Rachel W. Winter

Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of crohn's disease

BACKGROUND & AIMS Genetic susceptibility loci for Crohns disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. METHODS We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. RESULTS The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. CONCLUSIONS Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.

Higher 25-hydroxyvitamin D levels are associated with greater odds of remission with anti-tumour necrosis factor-α medications among patients with inflammatory bowel diseases

Vitamin D has been linked to disease activity among patients with inflammatory bowel diseases (IBD). Prior investigation has also suggested that vitamin D levels may affect duration of therapy with anti‐tumour necrosis factor‐α (anti‐TNF‐α) medications among patients with IBD.

Hospitalizations for Acute Myocardial Infarction Are Decreased Among Patients with Inflammatory Bowel Disease Using a Nationwide Inpatient Database.

Background:Questions remain regarding the true prevalence of cardiovascular events such as myocardial infarction (MI) among patients with inflammatory bowel disease (IBD). Using the Nationwide Inpatient Sample (NIS), we aimed to compare the proportion of hospitalizations for acute MI among patients with IBD with that of the general population. Methods:This study used data from years 2000 to 2011 in Nationwide Inpatient Sample, the largest publicly available all-payer inpatient database in the United States. International Classification of Diseases, Ninth Revision, Clinical Modification discharge codes were used to identify adult patients with discharge diagnoses of IBD (ulcerative colitis or Crohns disease), acute MI, and multiple comorbid risk factors for cardiovascular disease. The independent effect of a diagnosis of IBD on risk of acute MI was examined using a multivariable logistic regression model controlling for multiple confounders. Data were analyzed using SAS survey procedures and weighted to reflect national estimates. Results:We identified 567,438 hospitalizations among patients with IBD and 78,121,000 hospitalizations among the general population. Patients with IBD were less likely to be hospitalized for acute MI than patients in the general population (1.3% versus 3.1%, P < 0.001). In adjusted analyses, the odds of hospitalization for acute MI among patients with IBD were decreased when compared with the general population (odds ratio, 0.51; 95% confidence interval, 0.50–0.52). Conclusions:Despite prior reports of a potentially increased risk of acute MI among patients with IBD, in a nationwide inpatient database, lower rates of acute MI were demonstrated in the IBD population when compared with the general population.

Treatment of the Pregnant Patient with Inflammatory Bowel Disease.

Abstract:Research regarding fertility, medication safety, and pregnancy outcomes is increasing, but there are still many knowledge gaps in these areas. Women with ulcerative colitis and Crohns disease may have decreased fertility because of voluntary childlessness and inflammatory bowel disease (IBD) surgery, and women with Crohns disease may also have decreased ovarian reserve. Initial studies show that in vitro fertilization is a viable option, and laparoscopic ileoanal pouch anastomosis surgery improves fertility rates. Additional research is needed on the effect of disease activity on fertility and on the rates of pregnancy loss and ectopic pregnancies. We do not know how to reliably measure disease activity during pregnancy or the effect of pregnancy on the microbiome. Although immunomodulators and anti–tumor necrosis factor medications are relatively safe during pregnancy, the long-term effects of these medications on the child are unknown. The recommended mode of delivery is still debated, especially for women after ileoanal pouch anastomosis. There are multiple studies on the relative safety of immunomodulators and anti–tumor necrosis factor medications during pregnancy, and we know how to safely treat a pregnant patient with a disease flare. The best way to manage women with IBD who are pregnant or contemplating pregnancy is a multidisciplinary approach. Team members often include a gastroenterologist, a high-risk obstetrician, an infertility specialist, a colorectal surgeon, and a pediatrician with experience in caring for children of mothers with IBD. By integrating expertise from these disciplines, women with even very complex IBD should be able to have a healthy pregnancy and delivery.

Birth outcomes after preconception paternal exposure to methotrexate: A nationwide cohort study

BACKGROUND Methotrexate (MTX), a folic acid antagonist, is often prescribed for moderate to severe inflammatory related diseases. The safety of paternal MTX use prior to conception is unknown. This study, using the National Danish Registries, aimed to examine the association between paternal MTX use three months before conception and adverse birth outcomes. RESULTS Children fathered by men treated with MTX within three months before conception constituted the exposed cohort (N=193), and children fathered by men not treated with MTX constituted the unexposed cohort (N=1,013,801). The adjusted odds ratio (OR) for preterm birth was 1.38 (95% CI:0.68-2.81). The adjusted ORs of congenital anomalies (CAs) and small for gestational age (SGA) were 1.10 (95% CI:0.57-2.13) and 0.98 (95% CI:0.39-2.50), respectively. CONCLUSION Our results regarding the effect of paternal use of MTX within 3 months before conception on birth outcomes of CAs, preterm birth and SGA are overall reassuring.

The Practical Pros and Cons of Complementary and Alternative Medicine in Practice: Integrating Complementary and Alternative Medicine into Clinical Care

Complementary and alternative medicine (CAM) is changing health care for individuals with inflammatory bowel disease. The move toward increasing patient autonomy and addressing lifestyle and psychosocial factors contributes to this shift. Numerous clinics and centers are offering new models to incorporate these elements. There is need for better and more robust data regarding CAM efficacy and safety. CAM offers a test kitchen for new approaches to care and care delivery, which are now being developed and studied, and has the possibility to affect patient quality of life, disease morbidity, cost, and use of health care.

How should we treat mild and moderate-severe Crohn’s disease in 2017? A brief overview of available therapies

Crohn’s disease (CD), one of two major subtypes of inflammatory bowel disease (IBD), is defined by chronic transmural inflammation that may affect any part of the gastrointestinal tract. The etiology of IBD is poorly understood, but genetic, environmental, dietary, and immunologic components all likely impact predisposition to development of Crohn’s disease. Differences in clinical courses may be related to disease location, extent, and severity of disease activity. Somepatients exhibitmild diseasewith few complications while others experience disease progression characterized by strictures, abscesses, and fistulae requiring immune-modulating therapy and/or surgery. In 2017, there are many new and established medical therapies available for the treatment of active CD. Althoughmany patients with Crohn’s respond tomedical therapy, at the present time, we are not able to predict a priori to which medications an individual will respond. While general guidelines and recommendations exist regarding management of mild and moderate-severe CD, it is important to personalize the care of each patient taking into account the location and the characterizationof the inflammatory response [1]. We offer options regarding disease management and medications, but emphasize that there is no single algorithm to follow in the medical management of Crohn’s disease.

Isolated gastric sarcoidosis: a rare entity

We present a case of isolated granulomatous gastritis in a 21-year-old woman. Initial symptoms included nausea, vomiting and inability to tolerate oral intake. An upper oesophagogastroduodenoscopy revealed nodular and thickened mucosa with histological findings of granulomatous gastritis. Infectious, inflammatory and malignant causes were excluded prior to making a diagnosis of gastric sarcoidosis.