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Challenges and Opportunities in Inflammatory Bowel Disease

Challenges and Opportunities in Inflammatory Bowel Disease

M’Koma, A. E. (2023b)

Abstract

Inflammatory bowel disease has an enormous impact on public health, medical systems, economies, and social conditions. Biologic therapy has ameliorated the treatment and clinical course of patients with inflammatory bowel disease. The efficacy and safety profiles of currently available therapies are still less that optimal in numerous ways, highlighting the requirement for new therapeutic targets. A bunch of new drug studies are underway in inflammatory bowel disease with promising results. This is an outlined guideline of clinical diagnosis and pharmaceutical therapy of inflammatory bowel disease. Outline delineates the overall recommendations on the modern principles of desirable practice to bolster the adoption of best implementations and exploration as well as inflammatory bowel disease patient, gastroenterologist, and other healthcare provider education. Inflammatory bowel disease encompasses Crohn’s disease and ulcerative colitis, the two unsolved medical inflammatory bowel disease-subtypes condition with no drug for cure. The signs and symptoms on first presentation relate to the anatomical localization and severity of the disease and less with the resulting diagnosis that can clinically and histologically be non-definitive to interpret and establish criteria, specifically in colonic inflammatory bowel disease when the establishment is inconclusive is classified as indeterminate colitis. Conservative pharmaceuticals and accessible avenues do not depend on the disease phenotype. The first line management is to manage symptoms and stabilize active disease; at the same time maintenance therapy is indicated. Nutrition and diet do not play a primary therapeutic role but is warranted as supportive care. There is need of special guideline that explore solution of groundwork gap in terms of access limitations to inflammatory bowel disease care, particularly in developing countries and the irregular representation of socioeconomic stratification with a strategic plan, for the unanswered questions and perspective for the future, especially during the surfaced global COVID-19 pandemic caused by coronavirus SARS-CoV2 impacting on both the patient’s psychological functioning and endoscopy services.  Establishment of a global registry system and accumulated experiences have led to consensus for inflammatory bowel disease management under the COVID-19 pandemic. Painstakingly, the pandemic has influenced medical care systems for these patients. I briefly herein viewpoint summarize among other updates the telemedicine roles during the pandemic and how operationally inflammatory bowel disease centers managed patients and ensured quality of care. In conclusion: inflammatory bowel disease has become a global emergent disease. Serious medical errors are public health problem observed in developing nations i.e., to distinguish inflammatory bowel disease and infectious and parasitic

diseases. Refractory inflammatory bowel disease is a still significant challenge in the management of patients with Crohn’s disease and ulcerative colitis. There are gaps in knowledge and future research directions on the recent newly registered pharmaceuticals. The main clinical outcomes for inflammatory bowel disease were maintained during the COVID-19 pandemic period.

Topličanin, A., & Milutinović, A. (2023)

Abstract

Ulcerative colitis and Crohn`s disease are chronic inflammatory bowel diseases characterized by a chronic course, relapsing nature, and significant cumulative, irreversible bowel damage if adequate treatment is not introduced early. Over the last decades, we have witnessed an increase in the prevalence of inflammatory bowel diseases. The diagnostic delay is the period from the onset of the first inflammatory bowel disease-related symptoms to the moment of diagnosis. The prognosis of inflammatory bowel disease patients largely depends on a timely diagnosis and early treatment. Diagnostic delay is more frequent in Crohn`s disease than in ulcerative colitis due to the presence of more unspecific symptoms and the lack of blood in the stools of some Crohn`s disease patients. Early Crohn`s disease is defined as a disease diagnosed within 18 months from symptom onset, without complications and previous treatment. In these patients, therapeutic goals, presently set on transmural healing, are easier to achieve than in those diagnosed with significant diagnostic delay that, according to the available data in the literature, varies from 2 months to several years. Diagnostic delay in Crohn`s disease patients depends on many risk factors that are not well-defined in the available literature. Early diagnosis, followed by early therapeutic intervention, has been proven to significantly reduce the risk of complications and the need for surgical treatment. Patient risk stratification and subsequent therapy choice during the early stages of Crohn`s disease improve patient long-term outcomes and allow the change of the natural course of the disease. Therefore, overcoming diagnostic delay in Crohn`s disease patients is one of the crucial tasks for the future. A possible solution for diagnostic delay in Crohn`s disease patients is the development and implementation of efficient screening tools like the Red Flags Index and education of general practitioners to suspect possible Crohn`s disease and refer patients to gastroenterologists. There is a strong need for proper use of available biomarkers like fecal Ucalprotectin and the development of new, more specific ones. Only when this problem is overcome will more Crohn`s disease patients receive proper therapy on time which will ultimately improve their long-term outcomes and quality of life.

Rispo, A., Testa, A., Nardone, O. M., Guarino, A. D., Imperatore, N., Fierro, G., Castiglione, F., & Calabrese, G. (2023)

Abstract

Inflammatory bowel disease, comprising Crohn’s disease and ulcerative colitis, defines as an idiopathic, chronic, relapsing, inflammatory disease affecting the gastrointestinal tract and leading to chronic damage. Endoscopy with biopsies is considered the gold standard for inflammatory bowel disease diagnosis, whereas magnetic resonance for Crohn’s disease extension and complication assessment. However, colonoscopy is an invasive procedure, while magnetic resonance is relatively not easily accessible for patients; thus, the need for a reliable, accessible and non-invasive way to perform inflammatory bowel diseases diagnosis and monitoring in the tight control era, like intestinal ultrasound is. Compared to endoscopy and magnetic resonance, ultrasound has shown reliable diagnostic accuracy in assessing Crohn’s disease diagnosis and evaluation of localisation, extension and complications. On the other hand, intestinal ultrasound is emerging as a valid tool also for ulcerative colitis severity and extension assessment. Moreover, performing ultrasonography in a point-of-care setting can guide the clinician in driving the diagnostic and therapeutic pathway, thus accelerating clinical decisions. As a novelty, point-of-care intestinal ultrasound performed with pocket devices could represent a promising item for the future of physical examination in outpatient or inpatient examination. The need for reproducibility of intestinal ultrasound among sonographers has emerged as a key-point in inflammatory bowel disease research field: the development of new scores for the evaluation of disease severity together with an intensive dedicated trainship could potentially reduce the differences between clinicians reporting.

Accordingly, our aim was to perform a narrative review about the application of intestinal ultrasound in Crohn’s disease and ulcerative colitis diagnosis and monitoring. Furthermore, technical aspects of this imaging technique and its application in a point-of-care setting through traditional and handheld sonographers were explored.

Tinguria, M. (2023b)

Abstract

Celiac disease (CD) is an immune mediated disorder characterised by intolerance to glutens in certain grains like whet, barley, and rye. The exposure to gliadin protein component in the susceptible individuals leads to an inflammatory reaction damaging small bowel mucosa with progressive disappearance of intestinal villi. The damaged intestinal mucosa leads to malabsorption. The usual symptoms of celiac disease include diarrhea, steatorrhea, weight loss, fatigue, and abdominal pain. Diagnosis is based on clinical features, duodenal biopsy, elevated levels of anti-gliadin antibodies and response to gluten free diet. Contrary to common belief, celiac disease is a protein systemic disease rather than merely a pure digestive alteration. Celiac disease is closely associated with genes that code HLA -II antigens mainly of DQ2 and DQ8 classes, production of disease specific antibodies (i.e., endomysial antibodies), multiorgan involvement, comorbidity with other autoimmune diseases (shared autoimmunity), familial aggregation, and immune system dysregulation.

The clinical presentation of celiac disease can be variable. In mild form, patients can be almost asymptomatic whereas in the most severe form, the patients are at increased risk of life-threatening complications. Celiac disease has a well-known association with other autoimmune diseases such as autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), diabetes mellitus, autoimmune thyroid diseases, skin diseases such as dermatitis herpetiformis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren’s syndrome, psoriasis, sarcoidosis, immune thrombocytopenic purpura, and pancreatitis. In addition, celiac disease may be associated with rare but potentially serious complications such as, collagenous sprue, ulcerative jejunoileitis, refractory celiac disease (RCD), enteropathy associated T-cell lymphoma, small bowel adenocarcinoma (SBA), hyposplenism, and cavitating mesenteric lymph node syndrome (CMLNS). The present article describes clinicopathologic features of these rare but serious complications of celiac disease.

M’Koma, A. E., Ware, J. M., Nabaweesi, R., & Chirwa, S. (2023)

Abstract

Inflammatory bowel disease (IBD) is a term for two autoimmune diseases encompassing Crohn’s disease (CD) and ulcerative colitis (UC) which are lifelong diseases affecting more than 3 million adults (1.3%) in the United States. IBD is characterized by chronic inflammation of the whole digestive system which results in damage to the gastrointestinal (GI) tract. IBD often emerges during adolescence and young adulthood. Maternal morbidity includes physical and psychological conditions that result from or are aggravated by pregnancy and have an adverse effect on a woman’s health, the baby’s health or both.  Some women have health challenges that arise before or during pregnancy that could lead to complications. It is recommended for women to receive health care counseling before and during pregnancy. Compared to other developed countries, the United States has the highest rate of women dying of pregnancy related complications. During the past 25 years maternal mortality has been getting worse. African American women (AAW) with and/or without IBD are dying at significantly higher rates than other groups. This is linked to several factors, i.e., systemic, institutionalized, and structural racism in health-care delivery and subsequent toxic stress from people’s lived experiences of racism, limited knowledge about healthcare system function, lack of access to healthcare, (inclusiveness and insurance policies) all of which negatively impact these patients. African Americans (AAs) are also up to three times as likely to experience severe maternal morbidity: unexpected outcomes of labor and delivery, deficient or lacking prenatal care and social determinants of health like lack of transportation, adequate employment, limited literacy, and limited healthcare access contribute to poor health outcomes. Studies on IBD patients indicate Medicaid expansion is associated with reduced rates of maternal morbidity, particularly for African American Women (AAW) and increased access to preconception and prenatal services that make pregnancy and childbirth safer for parent and baby. Herein we examine the physiological changes of pregnancy in patients diagnosed with inflammatory bowel disease and their relationship perinatal outcomes and parenthood.

Kyriacou, M., Vuyyuru, S. K., & Moran, G. W. (2023)

Abstract

Inflammatory Bowel Disease (IBD), which encompasses Crohn’s disease and ulcerative colitis, represents a chronic and progressive condition characterised by periods of active inflammation interspersed with periods of remission. The resulting disease burden, arising from patient symptoms and complications, leads to a diminished quality of life for individuals with IBD. Despite significant advancements in the management of IBD, the ideal treatment targets are uncertain. The evolution of treatment targets in IBD signifies a paradigm shift from mere symptom control to a more holistic approach that aims at achieving deeper remission and improving patients’ quality of life. The “treat-to-target” paradigm, guided by international consensus and expert insights, emphasises the importance of tailoring therapeutic goals to individual patient needs and disease severity. As our understanding of IBD’s underlying mechanisms deepens and therapeutic options expand, treatment goals have evolved to include not only clinical response but also the pursuit of more objective endpoints such as endoscopic healing. Emerging targets, such as the assessment of transmural healing through cross-sectional imaging and the focus on histologic remission as a predictor of long-term outcomes, hold great promise in further refining IBD management strategies. However, further research is needed to recommend these treatment targets in clinical practice. In the review we explore the ongoing evolution of treatment targets in IBD aimed at optimising patient outcomes and ultimately improving quality of life (QoL).

Andersson, U. (2022)

Abstract

The recent insight that the immune system is innervated has initiated a search for neural reflex circuits suitable for therapeutic targeting in human inflammatory diseases. The inflammatory reflex, signaling along the vagus system to maintain immune system homeostasis, is the best characterized such circuit. Proinflammatory molecules, extracellularly released during infectious or sterile injury, are sensed by afferent vagal nerves that transmit this information to the nucleus of tractus solitarius in the brainstem. The afferent signals generate efferent action potentials that travel from the brainstem via efferent vagal nerves to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors on immunocompetent cells to inhibit proinflammatory cytokine release. These mobile anti-inflammatory T lymphocytes thus operate both inside and outside compartments innervated by the vagus system.  Therapeutic proof-of-concept anti-inflammatory studies following surgical implantation of electrical vagus nerve stimulators were first conducted in rheumatoid arthritis and Crohn´s disease. Long term use of these devices was uneventful, while the initial surgical procedure caused adverse effects in some patients. The auricular branch of the vagus nerve reaches superficial parts in the concha and tragus in both ears, enabling transcutaneous electrical auricular vagus nerve stimulation (taVNS) as a safer therapeutic alternative. Invasive VNS and taVNS activate similar parts of the central nervous system indicated by functional imaging methods. Pilot taVNS studies in patients with inflammatory diseases have so far been conducted to treat rheumatoid arthritis, osteoarthritis, lupus, pediatric inflammatory bowel diseases, and pediatric nephrotic syndromes.

Ramos, R. J., Zhu, C., Joseph, D., Thaker, S., LaComb, J. F., Markarian, K., Lee, H. J., Petrov, J. C., Monzur, F., Buscaglia, J. M., Chawla, A., Small-Harary, L., Gathungu, G., Morganstern, J., Yang, J., Li, J., Pamer, E. G., Robertson, C. E., Frank, D. N., . . . Li, E. (2022). Metagenomic and bile acid metabolomic analysis of fecal microbiota transplantation for recurrent clostridi

Abstract

Background. Fecal microbiota transplantation (FMT) is an effective treatment of recurrent Clostridioides difficile infections (rCDI), but has more limited efficacy in treating either ulcerative colitis (UC) or Crohn’s disease (CD), two major forms of inflammatory bowel diseases (IBD). We hypothesize that FMT recipients with rCDI and/or IBD have baseline fecal bile acid (BA) compositions that differ significantly from that of their healthy donors and that FMT will normalize the BA compositions.

Aim. To study the effect of single colonoscopic FMT on microbial composition and function in four recipient groups: 1.) rCDI patients without IBD (rCDI-IBD); 2.) rCDI with IBD (rCDI+IBD); 3.) UC patients without rCDI (UC-rCDI); 4.) CD patients without rCDI (CD-rCDI).

Methods. We performed 16S rRNA gene sequence, shotgun DNA sequence and quantitative bile acid metabolomic analyses on stools collected from 55 pairs of subjects and donors enrolled in two prospective single arm FMT clinical trials (Clinical Trials.gov ID NCT03268213, 479696, UC no rCDI ≥ 2x IND 1564 and NCT03267238, IND 16795). Fitted linear mixed models were used to examine the effects of four recipient groups, FMT status (Donor, pre-FMT, 1-week post-FMT, 3-months post-FMT) and first order Group*FMT interactions on microbial diversity and composition, bile acid metabolites and bile acid metabolizing enzyme gene abundance.

Results. The pre-FMT stools collected from rCDI ± IBD recipients had reduced α-diversity compared to the healthy donor stools and was restored post-FMT. The α-diversity in the pre-FMT stools collected from UC-rCDI or CD-rCDI recipients did not differ significantly from donor stools. FMT normalized some recipient/donor ratios of genus level taxa abundance in the four groups. Fecal secondary BA levels, including some of the secondary BA epimers that exhibit in vitro immunomodulatory activities, were lower in rCDI±IBD and CD–rCDI but not UC-rCDI recipients compared to donors. FMT restored secondary BA levels. Metagenomic baiE gene and some of the eight bile salt hydrolase (BSH) phylotype abundances were significantly correlated with fecal BA levels.

Conclusion. Restoration of multiple secondary BA levels, including BA epimers implicated in immunoregulation, are associated with restoration of fecal baiE gene counts, suggesting that the 7-α-dehydroxylation step is rate-limiting.

M’Koma, A. E., Breaux, W. A., & Bragg, M. (2023)

Abstract

Background: Inadequate differentiated diagnostic features of predominantly colonic inflammatory bowel diseases i.e., ulcerative colitis and Crohn’s colitis, may lead to inexact diagnosis of “indeterminate colitis”. About 15% of indeterminate colitis patients are diagnosed at colonoscopy, in colonic biopsies, and/or at colectomy. Managing outcomes of indeterminate colitis, given its unpredictable clinical presentation, depends on future diagnosis of colitis, Crohn’s colitis or ulcerative colitis.

Objective: Overview the diagnostic efficacy of ectopic colonic ileal metaplasia and human α-defens 5 (DEFA5 alias HD5) for accurate delineation of indeterminate colitis into authentic Crohn’s colitis and/ or ulcerative colitis.

Design: We describe a targeted protein for potentially differentiating indeterminate colitis into an accurate clinical subtype diagnosis of inflammatory bowel diseases i.e., ulcerative colitis and Crohn’s colitis.

Patients: Twenty-one patients with the clinically inexact diagnosis of indeterminate colitis were followed, reassessed and data analyzed.

Main outcome measures: We observed that (i) some patients had their original diagnosis changed from indeterminate colitis to either ulcerative colitis or Crohn’s colitis; and (ii) human α-defensin 5 is aberrantly overexpressed in Crohn’s colitis.

Results: Fifteen of the twenty-one (71.4%) patients with indeterminate colitis had their inconclusive diagnosis changed; nine patients changed to ulcerative colitis and six to Crohn’s colitis. In human colon surgical samples, Human α-defensin-5 was significantly upregulated in Crohn’s colitis. In addition, Human α-defensin 5 processing enzyme, matrix metalloptotease-7 was inversely expressed compared to Human α- Defensin 5.

Limitation: Due to the sequence homology of the α-defensin class of proteins, preceding efforts to raise antibodies (Abs) against DEFA5 have limitations to produce adequate specificity. The Abs used in previous assays recognizes the α-defensins, active α-defensins 5 and inactive pro- α-defensins 5. Monoclonal antibodies (mAbs) to determine specificity and sensitivity of α-defensins 5, which is diagnostic of CC disease, and NOT other α-defensins is the limitation to overcome.

Conclusion: It is feasible to differentiate ulcerative colitis from Crohn’s colitis among patients with inexact diagnosis of indeterminate colitis using Human α-defensin 5 as a molecular biosignature delineator.

Rabinowitz, S. S., Sharma, S., & Grossman, E. (2023)

Abstract

Introduction: The present review details the evolution of endoscopic ultrasound, the acquisition of subepithelial imaging of the gastrointestinal tract during endoscopy, in pediatrics. Similar to its use in adults, the majority of its present applications involve obtaining fluid and or tissue for diagnosis. Simultaneously, the indications for point of care ultrasound, in which physicians caring for a patient personally obtains images which can be incorporated immediately into diagnosis and management, are also expanding. A history of endoscopic ultrasound from its inception to its current utilization is presented. The data reflecting its successful current employment  as the procedure of choice to analyze and drain pancreatic cysts, to diagnose biliary tract and pancreatic diseases, to direct subepithelial biopsies, and to evaluate gastrointestinal tumors as well as less common gastrointestinal pathologies, is summarized with an emphasis on pediatric studies. In addition, the recent expansion of point of care ultrasound and endoscopic ultrasound to yield images to analyze subepithelial pathology including fibrosis in eosinophilic esophagitis and in inflammatory bowel disease is highlighted. A brief summary of the challenges, range of instruments, costs, and safety provides the reader with the background to fully appreciate this emerging technique. Finally, there is an overview of exciting new developments that will further extend its indications. Conclusions: With anticipated improvements including better resolution of endoscopic ultrasound probes, the routine incorporation of point of care elastography and contrast enhanced ultrasound, and the potential of artificial intelligence to provide more reproducible and uniform analysis of endosonographic images, new indications are anticipated to enable endoscopic point of care ultrasound, E-POCUS, to further improve patient care in the near future.