Advances in Diagnoses and Treatment Options for Celiac Disease, IBS, IBD, and EoE
“Important advances in the clinical practice of gastroenterology were addressed during this year’s Digestive Disease Week (DDW). This review briefly summarizes the relevant concepts that emerged, and highlights the pace of progress in diagnosing and managing the commonly encountered issues of celiac disease, irritable bowel syndrome, inflammatory bowel disease, and eosinophilic esophagitis.” November 06, 2015 – William F. Balistreri, MD, Digestive Disease Week (DDW) 2015 published by Medscape
Table of Contents
- Celiac Disease
- Diagnosis Using Serology Alone
- Isolated to the Duodenal Bulb
- Early Diagnosis
- Nonceliac Gluten Sensitivity
- Irritable Bowel Syndrome
- FODMAP Elimination
- Inflammatory Bowel Disease
- Vedolizumab
- Eosinophilic Esophagitis
- Oral Budesonide Suspension
- The Six-Food Elimination Diet
- Cost-Effectiveness of Treatment Options
Celiac Disease – Diagnosis Using Serology Alone
The standard methods used to diagnose celiac disease rely on serology and duodenal mucosal biopsy. Although current adult guidelines require histologic confirmation of celiac disease, recent pediatric guidelines from the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) have proposed algorithms to reduce the need for biopsy in genetically susceptible symptomatic children.
Efthymakis and colleagues explored the applicability of these somewhat controversial proposed criteria by assessing the accuracy of serology alone in detecting mucosal abnormalities consistent with celiac disease in a prospective cohort of symptomatic adult patients. They reported that anti-tissue transglutaminase (anti-tTG) titers correlated with the degree of villous atrophy. Of 199 adults with elevated anti-tTG titers, epithelial membrane antigen positivity, and genetic susceptibility, 10% showed no villous atrophy, 37% had partial villous atrophy, and 54% had total villous atrophy.
After applying the ESPGHAN criterion of anti-tTG > 10 times the upper limit of normal, the investigators found a sensitivity of 56%, a specificity of 84%, and a positive predictive value of 97%. They concluded that further studies are required to determine the validity of these criteria and optimal serologic cut-off levels.
Celiac Disease – Isolated to the Duodenal Bulb
Mooney and colleagues suggested that obtaining an additional duodenal bulb biopsy may increase the diagnostic yield for celiac disease. However, it is not clear whether patients with villous atrophy detected only in the duodenal bulb have the same phenotype and outcome as those with more diffuse disease. They now report that persons with celiac disease that is manifest only in the duodenal bulb appear to be a subgroup characterized by early-onset disease and lower anti-tTG titers. This may represent a milder form of celiac disease with lower rates of diarrhea and folate deficiency. Long-term follow-up of patients is required to fully characterize this phenotype and assess the long-term impact.
Celiac Disease – Early Diagnosis
Yang and colleagues evaluated the cost-effectiveness of performing routine duodenal biopsy during esophagogastroduodenoscopy for diagnosing celiac disease in patients with seemingly unrelated gastrointestinal disorders, such as refractory gastroesophageal reflux disease. They concluded that routine duodenal biopsy performed during esophagogastroduodenoscopy to determine the etiology and severity of gastroesophageal reflux disease can detect the majority of cases of celiac disease. However, they emphasized that this strategy will only approach cost-effectiveness thresholds when the prevalence of celiac disease in this population is slightly greater (> 1.8%) than that of the general population.
Celiac Disease – Gluten-Free Products
The standard treatment for celiac disease is lifelong exclusion of gluten. However, this remains challenging because inadvertent gluten exposure is common. The US Food and Drug Administration (FDA) currently labels a food product as “gluten-free” if it has <20 parts per million (ppm) of gluten; does not contain wheat, rye, or barley; and does not contain an ingredient derived from these grains.
At present, the FDA does not regulate dietary supplements and herbal products, although up to 25% of patients with celiac disease report their use, most commonly probiotics. Patients ingesting supplements also reported more celiac disease-related symptoms than those who did not take supplements.
Nazareth and colleagues sought to determine whether gluten was present in 22 popular probiotic preparations, including those that were labeled gluten-free. They found that 55% of them contained gluten. Of these gluten-containing items, 67% were labeled gluten-free. Of the 15 probiotics that were labeled gluten-free, 53% contained gluten, including 13% that contained > 20 ppm. Of the probiotics that were not labeled gluten-free, 57% tested positive for gluten, including 29% that contained > 20 ppm. More than one gluten component (eg, wheat, rye, barley) was detectable in 18% of the probiotics.
Thus, the amount of gluten in probiotics may be significant, especially if one considers the cumulative number of capsules consumed. Because gluten-free labeling does not accurately reflect the gluten content of probiotics, patients with celiac disease should be advised of the potential contamination of probiotics with gluten regardless of labeling.
Nonceliac Gluten Sensitivity
Nonceliac gluten sensitivity (NCGS), a syndrome characterized by the rapid onset of gastrointestinal symptoms after gluten ingestion, is thought to be present among patients with functional gastrointestinal diseases. However, uniform diagnostic criteria are lacking.
Elli and colleagues reported the results of a prospective, placebo-controlled, double-blind gluten challenge in a multicenter trial of patients reporting symptoms consistent with functional gastrointestinal disorders. Of the patients enrolled (90 of whom were female), 55 had irritable bowel syndrome, 36 had functional dyspepsia, and nine had unspecified functional nonspecific symptoms by Rome III criteria. Celiac disease had been excluded in all patients.
Patients reporting symptomatic improvement after 21 days on the gluten-free diet underwent a 7-day placebo-controlled gluten challenge, in which gluten was administered by capsules. A severe symptomatic relapse after the blind gluten ingestion was reported by 25% of patients; thus, they were classified as having NCGS.
Of note, 56% of enrolled patients who responded to the gluten-free diet did not show symptoms with the gluten double-blind challenge. This group deserves further study.
The authors suggested that a simple dietary challenge may help identify NCGS in patients with functional gastrointestinal disorders and thereby select those who are most likely to respond to a gluten-free diet.
Irritable Bowel Syndrome – FODMAP Elimination
A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) decreases the frequency and severity of gastrointestinal symptoms in adults and children with irritable bowel syndrome (IBS). The mechanism of action is believed to be via changes in gut microbiome composition, with decreased fermentation and gas production. However, > 25% of patients do not respond.
Chumpitazi and colleagues sought to determine whether microbiome composition or metagenomic functional potential before starting the low FODMAP diet predicted clinical response. After a baseline period, participants ingested a low-FODMAP diet and a typical American diet in a crossover design. The preliminary results of this study suggest that microbiome composition and metabolic pathway biomarkers are associated with clinical response to a low-FODMAP diet in patients with IBS. Given the burden of adherence to a low-FODMAP diet, microbiome-related biomarkers may help to identify individuals with IBS who are most likely to respond to a low-FODMAP diet.
Piacentino and colleagues also evaluated the effectiveness of various dietary interventions on abdominal bloating and pain: (1) a low-FODMAP and gluten-free (FOD-GF) diet; (2) a low-FODMAP and normal-gluten (FOD-NG) diet; and (3) a normal-FODMAP and normal-gluten (unrestricted) diet. Patients who ingested the FOD-GF and FOD-NG diets had improvement in the intensity of abdominal bloating and frequency of abdominal pain. Of those who ingested the FOD-NG diet, 72% continued the diet with benefit. The remainder found it “too monotonous.” Of those who ingested the FOD-GF diet, 52% continued the diet. The remainder considered it too restrictive or reported only partial benefit.
Thus, the majority of patients with IBS have medium- and long-term benefits from compliance with a low-FODMAP diet. Gluten avoidance does not seem to offer any additional benefit and negatively affects compliance.
Inflammatory Bowel Disease – Vedolizumab
Vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against integrin that inhibits T-lymphocyte migration into intestinal tissue, was approved recently for adults with inflammatory bowel disease (IBD). Although no published data on the use of vedolizumab in pediatric patients are available, it may be a therapeutic option for children with disease that is refractory to current standard therapy.
Two studies were presented at this year’s meeting describing clinical experiences using vedolizumab in children with IBD. Singh and colleagues initiated vedolizumab therapy at a dose of 6 mg/kg, with a maximum of 300 mg/dose, infused at 0, 2, and 6 weeks and then every 8 weeks thereafter. In their experience, vedolizumab was safe, with efficacy similar to that reported in adult trials. The efficacy of vedolizumab was higher in patients with ulcerative colitis and in patients with Crohn disease who had colonic involvement.
Conrad and colleagues evaluated the use of vedolizumab in children with refractory IBD. Dosing was the same as in the previous study (ie, standard adult regimen of 300 mg at weeks 0, 2, and 6, followed by maintenance at 8-week intervals). Clinical improvement from baseline to 14 weeks was seen in 50% of patients, and there were no infusion reactions.
Although these studies were limited by the small number of patients, there appears to be modest improvement in disease activity and steroid reduction in the majority of patients. Further prospective follow-up of a larger cohort treated with vedolizumab will provide additional data regarding its efficacy and safety in children with IBD.
Eosinophilic Esophagitis – Oral Budesonide Suspension
Therapeutic efficacy in patients with eosinophilic esophagitis (EoE) is currently based on improvement in symptoms and histology. Symptom assessment is considered to be unreliable owing to methodological concerns, placebo effects, and adaptive patient behaviors. In addition, eosinophil density in esophageal biopsies has limited correlation with symptom outcomes.
Topical steroids are the first-line pharmacologic treatment option for patients with EoE. However, none are FDA-approved, and none have been studied using a validated patient-reported outcome measure.
Hirano and colleagues determined the degree of endoscopically documented healing in response to therapeutic intervention with a muco-adherent topical steroid formulation: oral budesonide suspension (OBS). They used EoE Reference Score for Endoscopic Abnormalities (EREFS), a validated system for the classification and assessment of the severity of endoscopically identified EoE.
Participants were randomly assigned in a 1 to 1 ratio to receive either OBS 2 mg twice daily or a placebo twice daily for 12 weeks. EREFS scores significantly improved after treatment with OBS but not with placebo. Edema, rings, exudates, and furrows showed significant improvement with OBS but not with placebo. Strictures did not significantly change after treatment with OBS or placebo, although patients with high-grade strictures were excluded from trial entry. Proximal, distal, and total EREFS correlated with peak eosinophil counts after treatment.
Significant benefit was demonstrated in the inflammatory (ie, edema, exudates, furrows), ring, and total EREFS scores. Thus, endoscopic outcomes may be important endpoints of EoE clinical trials that complement symptom and histologic assessments.
Dellon and colleagues also reported the results of their study that was designed to determine whether OBS is superior to placebo for decreasing symptoms of dysphagia and esophageal eosinophil counts in adolescents and adults with EoE. Participants were randomly assigned in a 1 to 1 ratio to receive either OBS 2 mg twice daily or a placebo suspension. Compared with placebo, 12 weeks of OBS treatment significantly improved symptoms of dysphagia and esophageal eosinophilia in adolescents and adults with active EoE, and had a favorable safety profile.
Eosinophilic Esophagitis – The Six-Food Elimination Diet
In addition to topical corticosteroids, the six-food elimination diet (SFED) can be used as first-line therapy for EoE. Empirical SFED is effective in inducing clinical and histologic remission in most children and adults with EoE. Milk, wheat, egg, and soy were identified as the most common food triggers in SFED.
In a prospective study, Kagalwalla and colleagues sought to assess the clinical, endoscopic, and histologic efficacy of a four-food elimination diet (4-FED) in children with EoE. Abdominal pain, slow eating, and dysphagia were the most common presenting symptoms. Histologic remission was achieved in 71% of participants, on the basis of pre- and post-treatment peak eosinophil counts in esophageal biopsy samples. All symptoms resolved in 18% of the responders. The remainder had resolution of one or more of their presenting symptoms after following the 4-FED. Improvements in the severity of endoscopic findings were seen in 83% of the responders, with 31% completely normalizing.
The 4-FED identified specific foods that triggered inflammation upon reintroduction. The results of this prospective study support that 4-FED is an effective dietary treatment option for children with EoE and compared favorably to SFED.
Eosinophilic Esophagitis – Cost-Effectiveness of Treatment Options
Cotton and colleagues determined whether topical corticosteroid therapy or dietary therapy is most cost-effective for the treatment of EoE by performing a cost-utility analysis from a payer’s perspective. Compared with dietary therapy, a swallowed topical corticosteroid is not a cost-effective option for the treatment of EoE. Dietary therapy dominates steroids over the long term. From the perspective of a payer, steroid therapy is markedly more expensive, particularly if a sizable proportion of patients require long-term use.
