Unraveling the Immunopathological Landscape of Celiac Disease: A Comprehensive Review.

Celiac disease (CD) presents a complex interplay of both innate and adaptive immune responses that drive a variety of pathological manifestations. Recent studies highlight the role of immune-mediated pathogenesis, pinpointing the involvement of antibodies against tissue transglutaminases (TG2, TG3, TG6), specific HLA molecules (DQ2/8), and the regulatory role of interleukin-15, among other cellular and molecular pathways. These aspects illuminate the systemic nature of CD, reflecting its wide-reaching impact that extends beyond gastrointestinal symptoms to affect other physiological systems and giving rise to a range of pathological landscapes, including refractory CD (RCD) and, in severe cases, enteropathy-associated T cell lymphoma. The existing primary therapeutic strategy, a gluten-free diet (GFD), poses significant challenges, such as low adherence rates, necessitating alternative treatments. Emerging therapies target various stages of the disease pathology, from preventing immunogenic gluten peptide absorption to enhancing intestinal epithelial integrity and modulating the immune response, heralding potential breakthroughs in CD management. As the understanding of CD deepens, novel therapeutic avenues are emerging, paving the way for more effective and sophisticated treatment strategies with the aim of enhancing the quality of life of CD patients. This review aims to delineate the immunopathology of CD and exploring its implications on other systems, its complications and the development of novel treatments.

Ankylosing Spondylitis and the Risk of Hip Fractures: a Matched Cohort Study.

BACKGROUNDS: It has been hypothesized that ankylosing spondylitis is associated with an increased risk of incident hip fractures due to osteoporosis and risk of falls but the supporting evidence is limited and mixed. OBJECTIVES: To assess the risk of hip fractures in a large cohort of patients with ankylosing spondylitis compared to a matched cohort. DESIGN: A retrospective cohort study. SUBJECTS: Men and women diagnosed with ankylosing spondylitis from 1 January 2002 to 31 December 2018. Matching in a 5:1 ratio was based on age and sex. Follow-up ended on 23 June 2019. MAIN MEASURES: Cox regression models adjusting for confounders defined in a causal inference framework were used to determine the hazard ratio for hip fractures. KEY RESULT: The final cohorts included 5,909 ankylosing spondylitis patients and 28,671 matched patients. The ankylosing spondylitis cohort had a mean age of 49 (17) years and was composed of 3,762 (64%) men, 3,638 (62%) patients born in Israel, and 1,532 (26%) patients of low residential socioeconomic status. During 45,388 and 224,192 cumulative person-years of follow-up, the ankylosing spondylitis and matched cohorts had 2.47 and 1.63 cases of hip fractures per 1,000 person-years, respectively. Ankylosing spondylitis patients also developed hip fractures earlier (74 [13] vs. 79 [10] years, p = 0.002). Ankylosing spondylitis was associated with hip fractures in the unadjusted (HR = 1.52, 95% CI [1.23-1.88]) and adjusted (HR = 1.56, 95% CI [1.27-1.93]) models. The association was evident in men (HR = 1.65, 95% CI [1.25-2.18]) and women (HR = 1.48, 95% CI [1.07-2.05]). CONCLUSION: This study found that ankylosing spondylitis patients developed hip fractures earlier and more often compared to a matched cohort. This study suggests that ankylosing spondylitis patients might benefit from more proactive screening, mitigation, and prevention of risk factors for hip fractures.

Dysautonomia Following Tetanus, Diphtheria, and Pertussis Vaccine (Tdap): The First Case of Extreme Cachexia Caused by Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA Syndrome) in a Human.

Autoimmune/inflammatory Syndrome Induced by Adjuvants (ASIA; Shoenfeld's syndrome) comprehends a group of autoimmune conditions that flourish in genetically predisposed individuals, following an external stimulus by the so-called adjuvants. Many adjuvants were described, such as vaccines, aluminum and other metals, silicone, tattoos, among others. Those conditions entail defined diseases, such as sarcoidosis and Sjogren's syndrome, and generalized complex symptoms, for example, fatigue, sleep disturbance, orthostatic intolerance, and other dysautonomic manifestations. Those complaints were previously associated with autoantibodies against nervous system autonomic receptors, especially antibeta 1 adrenergic receptor antibodies, suggesting the autoimmune component of the condition. Here we report on a case of an 18-year-old woman who presented with extreme cachexia due to severe dysautonomia caused by the ASIA syndrome induced by the tetanus, diphtheria, and pertussis vaccine (Tdap).

The Smell in COVID-19 Infection: Diagnostic Opportunities.

BACKGROUND: There is a high prevalence of olfaction changes, especially in the early presentation, in COVID-19 patients. The mechanisms through which the virus leads to anosmia/hyposmia is still not fully understood. However, olfaction changes could be used as an indication for testing or quarantine. Screening for infections and other diseases by recognizing volatile organic compounds (VOCs) has been previously conducted. Hence, if the coronavirus infection also results in VOCs excretion, physicians could "smell" the virus by using electronic noses. We conducted a literature review on olfaction changes and the COVID-19. Our results suggest that these changes could be used an indication for early testing, even as an isolated symptom. We propose that the electronic nose be used as a future screening tool, especially in agglomeration spaces such as airports, for screening for the COVID-19 infection.

Seasonality and autoimmune diseases: The contribution of the four seasons to the mosaic of autoimmunity.

Autoimmune diseases (ADs) are a heterogeneous groups of diseases that occur as a results of loss of tolerance to self antigens. While the etiopathogeneis remain obscure, different environmental factors were suggested to have a role in the development of autoimmunity, including infections, low vitamin D levels, UV radiation, and melatonin. Interestingly, such factors possess seasonal variation patterns that could influence disease development, severity and progression. Vitamin D levels which reach a nadir during late winter and early spring is correlated with increased disease activity, clinical severity as well as relapse rates in several disease entities including multiple sclerosis (MS), non-cutaneous flares of systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis (RA). Additionally, immunomodulatory actions of melatonin secretion ameliorate the severity of several ADs including MS and SLE. Melatonin levels are lowest during spring, a finding that correlates with the highest exacerbation rates of MS. Further, melatonin is postulated to be involved in the etiopathogenesis of inflammatory bowel diseases (IBD) through it influence on adhesion molecule and therefore transcription factor expression. Moreover, infections can mount to ADs through pro-inflammatory cytokine release and human antigen mimicry. Seasonal patterns of infectious diseases are correlated with the onset and exacerbation of ADs. During the winter, increased incidence of Epstein-Barr virus (EBV) infectious are associated with MS and SLE flares/onset respectively. In addition, higher Rotavirus infections during the winter precedes type 1 diabetes mellitus onset (T1DM). Moreover, Escherichia coli (E. coli) infection prior to primary biliary cirrhosis (PBC) and T1DM disease onset subsequent to Coxachievirus infections are seen to occur during late summer, a finding that correlate with infectious agents' pattern of seasonality. In this review, the effects of seasonality on the onset, relapses and activity of various ADs were discussed. Consideration of seasonal variation patterns of ADs can possibly provide clues to diseases pathogenesis and lead to development of new approaches in treatment and preventative care.

Pronounced benefits of JAK inhibition with baricitinib in COVID-19 pneumonia in obese but not lean subjects.

OBJECTIVE: Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19. METHODS: A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25-30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years. RESULTS: In the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05). CONCLUSION: The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

Unraveling the connection: Uveitis prevalence and risk factors in psoriasis patients - a population-based study.

The association between uveitis and spondyloarthropathy (SpA)-related conditions is well-established. However, evidence describing the link between uveitis and psoriasis, and psoriasis without concomitant SpA-related conditions is scarce and conflicting. This large-scale population-based study sought to describe the prevalence and features of uveitis among psoriasis patients in Israel as well as investigating the risk for uveitis in different subgroups of psoriasis patients compared to the general population. We conducted a retrospective study utilizing the electronic database of the Meuhedet Health Maintenance Organization. The study included all patients diagnosed with psoriasis between 2000 and 2020, each patient was matched with four controls based on age, sex, place of residence, and index date. Logistic regression models were employed to assess the association between psoriasis and uveitis while adjusting for the presence of SpA-related conditions. A total of 61 003 psoriasis patients and 244 012 matched controls were included. The prevalence of uveitis was 1.3% versus 1.1% respectively (OR 1.12; 95% CI 1.10-1.30; p < 0.001). When adjusting to psoriasis severity, concurrent SpA, and psoriasis treatment no significant association was found. The rates of uveitis among psoriasis patients with concurrent SpA-related conditions was 3.2% compared to 1.4% in controls without psoriasis or SpA (OR 2.38; 95% CI 2.00-2.83; p < 0.001), while in psoriasis patients without SpA, the rate of uveitis was 1.0% and was similar to controls. Although crude rates of uveitis were higher in patients with severe psoriasis compared to mild psoriasis (2.1% vs. 1.1%), after adjustment, no significant association compared to controls was found in either group. Our findings suggest that the positive association between psoriasis and uveitis is primarily mediated by the coexistence of other SpA-related conditions. These findings imply the presence of a shared pathogenetic mechanism and set the direction for a phenotypic-targeted screening strategy.

Ecogastroenterology: cultivating sustainable clinical excellence in an environmentally conscious landscape.

Gastrointestinal practices, especially endoscopy, have a substantial environmental impact, marked by notable greenhouse gas emissions and waste generation. As the world struggles with climate change, there emerges a pressing need to re-evaluate and reform the environmental footprint within gastrointestinal medicine. The challenge lies in finding a harmonious balance between ensuring clinical effectiveness and upholding environmental responsibility. This task involves recognising that the most significant reduction in the carbon footprint of endoscopy is achieved by avoiding unnecessary procedures; addressing the use of single-use endoscopes and accessories; and extending beyond the procedural suites to include clinics, virtual care, and conferences, among other aspects of gastrointestinal practice. The emerging digital realm in health care is crucial, given the potential environmental advantages of virtual gastroenterological care. Through an in-depth analysis, this review presents a path towards sustainable gastrointestinal practices, emphasising integrated strategies that prioritise both patient care and environmental stewardship.

Poly-Refractory Rheumatoid Arthritis: An Uncommon Subset of Difficult to Treat Disease With Distinct Inflammatory and Noninflammatory Phenotypes.

OBJECTIVE: To investigate the prevalence of poly-refractory rheumatoid arthritis (RA) defined as failure of all biological (b)/targeted synthetic (ts)-disease-modifying drugs (DMARDs). To further investigate whether patients with persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA), determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult-to-treat RA (D2T-RA) and poly-refractory RA groups. METHODS: A cross-sectional study of 1,591 patients with RA on b/tsDMARDs that evaluated D2T-RA criteria and subclassified as poly-refractory if inefficacy/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in one or more swollen joint and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly-refractory, PIRRA, and NIRRA phenotypes. RESULTS: 122 of 1,591 were excluded due to missing data. 247 of 1,469 (16.8%) had D2T-RA and only 40 of 1,469 (2.7%) poly-refractory RA. This latter group had higher disease activity score 28 C-reactive protein (CRP) (median 5.4 vs 5.02, P < 0.05), CRP levels (median 13 vs 5 mg/l, P < 0.01), and smoking (ever) rates (20% vs 4%, P < 0.01) compared with other D2T patients. Smoking was associated with poly-refractory RA (odds ratio 5.067, 95% CI 1.774-14.472, P = 0.002). Of 107 patients with D2T-RA with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. Patients with NIRRA had elevated body mass index (median 30 vs 26, P < 0.001) and higher fibromyalgia prevalence (15% vs 3%, P < 0.05), lower swollen joint count (median: 2 vs 5, P < 0.001), and lower CRP levels (5 vs 10, P < 0.01). CONCLUSION: Only 2.7% of D2T-RA failed all classes of b/tsDMARDs. Among D2T-RA, less than 60% had objective signs of inflammation, representing a target for innovative strategies.

MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

Sleep, function and HIV: a multi-method assessment.

Amongst HIV+ individuals, sleep complaints have been recognized as common and debilitating; but have rarely been formally assessed or compared to controls using validated sleep tools. In this study we conducted structured interview for sleep disorders, polysomnography, 2-week home (ambulatory) monitoring and validated sleep/functional questionnaires. 56 % (14/25) of HIV+ participants and 0 % (0/19) of controls fulfilled the diagnostic criteria for insomnia. Insomnia severity scores were correlated with fatigue and anxiety symptoms. Sleep latency on 2-week actigraphy was significantly longer (P = 0.027) for HIV+ participants and associated with lower MOS-HIV scores. Sleep quality was significantly reduced in HIV+ participants based on validated questionnaires of overall sleep quality (P = 0.0017) and insomnia related symptoms (P < 0.001) even after adjusting for education and affective symptoms. HIV+ individuals are suffering with under-diagnosed sleep disorders that are negatively impacting quality of life and functional capabilities. Further studies aimed at improving recognition of sleep disorders and implementation of efficacious medical and behavioral treatment could improve functioning and disease management.

Predominant ligament-centric soft-tissue involvement differentiates axial psoriatic arthritis from ankylosing spondylitis.

Since the original description of spondyloarthritis 50 years ago, results have demonstrated similarities and differences between ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA). HLA-B27 gene carriage in axial inflammation is linked to peri-fibrocartilaginous sacroiliac joint osteitis, as well as to spinal peri-entheseal osteitis, which is often extensive and which provides a crucial anatomical and immunological differentiation between the AS and PsA phenotypes. Specifically, HLA-B27-related diffuse bone marrow oedema (histologically an osteitis) and bone marrow fatty corners detected via magnetic resonance imaging, as well as radiographic changes such as sacroiliitis, vertebral squaring, corner erosions and Romanus lesions, all indicate initial bone phenotypes in HLA-B27+ axial disease. However, in much of PsA with axial involvement, enthesitis primarily manifests in ligamentous soft tissue as 'ligamentitis', with characteristic lesions that include para-syndesmophytes and sacroiliac joint bony sparing. Like axial PsA, diffuse idiopathic skeletal hyperostosis phenotypes, which can be indistinguishable from PsA, exhibit a thoracic and cervical spinal ligamentous soft-tissue tropism, clinically manifesting as syndesmophytosis that is soft-tissue-centric, including paravertebral soft-tissue ossification and sacroiliac soft-ligamentous ossification instead of joint-cavity fusion. The enthesis bone and soft tissues have radically different immune cell and stromal compositions, which probably underpins differential responses to immunomodulatory therapy, especially IL-23 inhibition.

Autoimmunity, COVID-19 Omicron Variant, and Olfactory Dysfunction: A Literature Review.

Smelling is a critical sense utilized daily. Consequently, smelling impairment or anosmia may lead to a reduction in life quality. Systemic diseases and particular autoimmune conditions can impair olfactory function; among others are Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis. Interactions between the olfactory process and the immune systems cause this phenomenon. Alongside autoimmune conditions, in the recent COVID-19 pandemic, anosmia was also described as a prevalent infection symptom. Nevertheless, the occurrence of anosmia is significantly less common in Omicron-infected patients. Several theories have been proposed to explain this phenomenon. One possibility is that the Omicron variant preferentially enters host cells via endocytosis, rather than plasma cell membrane fusion. This endosomal pathway is less dependent on the activation of Transmembrane serine protease 2 (TMPRSS2), expressed at the olfactory epithelium. As a result, the Omicron variant may have reduced efficiency in penetrating the olfactory epithelium, leading to a lower prevalence of anosmia. Furthermore, olfactory changes are known to be associated with inflammatory conditions. The Omicron variant elicits a less robust autoimmune and inflammatory response, believed to reduce the probability of anosmia. This review elaborates on the commonalities and differences in autoimmune and COVID-19 omicron-associated anosmia.

Susac syndrome following COVID-19 vaccination: a case-based review.

COVID-19 vaccine circulation approval was a turning point for the coronavirus pandemic. The current approved COVID-19 vaccines, including messenger ribonucleic acid (mRNA)-based and adenovirus vector-based vaccines, were shown to significantly reduce the disease mortality and severity, and its adverse reactions are mainly mild ones. However, few cases of autoimmune conditions, both flare-ups and new-onset, were described in association with these vaccines. Susac vasculitis (SaS) is a rare autoimmune disease characterized by the clinical triad of encephalopathy, visual disturbances, and sensorineural hearing loss. Its pathogenesis is still not fully understood but is believed to be related to autoimmune processes, including autoantibodies to anti-endothelial cells and cellular immune processes that lead to microvascular damage and, consequently, micro-occlusions of the cerebral, inner ear, and retinal vessels. It has been previously described following vaccination and, most recently, few cases following coronavirus vaccines. We here describe a case of a previously healthy 49-year-old man diagnosed with SaS 5 days following the first dose of the BNT162b2 COVID-19 vaccine.

Deep Learning in Coeliac Disease: A Systematic Review on Novel Diagnostic Approaches to Disease Diagnosis.

BACKGROUND: Coeliac disease affects approximately 1% of the global population with the diagnosis often relying on invasive and time-demanding methods. Deep learning, a powerful tool in medical science, shows potential for non-invasive, accurate coeliac disease diagnosis, though challenges remain. OBJECTIVE: This systematic review aimed to evaluate the current state of deep-learning applications in coeliac disease diagnosis and identify potential areas for future research that could enhance diagnostic accuracy, sensitivity, and specificity. METHODS: A systematic review was conducted using the following databases: PubMed, Embase, Web of Science, and Scopus. PRISMA guidelines were applied. Two independent reviewers identified research articles using deep learning for coeliac disease diagnosis and severity assessment. Only original research articles with performance metrics data were included. The quality of the diagnostic accuracy studies was assessed using the QUADAS-2 tool, categorizing studies based on risk of bias and concerns about applicability. Due to heterogeneity, a narrative synthesis was conducted to describe the applications and efficacy of the deep-learning techniques (DLT) in coeliac disease diagnosis. RESULTS: The initial search across four databases yielded 417 studies with 195 being removed due to duplicity. Finally, eight studies were found to be suitable for inclusion after rigorous evaluation. They were all published between 2017 and 2023 and focused on using DLT for coeliac disease diagnosis or assessing disease severity. Different deep-learning architectures were applied. Accuracy levels ranged from 84% to 95.94% with the GoogLeNet model achieving 100% sensitivity and specificity for video capsule endoscopy images. CONCLUSIONS: DLT hold substantial potential in coeliac disease diagnosis. They offer improved accuracy and the prospect of mitigating clinician bias. However, key challenges persist, notably the requirement for more extensive and diverse datasets, especially to detect milder forms of coeliac disease. These methods are in their nascent stages, underscoring the need of integrating multiple data sources to achieve comprehensive coeliac disease diagnosis.

Autoimmune disorders caused by intravesical bacillus Calmette-Guerine treatment: A systematic review.

Intravesical bacillus Calmette-Guérin (BCG) is a common and highly effective treatment for non-muscle invasive urothelial carcinoma of the urinary bladder. BCG may cause an autoimmune reaction in some patients. One hundred and fifty-eight papers were analyzed, for a total of hundred and thirty patients with reactive arthritis, sixty patients with ocular manifestations and eighteen patients with other rheumatologic diseases. Among 130 subjects with reactive arthritis, an autoimmune symptom occurred after 5 instillations of intravesical BCG (IQR 4-6), which represents 5 weeks in most cases. Fifty-one patients had concurrent ocular involvement. The resolution of symptoms was achieved in a median of 32.5 days (IQR 14-90). Forty-two men and twenty women had ocular manifestations, most commonly conjunctivitis. Patients with HLA-B27 typing had earlier presentation of ocular symptoms related to the number of instillations (4.5 vs 6 [p < 0.05]. Resolution of symptoms was achieved at a median of 128 days (IQR 21-150). Among patients treated with NSAIDs (either with or without steroids), the duration of the disease was significantly shorter in both the articular and the ocular groups (28 vs. 120 [p < 0.05] and 30 vs.105 [p < 0.05], respectively). Other autoimmune manifestations included general autoimmune diseases, such as vasculitis, psoriasis and myasthenia gravis.