryma Whipplei. A classic presentation is characterized by arthropathy, diarrhea and weight loss but a broad spectrum of manifestations is possible. We present a case of a patient with mesenteric panniculitis as a manifestation of WD. A comprehensive review of the literature is provided. PATIENT: A 50 year old male presented at the outpatient clinic after an episode of fever and abdominal pain abroad. CT scan showed mesenteric infiltration with associated lymphadenopathies consistent with mesenteric panniculitis. After receiving 6 months of antibiotic therapy abdominal and joint pains improved. CONCLUSION: Clinicians should be aware of Whipple's disease. Mesenteric panniculitis is a rare presentation of this possible lethal infection. The golden standard for diagnosing WD is a PAS positive small bowel biopsy. Adequate antibiotic therapy is the cornerstone of treatment and usually leads to an amelioration of symptoms.

Short- and Long-term Outcomes Following Side-to-side Strictureplasty and its Modification Over the Ileocaecal Valve for Extensive Crohn's Ileitis.

BACKGROUND AND AIMS: Postoperative recurrence remains a challenging problem in patients with Crohn's disease [CD]. To avoid development of short bowel syndrome, strictureplasty techniques have therefore been proposed. We evaluated short- and long-term outcomes of atypical strictureplasties in CD patients with extensive bowel involvement. METHODS: Side-to-side isoperistaltic strictureplasty [SSIS] was performed according to the Michelassi technique or modification of this over the ileocaecal valve [mSSIS]. Ninety-day postoperative morbidity was assessed using the comprehensive complication index [CCI]. Clinical recurrence was defined as symptomatic, endoscopically or radiologically confirmed, stricture/inflammatory lesion requiring medical treatment or surgery. Surgical recurrence was defined as the need for any surgical intervention. Endoscopic remission was defined as ≤i1, according to the modified Rutgeerts score. Deep remission was defined as the combination of endoscopic remission and absence of clinical symptoms. Perioperative factors related to clinical recurrence were evaluated. RESULTS: A total of 52 CD patients [SSIS n = 12; mSSIS n = 40] were included. No mortality occurred. Mean CCI was 10.3 [range 0-33.7]. Median follow-up was 5.9 years [range 0.8-9.9]. Clinical recurrence [19 patients] was 29.7% and 39.6% after 3 and 5 years, respectively. Surgical recurrence [seven patients] was 2% and 14.1% after 3 and 5 years, respectively. At the end of the follow-up, 92% of patients kept the original strictureplasty and deep remission was observed in 25.7% of the mSSIS patients. None of the perioperative variables considered showed a significant association with clinical recurrence. CONCLUSIONS: SSIS is safe, effective, and provides durable disease control in patients with extensive CD ileitis.

Quality of care in an inflammatory bowel disease clinical trial center : a prospective study evaluating patients' satisfaction.

BACKGROUND AND STUDY AIMS: Quality of care is a very timely topic in medicine. We designed a questionnaire to measure perceived quality of care and to explore areas of improvement. PATIENTS AND METHODS: In this prospective study a questionnaire was developed and administered to all patients with inflammatory bowel disease participating in a randomized clinical trial. The questionnaire was based on validated surveys and supplemented with novel, relevant questions. Factors associated with (poor) quality of care were identified. RESULTS: Between October 2016 and January 2017, all 107 patients participating in a randomized controlled trial completed the questionnaire (63% male, 76% ulcerative colitis, median age of 47 years). The median satisfaction score was 9 out of 10. Areas of improvement were that too little attention was paid to the disease impact on family and work, dietary and exercise pattern, daily activities and quality of life. Multivariate analysis showed that clinical remission [5.77 (2.03-16.39), p=0.001] was a predictor of good quality of care. CONCLUSIONS: In this large IBD trial bureau, inflammatory bowel disease patients were very satisfied with the quality of care. Domains for quality improvement, such as attention to the impact of IBD on family and work, were identified.

Osteonecrosis of the jaw in patients with inflammatory bowel disease treated with tumour necrosis factor alpha inhibitors.

Previous reports have suggested a possible association between tumour necrosis factor alpha (TNF-α) inhibitors, used in the treatment of immune-mediated inflammatory diseases, and medication-related osteonecrosis of the jaw (MRONJ). However, a comprehensive assessment of the frequency and severity of MRONJ caused by these agents is lacking. The aim of this cohort study was to investigate the occurrence of MRONJ in a population of patients with inflammatory bowel disease (IBD) treated with TNF-α inhibitors at a tertiary care medical centre. A total of 2701 IBD patients under current or former treatment with TNF-α inhibitors were identified in an IBD registry covering the period 1994-2018. These patients were cross-matched with all patients diagnosed with MRONJ. This resulted in three patients with a definite diagnosis of MRONJ, without concomitant treatment with bisphosphonates. All three patients required surgical treatment with sequestrectomy. Mucosal healing occurred at 4-15 months and one patient developed recurrence. In conclusion, this study identified and described anti-TNF-α-related MRONJ occurring in a large cohort of IBD patients, and reported the severity and treatment strategies used.

Cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn's disease.

Introduction: Given the well-documented difficulty to treat perianal fistulizing Crohn's disease (pCD), with 40% of patients experiencing recurrence even after reiterative surgery and advanced medical therapy, research in this field has focused on the role of mesenchymal stem cells (MSC). Areas covered: The aim of this article is to furnish an overview of the pathogenetic mechanisms, clinical applications and evidences for the use of MSC for pCD with particular focus on adipose-derived allogenic MSC including darvadstrocel. Expert Opinion: The effect of MSC on fistula healing is probably mediated by their anti-inflammatory properties more than by their ability to engraft and trans-differentiate in the healthy tissue. A holistic treatment of pCD, addressing different pathophysiological factors, may represent the key for an improvement in the healing rate. In this setting, MSC might play a role as 'augmentation' therapy in combination with more conventional treatments. Whether MSC have benefit in non-complex fistula in biological naïve patients, in complex fistula with many tracts and/or in rectovaginal fistulas, are unexplored fields that need further investigation. A central registry of pCD patients undergoing treatment with MSC should be created in order to elucidate the efficacy, safety and costs of stem cells treatment on long term follow up.

Physicians' perspective on the clinical meaningfulness of inflammatory bowel disease trial results: an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) survey.

BACKGROUND: Several novel compounds are being developed for inflammatory bowel diseases (IBD). In addition, biosimilar drugs are being approved. An increasing number of head-to-head, superiority and non-inferiority trials in patients with IBD are expected in the future. The clinical relevance of the magnitude of the effect size is often debated. AIM: To better understand physicians' perspectives on the clinical meaningfulness of IBD trial results. METHODS: We conducted an online survey among all IOIBD (International Organization for the Study of Inflammatory Bowel Diseases) members, asking their opinion on the clinical relevance of the results of IBD trials. RESULTS: Forty-six IOIBD members responded to the survey (52.3%). In biologic-naïve ulcerative colitis (UC) and Crohn's disease (CD) patients, most of the participants considered a 15% difference with placebo for clinical remission and endoscopic remission to be clinically relevant. In head-to-head trials, most of participants considerer a 10% difference between groups for clinical remission and endoscopic remission to be clinically relevant. Half of respondents considered 10% to be an adequate margin in non-inferiority trials. In bioequivalence studies, most of the participants considered adequate a ± 5% difference between a biosimilar and the originator for pharmacokinetic parameters, efficacy, safety and immunogenicity. Regarding safety, the difference between two drugs considered clinically relevant varied from 1% to 5%, depending on the type of adverse event. CONCLUSIONS: This is the first survey exploring how physicians perceive IBD trial results, providing an estimation of the magnitude of the difference between treatment arms that may directly influence clinical practice.

Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.

Anti-infliximab antibody concentrations can guide treatment intensification in patients with Crohn's disease who lose clinical response.

BACKGROUND: The presence of antibodies towards infliximab (ATI) is associated with lower infliximab (IFX) trough concentrations and loss of response. IFX treatment intensification is effective for restoring response in most, but not all patients with Crohn's disease (CD). AIM: To compare outcome, pharmacokinetics and immunogenicity of treatment intensification strategies in patients with CD who lost clinical response to IFX. METHODS: A retrospective cohort study was conducted, including 103 patients with CD who lost clinical response during IFX maintenance therapy and therefore received a double dose IFX (10 mg/kg) and/or a next infusion after a shortened interval. IFX and ATI concentrations were measured in consecutive trough samples, just before (T0) and after (T+1) treatment intensification. RESULTS: Clinical response (physicians' global assessment) and biological response and remission (CRP) were restored in 63%, 42% and 24% of patients (evaluated at T+1). Treatment intensification increased IFX trough concentrations from 1.2 µg/mL [0.3-3.6] at T0 to 3.6 µg/mL [0.5-10.2] at T+1 (P < .0001). Using a drug tolerant assay, ATI were detected in the T0 sample of 47% of patients. ATI negatively impacted the achieved IFX trough concentration (Spearman r -0.57, P < .0001) and the probability of clinical response (P = 0.034) at T+1. When ATI were quantifiable but <282 ng/mL eq. at T0, combined interval shortening and dose doubling was more effective for restoring therapeutic IFX trough concentrations (≥3 µg/mL at T+1) than dose doubling alone, which in turn was more effective than interval shortening alone (P < .001). CONCLUSION: Antibodies towards infliximab can guide clinical decision-making on treatment intensification.

Outcome of restorative proctocolectomy with an ileo-anal pouch for ulcerative colitis: effect of changes in clinical practice.

AIM: Surgery for ileal pouch-anal anastomosis (IPAA) has evolved over time, especially since the introduction of laparoscopy. The aim of this retrospective study was to report the impact of surgical evolution on outcome over a period of 25 years. METHOD: All patients who had IPAA surgery for ulcerative colitis from 1990 to 2015 at the University Hospitals of Leuven were included. Patients were divided into three period arms (period A 1990-1999; period B 2000-2009; period C 2010-2015). The main outcome measure was anastomotic leakage. RESULTS: A total of 335 patients (58.8% male) with a median age of 39 years (interquartile range 32-49 years) at surgery were included. Median follow-up was 5 years (interquartile range 2-10 years). Overall anastomotic leakage (grades A-C) was 14.9%. A significant decrease in leakage rate was observed over time (from 21.4% in period A to 12.1% in period B to 10.0% in period C; P = 0.04). The defunctioning ileostomy rate at the time of pouch construction decreased from 91.7% (period A) to 40.3% (period B) to 11.1% (period C) (P < 0.001). We observed an increase in the use of laparoscopy (23.9% in period A vs 72.6% in period B, vs 84.4% in period C; P = 0.001) and a shift to a modified two-stage procedure (4.1% in period A, vs 66.7% in period C; P < 0.0001). In a monocentric study with some of the data retrieved retrospectively it was not possible to account for the impact of preoperative nutritional status (weight loss, serum albumin level) or disease burden. Other outcome factors were not measured, for example sexual function and fecundity. CONCLUSION: A higher rate of laparoscopic IPAA surgery, together with a shift towards modified two-stage procedures, was associated with a lower leakage rate despite a reduction in the use of defunctioning ileostomy.