Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease.

BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker. METHODS: In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography-tandem mass spectrometry. RESULTS: From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PGtotal was MTX-PG5. MTX-PG6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

Therapeutic drug monitoring of methotrexate in patients with Crohn's disease.

BACKGROUND: Therapeutic drug monitoring (TDM) has the potential to improve efficacy and diminish side effects. Measuring methotrexate-polyglutamate (MTX-PG) in erythrocytes might enable TDM for methotrexate in patients with Crohn's disease (CD). AIM: To investigate the relationship between MTX-PGs and methotrexate drug survival, efficacy and toxicity METHODS: In a multicentre prospective cohort study, patients with CD starting subcutaneous methotrexate without biologics were included and followed for 12 months. Primary outcome was subcutaneous methotrexate discontinuation or requirement for step-up therapy. Secondary outcomes included faecal calprotectin (FCP), Harvey Bradshaw Index (HBI), hepatotoxicity and gastrointestinal intolerance. Erythrocyte MTX-PGs were analysed at weeks 8, 12, 24 and 52 or upon treatment discontinuation. RESULTS: We included 80 patients with CD (mean age 55 ± 13y, 35% male) with a median FCP of 268 µg/g (IQR 73-480). After the 12-month visit, 21 patients (26%) were still on subcutaneous methotrexate monotherapy. Twenty-one patients stopped because of disease activity, 29 because of toxicity, and four for both reasons. Five patients ended study participation or stopped methotrexate for another reason. A higher MTX-PG3 concentration was associated with a higher rate of methotrexate drug survival (HR 0.86, 95% CI 0.75-0.99), lower FCP (ß -3.7, SE 1.3, p < 0.01) and with biochemical response (FCP ≤250 if baseline >250 µg/g; OR 1.1, 95% CI 1.0-1.3). Higher MTX-PGs were associated with less gastrointestinal intolerance. There was no robust association between MTX-PGs and HBI or hepatotoxicity. CONCLUSIONS: Higher MTX-PG3 concentrations are related to better methotrexate drug survival and decreased FCP levels. Therefore, MTX-PG3 could be used for TDM if a target concentration can be established.

Effectiveness of Mindfulness-Based Cognitive Therapy in reducing psychological distress and improving sleep in patients with Inflammatory Bowel Disease: study protocol for a multicentre randomised controlled trial (MindIBD).

BACKGROUND: Many patients with Inflammatory Bowel Diseases (IBD) suffer from psychological distress, fatigue and sleep disturbances, which are associated with reduced quality of life (QoL) and increased societal costs. Only limited psychosocial treatment options are available. As Mindfulness-Based Cognitive Therapy (MBCT) has demonstrated to improve psychological distress, QoL and sleep in other populations, MBCT might also be effective in patients with IBD. METHODS: The MindIBD study is a prospective, multicentre, randomised controlled trial comparing MBCT plus Treatment As Usual (TAU) versus TAU alone in a targeted number of 136 IBD patients in remission, aged 16 years and older with at least mild psychological distress (Hospital Anxiety and Depression Scale (HADS) total score ≥ 11). Primary outcome is reduction of psychological distress post-intervention, measured by the HADS. In addition, the effect of MBCT on sleep quality (including actigraphy and electroencephalography recordings), fatigue, disease activity, perceived disease control, QoL and positive mental health will be examined. Assessments will be conducted at baseline and at 3, 6, 9 and 12 months follow-up. Cost-effectiveness will be determined and a process evaluation will be conducted. DISCUSSION: This study will provide valuable insight into the clinical effect of MBCT on psychological distress, sleep quality, fatigue and QoL in IBD patients and into the cost-effectiveness. If effective, MBCT can be a valuable addition to the available psychosocial interventions for patients with IBD. Moreover, findings from this study may also be applicable in patients with other chronic conditions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04646785, registered on 30/11/2020.

Increased risk of high-grade dysplasia and colorectal cancer in inflammatory bowel disease patients with recurrent low-grade dysplasia.

BACKGROUND AND AIMS: The impact of recurrent low-grade dysplasia (LGD) on the risk of advanced neoplasia (high-grade dysplasia and colorectal cancer) in inflammatory bowel disease (IBD) patients is unknown. In addition, it is unclear how a neoplasia-free period after index LGD impacts this risk. We aimed to determine whether recurrent LGD is a risk factor for advanced neoplasia development and to evaluate the impact of a neoplasia-free time period after initial LGD diagnosis on the advanced neoplasia risk. METHODS: This is a nationwide cohort study using data from the Dutch National Pathology Registry to identify all IBD patients with LGD and ≥1 follow-up colonoscopy between 1991 and 2010 in the Netherlands. Follow-up data were collected until January 2016. We compared the cumulative advanced neoplasia incidence between patients with and without recurrent LGD at first follow-up colonoscopy using log-rank analysis. We subsequently studied the impact of a neoplasia-free period after initial LGD on the advanced neoplasia incidence. RESULTS: We identified 4284 IBD patients with colonic LGD with a median follow-up of 6.4 years. Recurrent LGD was a risk factor for advanced neoplasia (hazard ratio, 1.66; 95% confidence interval, 1.22-2.25; P = .001). A neoplasia-free period of at least 3 years after LGD protected against advanced neoplasia. CONCLUSIONS: Recurrent LGD at follow-up colonoscopy after initial LGD was a risk factor for advanced neoplasia. A neoplasia-free period of at least 3 years after initial LGD was associated with a reduced subsequent risk of advanced neoplasia.

Inflammatory bowel disease in Shwachman-Diamond syndrome; is there an association?

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency with malabsorption, malnutrition, growth failure and bone marrow failure. Furthermore, duodenal inflammatory enteropathy features may be present. For the first time, we report here a SDS case that is also diagnosed with inflammatory bowel disease (IBD). He was diagnosed with SDS at the age of two based on poor growth, severe exocrine pancreatic insufficiency with steatorrhea, neutropenia, recurrent infections and thoracic skeletal abnormalities. Ileocolonoscopy and histopathology revealed colonic Crohn's disease at the age of sixteen. Our report may encourage further studies elucidating the possible association between the SDS genetic defect and inflammatory bowel disease.

Long-term Risk of Advanced Neoplasia After Colonic Low-grade Dysplasia in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

BACKGROUND AND AIMS: The long-term risk of high-grade dysplasia [HGD] and colorectal cancer [CRC] following low-grade dysplasia [LGD] in inflammatory bowel disease [IBD] patients is relatively unknown. We aimed to determine the long-term cumulative incidence of advanced neoplasia [HGD and/or CRC], and to identify risk factors for advanced neoplasia in a nationwide IBD cohort with a history of LGD. METHODS: This is a nationwide cohort study using data from the Dutch National Pathology Registry [PALGA] to identify all IBD patients with LGD between 1991 and 2010 in the Netherlands. Follow-up data were collected until January 2016. We determined the cumulative incidence of advanced neoplasia and identified risk factors via multivariable Cox regression analysis. RESULTS: We identified 4284 patients with colonic LGD with a median follow-up of 6.4 years after initial LGD diagnosis. The cumulative incidence of subsequent advanced neoplasia was 3.6, 8.5, 14.4 and 21.7%, after 1, 5, 10 and 15 years, respectively. The median time to develop advanced neoplasia after LGD was 3.6 years. Older age [≥ 55 years] at moment of LGD (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.44-2.06), male sex [HR 1.33, 95% CI 1.10-1.60], and follow-up at an academic [vs non-academic] medical centre [HR 1.37, 95% CI 1.07-1.76] were independent risk factors for advanced neoplasia following LGD. CONCLUSIONS: In a large nationwide cohort with long-term follow-up of IBD patients with LGD, the cumulative incidence of advanced neoplasia was 21.7% after 15 years. Older age at LGD [≥55 years], male sex and follow-up by a tertiary IBD referral centre were independent risk factors for advanced neoplasia development after initial LGD.

Thoracic and abdominal pain in a 28-year-old woman with a failing kidney transplant.

This case report describes a young, immunocompromised patient who presented with thoracic pain. After an extensive workup, she was diagnosed with a varicella zoster virus infection with involvement of the gastric mucosa, pancreas and lungs for which she was treated with acyclovir. Although the viral load decreased significantly, the patient had persistent postherpetic neuralgia and nausea.

Risk Factors and Clinical Outcomes of Head and Neck Cancer in Inflammatory Bowel Disease: A Nationwide Cohort Study.

Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to develop extra-intestinal malignancies. Immunosuppressed transplant patients show increased incidence of head and neck cancer with impaired survival. This study aims to identify risk factors for oral cavity (OCC) and pharyngeal carcinoma (PC) development in IBD, to compare clinical characteristics in IBD with the general population, and to assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all IBD patients with OCC and PC between 1993 and 2011. Two case-control studies were performed: We compared cases with the general IBD population to identify risk factors, and we compared cases with non-IBD cancer patients for outcome analyses. Results: We included 66 IBD patients and 2141 controls with OCC, 31 IBD patients and 1552 controls with PC, and 1800 IBD controls. Age at IBD diagnosis was a risk factor for OCC development, Crohn's disease (CD; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07), and ulcerative colitis (UC; OR, 1.03; 95% CI, 1.01-1.06). For PC, this applied to UC (OR, 1.05; 95% CI, 1.01-1.06). IBD OCC cases showed impaired survival (P = 0.018); in PC, survival was similar. There was no effect of immunosuppression on survival. Human papillomavirus (HPV) testing of IBD cases revealed 52.2% (12/23) HPV-positive oropharyngeal carcinomas (OPCs). Conclusion: This study shows that IBD is associated with impaired OCC survival. Higher age at IBD diagnosis is a risk factor for OCC development. We found no influence of immunosuppression on survival; 52.2% of OPC in IBD contained HPV.

Risk Factors and Clinical Outcomes in Patients with IBD with Melanoma.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk to develop malignant melanoma and this risk may increase with use of anti-tumor necrosis factor (TNF) therapy. Impaired survival of immunosuppressed melanoma patients is reported in transplant and rheumatology patients. This study aims to (1) identify risk factors for melanoma development in patients with IBD, (2) compare clinical characteristics of melanoma in patients with IBD to the general population, and (3) assess the influence of immunosuppressive medication on survival. METHODS: We retrospectively searched the Dutch Pathology Database to identify all Dutch patients with IBD with cutaneous melanoma between January 1991 and December 2011. We then performed 2 case-control studies. To identify risk factors for melanoma development in IBD, we compared patients with IBD with melanoma to the general IBD population. To compare outcome and survival after melanoma diagnosis, we compared cases with non-IBD melanoma patients. RESULTS: We included 304 patients with IBD with melanoma, 1800 IBD controls, and 8177 melanoma controls. IBD cases had more extensive IBD (ulcerative colitis: pancolitis: cases 44.5% versus IBD controls without melanoma 28.1%; P < 0.01; Crohn's disease: ileal and colonic disease: cases 57.9% versus controls 48.9%; P = 0.02). Despite a lower Nodes (N)-stage in patients with IBD (N1+ 8.3% versus 18.2%; P < 0.01) with comparable Tumor (T) and Metastasis (M) stages, survival was similar between groups, regardless of immunosuppressive or anti-TNF therapy. CONCLUSIONS: This study showed that IBD extent is a risk factor for melanoma development. Despite the lower N-stage in patients with IBD, we could not confirm impaired survival after melanoma in patients with IBD, regardless of anti-TNF and/or thiopurine use.

Impaired Gastric Cancer Survival in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in inflammatory bowel disease (IBD). Previous literature suggests that especially Crohn's disease patients are at an increased risk for developing gastric cancer (GC). This study aimed to identify risk factors for GC development in IBD and to compare the clinical characteristics of GC in IBD to those in the general population. METHODS: We retrospectively searched the Dutch Pathology Database to identify all Dutch IBD patients with GC between January 2004 and December 2008. Two case-control studies were performed. I: to identify risk factors for GC in IBD, with controls from the IBD South Limburg (IBDSL) population-based cohort; and II: to compare GC disease course in IBD patients with the general population. General population data were obtained from the Eindhoven Cancer Registry (ECR). RESULTS: We included 59 patients with IBD and GC (cases). Cases were significantly older at IBD diagnosis than IBDSL controls (median age 61 years versus 40; p<0.01), and ulcerative colitis (UC) was more frequent in the case group (69.5% versus 51.4%; p<0.01). We found no difference in age at diagnosis, gender, tumor location and tumor differentiation between IBD GC patients and ECR controls. When corrected for confounders and TNM-stage, IBD patients showed impaired survival (p=0.035; HR 1.385). CONCLUSIONS: Survival is significantly reduced in IBD patients compared to the general population in the multivariate analysis of our study, but age at GC diagnosis and TNM-stage were comparable between IBD cases and controls. Elderly onset IBD emerged as a risk factor for GC development in IBD patients, particularly in UC.

Controversies in Pouch Surveillance for Patients with Inflammatory Bowel Disease.

CASE 1: Following 2 years of rectal blood loss, a 31-year-old male was diagnosed with ulcerative pancolitis in 1978. Initial treatment consisted of both topical and systemic 5-aminosalicylic acids [5-ASAs], and remission was achieved. In both 1984 and 1986 he was hospitalised due to exacerbations necessitating treatment with intravenous corticosteroids. The following years went well, without disease activity, under treatment with 5-ASA. In 1997, at the age of 50 years, a surveillance colonoscopy showed a stenotic process with a macroscopic irregularity in the sigmoid region. Histology revealed at least high-grade dysplasia [HGD] and signs of an invasive growth pattern which could indicate colorectal cancer [CRC]. The patient underwent restorative proctocolectomy with ileal pouch-anal anastomosis [IPAA]. Histology of the resection specimen confirmed active inflammation in the colon and rectum and a carcinoma in situ was identified in the sigmoid colon without invasive growth. This patient did not have significant comorbidities-for example primary sclerosing cholangitis [PSC]-and the CRC family history was negative. What pouch surveillance strategy should be recommended? CASE 2: A 34-year-old man presented at our inflammatory bowel disease [IBD] centre with ulcerative proctitis. Ten years later, after an initially mild disease course, his disease progressed to a pancolitis. An 11-year period with multiple exacerbations [on average every 2 year, including hospitalisation] followed and treatment consisted of topical and systemic 5-ASAs with intermittent corticosteroids. In 1998, at the age of 65 years, a two-stage restorative proctocolectomy with IPAA was performed due to disease activity refractory to systemic corticosteroids. The colectomy specimen confirmed the diagnosis of ulcerative pancolitis without evidence for colorectal dysplasia or carcinoma. Other than steroid-induced diabetes mellitus, this patient had no comorbidities. His father died from CRC at unknown age. What pouch surveillance strategy should be recommended?

Cytomegalovirus in inflammatory bowel disease: A systematic review.

AIM: To identify definitions of cytomegalovirus (CMV) infection and intestinal disease, in inflammatory bowel disease (IBD), to determine the prevalence associated with these definitions. METHODS: We conducted a systematic review and interrogated PubMed, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both MeSH-terms and free searches were performed. We included all types of English-language (clinical) trials concerning diagnostics and prevalence of CMV in IBD. RESULTS: The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR > 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia. CONCLUSION: We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.

Hepatosplenic T-cell lymphoma in a 47-year-old Crohn's disease patient on thiopurine monotherapy.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare non-Hodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger than 35 years, and have been treated with thiopurine and tumor necrosis factor (TNF)-α inhibitor combination therapy for over 2 years. In this case report we describe a 47-year-old patient with Crohn's disease (CD) who developed HSTCL after having been treated with thiopurine monotherapy for 14 years. To our best knowledge, only eleven cases exist of patients with CD who developed HSTCL while on thiopurine monotherapy. We report the first patient with CD, older than 35 years, who developed HSTCL while on thiopurine monotherapy. This emphasizes that HSTCL risk is not limited to young men receiving both thiopurines and TNF-α inhibitors.

Risk of Neoplasia After Colectomy in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Colorectal neoplasia can still develop after colectomy for inflammatory bowel disease. However, data on this risk are scare, and there have been few conclusive findings, so no evidence-based recommendations have been made for postoperative surveillance. We conducted a systematic review and meta-analysis to determine the prevalence and incidence of and risk factors for neoplasia in patients with inflammatory bowel disease who have undergone colectomy, including the permanent-end ileostomy and rectal stump, ileorectal anastomosis (IRA), and ileal pouch-anal anastomosis (IPAA) procedures. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library through May 2014 to identify studies that reported prevalence or incidence of colorectal neoplasia after colectomy or specifically assessed risk factors for neoplasia development. Studies were selected, quality was assessed, and data were extracted by 2 independent researchers. RESULTS: We calculated colorectal cancer (CRC) prevalence values from 13 studies of patients who underwent rectal stump surgery, 35 studies of IRA, and 33 studies of IPAA. Significantly higher proportions of patients in the rectal stump group (2.1%; 95% confidence interval [CI], 1.3%-3.0%) and in the IRA group (2.4%; 95% CI, 1.7%-3.0%) developed CRC than in the IPAA group (0.5%; 95% CI, 0.3%-0.6%); the odds ratio (OR) for CRC in the rectal stump or IRA groups compared with the IPAA group was 6.4 (95% CI, 4.3-9.5). A history of CRC was the most important risk factor for development of CRC after colectomy (OR for patients receiving IRA, 12.8; 95% CI, 3.31-49.2 and OR for patients receiving IPAA, 15.0; 95% CI, 6.6-34.5). CONCLUSIONS: In a meta-analysis of published studies, we found the prevalence and incidence of CRC after colectomy to be less than 3%; in patients receiving IPAA it was less than 1%. Factors that increased risk of cancer development after colectomy included the presence of a residual rectum and a history of CRC. These findings could aid in development of individualized strategies for post-surgery surveillance.

Better survival of renal cell carcinoma in patients with inflammatory bowel disease.

BACKGROUND: Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population. METHODS: A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991-2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes. RESULTS: 180 IBD patients with RCC were identified. Pancolitis (OR 1.8-2.5), penetrating Crohn's disease (OR 2.8), IBD related surgery (OR 3.7-4.5), male gender (OR 3.2-5.0) and older age at IBD onset (OR 1.0-1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression. CONCLUSIONS: IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.

Epstein-Barr virus in inflammatory bowel disease: the spectrum of intestinal lymphoproliferative disorders.

BACKGROUND: Inflammatory bowel disease (IBD) patients on thiopurine therapy are at increased risk of Epstein-Barr virus (EBV)-associated lymphomas. This virus is frequently detected in the intestinal mucosa of IBD patients and may cause a wide spectrum of lymphoproliferations similar to post-transplantation lymphoproliferative disorders (PTLDs). We aimed to assess whether histological aberrations aid in predicting EBV presence and to correlate histological assessment and EBV load with disease outcome in IBD. METHODS: We included all IBD patients from our centre who underwent EBV testing of intestinal biopsies between January 2004 and October 2013. All biopsies were classified according to the WHO PTLD classification and the EBV load was scored per high-power field (HPF). Clinical data were collected from patient charts. Reported clinical outcomes included colectomy, need for chemotherapy and mortality. RESULTS: Our cohort included 58 patients: 28 were EBV-positive and 30 EBV-negative. An atypical infiltrate was seen more frequently in EBV-positive than in EBV-negative patients (57.1 versus 3.3%; p < 0.001). A high EBV load occurred more frequently in EBV-positive patients undergoing colectomy than in EBV-positive patients without colectomy (50.0 versus 10.0%; p = 0.048). Monomorphic lymphoproliferative disorders, including two overt lymphomas, were present in 10 patients. Reduction of immunosuppression resulted in histological normalization and loss of EBV expression in seven of eight non-lymphoma patients. CONCLUSION: The presence of atypical infiltrate in the intestinal mucosa of IBD patients warrants EBV testing. Reduction of immunosuppression is an effective strategy to achieve morphological normalization and loss of EBV. Lymphoproliferation related to IBD appears to have less aggressive clinical behaviour than PTLDs.