From an understanding of etiopathogenesis to novel therapies-what is new in the treatment of celiac disease?

Celiac disease, a chronic autoimmune disorder caused by genetic factors and exposure to gluten, is increasingly being recognized and diagnosed in both children and adults. Scientists have been searching for a cure for this disease for many years, but despite the impressive development of knowledge in this field, a gluten-free diet remains the only recommended therapy for all patients. At the same time, the increasing diagnosis of celiac disease in adults, which was considered a childhood disease in the 20th century, has opened a discussion on the etiopathology of the disease, which is proven to be very complex and involves genetic, immunological, nutritional, environmental and gut microbiota-related factors. In this review, we extensively discuss these factors and summarize the knowledge of the proposed state-of-the-art treatments for celiac disease to address the question of whether a better understanding of the etiopathogenesis of celiac disease has opened new directions for therapy.

Autoimmune Polyendocrine Syndromes in Adult Italian Celiac Disease Patients.

Celiac disease (CD) is frequently associated with other autoimmune disorders. Different studies have explored the association between CD and single autoimmune endocrine disease (AED), especially autoimmune thyroiditis (AIT) and type-1 diabetes mellitus (T1DM). Data about CD as a component of autoimmune polyendocrine syndrome (APS) are scant. We analyzed a large dataset including prospectively collected data from 920 consecutive adult CD patients diagnosed in a third-level Italian institution in the 2013-2023 period, The prevalence of isolated autoimmune endocrine diseases and APS were collected. A total of 262 (28.5%) CD patients had at least one associated AED, with AIT (n = 223, 24.2%) and T1DM (n = 27, 2.9%) being the most frequent conditions. In most cases (n = 173, 66%), AEDs were diagnosed after CD. Thirteen patients (1.4%) had at least two of the requested three endocrinopathies, satisfying the diagnosis of type 2 APS. APS-2 is a rare but not exceptional occurrence among Italian CD patients, underscoring the intricate and multifaceted nature of autoimmune disorders. Periodic evaluations of thyroid function and glycaemia should be recommended after the diagnosis of CD together with testing for autoantibodies that may be helpful in assessing disease risk before disease onset. Likewise, implementation of a systematic screening for CD amongst T1DM and other autoimmune endocrine diseases are paramount.

Genetic, Immunological, Dietary, Gut Microbiota, and Environmental Determinants of Osteoporosis in the Course of Celiac Disease: Which Factor Plays the First Violin in This Orchestra?

Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The worldwide prevalence of CD is estimated to be 0.7-1.4% of the general population. Etiopathology of this disease is multifactorial, with genetic determinants being a major contributing player to CD susceptibility. Its manifestation embraces different organs, including the musculoskeletal apparat. Patients with CD have increased risk of bone disorders. According to data, bone disorders - osteopenia and osteoporosis - can affect up to 70% of patients with CD at diagnosis, and it decreases after the initiation of a gluten-free diet. Gluten consumption in patients with CD triggers an inflammatory reaction followed by tissue damage, and both; local and systemic inflammation can increase the risk of bone mass deterioration. Other theory assumes shortages of vitamin D and an impaired calcium absorption mechanism leading to secondary hyperparathyroidism. Taking into account the increasing prevalence of CD and osteoporosis, we broadly discuss genetic, immunological, dietary, gut microbiota, and environmental factors that could increase the risk of osteoporosis in CD. Furthermore, we discuss lifestyle and pharmacological preventing and treatment measures.

Evolution of bone densitometry parameters and risk of fracture in coeliac disease: a 10-year perspective.

BACKGROUND: Metabolic bone disease is frequently found in patients with coeliac disease (CD). Despite its high prevalence, international guidelines are partially discordant about its management due to the lack of long-term data. METHODS: We retrospectively evaluated a large dataset of prospectively collected data of CD patients assessing the variation of DXA parameters and estimated fracture risk according to the FRAX® score in a 10-year follow-up. Incident fractures are reported, and the predictive ability of the FRAX® score is verified. RESULTS: We identified 107 patients with low bone density (BMD) at the diagnosis of CD and a 10-year follow-up. After improving at the first follow-up, T-scores slowly reduced over time but with no clinically relevant differences between the first and last examination (lumbar spine: from - 2.07 to - 2.07, p = 1.000; femoral neck: from - 1.37 to - 1.55, p = 0.006). Patients with osteoporosis at the index measurement had more marked fluctuations than those with osteopenia; the latter group also showed minimal modifications of the FRAX® score over time. Six incident major fragility fractures occurred, with a good predictive ability of the FRAX® (AUC 0.826). CONCLUSION: Adult CD patients with osteopenia and no risk factors had substantially stable DXA parameters and fracture risk during a 10-year follow-up. A dilated interval between follow-up DXA for these patients could be considered to reduce diagnosis-related time and costs, maintaining a 2-year interval for patients with osteoporosis or risk factors.

Acetylsalicylic acid challenge or desensitization in sensitive patients with cardiovascular disease.

The use of acetylsalicylic acid (ASA) is problematic in subjects with histories of hypersensitivity reactions (HRs) to it or with cross-reactive types of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. We sought to evaluate the efficacy of low-dose ASA challenge (LDAC) and desensitization to allow ASA therapy at an antiplatelet dose in patients with atherosclerotic cardiovascular disease (ASCVD) or multiple related risk factors and histories of HRs to ASA or ≥ 2 chemically unrelated NSAIDs. We studied prospectively all patients with such histories and ≥ 3 risk factors for ASCVD (group I), chronic coronary syndrome (CCS, group II), and acute coronary syndrome (ACS) with indication for ASA desensitization (group III). Patients from groups I and II underwent LDACs (cumulative dose of 110 mg), while those from group III were desensitized (cumulative dose of 100.1 mg). We evaluated 103 patients: 62 from group I, 24 from group II, and 17 from group III. Eighty-two of the 86 patients from the first two groups underwent LDACs and 2 reacted. Subsequently, 22 (27.5%) of the 80 patients with negative LDACs were administered dual antiplatelet therapy with ASA after successful percutaneous coronary interventions, thus sparing desensitizations. The remaining 4 patients with CCS and all 17 patients from group III were successfully desensitized. In this pragmatic study, LDAC proved to be a safe and reliable diagnostic tool for identifying patients with histories of HRs to ASA or ≥ 2 different NSAIDs who can tolerate ASA at antiplatelet doses. Routine LDAC is advisable in all patients at high risk for ASCVD or with CCS who report HRs to ASA or ≥ 2 NSAIDs. ASA desensitization remains a safe and effective option in patients with ACS. Study flow-chart. ASCVD atherosclerotic cardiovascular disease; CCS chronic coronary syndrome; ACS acute coronary syndrome; ASA acetylsalicylic acid; DAPT dual antiplatelet therapy; PCI percutaneous coronary intervention; NSAIDs nonsteroidal anti-inflammatory drugs; NERD NSAID-exacerbated respiratory disease; NECD NSAID-exacerbated cutaneous disease; NIUAA NSAID-induced urticaria-angioedema or anaphylaxis; SNIUAA single NSAID-induced urticaria-angioedema or anaphylaxis; SNIDHR single NSAID-induced delayed hypersensitivity reaction.

Hepatic Steatosis in Patients with Celiac Disease: The Role of Packaged Gluten-Free Foods.

Background: An increased risk of nonalcoholic fatty liver disease (NAFLD) in patients with celiac disease (CD) adhering to a gluten-free diet (GFD) was recently reported. The nutritional composition of packaged gluten-free foods (PGFF) has been proposed as a possible cause. This hypothesis has not been investigated further, since a systematic structural nutritional interview for all patients would be problematic in clinical practice. Methods: We administered a simple questionnaire based on a Recency, Frequency, and Monetary value (RFM) analysis (a cornerstone of direct marketing segmentation) to consecutive CD patients on a GFD for >6 months and verified its association with NAFLD. Subgroup analyses were performed to understand whether specific patterns of PGFF consumption were significantly associated with NAFLD. Results: Amongst 147 patients (female 82%, median age 42 years), 45 (30.6%) had NAFLD. Total RFM score (adjusted odds ratio = 1.223, 95% CI: 1.059−1.413, p = 0.006), body mass index, and total cholesterol and triglycerides were independently related to NAFLD, and "Bread and bakery" (p = 0.002), "salty convenience" (p = 0.005), and "sweet convenience" (p = 0.049) products were significantly related with NAFLD. Also, questions about the number of purchased PGFF in the last month (monetary value) and different categories of PGFF consumed in the last week (recency) were particularly able to identify NAFLD patients. Conclusions: The specific GFD dietary habits of CD patients were correlated with the degree of risk of NAFLD. Information was obtained through a questionnaire which could be used in clinical practice to favor a patient-tailored approach and in future studies to verify the reproducibility of our results in different geographical areas.

Risk of Drop-Out from Follow-Up Evaluations for Celiac Disease: Is It Similar for All Patients?

Background: Celiac disease (CD) follow-up is a relatively underevaluated topic. However, correct adherence to follow-up procedures is central to the early recognition of complicated CD and other conditions typically associated with CD. Establishing whether patients at increased risk of complications follow clinicians' recommendations has multiple repercussions. Methods: We retrospectively analyzed the records of patients consecutively diagnosed with CD in our outpatient clinic between January 2004 and October 2017 to investigate the factors associated with drop-out from follow-up procedures. Results: Among the 578 patients analyzed, 40 (6.9%) dropped out during the first six months and 272 (50.6%) during the observation period. The median time to drop-out was 7.4 years (95% confidence interval: 6.8−8.0). No factors were associated with early drop-out. Instead, age at diagnosis >40 years (40−59 years, p < 0.001; ≥60 years, p = 0.048) and classical clinical presentation (p = 0.016) were significantly associated with a lower risk of later drop-out. Conclusions: Patients at increased risk of complicated CD are more compliant with follow-up procedures than patients at lower risk, despite being prescribed the same controls. These results indirectly support the hypothesis of tailored follow-up strategies, differentiated according to the risk of complications.

Current guidelines for the management of celiac disease: A systematic review with comparative analysis.

BACKGROUND: Wheat and other gluten-containing grains are widely consumed, providing approximately 50% of the caloric intake in both industrialised and developing countries. The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence. This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media. However, in recent years, the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease (CD) from obscurity to global prominence. These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD. Different scientific societies, mainly from Europe and America, have proposed guidelines based on CD's most recent evidence. AIM: To identify the most recent scientific guidelines on CD, aiming to find and critically analyse the main differences. METHODS: We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language. PubMed was lastly accessed on 1 March 2021. RESULTS: We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions. Differences were noted in the possibility of a no-biopsy diagnosis, HLA testing, follow-up protocols, and procedures. CONCLUSION: We found a relatively high concordance between the guidelines for CD. Important modifications have occurred in the last years, especially about the possibility of a no-biopsy diagnosis in children. Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.

Efficacy of a short course of lung ultrasound for primary care physicians in the assessment of COVID-19-positive patients.

INTRODUCTION: Lung ultrasound (LUS) has become the first diagnostic imaging approach to assess lung involvement in COVID-19. While LUS proved to be safe, reliable, and accurate, not many primary care physicians (PCP) are capable to employ this instrument in the first evaluation of COVID-19 outpatients. The aim of this study was to determine the effectiveness of a brief training program in LUS for PCP. METHODS: Italian local authorities promoted a training program in LUS for PCP engaged in COVID-19 outpatients' evaluation. The course took place in a COVID-19 unit and included a hands-on practice on real COVID-19 patients. We conducted a qualitative and quantitative analysis of the results of the training program. RESULTS: A total of 32 PCP completed the training. About 100% of participants reported an increase in competence and confidence in the use of LUS after the training. Self-reported confidence in detecting major COVID-19 LUS abnormalities was high (B-lines 8/10, pleural abnormalities 6.5/10). B-lines were accurately identified with a reliability of 81%, with a sensitivity of 96%, and a negative predictive value of 98%. Trainees were some less accurate in detecting pleural abnormalities (reliability 63%) but with a high specificity (99%). CONCLUSIONS: This study showed that a short training program, but comprising a hands-on practice, is capable to bring even almost novices to achieve a high overall accuracy and reliability in detecting lung involvement in COVID-19. This may result in a significant improvement of the performances of PCP involved in the first evaluation of COVID-19 cases in primary care facilities.

Tocilizumab: From Rheumatic Diseases to COVID-19.

Tocilizumab is a humanised interleukin-6 receptor-inhibiting monoclonal antibody that is currently approved for the treatment of rheumatoid arthritis and other immune-related conditions. Recently, tocilizumab has been investigated as a possible treatment for severe coronavirus-induced disease 2019 (COVID-19). Despite the lack of direct antiviral effects, tocilizumab could reduce the immune-induced organ damage caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) infection. Until recently, most reports on tocilizumab for COVID-19 included a limited number of patients, preventing an overall evaluation of its efficacy and safety for this specific condition. Therefore, we reviewed the literature regarding the physiopathological rationale of tocilizumab for COVID-19 and its outcomes. We searched the MEDLINE database with the string "(SARS-CoV-2 OR coronavirus OR COVID-19 OR MERS- cov OR SARS-cov) AND (IL-6 OR interleukin 6 OR tocilizumab)". While the scientific rationale supporting tocilizumab for COVID-19 is solid, the evidence regarding the outcomes remains controversial. Available data and results from ongoing trials will provide useful information in the event of new COVID-19 outbreaks or future pandemics from different coronaviruses.

Lung Ultrasound Is Often, but Not Always, Normal in Healthy Subjects: Considerations for COVID-19 Pandemic.

BACKGROUND: Lung ultrasound (LU) is becoming an increasingly important diagnostic tool in detecting lung involvement in Corona Virus Disease 2019 (COVID-19). The aim of this study was to ascertain the likelihood of finding LU abnormalities; mimicking lung involvement; in COVID-19 negative healthy individuals. METHODS: We performed LU on 265 healthcare workers; not presenting COVID-19 major symptoms and in good health; during the course of a serological screening program for COVID-19 in our General Hospital. LU results were reported as total Lung Ultrasound Score (LUS) using a 12-zone method of reporting. RESULTS: 250/265 subjects were included in the COVID-19 negative group. LU was not completely normal (LUS ≠ 0) in 65/250 COVID-19 negative subjects (26%) and in 12/15 (80%) poorly symptomatic COVID-19 positive subjects; with a multifocal pattern in 12.7% vs. 66.7% of cases respectively. Age and COVID-19 positivity were independent predictors of total LUS. A total LUS ≥ 2 had a sensitivity of 66.67% and a specificity of 85.60% in detecting COVID-19 positivity. CONCLUSIONS: A slightly altered LU can be quite frequent in healthy COVID-19 negative subjects. LU can have a role in confirming but not screening COVID-19 poorly symptomatic cases.

The Relationship Between Child Mortality Rates and Prevalence of Celiac Disease.

OBJECTIVES: Some evidence suggests that prevalence of celiac disease in the general population is increasing over time. Because the prognosis of celiac disease was a dismal one before discovering the role of gluten, our aim was to investigate a possible relationship between children under-5 mortality rates and prevalence rates of celiac disease. METHODS: Thanks to a literature review, we found 27 studies performed in 17 different countries describing the prevalence of celiac disease in schoolchildren; between 1995 and 2011, 4 studies were performed in Italy. A meta-analysis of prevalence rates was performed. Prevalence was compared between specific country under-5 mortality groups, publication year, and age. RESULTS: In the last decades, under-5 mortality rates have been decreasing all over the world. This reduction is paralleled by an increase of the prevalence of celiac disease. The Spearman correlation coefficient was -63%, 95% confidence interval -82% to -33% (P < 0.001). So, the higher the mortality rate, the lower the prevalence of CD. This finding is confirmed by the meta-analysis of the 4 studies conducted in Italy over time. CONCLUSIONS: The under-5 mortality rate seems to influence the prevalence of celiac disease in the general population. In the near future, the number of patients with celiac disease will increase, thanks to the better environmental conditions that nowadays allow a better survival of children with celiac disease.