Effect of Proton Pump Inhibitor Treatment in "PPI Non-responsive" Patients with Eosinophilic Esophagitis.

BACKGROUND AND AIMS: Some eosinophilic esophagitis (EoE) patients can have a decline in eosinophil count after proton pump inhibitor (PPI) treatment without achieving histologic response, but little is known about this group. We aimed to determine the effect of PPIs on reducing esophageal eosinophilia in patients deemed non-responsive to PPI therapy. METHODS: We analyzed prospectively collected cohort data from newly diagnosed adults with EoE who were histologic non-responders (≥15 eos/hpf) to PPI-only therapy. Symptoms, endoscopic histologic features were assessed before and after PPI. Pre- and post-PPI treatment esophageal biopsies were read by pathologists to determine peak eosinophil counts and other histologic findings. RESULTS: Of 125 patients, peak eosinophil counts were 102.1 ± 69.8 and 102.9 ± 101.1 (p=0.93) before and after PPI treatment, respectively, but lamina propria fibrosis decreased from 97% to 41% (p<0.001). Heartburn frequency also decreased (19% to 11%; p=0.006), though endoscopic findings did not change. There were 75 patients (60%) who had some decrease in eosinophil counts, with 30 patients (24%) having ≥50% decrease in counts. When comparing the ≥50% and <50% decrease groups, differences in endoscopic features were identified, but the ≥50% group had improvement in eosinophil degranulation, microabscesses, spongiosis, and basal cell hyperplasia. CONCLUSION: Peak eosinophil counts did not decrease overall after PPI treatment, but symptoms of heartburn improved. Approximately a quarter had ≥50% decrease in eosinophil counts, with associated decreases in other histologic findings. Further research may consider what role PPIs have in this subset of non-responders or in combination therapies.

Anti-tumour necrosis factor-induced skin rashes in inflammatory bowel disease: a systematic review and evidence-based management algorithm.

BACKGROUND: Anti-tumour necrosis factor alpha (anti-TNF) agents are a highly effective treatment for inflammatory bowel disease (IBD). Skin lesions, including psoriasiform, eczematous and lupoid eruptions, may paradoxically result from anti-TNF use and cause significant morbidity leading to discontinuation of therapy. There are no consensus guidelines on the management of these lesions. AIMS: This systematic review considers the existing evidence regarding cutaneous complications of anti-TNF therapy in IBD and the development of an algorithm for management. METHODS: A systematic review was performed by searching Medline (Pubmed) and Embase for articles published from inception to January 2021. The following search terms were used 'anti-tumour necrosis factor alpha', 'infliximab', 'adalimumab', 'certolizumab', 'golimumab', 'inflammatory bowel disease', 'Crohn disease', 'Ulcerative colitis', 'psoriasis', 'psoriasiform', 'dermatitis', 'lupus', 'skin lesion' and 'skin rash'. Reference lists of relevant studies were reviewed to identify additional suitable studies. RESULTS: Thirty-four studies were included in the review. Eczema can generally be managed with topical agents and the anti-TNF can be continued, while the development of lupus requires immediate cessation of the anti-TNF and consideration of alternative immunomodulators. Management of psoriasis and psoriasiform lesions may follow a step-wise algorithm where topical treatments will be trialled in less severe cases, with recourse to an alternative anti-TNF or a switch to an alternative class of biological agent. CONCLUSION: Assessment of anti-TNF skin lesions should be performed in conjunction with a dermatologist and rheumatologist in complex cases. High-quality prospective studies are needed to clarify the validity of these algorithms in the future.

Pathophysiology of Dysphagia in Eosinophilic Esophagitis: Causes, Consequences, and Management.

Eosinophilic esophagitis (EoE) is a leading cause of food bolus impaction in children and adults. The mechanism of dysphagia in EoE, particularly non-obstructive dysphagia, remains incompletely understood. While fibrostenotic processes appear to be critical in the development of dysphagia, somatosensory dysfunction and dysmotility also contribute. This review considers potential mechanisms of dysphagia and evaluates the utility of current and future treatment strategies in this context.

Mucosal imaging in colon polyps: New advances and what the future may hold.

An expanding range of advanced mucosal imaging technologies have been developed with the goal of improving the detection and characterization of lesions in the gastrointestinal tract. Many technologies have targeted colorectal neoplasia given the potential for intervention prior to the development of invasive cancer in the setting of widespread surveillance programs. Improvement in adenoma detection reduces miss rates and prevents interval cancer development. Advanced imaging technologies aim to enhance detection without significantly increasing procedural time. Accurate polyp characterisation guides resection techniques for larger polyps, as well as providing the platform for the "resect and discard" and "do not resect" strategies for small and diminutive polyps. This review aims to collate and summarise the evidence regarding these technologies to guide colonoscopic practice in both interventional and non-interventional endoscopists.

Endoscopic diagnosis and treatment of gastric dysplasia and early cancer: Current evidence and what the future may hold.

Gastric cancer accounts for a significant proportion of worldwide cancer-related morbidity and mortality. The well documented precancerous cascade provides an opportunity for clinicians to detect and treat gastric cancers at an endoscopically curable stage. In high prevalence regions such as Japan and Korea, this has led to the implementation of population screening programs. However, guidelines remain ambiguous in lower prevalence regions. In recent years, there have been many advances in the endoscopic diagnosis and treatment of early gastric cancer and precancerous lesions. More advanced endoscopic imaging has led to improved detection and characterization of gastric lesions as well as superior accuracy for delineation of margins prior to resection. In addition, promising early data on artificial intelligence in gastroscopy suggests a future role for this technology in maximizing the yield of advanced endoscopic imaging. Data on endoscopic resection (ER) are particularly robust in Japan and Korea, with high rates of curative ER and markedly reduced procedural morbidity. However, there is a shortage of data in other regions to support the applicability of protocols from these high prevalence countries. Future advances in endoscopic therapeutics will likely lead to further expansion of the current indications for ER, as both technology and proceduralist expertise continue to grow.

EoE Down Under Is Still EoE: Variability in Provider Practice Patterns in Australia and New Zealand Among Pediatric Gastroenterologists.

BACKGROUND: There is likely variation in approach and management of patient with EoE due to lack of standardized care and variation in guidelines. We aimed to identify current practices regarding diagnosis and treatment in children with eosinophillic esophagitis (EoE) in Australia and New Zealand (ANZ). METHODS: Information on current diagnostic and management approaches for pediatric EoE was collected via an online survey sent to pediatric gastroenterologists (pGE) in ANZ. We performed a cross-sectional study of pGE using a 49-question instrument regarding evaluation, diagnostic, and therapeutic aspects of EoE between October 2019 and December 2019. RESULTS: Eighty-five percent of the survey responders were from Australia, and 66% were academic. 30% pGE perform > 3 esophageal biopsies for diagnosis of EoE, 40% involve an allergist, 30% use a twice daily PPI trial, and 70% do not exclude other cause of esophageal eosinophilia. For management, only 3% use dietary elimination as an initial therapy, and 24% use less than the recommended doses of swallowed fluticasone. Forty-nine percent were likely to stop treatment in after remission is achieved for 12 months. The EoE endoscopic reference score (EREFS) was not routinely used (49%). Two-thirds of pGE are concerned about long-term effects of recurrent need of general anesthesia. CONCLUSIONS: Diagnostic and management strategies for EoE differed widely among pGE in ANZ, including in diagnostic biopsies, assessing competing causes of esophageal eosinophilia, initials selection of treatments, and maintenance strategies. This variability likely reflects continued uncertainty regarding optimal management strategies and stresses the need for pediatric-specific ANZ guidelines to standardize EoE care.

Anticoagulation and antiplatelet management in gastrointestinal endoscopy: A review of current evidence.

The role of endoscopic procedures, in both diagnostic and therapeutic purposes is continually expanding and evolving rapidly. In this context, endoscopists will encounter patients prescribed on anticoagulant and antiplatelet medications frequently. This poses an increased risk of intraprocedural and delayed gastrointestinal bleeding. Thus, there is now greater importance on optimal pre, peri and post-operative management of anticoagulant and/or antiplatelet therapy to minimise the risk of post-procedural bleeding, without increasing the risk of a thromboembolic event as a consequence of therapy interruption. Currently, there are position statements and guidelines from the major gastroenterology societies. These are available to assist endoscopists with an evidenced-based systematic approach to anticoagulant and/or antiplatelet management in endoscopic procedures, to ensure optimal patient safety. However, since the publication of these guidelines, there is emerging evidence not previously considered in the recommendations that may warrant changes to our current clinical practices. Most notably and divergent from current position statements, is a growing concern regarding the use of heparin bridging therapy during warfarin cessation and its associated risk of increased bleeding, suggestive that this practice should be avoided. In addition, there is emerging evidence that anticoagulant and/or antiplatelet therapy may be safe to be continued in cold snare polypectomy for small polyps (< 10 mm).

Impact of food challenge on local oesophageal immunophenotype in eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EoE) is caused by the ingestion of food antigens. Dietary avoidance can result in clinical and histological remission, while food reintroduction can cause recurrence. It is uncertain if food antigen processing and immune activation occurs locally, in the oesophagus. Therefore, we performed a comparative study of the density of cell surface proteins (known to be involved with antigen presentation) on oesophageal tissue prior to, and following food antigen induced disease recurrence. A secondary aim was to consider novel biomarkers. METHOD: Adult patients with a diagnosis of EoE, who had achieved histological remission with an elimination diet (<15 eosinophils per high power field at oesophageal biopsy), and who underwent food challenge with proven recurrence were included. Immunohistochemistry/immunofluorescence for CD1a, CD3, CD28, CD40, CD69, CD80, CD138, CXCR3 and HLA-DR was performed. Staining intensity of each biomarker (pixels/mm2 ) was quantified by semi-automated analysis (Studio-FL software). RESULTS: Fourteen cases of EoE (pre and post food challenge), 6 GORD and 5 healthy controls were included. HLA-DR, CD3, CD28, CD40 and CD 138 significantly increased with food reintroduction (P = <0.05). CD1a, CD 69, CD 80 and CXCR3 did not measurably change. CONCLUSION: The presence of cell surface proteins typically associated with antigen presentation (following food antigen induced recurrence) suggests immune activation occurs in the oesophagus, and the relative lack of langerhans cells (CD1a) may indicate this cell type is unimportant. The cell surface protein CD 138 increases with disease recurrence, is not elevated in GORD or healthy controls, and has promise as a biomarker.

Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the AGREE Conference.

BACKGROUND & AIMS: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis. METHODS: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences. RESULTS: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement. CONCLUSIONS: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm2) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.

Histologic improvement after 6 weeks of dietary elimination for eosinophilic esophagitis may be insufficient to determine efficacy.

BACKGROUND: Elimination diets are used to treat eosinophilic esophagitis (EoE), with success (remission) defined at endoscopy and oesophageal biopsy as fewer than 15 eosinophils per high power field (HPF). Response is assessed after 6 weeks of treatment by convention, but we have observed that this period of time may be insufficient. OBJECTIVE: To characterise a subset of patients with EoE who require prolonged (>6 weeks) of dietary therapy to achieve histologic remission. METHODS: A retrospective search of electronic medical records of 2 cohorts with EoE attending the Department of Gastroenterology, University of Chapel Hill North Carolina, and Eastern Health, Melbourne Australia. Patients who underwent elimination diet, had esophageal biopsy after 6 or more weeks of dietary restriction that demonstrated ongoing esophageal inflammation (>15 eosinophils per HPF), and who then continued dietary therapy followed by repeat endoscopy demonstrating remission (<15 eosinophils per HPF) were included. RESULTS: Seven patients met inclusion criteria, average esophageal eosinophil counts prior to diet was 38.5 (range, 15-65). Following the initial period of diet (mean of 6 weeks and 4 days) eosinophil count decreased (average, 21.5/HPF; range 15-40/HPF). After extended dietary elimination (mean, 13 weeks; range, 7-22 weeks), histological resolution was achieved (average peak eosinophil count of 5.2; range, 0-14) in all cases. Endoscopic appearance and symptoms both improved following the initial period of dietary elimination, thereby preceding the histological resolution, and were sustained. CONCLUSION: A subset of patients has full histologic response to prolonged elimination diet, that lags initial symptomatic and endoscopic improvement.

The role of maintenance therapy in eosinophilic esophagitis: who, why, and how?

In patients with eosinophilic esophagitis (EoE) who do not respond to proton pump inhibitors, initial anti-inflammatory/anti-eosinophilic treatment is with either topical corticosteroids or dietary elimination. A large body of literature supports the efficacy of these approaches, with histologic response rates in the 50-90% range for steroids and 70% range for the six-food elimination diet. However, these studies are almost all short-term and data evaluating long-term safety and efficacy of either treatment are limited. Nevertheless, because EoE is chronic, symptomatic, endoscopic, and histologic disease activity recurs when successful treatments are stopped. An emerging body of data also suggest that left untreated, persistent eosinophilic esophageal inflammation may progress to fibrostenosis over time. Therefore, maintenance therapy in EoE is intuitively attractive. This paper reviews the rationale for maintenance treatment in EoE, the available long-term pharmacologic and dietary response data for EoE, and discusses who may benefit the most from ongoing treatment. While all patients with EoE can be offered maintenance treatment, this option should be strongly recommended in patients with severe disease phenotypes or complications, including malnutrition or failure to thrive, esophageal fibrostenosis, strictures requiring dilation, recurrent food bolus impaction, history of perforation, and symptoms that recur quickly after treatment discontinuation. In all EoE patients, regular follow-up is also advised.

Dysphagia: Thinking outside the box.

Dysphagia is a common symptom that is important to recognise and appropriately manage, given that causes include life threatening oesophageal neoplasia, oropharyngeal dysfunction, the risk of aspiration, as well as chronic disabling gastroesophageal reflux (GORD). The predominant causes of dysphagia varies between cohorts depending on the interplay between genetic predisposition and environmental risk factors, and is changing with time. Currently in white Caucasian societies adopting a western lifestyle, obesity is common and thus associated gastroesophageal reflux disease is increasingly diagnosed. Similarly, food allergies are increasing in the west, and eosinophilic oesophagitis is increasingly found as a cause. Other regions where cigarette smoking is still prevalent, or where access to medical care and antisecretory agents such as proton pump inhibitors are less available, benign oesophageal peptic strictures, Barrett's oesophagus, adeno- as well as squamous cell carcinoma are endemic. The evaluation should consider the severity of symptoms, as well as the pre-test probability of a given condition. In young white Caucasian males who are atopic or describe heartburn, eosinophilic esophagitis and gastroesophageal reflux disease will predominate and a proton pump inhibitor could be commenced prior to further investigation. Upper gastrointestinal endoscopy remains a valid first line investigation for patients with suspected oesophageal dysphagia. Barium swallow is particularly useful for oropharyngeal dysphagia, and oesophageal manometry mandatory to diagnose motility disorders.

Hiatus Hernia as a Cause of Dysphagia.

PURPOSE OF REVIEW: This review aims to discuss the putative relationship between hiatus hernia and dysphagia. RECENT FINDINGS: Proposed mechanisms of dysphagia in patients with hiatus hernia are usually difficult to identify, but recent advances in technology (high-resolution manometry with or without concomitant impedance, ambulatory pH with impedance, videofluoroscopy, and the endoluminal functional lumen imaging probe (EndoFLIP)) and methodology (inclusion of swallows of various consistencies and volumes or shifting position during the manometry protocol) can help induce symptoms and identify the underlying disorder. Chronic reflux disease is often associated with hiatus hernia and is the most common underlying etiology. Dysmotility because of impaired contractility and vigor can occur as a consequence of repeated acid exposure from the acid pocket within the hernia, and the resultant poor clearance subsequently worsens this insult. As such, dysphagia appears to be more common with increasing hiatus hernia size. Furthermore, mucosal inflammation can lead to fibrotic stricture formation and in turn obstruction. On the other hand, there appears to be a difference in the pathophysiology of smaller sliding hernias, in that those with dysphagia are more likely to have extrinsic compression at the crural diaphragm as compared to those with reflux symptoms only. Sliding hiatus hernia, especially when small, does not commonly lead to dysmotility and dysphagia; however, in those patients with symptoms, the underlying etiology can be sought with new technologies and, in particular, the reproduction of normal eating and drinking during testing.