Celiac Disease Research Articles

Immune Checkpoint Inhibitor-Associated Celiac Disease: A Retrospective Analysis and Literature Review

Introduction: Immune checkpoint inhibitors (ICI) are used to treat various malignancies. They block the inhibitory signals of tumor cells and enhance the inflammatory cascade, which results in tumor killing. However, this can lead to unchecked inflammation throughout the body, leading to various adverse effects. A rare gastrointestinal adverse effect of ICI therapy is the development of immune-mediated celiac disease. This entity has a similar clinical presentation to the more common ICI-induced enterocolitis. Our study aims to determine the clinical characteristics and optimal treatment strategies for this rare ICI toxicity and differentiate it from ICI-induced enterocolitis. Methods and Material: We conducted a retrospective analysis of eight cases of ICI-induced celiac disease and 24 cases of ICI-induced enterocolitis from the literature. Data on patient demographics, clinical history, therapeutic interventions and outcomes were collected. A comparative analysis was performed to identify the key differences between the two groups. Results: Patients with ICI-induced celiac disease were more likely to have a pre-existing autoimmune condition and HLA-DQ2 positivity. Significant differences in clinical manifestations, histological findings, and treatment outcomes were observed. Notably, weight loss, nutritional deficiencies and electrolyte abnormalities were more commonly associated with ICI-induced celiac disease. Regarding pathology, duodenal villous blunting was noted more commonly with ICI-induced celiac disease. Initiating a gluten-free diet led to a rapid improvement in patients with ICI-induced celiac disease, while immunosuppressive therapy did not have an impact. Conclusion: ICI-induced celiac disease is a rare and underrecognized gastrointestinal adverse effect of ICI therapy, often misdiagnosed as ICI-induced enterocolitis. Early recognition and treatment with a gluten-free diet can lead to rapid symptom resolution, sparing patients from unnecessary systemic immunosuppression and the discontinuation of antineoplastic immunotherapy.

Proteomic analysis of plasma and duodenal tissue in celiac disease patients reveals potential noninvasive diagnostic biomarkers

The pathogenesis of celiac disease (CeD) remains incompletely understood. Traditional diagnostic techniques for CeD include serological testing and endoscopic examination; however, they have limitations. Therefore, there is a need to identify novel noninvasive biomarkers for CeD diagnosis. We analyzed duodenal and plasma samples from CeD patients by four-dimensional data-dependent acquisition (4D-DIA) proteomics. Differentially expressed proteins (DEPs) were identified for functional analysis and to propose blood biomarkers associated with CeD diagnosis. In duodenal and plasma samples, respectively, 897 and 140 DEPs were identified. Combining weighted gene co-expression network analysis(WGCNA) with the DEPs, five key proteins were identified across three machine learning methods. FGL2 and TXNDC5 were significantly elevated in the CeD group, while CHGA expression showed an increasing trend, but without statistical significance. The receiver operating characteristic curve results indicated an area under the curve (AUC) of 0.7711 for FGL2 and 0.6978 for TXNDC5, with a combined AUC of 0.8944. Exploratory analysis using Mfuzz and three machine learning methods identified four plasma proteins potentially associated with CeD pathological grading (Marsh classification): FABP, CPOX, BHMT, and PPP2CB. We conclude that FGL2 and TXNDC5 deserve exploration as potential sensitive, noninvasive diagnostic biomarkers for CeD.

A feasibility study using quantitative and interpretable histological analyses of celiac disease for automated cell type and tissue area classification

Histological assessment is essential for the diagnosis and management of celiac disease. Current scoring systems, including modified Marsh (Marsh–Oberhuber) score, lack inter-pathologist agreement. To address this unmet need, we aimed to develop a fully automated, quantitative approach for histology characterisation of celiac disease. Convolutional neural network models were trained using pathologist annotations of hematoxylin and eosin-stained biopsies of celiac disease mucosa and normal duodenum to identify cells, tissue and artifact regions. Biopsies of duodenal mucosa of varying celiac disease severity, and normal duodenum were collected from a large central laboratory. Celiac disease slides (N = 318) were split into training (n = 230; 72.3%), validation (n = 60; 18.9%) and test (n = 28; 8.8%) datasets. Normal duodenum slides (N = 58) were similarly divided into training (n = 40; 69.0%), validation (n = 12; 20.7%) and test (n = 6; 10.3%) datasets. Human interpretable features were extracted and the strength of their correlation with Marsh scores were calculated using Spearman rank correlations. Our model identified cells, tissue regions and artifacts, including distinguishing intraepithelial lymphocytes and differentiating villous epithelium from crypt epithelium. Proportional area measurements representing villous atrophy negatively correlated with Marsh scores (r = − 0.79), while measurements indicative of crypt hyperplasia positively correlated (r = 0.71). Furthermore, features distinguishing celiac disease from normal duodenum were identified. Our novel model provides an explainable and fully automated approach for histology characterisation of celiac disease that correlates with modified Marsh scores, potentially facilitating diagnosis, prognosis, clinical trials and treatment response monitoring.

Impact of a Gluten-Free Diet in Adults With Celiac Disease: Nutritional Deficiencies and Challenges

Impact of a Gluten-Free Diet in Adults With Celiac Disease: Nutritional Deficiencies and Challenges

A comprehensive analysis of demographics, comorbidities, and laboratory findings in adult celiac disease patients: a single center experience

Aims: This study aims to evaluate the demographics, comorbidities, and laboratory findings of patients with celiac disease in our clinic. Methods: A total of 91 celiac patients who were followed in our centre between January 2020 and September 2023 were included in the study. Demographic, laboratory and comorbidities data were analysed retrospectively. Results: 72 (79.1%) patients were female, and the mean age of the participants was 42.3 (+-) 15.1 years. Deficiency of iron was observed in 46 (50.6%) participants, vitamin B12 in 9 (9.9%) participants, folat in 11 (12.1%) participants, and vitamin D in 37 (40.7%) participants. Hypothyroidism and diabetes mellitus were found to be the two most common comorbidities of celiac disease. In addition, liver enzymes were demonstrated to be elevated in the 9 (9.9%) patients. Conclusion: Celiac disease is associated with mineral and vitamine deficiency. In addition, mildly elevated liver enzymes may be observed in the clinical course. Notably, extraintestinal manifestations, especially hypothyroidism and diabetes, may accompany the disease.

Gastrointestinal dysfunction in Parkinson's Disease: absence of anti-gliadin antibodies.

Parkinson disease (PD), which is a neurodegenerative disorder, includes several gastrointestinal symptoms that are similar to those of Celiac disease (CD). However, the presence of celiac antibodies in PD patients has not yet been studied. Our aim in this study is to compare anti-transglutaminase (ATA) and antigliadin antibodies (AGA) as well as gastrointestinal symptoms and nutrition habits between patients with Parkinson's disease (PD) and healthy controls. Serum AGA IgG and IgA and the ATA antibodies IgA and IgG were studied in 102 PD patients and 91 healthy controls. Gastrointestinal symptoms, specifically constipation, were investigated using the gastrointestinal system rating scale (GSRS) and the constipation rating scale (CRS). Dietary habits were also investigated and compared between the groups. No significant differences were found between the two groups in terms of celiac antibodies. As expected, the hypokinetic GSRS and CRS scores were significantly higher in the PD group (p<0.001). Dietary habits, especially carbohydrate-rich diets, had a negative impact on gastrointestinal symptoms in the PD patients. Studies have suggested a connection between PD and CD, which infers a probable non-celiac gluten intolerance and the need to offer PD patients an elimination diet. However, the results of our study did not support any link between celiac antibodies and PD. Notwithstanding, the negative impact of a carbohydrate-rich diet in PD patients still leaves a question regarding gluten sensitivity in these patients.

120 Neuropsychiatric diseases in patients with dermatitis herpetiformis and other phenotypes of celiac disease: a cohort study

120 Neuropsychiatric diseases in patients with dermatitis herpetiformis and other phenotypes of celiac disease: a cohort study

Molecular Estimation of IL-15 Gene Effect and H. Pylori Prevalence in Celiac Disease

Remarkable positive associations across IL-15 values and the histopathological severity of celiac disease (CeD) indicate that interleukin (IL)-15 plays an essential part in the immunopathogenesis of the illness. There has been inconsistent evidence in certain research linking Helicobacter pylori to CeD. The goal of this meta-analysis was to measure the connection between CeD and H. pylori. Furthermore, the investigation examined the influence of H. pylori on the indications and categorization of CeD. This study includes 35 patients with CeD. They were fully informed of the study's goals before providing their signed consent. A group of 35 healthy blood donors made up the control group. Blood was drawn, transferred into gel tubes, and centrifuged. Serum specimens from both participants and controls have been obtained and then kept at -20°C in a deep freezer for subsequent use. It have been investigated the molecular relationship between IL-15 gene and CeD. It have been investigated the prevalence of H. pylori and CeD. The result of age and CeD incidence correlation indicates that there is no significance between age samples parameter and CeD incidence (control= 12.83 ± 0.4211, n=35 patients=12.23 ± 0.3358, n=35, p value=0.2692). Results of correlation between gender and CeD incidence indicates that number of male samples (24) and CeD incidence is more than that of female samples (11). Results of correlation between urban-rural residence and CeD incidence indicate that the average CDAT score for those who live in rural was higher in the urban area (good adherence to a gluten-free diet).

Genetic variants in the HLA-DQ2 and HLA-DQ8 genes and their involvement in the predisposition to celiac disease

Celiac disease is a multisystem disorder that is triggered by the consumption of gluten in genetically predisposed people, particularly those who carry the HLA-DQ2 and HLA-DQ8 alleles. Environmental factors and certain epigenetic mechanisms play a fundamental role in the manifestation of the disease. It has been shown that the gut microbiome can influence disease progression to some extent. Celiac disease presents with gastrointestinal and extraintestinal symptoms that complicate the diagnosis. Classic symptoms include digestive disorders, while non-classic symptoms include anemia, osteoporosis, and unexplained fatigue. Serological antibody tests and duodenal biopsy are key to a diagnosis, especially in atypical cases. At present, the only treatment is a strict gluten-free diet, although this presents certain problems due to the high cost and nutritional deficiencies. New research is looking for alternatives such as gluten-breaking enzymes as well as immunomodulatory treatments in hopes of more comprehensive options in the future.

Patient perceptions of the Finnish guidelines enabling coeliac disease diagnosis without biopsies in adults

Objectives Diagnosis of coeliac disease based on serology only has been allowed since 2018 in Finland for adults meeting specific criteria. We studied the patient experiences and perceptions of this novel diagnostic option. Methods Altogether 194 adult patients were questioned on socio‐demographic and health-related characteristics, quality of life and various coeliac disease-related issues. The results were compared between patients diagnosed with intestinal biopsy or based on serology only. Results Altogether 69 (36%) of the patients were diagnosed without duodenal biopsies. They were younger (median 43 vs. 51 years, p = 0.046), diagnosed more recently (2021 vs. 2020, p < 0.001) and more often in primary health care (78% vs. 43%, p = 0.001), had fewer esophageal symptoms at diagnosis (17% vs. 30%, p = 0.046) and considered the diagnostic process easier (49% vs. 30%, p = 0.032) than those diagnosed by duodenal biopsy (n = 125). The no-biopsy group received less often dietician follow-up (4% vs. 17%, p = 0.012), reported more persistent symptoms (36% vs. 21%, p = 0.026) and experienced more stress due to the diet (68% vs. 47%, p = 0.039). Symptom persistence or stress were not associated with year of diagnosis or dietician follow-up. The groups were comparable in socio-economic characteristics, general health, quality of life, diagnostic delay, dietician guidance at diagnosis, and dietary adherence. Conclusions The non-invasive approach resulted in de-centralized diagnosis and easier patient-experienced diagnostic process of coeliac disease, but was associated with increased risk for persistent symptoms and stress due to gluten-free diet. These results highlight the significance of appropriate patient guidance and support regardless of the diagnostic strategy.

Degradation of gluten using plant proteases

The paper describes the fact of the presence of a proteolytic enzyme in the leaves of the natural hybrid variety of grape - Isabella (Vitis Labrusca L.) and the perspective of its practical application for breaking down wheat gluten. As our research has shown, this enzyme effectively degradates the constituent components of the protein fraction of wheat flour-the gluten fraction. It is known that the wheat gluten is a strong allergen for many people, which can initiate a disease such as celiac disease. Protease from Isabella leaves carries out deep hydrolysis of gluten to low molecular weight soluble peptides and amino acids. This effect can be successfully used in the production of gluten-free bread products.

Medical and Demographic Characteristics of Patients With Eosinophilic Esophagitis and Celiac Disease

Background: Eosinophilic esophagitis (EoE) and celiac disease are both chronic T helper cell-mediated inflammatory conditions of the digestive tract. Although an association between these two conditions has been suggested, it has not been well characterized in a real-world setting. Goals: Our objective was to better examine the association between celiac disease and EoE using a real-world population database. Study: This was a retrospective cohort study of data using TriNetX, a global population database, to identify patient records using International Classification of Disease 10 (ICD-10) codes. We organized participants into six distinct cohorts predicated on age and diagnoses of celiac disease and EoE between April 28, 2003, and April 28, 2023. Patient demographics, prevalence, incidence, and medical characteristics of each cohort were extracted. Results: Among 46,398 patients with EoE and 84,383 patients with celiac disease, individuals with EoE demonstrated a higher prevalence (2.76%) and incidence (329/100,000 persons/year) of celiac disease compared with those without EoE (0.21% prevalence and 146/100,000 incidence, between 2021 and 2023). A concurrent diagnosis of both conditions increased the risk of asthma (RR: 2.00 pediatric, 1.82 adult), allergic rhinitis (RR: 2.35 pediatric, 1.81 adult), atopic dermatitis (RR: 3.28 pediatric, 2.07 adult), and rheumatoid arthritis (RR: 3.53 pediatric, 1.41 adult). In addition, patients with celiac disease with EoE exhibited a heightened risk for iron deficiency anemia (aHR 1.789; 95% CI: 1.166 to 2.745). Conclusions: Both the incidence and prevalence of EoE are elevated in patients with celiac disease and vice versa. These concurrent diagnoses affect disease characteristics and heighten the risk of complications in celiac disease.

Role of Protein Tyrosine Phosphatases in Inflammatory Bowel Disease, Celiac Disease and Diabetes: Focus on the Intestinal Mucosa

Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, such as cell growth, inflammation, differentiation, immune-mediated responses and oncogenic transformation. The aim of this review is to review the literature concerning the role of several PTPs—PTPN22, PTPN2, PTPN6, PTPN11, PTPσ, DUSP2, DUSP6 and PTPRK—at the level of the intestinal mucosa in inflammatory bowel disease (IBD), celiac disease (CeD) and type 1 diabetes (T1D) in both in vitro and in vivo models. The results revealed shared features, at the level of the intestinal mucosa, between these diseases characterized by alterations of different biological processes, such as proliferation, autoimmunity, cell death, autophagy and inflammation. PTPs are now actively studied to develop new drugs. Also considering the availability of organoids as models to test new drugs in personalized ways, it is very likely that soon these proteins will be the targets of useful drugs.

LINE-1 hypomethylation characterizes the inflammatory response in coeliac disease associated-intestinal mucosa and small bowel adenocarcinomas.

Long interspersed nuclear elements 1 (LINE-1) are the most abundant and the only autonomous mobile elements in the human genome. When their epigenetic repression is removed, it can lead to disease, such as autoimmune diseases and cancer. Coeliac disease (CeD) is an immune-mediated disease triggered by an abnormal T-cell response to dietary gluten and a predisposing condition of small bowel adenocarcinoma (SBA), frequently characterized by epigenetic alterations. The aim of this work was to assess LINE-1 methylation by bisulphite pyrosequencing and NanoString® gene transcription analysis in 38 CeD-SBAs compared with 25 SBAs associated with Crohn's disease (CrD-SBAs) and 25 sporadic SBAs (S-SBA). Both analyses were also performed in duodenal mucosae from 12 untreated CeD patients (UCD) and 19 treated CeD patients (TCD), and in 11 samples of normal intestinal mucosa to better investigate the role of LINE-1 deregulation in CeD and in CeD-SBA. A significant loss of LINE-1 methylation was observed in CeD-SBAs and in mucosae from UCD patients (with very similar methylation levels) compared with controls. By contrast, a restoration of normal LINE-1 methylation levels was found in TCD mucosae after a strict gluten-free diet. LINE-1 hypomethylation does not lead to expression of ORF1 and ORF2, with the only exception being for one CeD-SBA. The expression analysis of enzymes modulating DNA methylation and inflammatory genes confirmed that CeD-SBA shared a very similar expression profile of UCD mucosae showing a strong upregulation of genes involved in inflammation, immune response, and T-cell activity compared with TCD mucosae. For the first time, this work demonstrates that loss of DNA methylation is an intrinsic epigenetic feature of CeD, accompanying the immune response as a reversible mechanism in patients following a strict gluten-free diet, and suggests the possible role of LINE-1 hypomethylation in promoting cell adaptability during the gliadin-related inflammatory process. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Celiac disease is common in adults with cryptogenic cirrhosis and responds favourably to gluten-free diet

Introduction: Liver involvement is common in celiac disease (CeD), and upto 4.6% of patients with cryptogenic cirrhosis have CeD. We investigated the prevalence of CeD in patients with cryptogenic cirrhosis and assessed liver-related outcomes in them on GFD when compared to a propensity-score matched (PSM) cohort of patients with cryptogenic cirrhosis without CeD. Methods: Consecutive patients with cryptogenic cirrhosis were screened for CeD using IgA anti-tissue-transglutaminase antibody(anti-tTG) followed by anti-endomysial antibody (AEA) and duodenal and liver biopsies, on which IgA/anti-tTG colocalization studies were performed. These patients and a cohort of patients with cryptogenic cirrhosis without CeD [1:4 CeD: no CeD matched using PSM for age, sex, Child-Turcotte-Pugh(CTP) and model for end-stage-liver-disease(MELD)] were initiated on GFD plus standard of care (SOC) and SOC, respectively and followed up for liver-related outcomes for one year. Results: Of 232 patients with cryptogenic cirrhosis, 14 had high anti-tTG Ab (16.9±10.5 fold rise), with 9 AEA positive and 11(4.7%) biopsy-proven CeD. IgA/ anti-tTG-Ab colocalization was demonstrated in 7/8 liver and 10/11 duodenal biopsies. Patients with cryptogenic cirrhosis with definite CeD (n=11) and matched cohort without CeD (n=44) were similar at baseline [age:31.3±7.7 vs 31.8±9.3 years; 5(45.5%) vs 15(34.1%) females; MELDNa 9 (interquartile-range[IQR]: 8-15.5) vs 12(9-15); CTP 7(6-7.5) vs 6(5.75-7)]. Patients with CeD on GFD improved significantly on follow-up compared to those without CeD [follow-up MELDNa:9 (7.5-10.5) vs 18.5 (12-20);p=0.001 and follow-up CTP: 5 (5-5) vs 8(7-9);p&lt;0.001] with less frequent further decompensations and similar mortality (9.1% vs 18.2%;p=0.67). Conclusion: Approximately 4.7% of patients with cryptogenic cirrhosis have biopsy-proven CeD and their liver-related outcomes improve with GFD.

Vaccine Efficacy and Safety in Patients with Celiac Disease

Celiac disease (CD) is an autoimmune disorder caused by gluten intake in genetically predisposed individuals. This article provides an overview of the available data on the risks of infectious diseases and the mechanisms involved in CD, including a detailed analysis of vaccine efficacy, immunogenicity, and safety. The published articles were retrieved from the PubMed database using the terms “celiac disease,” “efficacy,” “hyposplenism,” “immune response,” “infections,” “immunization,” “immunogenicity,” “safety,” “vaccination,” and “vaccine.” CD can be associated with several autoimmune diseases, including selective immunoglobulin A deficiency (SIgAD), altered mucosal permeability, and hyposplenism. These conditions entail an increased risk of infections, which can be prevented by targeted vaccinations, although specific recommendations on immunization practices for subjects with CD have not been released. Regarding vaccinations, the immune response to the Hepatitis B virus (HBV) vaccine can be impaired in patients with CD; therefore, proposed strategies to elicit and maintain protective specific antibody titers are summarized. For patients with conditions that put them at risk of infections, vaccinations against Pneumococcus and other encapsulated bacteria should be recommended. Based on the available evidence, the Rotavirus vaccine offered to children could be useful in preventing CD in at-risk subjects. Overall, except for the HBV vaccine, vaccine efficacy in patients with CD is comparable to that in the general population, and no safety concerns have arisen.

Clinical Characteristics and Prevalence of Celiac Disease in a Large Cohort of Type 1 Diabetes from Saudi Arabia

Background and Objectives: The link between celiac disease (CD) and type 1 diabetes (T1D) has been well-documented in the medical literature and is thought to be due to a shared genetic predisposition in addition to environmental triggers. This study aimed to determine the seroprevalence and biopsy-proven CD (PBCD) prevalence in individuals with T1D from Saudi Arabia and identify their clinical characteristics and the impact on glycemic control. Materials and Methods: A total of 969 children and adolescents with confirmed T1D were investigated. Prospective and retrospective data were collected to include clinical, anthropometric, and biochemical data. Total IgA and anti-TTG-IgA antibodies were screened to detect seropositive cases. Upper intestinal endoscopy and biopsy were performed to find BPCD. Results: The seroprevalence of CD was 14.6% (141/969), while BPCD prevalence was 7.5%. Females had a higher prevalence than males: 17.8% vs. 9.8%, p &lt; 0.001. The CD group had lower HbA1c and more frequent hypoglycemia than the seronegative group. Conclusions: This study highlighted the high prevalence of CD in T1D Saudi patients. CD has multiple effects on glycemic control, growth, and puberty in children and adolescents with T1D. We emphasize the importance of early screening for CD at the time of diabetes diagnosis and periodically after that or if any atypical features present, especially anemia, growth delay, underweight, or frequent hypoglycemia.

Assessing the causal association between celiac disease and autism spectrum disorder: A two-sample Mendelian randomization approach.

The association between celiac disease (CD) and autism spectrum disorder (ASD) remains inconclusive. Reports from different observational studies have become controversial, necessitating exploration of the causal relationship between CD and ASD. To assess true causality, this study used a two-sample Mendelian randomization (MR) analysis to determine the causal association between CD and ASD. Summary-level data from a genome-wide association study (GWAS) of the European population were used to select instrument variables (IVs) at genome-wide significance (p < 5 × 10-8). The strength of IVs was also evaluated with F-statistics. The inverse variance weighted method (IVW) was the primary MR analysis, supported by other MR tests such as the weighted median method and weighted mode. The presence of horizontal pleiotropy was tested with MR-Egger and MR-PRESSO while other sensitivity analyses such as heterogeneity, leave-one-out analysis, and scatterplot were used to assess the validity of our MR results. Our study did not show an association between CD and ASD (OR, 0.994; 95% CI, 0.935-1.057; p = 0.859). There was also no evidence of horizontal pleiotropy (MR-Egger intercept = 0.015; p-value = 0.223) and heterogeneity (Q = 14.029; p-value = 0.051). These results were also complemented by the leave-one-out analyses, forest plot, and scatter plot, which showed that none of the SNPs influenced the result. The result of this study shows that CD is not causally associated with ASD.

Mendelian randomization analysis reveals causal effects of inflammatory bowel disease and autoimmune hyperthyroidism on diffuse large B-cell lymphoma risk

The clinical phenomenon whereby diffuse large B-cell lymphoma (DLBCL) occurs in patients with a history of autoimmune disease (AD) has been noted, but it remains controversial. This study aimed to evaluate the causal associations between nine ADs and DLBCL via a Mendelian randomization (MR) study. Single-nucleotide polymorphism (SNP) obtained from published genome-wide association studies (GWAS) was chosen as instrumental variable (IV). A total of nine ADs of European ancestry including asthma (56,167 cases and 352,255 controls), psoriasis (4,510 cases and 212,242 controls), autoimmune hyperthyroidism (962 cases and 172,976 controls), inflammatory bowel disease (31,665 cases and 33,977 controls), type 1 diabetes (6,683 cases and 12,173 controls), multiple sclerosis (14,498 cases and 24,091 controls), sarcoidosis (2,046 cases and 215,712 controls), ankylosing spondylitis (9,069 cases and 1,550 controls), and celiac disease (12,041 cases and 12,228 controls), were set as the exposure and DLBCL (209 cases and 218,583 controls) of European ancestry as the outcome. Inverse-variance weighted (IVW) was used as the primary analysis method, and the weighted median and MR-Egger method were used as supplementary methods. The sensitivity analyses employed in this study include the MR-Egger intercept, MR-PRESSO global test, Cochran’s Q test, leave-one-out analysis, and funnel plot. IVW showed that inflammatory bowel disease (OR = 1.241, 95% CI 1.009–1.526, P = 0.040) and autoimmune hyperthyroidism (OR = 1.464, 95% CI 1.103–1.942, P = 0.008) increased the risk of DLBCL without significant heterogeneity or horizontal pleiotropy, and the results remained stable according to the leave-one-out analysis. The IVW results revealed no associations between the other seven ADs and DLBCL: asthma (OR = 0.782, 95% CI 0.395–1.546, P = 0.159), psoriasis (OR = 0.842, 95% CI 0.669–1.060, P = 0.143), type 1 diabetes (OR = 1.071, 95% CI 0.860–1.334, P = 0.537), multiple sclerosis (OR = 1.331, 95% CI 0.941–1.883, P = 0.105), sarcoidosis (OR = 1.324, 95% CI 0.861–2.038, P = 0.200), ankylosing spondylitis (OR = 1.884, 95% CI 0.776–4.573, P = 0.161), and celiac disease (OR = 1.003, 95% CI 0.854–1.178, P = 0.969). Although no significant heterogeneity or horizontal pleiotropy was detected in these seven ADs and DLBCL, these results did not pass the leave-one-out analysis; therefore, the results need to be interpreted with caution. Inflammatory bowel disease and autoimmune hyperthyroidism may increase the onset of DLBCL. The risk of DLBCL should be considered in specific types of ADs.

Optimization of Functional Gluten‐Free Cake Formulation Using Rice Flour, Coconut Flour, and Xanthan Gum via D‐Optimal Mixture Design

ABSTRACTProlamins in wheat, barley, and rye cause celiac disease (CD), non‐celiac gluten sensitivity (NCGS), and wheat allergies (WA). Although rice can be a suitable alternative, gluten‐free rice flour products are less technologically advanced. However, coconut flour and xanthan gum could enhance product quality, fiber content, and functional properties. This study employed a response surface D‐optimal mixture design to investigate the impact of substituting Sadri Hashemi rice flour (RF) (15.60%–31.19%) with low‐fat desiccated coconut flour (CF) (0%–15.59%) and xanthan gum (XG) (0%–0.31%) in 17 runs based on batter weight. Eleven responses were analyzed and exhibited significant and valid models (p &lt; 0.0001), with satisfactory coefficient of determination (R2 &gt; 0.85) values and non‐significant lack of fit (p &gt; 0.1). Substitution at all levels significantly increased batter viscosity (R2 = 0.990) and specific weight (R2 = 0.995). Differences in cake crumb color (ΔE) decreased when RF was substituted with CF, while maximum ΔE elevation was observed with 0.31% XG due to synergistic effects with 5.09% CF (R2 = 0.974). Increasing the RF/XG ratio (0% CF) resulted in decreased water activity (aw), while increasing CF increased aw synergistically (R2 = 0.986). Moisture and texture hardness increased significantly with RF substitution up to 7.518% CF and 0.170% XG and 8.944% CF and 0.285% XG, respectively (R2 = 0.976 and 0.993). The volume index decreased with CF and XG (R2 = 0.989). Sensory acceptances were reduced by increasing XG while improved with optimal CF levels, predicted at 6.415% (R2 = 0.997), 6.784% (R2 = 0.999), 9.001% (R2 = 0.999), and 5.924% (R2 = 0.999) for color, taste, texture, and overall acceptance, respectively. Two‐sided prediction interval confirmation runs with 95% confidence (p ≤ 0.05) validated the models' accuracy and prediction of optimized combinations. The optimized gluten‐free cake formula (23.395% RF, 7.795% CF, 0% XG) achieved an 88.0% desirability score. Developing valid regression models facilitates a comprehensive investigation of cake quality and sensory properties, ensuring a viable gluten‐free product for individuals with gluten‐related disorders.