Genetically modified helminths as pharmaceutical biofactories.

Celiac disease and drug absorption: implications for cardiovascular therapeutics.

Covering the Cover

Background: Human herpesviruses are double-stranded DNA viruses of which eight types have been identified at present. Herpesvirus infection comprises an active lytic phase and a lifelong latency phase with the possibility of reactivation. These infections are highly prevalent worldwide and can lead to a broad spectrum of clinical manifestations, ranging from mild symptoms to severe disease, particularly in immunocompromised individuals. Clustered regularly interspaced palindromic repeats (CRISPR)-based therapy is an interesting alternative to current antiviral drugs, which fail to cure latent infections and are increasingly challenged by viral resistance. Objective: This scoping review aimed to summarize the current state of CRISPR-based antiviral strategies against herpesvirus infections, highlighting the underlying mechanisms, study design and outcomes, and challenges for clinical implementation. Design: A literature search was conducted in the databases PubMed and Web of Science, using both a general and an individual approach for each herpesvirus. Results: This scoping review identified five main mechanisms of CRISPR-based antiviral therapy against herpesvirus infections in vitro and/or in vivo. First, CRISPR systems can inhibit the active lytic replication cycle upon targeting viral lytic genes or host genes. Second, CRISPR technologies can remove latent viral genomes from infected cells by targeting viral genes essential for latency maintenance or destabilizing the viral genome. Third, reactivation of multiple latent herpesvirus infections can be inhibited by CRISPR-Cas-mediated editing of lytic viral genes, preventing a flare-up of clinical symptoms and reducing the risk of viral transmission. Fourth, CRISPR systems can purposefully induce viral reactivation to enhance recognition by the host immune system or improve the efficacy of existing antiviral therapies. Fifth, CRISPR technology can be applied to develop or enhance the efficiency of cellular immunotherapy. Conclusions: Multiple studies demonstrate the potential of CRISPR-based antiviral strategies to target herpesvirus infections through various mechanisms in vitro and in vivo. However, aspects regarding the delivery and biosafety of CRISPR systems, along with the time window for treatment, require further investigation before broad clinical implementation can be realized.

BACKGROUND A small fraction of Inflammatory bowel disease (IBD) subjects have celiac disease (CeD). We conducted a retrospective case-control study to compare disease characteristics of subjects with IBD vs IBD+ CeD. METHODS A retrospective study was conducted from January 2017 to June 2022 using appropriate ICD-10 codes for IBD and CeD. Data was collected including demographics, disease phenotype, and medication use patterns. Disease groups included IBD, IBD+ CeD with subgroup analyses being further performed as follows: Crohn’s disease (CD), CD+ CeD, ulcerative colitis (UC), UC+ CeD. RESULTS Females consisted of 59% of IBD (N=72) and 64% of IBD+ CeD (N=36) (p=0.62). Median age at diagnosis of IBD was 24.5 years in the IBD+CeD group compared to IBD group (43.5 years), p=0.003. Median duration of IBD since IBD diagnosis was longer (IBD:16.4 yrs vs IBD +CeD: 8.4 yrs, p< 0.001) with the age at the end of study being older in IBD subjects (64 yrs) vs. IBD+ CeD (34 yrs), p< 0.001. Subgroup analysis (Table 1) based on Montreal classification revealed a higher prevalence of A2 in CD+ CeD (56%) vs CD (24%) and A3 in CD (68%) vs CD+ CeD (22%), p=0.007. There was a higher prevalence of autoimmune conditions in the IBD+ CeD group (27%) in comparison to IBD group (6.9%), p< 0.003 with rheumatoid arthritis (RA) and thyroiditis occurring more commonly in the IBD+ CeD group (Fig 1). Immuno-modulator and biologic use (anti-TNF, anti-integrin and anti-IL12/23) use was significantly higher in the UC+ CeD group at 33%, 39%, 33%, 11% respectively when compared to 10%, 6.5%, 3.2% and 3.2% in UC subjects (p < 0.05 to < 0.001). Immuno-modulator and biologic use (anti-integrin and anti-IL12/23) use were significantly higher in the CD+ CeD group at 50%, 33%, and 33% respectively when compared to 24%, 2.4%, and 10% in CD subjects (p < 0.05 to < 0.001). CONCLUSIONS The prevalence of autoimmune diseases, especially autoimmune thyroiditis and RA is higher in IBD+ CeD subjects with a greater preponderance in UC+ CeD. Further, IBD+ CeD subjects tend to be younger at disease onset than subjects with IBD alone. Use of steroids and escalation to biologics is more common in IBD+ CeD subjects than IBD subjects. These findings should encourage clinicians to assess younger IBD patients for CeD and autoimmune conditions including thyroiditis and RA. Further, early use of biologics may become necessary in this subset of IBD patients.

Genetic modifications in humans is a fast‐advancing field of science, with very little legal regulation. Scientists recently have developed a technique, clustered regularly interspaced palindromic repeat (CRISPR), which will forever change this field. Before CRISPR, all methods were too expensive and time consuming to facilitate editing human genes. CRISPR is faster and cheaper, making it a very real possibility for all. Since the discovery of CRISPR, research on human embryos has begun, with a success rate showing that creating a genetically perfect family is very real. In 2015, all federal funding for human genome modifications was banned, leaving little federal control. This Note proposes a model statute that allows for research while providing restrictions to prevent harm.

INTRODUCTION: Inflammatory bowel disease (IBD) and celiac disease (CeD) are immune-mediated diseases characterized by chronic intestinal inflammation. Some studies have suggested that patients with both IBD and CeD carry a higher risk of hospitalization and severe disease as compared with non-celiac IBD patients. This study aimed to evaluate the prevalence of CeD, the impact of CeD on outcomes among IBD hospitalizations and compare outcomes in subgroups of Crohn’s disease (CD) and ulcerative colitis (UC). METHODS: The NIS was used to identify adult patients with IBD hospitalizations from 2010 to 2014 using ICD-9 codes. Primary outcomes were mortality, hospital charges, length of stay (LOS) and colorectal surgery. The secondary outcome was the trend of the prevalence of CeD in IBD hospitalizations. Subgroup analysis was performed for UC with vs without CeD and CD with vs without CeD. Propensity scoring methods and multivariate regressions were used. RESULTS: There were 516,891 IBD related hospitalizations from 2010 to 2014, of which 1582 patients had CeD. The control group consisted of 7913 IBD hospitalizations without CeD. The average age of patients having CeD with IBD was 43.5 years old, 32.0% were male and 81.6% were Caucasian. IBD with CeD was associated with a lower rate of colorectal surgery compared to IBD without CeD (4.06% vs 5.90%, aOR 0.62, 95% CI = 0.47–0.81, P-value <0.001), but differences in mortality rate, LOS, and hospital charges were not significant. The prevalence of CeD in patients with IBD related hospitalizations increased from 0.23% to 0.45%. The annual percentage change (APC) of the prevalence of CeD in patients with IBD related hospitalizations was 0.058 (95% CI = 0.026–0.089, P-value <0.05). Subgroup analysis showed CeD was associated with a lower rate of colorectal surgery in adult patients with CD (1.2% vs 2.1%, aOR 0.36, 95% CI = 0.18–0.72, P-value <0.05) and was not associated with different outcomes in UC hospitalizations. CONCLUSION: The prevalence of CeD in IBD hospitalizations from 2010 to 2014 increased. This may be a result of increased awareness and testing for CeD. CeD was associated with a lower rate of colorectal surgery in CD and was not associated with different outcomes in UC. This may be explained by CD phenotypes with CeD that elicits a small bowel predominant presentation leading to lower colorectal surgery rates. Further studies are required to evaluate the pathogenesis of CD with CeD and its effects on clinical outcomes of hospitalized patients.Figure 1.: The trend in prevalence of celiac disease in patients with inflammatory bowel disease-related hospitalizations from 2010 to 2014.Table 1.: Comparison of baseline characteristics of patients admitted for inflammatory bowel disease (IBD) with celiac disease vs. without celiac diseaseTable 2.: Crude and Adjusted results for inpatient outcomes in patients with inflammatory bowel disease (IBD) with vs. without celiac disease from 2010 to 2014 *Adjusted for age, gender, race, primary insurance payer, hospital type, hospital bed size, Elixhauser comorbidity index score and income quartile

We aimed to identify the clinical factors of celiac disease (CeD) and inflammatory bowel disease (IBD) associated with positive stool gastrointestinal (GI) polymerase chain reaction (PCR) test. Understanding the pattern of enteric infections in CeD and IBD may allow further insight into microbiome-mediated pathogeneses. This was a retrospective study of adult patients (age 18 y or above) with CeD and IBD at a large quaternary care institution. We identified patients with CeD or IBD who underwent stool GIPCR evaluation as outpatients (office visit or at endoscopy) between March 2015 and March 2019. Patients with a negative GIPCR test within the study time frame were randomly chosen as controls (1 : 1). The independent relationship between clinical characteristics and positive GIPCR was evaluated using multivariable logistic regression. A total of 266 patients met criteria for the study, including 92 (35%) with CeD and 174 (65%) with IBD. On multivariable analysis of factors associated with positive GIPCR test, CeD patients were more likely to have diarrheal presentation of illness [odds ratio (OR): 2.61, 95% confidence interval (CI) 1.05-6.72], experience extraintestinal manifestations (OR: 2.49, 95% CI: 1.01-6.31), and practice a gluten-free diet for at least 5 years (OR: 4.00, 95% CI: 1.36-11.67), relative to those with a negative GIPCR test. IBD patients with positive GIPCR were more likely to be on corticosteroids (OR: 2.23, 95% CI: 1.02-5.4.84), experience extraintestinal manifestations (OR: 2.60, 95% CI: 1.22-5.53), and use proton-pump inhibitors (OR: 4.07, 95% CI: 1.69-9.77). Intestinal infections in CeD and IBD are associated with important disease-specific characteristics.

P616 Natural history and phenotype of inflammatory bowel disease with co-existent celiac disease

Celiac Disease: From Pathogenesis to Novel Therapies

Respiratory diseases, such as influenza infection, acute tracheal bronchitis, pneumonia, tuberculosis, chronic obstructive pulmonary disease, asthma, lung cancer and nasopharyngeal carcinoma, continue to significantly impact human health. Diseases of the lung and respiratory tract are influenced by environmental conditions and socio-economic factors; however, many of these serious respiratory disorders are also rooted in genetic or epigenetic causes. Clustered regularly interspaced palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins, isolated from the immune system of prokaryotes, provide a tool to manipulate gene sequences and gene expression with significant implications for respiratory research. CRISPR/Cas systems allow preclinical modelling of causal factors involved in many respiratory diseases, providing new insights into their underlying mechanisms. CRISPR can also be used to screen for genes involved in respiratory processes, development and pathology, identifying novel disease drivers or drug targets. Finally, CRISPR/Cas systems can potentially correct genetic mutations and edit epigenetic marks that contribute to respiratory disorders, providing a form of personalized medicine that could be used in conjunction with other technologies such as stem cell reprogramming and transplantation. CRISPR gene editing is a young field of research, and concerns regarding its specificity, as well as the need for efficient and safe delivery methods, need to be addressed further. However, CRISPR/Cas systems represent a significant step forward for research and therapy in respiratory health, and it is likely we will see the breakthroughs generated from this technology continue.

Adult patients with both inflammatory bowel disease (IBD) and celiac disease (CeD) have peculiar phenotypic features. This study aimed at describing the characteristics and natural history of children with both IBD and CeD. This was a case-control study based on a national registry. Cases included children diagnosed with both IBD and CeD. Two matched IBD controls without CeD, and 2 matched CeD controls were selected for each case. Inflammatory bowel disease phenotype and natural history, comprising growth and pubertal development, were compared between groups. Forty-nine (1.75%) patients with IBD and CeD were identified out of 2800 patients with IBD. Compared with patients with IBD alone, patients with IBD and CeD presented more frequently with autoimmune diseases (odds ratio, 2.81; 95% CI, 0.97-8.37; P = 0.04). Ileocolonic localization (46.1% vs 73.1%), treatment with azathioprine (46.2% vs 71.2%), and anti-TNF biologics (46.2% vs 69.2%) were less common in patients with Crohn's disease and CeD than in patients with Crohn's disease alone. Patients with ulcerative colitis and CeD had an increased risk of colectomy despite similar medical treatments compared with patients with ulcerative colitis alone (13.0% vs 0%). Pubertal delay was more common in patients with IBD and CeD compared with patients with IBD alone (14.9% vs 3.2%; odds artio, 5.24; 95% CI, 1.13-33.0; P = 0.02) and CeD alone (14.9% vs 1.1%; P = 0.002). Children with IBD and CeD may have peculiar features with a higher risk for autoimmune diseases, colectomy, and pubertal delay compared with IBD alone.

INTRODUCTION: Dermatitis herpetiformis (DH) is an autoimmune eruption of pruritic inflammatory papules and vesicles that occur in a grouped arrangement on different parts of the body. It is characterized by granular deposits of immunoglobulin A (IgA) within the dermal papillae on immunofluorescence. Previous case studies (Alonso-Llamazares et al) and case reports have described an association between DH and ulcerative colitis, possibly arising due to an increased permeability of intestinal mucosal barrier in inflammatory bowel disease (IBD) that allows antigen to circulate in the blood and triggering IgA antibodies. Using a large database, we sought to describe the epidemiology and risk of DH in IBD patients. METHODS: We used a commercial database (Explorys Inc, Cleveland, OH), an aggregate of Electronic Health Record data from 26 US healthcare systems. We identified a cohort of patients with IBD, celiac disease and a diagnosis of DH between June 2015 and 2020. Patients were identified based on a Systemized Nomenclature of Medicine Clinical Terms. We calculated the prevalence of DH in patients with IBD, with celiac, general population, and in individuals with neither IBD nor celiac which served as controls. RESULTS: Out of the 39,212,680 patients active from 2015 to 2020, we identified a total of 5,240 patients with DH (0.013%), 280,460 patients with IBD (0.71%), and 115,020 patients with celiac disease (0.29%). Among those with DH, there were 1290 patients diagnosed with celiac disease (without IBD), 120 patients with IBD (without CD), 60 patients with both celiac and IBD, and 3770 patients with neither celiac nor IBD (control group). The prevalence of DH was 1.12% in celiac disease (without IBD) and 0.043% in IBD (without CD). The prevalence of DH among those without celiac nor IBD (in the control group) was 0.0096%. The risk of DH was higher in celiac [OR 116.6 (109.4–124.2)] and in IBD [OR 4.41 (3.68–5.29)] compared to individuals with neither IBD nor celiac. In the cohort with IBD, risk of DH was higher in females compared to males [OR 3.06 (1.77–5.30)], in elderly patients compared to adults aged 18–65 [4.0 (2.34–6.84)], and in Caucasians compared to non-Caucasians (OR 25.0 [12.7–49.3]). CONCLUSION: Using a large population database, we described the epidemiology and risk of DH in IBD patients. We found that the risk of DH is increased in patients with IBD, consistent with prior case series. Further studies are needed to confirm this association and elucidate the mechanism behind this association.Table 1.: Odd’s ratio comparing the prevalence of dermatitis herpetiformis in celiac disease and in IBD to patients with DH without celiac or IBDTable 2.: Gender-, Age- and Race-Based Prevalence of dermatitis herpetiformis in individuals with IBD in the United States between 2015 and 2020

Introduction: Inflammatory bowel disease (IBD) is associated with skin manifestation; Erythema :odosum and pyoderma gangrenosum being the most common but other skin disorder have been reported in IBD. Vitiligo is a rare autoimmune disease that is diagnosed based on clinical findings and examining the skin by wood lamp that reveals depigmentation patches. In the past, case studies (Shafa S et al) and case reports have suggested a link between Vitiligo and IBD. Using a large database, we aim to describe the epidemiology and risk of Vitiligo in IBD patients. Methods: We used a multi-instituitional database (Explorys Inc, Cleveland, OH), an aggregate of electronic health record data from 26 US healthcare systems. In this database, we identified patients with a Systemized Nomenclature of Medicine Clinical Terms diagnosis of IBD, CD, and vitiligo from 1999 to the present. We assessed the association of vitiligo in IBD patients without CD and CD patients without IBD and compared them with individuals with neither IBD nor CD. Results: Out of the 70,383,890 patients in the database, we identified a total of 50,020 patients with vitiligo (0.1%), 412,950 patients with IBD (0.6%), and 136,690 patients with CD (0.2%). Among those with vitiligo, there were 450 (0.4%) CD patients (without IBD), 880 (0.3%) IBD patients (without CD), 50 (0.2%) patients with both celiac and IBD, and 48,640 (0.07%) patients with neither CD nor IBD (control group). The prevalence of vitiligo was 0.4% in celiac disease (without IBD) and 0.3% in IBD (without CD). The risk of vitiligo was higher in the CD-only group [OR 5.65 (5.15–6.20)] and IBD-only group [OR 3.24 (3.03–3.46)] compared to the control group (Table). In the IBD-only group, vitiligo was more commonly associated with females compared to males [OR 1.44 (1.19–1.74), P< 0.0001], in adults aged 18–65 compared to elderly patients [2.52 (2.08–3.06), P< 0.0001], and in Caucasians compared to non-Caucasians (OR 9.0 [7.25–11.17], P< 0.0001) (Figure). Conclusion: Utilizing a large population database, we report a distinct increased association of vitiligo in IBD and CD. Further studies are necessary to confirm this association and discover the mechanism behind this association.Figure 1.: Gender-, Age- and Race-Based Prevalence ratio of vitiligo in individuals with IBD without history of celiac disease in the United States. Table 1. - Odd’s ratio comparing the prevalence of vitiligo in celiac disease and in IBD to patients with vitiligo without celiac or IBD OR, 95% CI, p-value*Compared to patients with vitiligo without celiac nor IBD Vitiligo in Celiac disease (Excluding those with IBD) OR 5.65 (5.15-6.20), P< 0.0001 Vitiligo in IBD (Excluding those with celiac) OR 3.24 (3.03-3.46), P< 0.0001 Univariate analysis used to calculate OROR; odds ratio, CI; confidence interval, IBD; Inflammatory bowel disease.

To determine the risk of inflammatory bowel disease (IBD) in patients with celiac disease (CeD) (and vice versa ) compared with general-population comparators. Using Swedish histopathology and healthcare register data, we identified 48,551 patients with CeD and 83,529 with IBD diagnosed in 1969-2016. Each patient was compared with age- and sex-matched general-population comparators (CeD: n = 240,136; IBD: n = 408,195). Cox regression estimated hazard ratios (HRs) for IBD in patients with CeD and vice versa . Our main analyses were limited to events beyond the first year of follow-up to reduce potential surveillance bias. During follow-up, 784 (1.6%) patients with CeD were diagnosed with IBD compared with 1,015 (0.4%) matched comparators. In patients with CeD, the HR for IBD was 3.91 (95% confidence interval [CI] 3.56-4.31), with largely similar HRs for Crohn's disease (4.36; 3.72-5.11) and ulcerative colitis (3.40; 3.00-3.85). During follow-up, 644 (0.8%) patients with IBD and 597 (0.1%) comparators were diagnosed with CeD. The HR for CeD in patients with IBD was 5.49 (95% CI 4.90-6.16), with the highest risk estimates seen in ulcerative colitis (HR = 6.99; 6.07-8.05), and the HR for Crohn's disease was 3.31 (2.69-4.06). In patients with CeD and IBD, the diagnostic interval was usually &lt;1 year; however, HRs of 3-4 were seen even after 10 years of follow-up. During 20 years of follow-up, 2.5% of patients with CeD developed incident IBD, and 1.3% of patients with IBD developed CeD. The bidirectional association between CeD diagnosis and IBD warrants attention in the initial assessment and follow-up of these conditions. Their co-occurrence, independent of temporal sequence, suggests shared etiology.

Tissue transglutaminase (tTg) has been identified as an autoantigen in coeliac disease (CD). There is a marked homology between different forms of transglutaminase, such as tTg and coagulation factor XIII. We compared titres of both IgA- and IgG-antibodies against these two antigens in 20 CD patients, 20 endomysial antibody (EMA)-negative controls and a group with inflammatory bowel disease (34 with Crohn's disease and 23 with ulcerative colitis). IgA-antibodies against tTg correlated with EMA titres and had high sensitivity and specificity in screening for CD. Only in two CD patients were high titres found of IgA-antibodies against factor XIII, non-reactive with tTg. Both lacked bleeding tendency. The presence of IgG-antibodies against tTg, in contrast, had low sensitivity and specificity in screening for CD and were frequently seen in inflammatory bowel disease. Similarly, factor XIII IgG-antibodies displayed a non-specific pattern with modestly elevated titres in patients with Crohn's disease and in both EMA-negative and positive patients. Despite a marked homology with tTg, the occurrence of high titre IgA-antibodies against factor XIII is infrequent in CD, but may--when present--be the result of epitope spreading. The presence of IgG-antibodies in CD and inflammatory bowel disease illustrates the complexity of autoantibody reactions in gastrointestinal disease.