Collagenous colitis associated with novel sprue-like intestinal diseases.

Almost a half-century ago, an unusual and distinct form of colitis was first recognized, collagenous colitis, characterized by sub-epithelial trichrome-positive deposits having the ultrastructural features of collagen. Later, other reports documented more extensive collagenous dis-ease in these patients, sometimes in the stomach and small bowel, a close linkage with other forms of microscopic colitis and its association with celiac and other immune-mediated diseases. Moreover, emerging genetic methods permitted large studies of collagenous colitis to complement these intriguing clinical and pathological studies. Finally, recent and related studies have further demonstrated these immune-based forms of colitis, with new sprue-like intestinal diseases caused by novel medications, recently detected viral infections and vaccinations.

Segmental Colitis Associated with Diverticulosis (SCAD).

PURPOSE OF REVIEW: A distinctive, possibly "novel" form of a segmental inflammatory colonic disease process associated with diverticular disease (so-called SCAD or segmental-colitis-associated-diverticulosis) is reviewed. RECENT FINDINGS: Although this phenotype of inflammatory colonic disease was initially recognized decades ago, mainly in the elderly, recent evidence from long term natural history studies along with meta-analyses confirms that its clinical course is usually benign and drug-responsive. Interestingly, its appearance in some treated with monoclonal agents (eg., ipilimumab associated colitis) or infected with coronavirus-19 may have critical implications for its pathogenesis. This review further explores the implications of recognition of this pattern of colonic inflammatory disease, with relevance for physicians involved in both clinical practice and clinical trials of newer therapeutic agents.

Role of biopsy in diagnosis and treatment of adult celiac disease.

Celiac disease (CD) is an immune-mediated enteropathy that characteristically responds to treatment with a gluten-free diet. In most, clinical features improve with resolution of diarrhea and weight loss. Serological studies also tend to normalize. Small intestinal biopsies from the duodenum reveal a severe to moderately severe architectural disturbance showing crypt epithelial hyperplasia with increased numbers of epithelial cell mitotic figures along with villous "flattening", increased numbers of lamina propria plasma cells and lymphocytes and increased numbers of intra-epithelial lymphocytes in untreated disease. With a gluten-free diet, these changes can be expected to resolve to normal. In some patients, this mucosal inflammatory process may persist, especially in the proximal small intestine for variable periods of time. In CD, resolution of histopathological changes can occur within 6 months, but often, more than a year is required, and sometimes, 2 years or more. Changes are not only time-dependent, but appear to be gender-dependent with resolution more readily achieved in females compared to males, and age-dependent with more persistence of the inflammatory process in the elderly compared to younger patients. Future studies need to take into account the individual nature of the normal mucosal healing process in CD treated with a gluten-free diet.

Dietary compliance in celiac disease.

Celiac disease is an immune-mediated disorder that causes severe architectural disturbance in the small intestinal mucosa of genetically-predisposed individuals. Impaired absorption of multiple nutrients results and diarrhea and weight loss develop. Evidence has accumulated that a strict gluten-free diet can result in resolution of diarrhea, weight gain and normalization of nutrient malabsorption. In addition, histopathological changes also normalize, but this histopathological response appears to be time-dependent, sex-dependent and age-dependent. Compliance to a gluten-free diet is difficult and costly resulting in poor compliance and only a limited clinical response. This poses a risk for later long-term complications, including malignancy. A major practical clinical problem is the assessment of compliance to the gluten-free diet. Although symptoms may resolve and serological antibody markers may improve, multiple studies have documented ongoing architectural disturbance and inflammatory change, and with these continued inflammatory changes, a persistent risk for long-term complications. Recent immunological studies have suggested that peptides can be detected in both urine and fecal specimens that may be indicative of limited compliance. At the same time, multiple biopsy studies have demonstrated that complete normalization of the mucosa may occur in some patients within 6 mo of initiation of a gluten-free diet, but more often, up to 2 years or more may be required before repeated biopsies eventually show mucosal recovery and mucosal healing.

Challenges in gluten-free diet in coeliac disease: Prague consensus.

BACKGROUND: New treatments in coeliac disease are being vigorously pursued to either replace or facilitate the difficult-tofollow gluten-free diet. DESIGN: The present review intends to summarise the challenges in gluten-free diet adherence during the transitional period, as reflected in the last Prague consensus, published in 2016. RESULTS: The honourable panel members recommended that dietary adherence and the consequences of nonadherence represent key components for discussion in the transitional period setting. CONCLUSIONS: There are numerous difficulties in adhering to gluten withdrawal, but the transition period from adolescence to young adulthood is considered a fragile and high-risk period for intentional and unintentional gluten intake.

Correction: Heterogeneity in Comparisons of Discontinuation of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis-A Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0168005.].

Heterogeneity in Comparisons of Discontinuation of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis - A Meta-Analysis.

OBJECTIVE: We did a systematic review of studies comparing discontinuation of tumor necrosis factor alpha (TNF) antagonists in rheumatoid arthritis (RA) patients, pooled hazard ratios and assessed clinical and methodological heterogeneity. METHODS: We searched MEDLINE and EMBASE until June 2015 for pairwise hazard ratios for discontinuing infliximab, etanercept, and adalimumab from cohorts of RA patients. Hazard ratios were pooled using inverse variance weighting and random effects estimates of the combined hazard ratio were obtained. Clinical and methodological heterogeneity was assessed using the between-subgroup I-square statistics and meta-regression. RESULTS: Twenty-four unique studies were eligible and large heterogeneity (I-square statistics > 50%) was observed in all comparisons. Type of data, location, and order of treatment (first or second line) modified the magnitude and direction of discontinuation comparing infliximab with either adalimumab or etanercept; however, some heterogeneity remained. No effect modifier was identified when adalimumab and etanercept were compared. CONCLUSION: Heterogeneity in studies comparing discontinuation of TNF antagonists in RA is partially explained by type of data, location, and order of treatment. Pooling hazard ratios for discontinuing TNF antagonists is inappropriate because largely unexplained heterogeneity was demonstrated when random effect estimates were calculated.

Segmental colitis associated diverticulosis syndrome.

Segmental colitis associated diverticulosis (SCAD) has become increasingly appreciated as a form of inflammatory disease of the colon. Several features suggest that SCAD is a distinct disorder. SCAD tends to develop almost exclusively in older adults, predominately, but not exclusively, males. The inflammatory process occurs mainly in the sigmoid colon, and usually remains localized to this region of the colon alone. SCAD most often presents with rectal bleeding and subsequent endoscopic visualization reveals a well localized process with non-specific histopathologic inflammatory changes. Granulomas are not seen, and if present, may be helpful in definition of other disorders such as Crohn's disease of the colon, an entity often confused with SCAD. Bacteriologic and parasitic studies for an infectious agent are negative. Normal rectal mucosa (i.e., "rectal sparing") is present and can be confirmed with normal rectal biopsies. SCAD often resolves spontaneously without treatment, or completely after a limited course of therapy with only a 5-aminosalicylate. Recurrent episodes may occur, but most often, patients with this disorder have an entirely self-limited clinical course. Occasionally, treatment with other agents, including corticosteroids, or surgical resection has been required.

Endocrine manifestations in celiac disease.

Celiac disease (CD) is an autoimmune small intestinal mucosal disorder that often presents with diarrhea, malabsorption and weight loss. Often, one or more associated endocrine disorders may be associated with CD. For this review, methods involved an extensive review of published English-language materials. In children and adolescents, prospective studies have demonstrated a significant relationship to insulin-dependent or type 1 diabetes, whereas in adults, autoimmune forms of thyroid disease, particularly hypothyroidism, may commonly co-exist. In some with CD, multiple glandular endocrinopathies may also occur and complicate the initial presentation of the intestinal disease. In others presenting with an apparent isolated endocrine disorder, serological screening for underlying subclinical CD may prove to be positive, particularly if type 1 diabetes, autoimmune thyroid or other autoimmune endocrine diseases, such as Addison's disease are first detected. A number of reports have also recorded hypoparathyroidism or hypopituitarism or ovarian failure in CD and these may be improved with a strict gluten-free diet.

Iron deficiency anemia in celiac disease.

Iron is an important micronutrient that may be depleted in celiac disease. Iron deficiency and anemia may complicate well-established celiac disease, but may also be the presenting clinical feature in the absence of diarrhea or weight loss. If iron deficiency anemia occurs, it should be thoroughly evaluated, even if celiac disease has been defined since other superimposed causes of iron deficiency anemia may be present. Most often, impaired duodenal mucosal uptake of iron is evident since surface absorptive area in the duodenum is reduced, in large part, because celiac disease is an immune-mediated disorder largely focused in the proximal small intestinal mucosa. Some studies have also suggested that blood loss may occur in celiac disease, sometimes from superimposed small intestinal disorders, including ulceration or neoplastic diseases, particularly lymphoma. In addition, other associated gastric or colonic disorders may be responsible for blood loss. Rarely, an immune-mediated hemolytic disorder with increased urine iron loss may occur that may respond to a gluten-free diet. Reduced expression of different regulatory proteins critical in iron uptake has also been defined in the presence and absence of anemia. Finally, other rare causes of microcytic anemia may occur in celiac disease, including a sideroblastic form of anemia reported to have responded to a gluten-free diet.

Clinical relevance of intestinal peptide uptake.

AIM: To determine available information on an independent peptide transporter 1 (PepT1) and its potential relevance to treatment, this evaluation was completed. METHODS: Fully published English language literature articles sourced through PubMed related to protein digestion and absorption, specifically human peptide and amino acid transport, were accessed and reviewed. Papers from 1970 to the present, with particular emphasis on the past decade, were examined. In addition, abstracted information translated to English in PubMed was also included. Finally, studies and reviews relevant to nutrient or drug uptake, particularly in human intestine were included for evaluation. This work represents a summary of all of these studies with particular reference to peptide transporter mediated assimilation of nutrients and pharmacologically active medications. RESULTS: Assimilation of dietary protein in humans involves gastric and pancreatic enzyme hydrolysis to luminal oligopeptides and free amino acids. During the ensuing intestinal phase, these hydrolytic products are transported into the epithelial cell and, eventually, the portal vein. A critical component of this process is the uptake of intact di-peptides and tri-peptides by an independent PepT1. A number of "peptide-mimetic" pharmaceutical agents may also be transported through this carrier, important for uptake of different antibiotics, antiviral agents and angiotensin-converting enzyme inhibitors. In addition, specific peptide products of intestinal bacteria may also be transported by PepT1, with initiation and persistence of an immune response including increased cytokine production and associated intestinal inflammatory changes. Interestingly, these inflammatory changes may also be attenuated with orally-administered anti-inflammatory tripeptides administered as site-specific nanoparticles and taken up by this PepT1 transport protein. CONCLUSION: Further evaluation of the role of this transporter in treatment of intestinal disorders, including inflammatory bowel disease is needed.

Celiac disease: a disorder emerging from antiquity, its evolving classification and risk, and potential new treatment paradigms.

Celiac disease is a chronic genetically based gluten-sensitive immune-mediated enteropathic process primarily affecting the small intestinal mucosa. The disorder classically presents with diarrhea and weight loss; however, more recently, it has been characterized by subclinical occult or latent disease associated with few or no intestinal symptoms. Diagnosis depends on the detection of typical histopathological biopsy changes followed by a gluten-free diet response. A broad range of clinical disorders may mimic celiac disease, along with a wide range of drugs and other therapeutic agents. Recent and intriguing archeological data, largely from the Gobleki Tepe region of the Fertile Crescent, indicate that celiac disease probably emerged as humans transitioned from hunter-gatherer groups to societies dependent on agriculture to secure a stable food supply. Longitudinal studies per-formed over several decades have suggested that changes in the prevalence of the disease, even apparent epidemic disease, may be due to superimposed or novel environmental factors that may precipitate its appearance. Recent therapeutic approaches are being explored that may supplement, rather than replace, gluten-free diet therapy and permit more nutritional options for future management.

Emerging drugs for celiac disease.

INTRODUCTION: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. AREAS COVERED: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. EXPERT OPINION: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed.