ABSTRACT
Celiac disease is a common gastrointestinal condition with an estimated global prevalence of up to 1%. Adequate long-term surveillance of patients is imperative to ensure strict adherence to treatment with a gluten-free diet and the ensuing clinical and histologic recovery. Traditionally, this has been accomplished by means of regular on-site attendance at specialist health care facilities, accompanied for most patients by follow-up endoscopic and laboratory tests. However, the rapidly increasing prevalence of celiac disease and the limited health care resources challenge the current centralized and nonindividualized follow-up strategies. The improved noninvasive surveillance tools and online health care services are further changing the landscape of celiac disease management. There is a clear need for more personalized and on-demand follow-up based on early treatment response and patient-related factors associated with long-term prognosis. Additional scientific evidence on the optimal implementation of follow-up for pediatric and adulthood celiac disease is nevertheless called for.
Subject(s)
Celiac Disease , Diet, Gluten-Free , Global Health , Celiac Disease/epidemiology , Celiac Disease/diagnosis , Celiac Disease/diet therapy , Celiac Disease/therapy , Humans , PrevalenceABSTRACT
Inflammatory intestinal diseases are characterized by abnormal immune responses and affect distinct locations of the gastrointestinal tract. Although the role of several immune subsets in driving intestinal pathology has been studied, a system-wide approach that simultaneously interrogates all major lineages on a single-cell basis is lacking. We used high-dimensional mass cytometry to generate a system-wide view of the human mucosal immune system in health and disease. We distinguished 142 immune subsets and through computational applications found distinct immune subsets in peripheral blood mononuclear cells and intestinal biopsies that distinguished patients from controls. In addition, mucosal lymphoid malignancies were readily detected as well as precursors from which these likely derived. These findings indicate that an integrated high-dimensional analysis of the entire immune system can identify immune subsets associated with the pathogenesis of complex intestinal disorders. This might have implications for diagnostic procedures, immune-monitoring, and treatment of intestinal diseases and mucosal malignancies.
Subject(s)
Celiac Disease/immunology , Crohn Disease/immunology , Image Cytometry/methods , Intestinal Mucosa/immunology , Lymphocyte Subsets/immunology , Lymphocytes/immunology , Lymphocytes/physiology , Lymphoma, T-Cell/immunology , Adult , Aged , Celiac Disease/diagnosis , Cohort Studies , Computational Biology , Crohn Disease/diagnosis , Female , HEK293 Cells , Humans , Immunologic Tests , Lymphoma, T-Cell/diagnosis , Male , Middle Aged , Monitoring, Immunologic , Organ Specificity , Single-Cell AnalysisABSTRACT
INTRODUCTION: Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea. Fidaxomicin and fecal microbiota transplantation (FMT) are effective, but expensive therapies to treat recurrent CDI (reCDI). Our objective was to develop a prediction model for reCDI based on the gut microbiota composition and clinical characteristics, to identify patients who could benefit from early treatment with fidaxomicin or FMT. METHODS: Multicentre, prospective, observational study in adult patients diagnosed with a primary episode of CDI. Fecal samples and clinical data were collected prior to, and after 5 days of CDI treatment. Follow-up duration was 8 weeks. Microbiota composition was analysed by IS-pro, a bacterial profiling technique based on phylum- and species-specific differences in the 16-23 S interspace regions of ribosomal DNA. Bayesian additive regression trees (BART) and adaptive group-regularized logistic ridge regression (AGRR) were used to construct prediction models for reCDI. RESULTS: 209 patients were included, of which 25% developed reCDI. Variables related to microbiota composition provided better prediction of reCDI and were preferentially selected over clinical factors in joint prediction models. Bacteroidetes abundance and diversity after start of CDI treatment, and the increase in Proteobacteria diversity relative to baseline, were the most robust predictors of reCDI. The sensitivity and specificity of a BART model including these factors were 95% and 78%, but these dropped to 67% and 62% in out-of-sample prediction. CONCLUSION: Early microbiota response to CDI treatment is a better predictor of reCDI than clinical prognostic factors, but not yet sufficient enough to predict reCDI in daily practice.
Subject(s)
Clostridium Infections , Feces , Gastrointestinal Microbiome , Humans , Clostridium Infections/microbiology , Clostridium Infections/therapy , Male , Prospective Studies , Female , Feces/microbiology , Middle Aged , Aged , Clostridioides difficile/genetics , Fecal Microbiota Transplantation , Adult , Recurrence , Anti-Bacterial Agents/therapeutic use , Aged, 80 and over , Fidaxomicin/therapeutic useABSTRACT
Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.
Subject(s)
Gastroenterology , Inflammatory Bowel Diseases , Humans , Thioguanine/therapeutic use , Off-Label Use , Inflammatory Bowel Diseases/drug therapy , Netherlands , Azathioprine/therapeutic use , Mercaptopurine/therapeutic use , Immunosuppressive Agents/therapeutic useABSTRACT
OBJECTIVES: Thioguanine (TG) has been shown as a safe alternative in adults with inflammatory bowel disease (IBD) who did not tolerate conventional thiopurines [azathioprine (AZA)/mercaptopurine]. However, data in pediatric IBD are scarce. Therefore, we aimed to assess the safety of TG as maintenance therapy. METHODS: A retrospective, multicenter cohort study of children with IBD on TG was performed in the Netherlands. TG-related adverse events (AE) were assessed and listed according to the common terminology criteria for AE. RESULTS: Thirty-six children with IBD (median age 14.5 years) on TG (median dose 15 mg/day) were included in 6 centers. Five AE occurred during follow-up [pancreatitis (grade 3), hepatotoxicity (grade 3) (n = 2), Clostridium difficile infection (grade 2), and abdominal pain (grade 2)]. All patients (n = 8) with a previously AZA-induced pancreatitis did not redevelop pancreatitis on TG. CONCLUSIONS: In pediatric IBD, TG seems a safe alternative in case of AZA-induced pancreatitis. Further research assessing long-term TG-related safety and efficacy is needed.
Subject(s)
Inflammatory Bowel Diseases , Pancreatitis , Humans , Adult , Child , Adolescent , Thioguanine/adverse effects , Retrospective Studies , Cohort Studies , Mercaptopurine/adverse effects , Azathioprine/therapeutic use , Inflammatory Bowel Diseases/drug therapy , Pancreatitis/chemically induced , Pancreatitis/drug therapy , Chronic Disease , Immunosuppressive Agents/adverse effectsABSTRACT
BACKGROUND: Beneficial response to first-line immunosuppressive azathioprine in patients with inflammatory bowel disease (IBD) is low due to high rates of adverse events. Co-administrating allopurinol has been shown to improve tolerability. However, data on this co-therapy as first-line treatment are scarce. AIM: Retrospective comparison of long-term effectiveness and safety of first-line low-dose azathioprine-allopurinol co-therapy (LDAA) with first-line azathioprine monotherapy (AZAm) in patients with IBD without metabolite monitoring. METHODS: Clinical benefit was defined as ongoing therapy without initiation of steroids, biologics or surgery. Secondary outcomes included CRP, HBI/SCCAI, steroid withdrawal and adverse events. RESULTS: In total, 166 LDAA and 118 AZAm patients (median follow-up 25 and 27 months) were evaluated. Clinical benefit was more frequently observed in LDAA patients at 6 months (74% vs. 53%, p = 0.0003), 12 months (54% vs. 37%, p = 0.01) and in the long-term (median 36 months; 37% vs. 24%, p = 0.04). Throughout follow-up, AZAm patients were 60% more likely to fail therapy, due to a higher intolerance rate (45% vs. 26%, p = 0.001). Only 73% of the effective AZA dose was tolerated in AZAm patients, while LDAA could be initiated and maintained at its target dose. Incidence of myelotoxicity and elevated liver enzymes was similar in both cohorts, and both conditions led to LDAA withdrawal in only 2%. Increasing allopurinol from 100 to 200-300 mg/day significantly lowered liver enzymes in 5/6 LDAA patients with hepatotoxicity. CONCLUSIONS: Our poor AZAm outcomes emphasize that optimization of azathioprine is needed. We demonstrated a long-term safe and more effective profile of first-line LDAA. This co-therapy may therefore be considered standard first-line immunosuppressive.
Subject(s)
Azathioprine , Inflammatory Bowel Diseases , Allopurinol/adverse effects , Azathioprine/adverse effects , Drug Therapy, Combination , Humans , Immunosuppressive Agents/adverse effects , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/drug therapy , Mercaptopurine/therapeutic use , Retrospective Studies , Treatment OutcomeABSTRACT
Immune-mediated enteropathies are caused by excessive reactions of the intestinal immune system towards non-pathogenic molecules. Enteropathy leads to malabsorption-related symptoms and include (severe) chronic diarrhea, weight loss and vitamin deficiencies. Parenteral feeding and immunosuppressive therapy are needed in severe cases. Celiac disease has long been recognized as the most common immune-mediated enteropathy in adults, but the spectrum of immune-mediated enteropathies has been expanding. Histological and clinical features are sometimes shared among these enteropathies, and therefore it may be challenging to differentiate between them. Here, we provide an overview of immune-mediated enteropathies focused on clinical presentation, establishing diagnosis, immunopathogenesis, and treatment options.
Subject(s)
Immune System Diseases/immunology , Immunosuppression Therapy/methods , Intestinal Diseases/immunology , Parenteral Nutrition , Animals , Clinical Trials as Topic , Disease Models, Animal , Humans , Immune System Diseases/diagnosis , Immune System Diseases/pathology , Immune System Diseases/therapy , Immunity, Mucosal , Intestinal Diseases/diagnosis , Intestinal Diseases/pathology , Intestinal Diseases/therapy , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Treatment OutcomeABSTRACT
BACKGROUND AND AIMS: Since 2008, a plethora of research studies has compared the efficacy of water-assisted (aided) colonoscopy (WAC) and underwater resection (UWR) of colorectal lesions with standard colonoscopy. We reviewed and graded the research evidence with potential clinical application. We conducted a modified Delphi consensus among experienced colonoscopists on definitions and practice of water immersion (WI), water exchange (WE), and UWR. METHODS: Major databases were searched to obtain research reports that could potentially shape clinical practice related to WAC and UWR. Pertinent references were graded (Grading of Recommendations, Assessment, Development and Evaluation). Extracted data supporting evidence-based statements were tabulated and provided to respondents. We received responses from 55 (85% surveyed) experienced colonoscopists (37 experts and 18 nonexperts in WAC) from 16 countries in 3 rounds. Voting was conducted anonymously in the second and third round, with ≥80% agreement defined as consensus. We aimed to obtain consensus in all statements. RESULTS: In the first and the second modified Delphi rounds, 20 proposed statements were decreased to 14 and then 11 statements. After the third round, the combined responses from all respondents depicted the consensus in 11 statements (S): definitions of WI (S1) and WE (S2), procedural features (S3-S5), impact on bowel cleanliness (S6), adenoma detection (S7), pain score (S8), and UWR (S9-S11). CONCLUSIONS: The most important consensus statements are that WI and WE are not the same in implementation and outcomes. Because studies that could potentially shape clinical practice of WAC and UWR were chosen for review, this modified Delphi consensus supports recommendations for the use of WAC in clinical practice.
Subject(s)
Adenoma , Water , Adenoma/diagnosis , Adenoma/surgery , Colonoscopy , Consensus , Delphi Technique , HumansABSTRACT
Climate change has been described as the greatest public health threat of the 21st century. It has significant implications for digestive health. A multinational team with representation from all continents, excluding Antarctica and covering 18 countries, has formulated a commentary which outlines both the implications for digestive health and ways in which this challenge can be faced.
Subject(s)
Climate Change , Gastroenterology , HumansABSTRACT
BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.
Subject(s)
Immunosuppressive Agents , Inflammatory Bowel Diseases , Methyltransferases , Thioguanine , Adult , Azathioprine , Female , Genotype , Guanine Nucleotides , Humans , Immunosuppressive Agents/pharmacokinetics , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Male , Mercaptopurine , Methyltransferases/genetics , Middle Aged , Phenotype , Retrospective Studies , Thioguanine/pharmacokinetics , ThionucleotidesABSTRACT
Although barium swallow imaging is established in the investigation of Zenker's diverticulum (ZD), no agreed measurement protocol exists. We developed a protocol for measuring ZD dimensions and aimed to correlate measurements with symptoms and post-operative outcomes. This prospective study included patients with confirmed ZD who underwent flexible endoscopic septal division (FESD) between 2014 and 2018. ZD was confirmed on barium radiology with measurements reviewed by two consultant radiologists. Symptom severity pre- and post-FESD was measured using the Dysphagia, Regurgitation, Complications (DRC) scale. Regression analyses were conducted to identify dimensions associated with therapeutic success, defined as remission (DRC score ≤ 1) 6 months after index FESD. In total, 67 patients (mean age 74.3) were included. Interobserver reliability (intraclass correlation coefficients-ICCs) was greatest for pouch width (0.981) and pouch depth (0.934), but not oesophageal depth (0.018). Male gender (60.9%) was associated with larger pouch height (P = 0.008) and width (P = 0.004). A positive correlation was identified between baseline DRC score and pouch depth (ρ 0.326, P = 0.011), particularly the regurgitation subset score (ρ 0.330, P = 0.020). The index pouch depth was associated with FESD procedure time (rho 0.358, P = 0.041). Therapeutic success was achieved in 64.2% and was associated with shorter pouch height (median 14.5 mm vs. 19.0 mm, P = 0.030), pouch width (median 19.9 mm vs. 28.8 mm, P = 0.34) and cricopharyngeal length (median 20.2 mm vs. 26.3 mm, P = 0.036). ZD dimensions may be feasible and were evaluated using Barium radiology. Specific parameters appear to correlate with severity and post-FESD outcomes, which aid with pre-procedural planning.
Subject(s)
Zenker Diverticulum , Aged , Barium , Esophagoscopy , Female , Humans , Male , Prospective Studies , Reproducibility of Results , Treatment Outcome , Zenker Diverticulum/diagnostic imaging , Zenker Diverticulum/surgeryABSTRACT
BACKGROUND: Thioguanine (TG) is a thiopurine which has been used for patients with inflammatory bowel disease (IBD), who have failed azathioprine (AZA) or mercaptopurine (MP) due to adverse events or suboptimal response. Its widespread use has been hampered due to concerns about nodular regenerative hyperplasia (NRH) of the liver. The aim of this study was to investigate the long-term efficacy and safety of low-dose TG therapy in IBD patients failing AZA and MP. METHODS: A retrospective multicentre study was performed in IBD patients who failed prior treatment with conventional thiopurines with or without following immunomodulation (thiopurine-allopurinol, biologicals, methotrexate, tacrolimus) and were subsequently treated with TG as rescue monotherapy between 2003 and 2019 at three hospitals in the United Kingdom. Clinical response, adverse events, laboratory results, imaging and liver biopsies were retrospectively collected. RESULTS: A total of 193 patients (57% female and 64% Crohn's disease) were included, with a median daily TG dose of 20 mg (range: 20-40 mg), a median treatment duration of 23 months (IQR 10-47) and a median follow-up of 36 months (IQR 22-53). The clinical response rate at 12 months was 65 and 54% remained on TG until the end of follow-up. Adverse events consisted primarily of elevated liver tests (6%), myelotoxicity (7%) and rash (5%). NRH was histologically diagnosed in two patients and two other patients (1%) developed non-cirrhotic portal hypertension. The median 6-TGN and TPMT levels were 953 pmol/8 × 105 RBC (IQR 145-1761) and 47 mu/L (IQR 34.5-96). CONCLUSIONS: Long-term follow-up suggests that TG can be an effective and well-tolerated therapy in more than half of difficult-to-treat and multi-therapy failing IBD patients. Findings of this study indicate that TG can be used safely and the occurrence of hepatotoxicity was low. The incidence rate of NRH was within the background incidence.
Subject(s)
Inflammatory Bowel Diseases , Pharmaceutical Preparations , Azathioprine/adverse effects , Female , Humans , Immunosuppressive Agents/adverse effects , Inflammatory Bowel Diseases/drug therapy , Male , Mercaptopurine , Retrospective Studies , Thioguanine/adverse effects , Treatment Outcome , United KingdomABSTRACT
OBJECTIVES: Flexible endoscopic septum division is an established treatment for Zenker's diverticulum (ZD); however, long-term outcome data are lacking. We aimed to evaluate the long-term efficacy of flexible endoscopic septal division (FESD) using the stag beetle knife for ZD and identify predictors of symptom recurrence. METHODS: Patients undergoing the procedure between 2013 and 2018 were prospectively enrolled. Procedures were performed by a single operator. Symptom severity pre- and postprocedure was recorded using the dysphagia, regurgitation, and complications scale. Symptom recurrence was defined as a total score > 1 after the index procedure. Time-to-event analyses were performed using Kaplan-Meier plots, with multivariable analyses performed using Cox regression models. RESULTS: Altogether, 65 patients (mean age 74.0 years, 60% male) were included. Previous stapling had been performed in 44.6% of patients. Over the mean posttreatment follow-up period of 19 months, 5.6% of the treatment naïve group and 34.5% of the recurrent group underwent repeated FESD (P = 0.003), with rates of symptom remission and improvement of 75.4% and 92.7%, respectively. Recurrence at 48 months was higher in patients with recurrent ZD (84.7%) than in treatment-naïve patients (10.7%). On multivariable analysis, recurrent disease (hazard ratio [HR] 20.8, P = 0.005) and younger age (HR 0.96/year, P = 0.047) were associated with symptom recurrence. CONCLUSIONS: In patients with treatment-naïve ZD, flexible endoscopic septal division is safe and provides durable symptom remission. However, in patients with poststapling recurrence, the risk of recurrence is high and time-dependent.
Subject(s)
Coleoptera , Deglutition Disorders , Zenker Diverticulum , Aged , Animals , Deglutition Disorders/etiology , Esophagoscopy , Female , Humans , Male , Retrospective Studies , Treatment Outcome , Zenker Diverticulum/surgeryABSTRACT
Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin-IELs) in the duodenum. In â¼50% of patients with RCDII, these Lin-IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin-IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin-IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin-IELs and CD3-CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.
Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Cell Proliferation/drug effects , Cytokines/pharmacology , Intraepithelial Lymphocytes/drug effects , Apoptosis/drug effects , Apoptosis/genetics , Celiac Disease/genetics , Celiac Disease/metabolism , Cell Proliferation/genetics , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Drug Synergism , Duodenum/metabolism , Humans , Interleukin-15/genetics , Interleukin-15/metabolism , Interleukin-15/pharmacology , Interleukin-2/genetics , Interleukin-2/metabolism , Interleukin-2/pharmacology , Interleukins/genetics , Interleukins/metabolism , Interleukins/pharmacology , Intraepithelial Lymphocytes/metabolism , Recombinant Proteins/pharmacology , Transcriptome/drug effects , Transcriptome/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
BACKGROUND: Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS: In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS: Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0·97, 95% CI 0·62-1·51; p=0·88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1·38, 95% CI 0·53-3·59, p=0·50), nor did any of the major complications included in the primary endpoint. INTERPRETATION: In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING: The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.
Subject(s)
Debridement , Drainage , Endoscopy, Digestive System , Pancreatitis, Acute Necrotizing/surgery , Video-Assisted Surgery , Aged , Female , Humans , Length of Stay , Male , Middle Aged , Netherlands , Treatment OutcomeABSTRACT
Nodular regenerative hyperplasia (NRH) is a poorly understood liver condition, which is increasingly recognized in thiopurine-treated patients with inflammatory bowel disease (IBD).1 It is difficult to establish an optimal approach to NRH patients, because its manifestations are highly variable (from asymptomatic to symptoms of noncirrhotic portal hypertension [NCPH]) and the prognosis is unknown.2 The aim of this study was to identify NRH cases in IBD patients treated with azathioprine, mercaptopurine, and/or thioguanine, and to describe its clinical course.
Subject(s)
Azathioprine/adverse effects , Hyperplasia/pathology , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/pathology , Liver Diseases/pathology , Mercaptopurine/adverse effects , Thioguanine/adverse effects , Adolescent , Adult , Aged , Azathioprine/administration & dosage , Female , Humans , Hyperplasia/chemically induced , Inflammatory Bowel Diseases/complications , Male , Mercaptopurine/administration & dosage , Middle Aged , Thioguanine/administration & dosage , Young AdultABSTRACT
BACKGROUND & AIMS: There have been few reproducible studies of mortality in patients with autoimmune hepatitis (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, with vs without cirrhosis, in the Netherlands. METHODS: We collected data from 449 patients with established AIH (77% female), from 6 academic and 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year-matched mortality for the general Dutch population. RESULTS: During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 33-94 years). Twenty-six causes of death were liver related (43%), whereas the others could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly higher mortality than the general population (SMR, 1.9; 95% CI, 1.2-3.4), whereas patients without cirrhosis did not (SMR, 1.2; 95% CI, 0.8-1.8). Patients with AIH-PSC had the largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5-14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis was not greater than the general population. Four or more relapses per decade or not achieving remission was associated with an increase in liver-related death or liver transplantation. Nine patients underwent liver transplantation; 2 died from non-liver related causes. Four of 9 patients on the waitlist for transplantation died before receiving a donated liver. CONCLUSION: In an analysis of data from a large national cohort of patients with AIH, we found increased mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the general Dutch population. Survival was significantly reduced in patients with AIH and features of concurrent PSC.
Subject(s)
Hepatitis, Autoimmune/complications , Hepatitis, Autoimmune/mortality , Liver Cirrhosis/mortality , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Hospitals , Humans , Male , Middle Aged , Netherlands/epidemiology , Survival Analysis , Young AdultABSTRACT
GOALS: To validate cut-off values of CD3 T-cell receptor gamma-delta chain (TCRγδ) intraepithelial lymphocyte (IEL) in the (differential) diagnosis of celiac disease (CD). BACKGROUND: CD is characterized by an increase in gamma-delta IEL (CD3TCRγδ IEL). STUDY: Percentages were determined by flow cytometric analysis of IELs from small bowel biopsies in 213 CD and 13 potential CD (PCD) patients and in total 112 controls. A cut-off value for percentages of CD3TCRγδ IEL to differentiate active CD and controls was obtained from a receiver operating characteristic curve and implemented in controls and PCD patients. RESULTS: Percentage of CD3TCRγδ IEL was significantly increased in the majority of CD patients, irrespective of the presence of villous atrophy. A cut-off value of 14% for CD3TCRγδ IEL resulted in 66.3% sensitivity and 96.6% specificity for CD diagnosis (area under the curve, 88.6%). CONCLUSIONS: A percentage of ≥14% CD3TCRγδ IEL has a high specificity for CD diagnosis and can be of diagnostic help in cases where diagnosis is not straightforward.
Subject(s)
Celiac Disease/diagnosis , Duodenum/pathology , Intestinal Mucosa/pathology , Intraepithelial Lymphocytes/cytology , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy , Child , Female , Flow Cytometry , Humans , Male , Middle Aged , Sensitivity and Specificity , Young AdultABSTRACT
Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.
Subject(s)
Inflammatory Bowel Diseases/drug therapy , Liver/pathology , Thioguanine/adverse effects , Adult , Biopsy , Chemical and Drug Induced Liver Injury/etiology , Cohort Studies , Disease Progression , Female , Focal Nodular Hyperplasia/chemically induced , Humans , Hypertension, Portal/chemically induced , Liver/drug effects , Male , Middle Aged , Netherlands , Thioguanine/administration & dosageABSTRACT
BACKGROUND AND AIM: The Inflammatory Bowel Disease Disability Index (IBD-DI) is a measure of disability in inflammatory bowel disease (IBD). The IBD-DI is validated for use as a clinical interview but not for use as a self-report questionnaire. We aimed to validate the IBD-DI for self-report (IBD-DI-SR) and to reduce the number of items, using IBD patients from two centers. METHODS: Between April and August 2017, ambulatory IBD patients were recruited from Christchurch Hospital, New Zealand and Concord Hospital, Australia. The IBD-DI clinical interview version was compared with a self-report version. Participants were randomized to do the clinical interview or self-report first. Validation of the IBD-DI-SR involved calculating the correlation coefficient between the clinician completed and self-reported version of the IBD-DI and Cronbach's α of internal consistency of the IBD-DI-SR. To create an item-reduced version, multiple linear regression was used. The R2 of the model described the overall association between the item-reduced IBD-DI-SR and the IBD-DI. RESULTS: One hundred fourteen patients (57 from Christchurch and 57 from Sydney) completed the IBD-DI-SR validation phase, of whom 63 had Crohn's disease and 51 had ulcerative colitis. The Pearson correlation coefficient between the IBD-DI-SR and IBD-DI is 0.90 (P < 0.001), and Cronbach's α of the IBD-DI-SR was 0.86. The item-reduced version of the IBD-DI-SR consisted of eight questions instead of 28, explaining 77% of the variance. CONCLUSIONS: The IBD-DI-SR has demonstrated reliability and validity. The item-reduced IBD-DI-SR is a concise self-report instrument for measuring IBD disability, which makes the IBD-DI more widely usable.