Infections and Autoimmunity-The Immune System and Vitamin D: A Systematic Review.

Both 25-autoimmunity and(25(OH)D: calcifediol) and its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D: calcitriol), play critical roles in protecting humans from invasive pathogens, reducing risks of autoimmunity, and maintaining health. Conversely, low 25(OH)D status increases susceptibility to infections and developing autoimmunity. This systematic review examines vitamin D's mechanisms and effects on enhancing innate and acquired immunity against microbes and preventing autoimmunity. The study evaluated the quality of evidence regarding biology, physiology, and aspects of human health on vitamin D related to infections and autoimmunity in peer-reviewed journal articles published in English. The search and analyses followed PRISMA guidelines. Data strongly suggested that maintaining serum 25(OH)D concentrations of more than 50 ng/mL is associated with significant risk reduction from viral and bacterial infections, sepsis, and autoimmunity. Most adequately powered, well-designed, randomized controlled trials with sufficient duration supported substantial benefits of vitamin D. Virtually all studies that failed to conclude benefits or were ambiguous had major study design errors. Treatment of vitamin D deficiency costs less than 0.01% of the cost of investigation of worsening comorbidities associated with hypovitaminosis D. Despite cost-benefits, the prevalence of vitamin D deficiency remains high worldwide. This was clear among those who died from COVID-19 in 2020/21-most had severe vitamin D deficiency. Yet, the lack of direction from health agencies and insurance companies on using vitamin D as an adjunct therapy is astonishing. Data confirmed that keeping an individual's serum 25(OH)D concentrations above 50 ng/mL (125 nmol/L) (and above 40 ng/mL in the population) reduces risks from community outbreaks, sepsis, and autoimmune disorders. Maintaining such concentrations in 97.5% of people is achievable through daily safe sun exposure (except in countries far from the equator during winter) or taking between 5000 and 8000 IU vitamin D supplements daily (average dose, for non-obese adults, ~70 to 90 IU/kg body weight). Those with gastrointestinal malabsorption, obesity, or on medications that increase the catabolism of vitamin D and a few other specific disorders require much higher intake. This systematic review evaluates non-classical actions of vitamin D, with particular emphasis on infection and autoimmunity related to the immune system.

Coronary Artery Ectasia as an Autoimmune Disease Paradigm in a Cross-Sectional Case-Control Study.

Coronary artery ectasia (CAE) is defined as local or generalized aneurysmal dilatation of the coronary arteries. CAE likely represents an exaggerated form of excessive vascular wall remodeling in different clinical settings such as atherosclerosis, vasculitides, connective tissue disorders, hereditary collagen defects, bacterial infections, and congenital malformations. In the present case-control study, we investigated whether the incidental finding of CAE in patients who undergo coronary angiography is associated with presence of autoimmune reactivity. From 2019 to 2022, we identified all consecutive patients with CAE (n = 319) on elective or emergency coronary angiography (n = 7,458). We furthermore included 90 patients with nonectatic coronary arteries as a control group. Antinuclear antibody (ANA) titer was measured in both groups using the indirect immunofluorescence method from peripheral blood samples. The prevalence of CAE in our study cohort was 4.3%. Among patients with CAE (n = 319), presence of positive Antinuclear antibody (ANA) titer was identified in 128 patients (40%). Only 18 patients (20%) from the control group had positive ANA titer. There was a statistically significant greater percentage of patients with positive ANA titer among patients with CAE than among controls (chi-square = 12.39; p <0.001), with an odds ratio of 2.68. Among patients with CAE, there is an increased prevalence of positive ANA titer, suggesting an underlying autoimmune disease. Screening for autoimmune reactivity could be a reasonable diagnostic strategy in patients who undergo coronary angiography with an incidental finding of coronary ectasia because the number needed to screen for positive ANA titer in this subgroup of patients is only 5.

Associations between vitamin D and autoimmune diseases: Mendelian randomization analysis.

OBJECTIVE: The VITAL trial of vitamin D supplementation suggested a possible protective effect for autoimmune diseases but uncertainties remain. We investigated potential causal effects of vitamin D on composite and individual autoimmune diseases using Mendelian randomization. METHODS: We used data from 332,984 participants of the UK Biobank of whom 23,089 had at least one autoimmune disease defined using ICD code and/or self-report. Diseases were further considered in mechanistic subgroups driven by "autoimmunity" (n = 12,774) or "autoinflammation" (n = 11,164), then individually. We selected variants within gene regions implicated in vitamin D biology to generate a weighted genetic score. We performed population-wide analysis using the ratio method, then examined non-linear effects across five quantiles based on 25-hydroxycholecalciferol levels. RESULTS: Genetically-predicted vitamin D was associated with lower risk of diseases in the autoinflammation group (OR 0.95 per 10 ng/ml increase in 25-hydroxycholecalciferol; 95%CI 0.91-0.99; p = 0.03) but not the autoimmunity group (OR 0.99; 95%CI 0.95-1.03; p = 0.64) or combined. When considering individual diseases, genetically-predicted vitamin D was associated with lower risk of psoriasis (OR 0.91; 95%CI 0.85-0.97; p = 0.005), the most common disease in the autoinflammation group, and suggestively with systemic lupus erythematosus (OR 0.84; 95%CI 0.69-1.02; p = 0.08); results were replicated using data from independent studies. We found no evidence for a plausible non-linear relationship between vitamin D and any outcome. CONCLUSIONS: We found genetic evidence to support a causal link between 25-hydroxycholecalciferol concentrations and psoriasis and systemic lupus erythematosus. These results have implications for potential disease prevention strategies, and the interpretation and design of vitamin D supplementation trials.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): past, present, and future implications.

Adjuvants, as the name indicates, are adjoined material aimed to assist in functioning as when added to vaccines they are meant to boost the effect and strongly stimulate the immune system. The response of the immune system can be unpredictable, and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was developed to address possible adverse reactions of an autoimmune and inflammatory type that may be caused by adjuvants. While ASIA, as a syndrome, was coined and defined in 2011; reports describing patients with vague and nonspecific clinical symptoms following vaccinations appeared much earlier. In other words, ASIA came to define, arrange, and unite the variety of symptoms, related to autoimmunity, caused not by the vaccine itself, rather by the adjuvant part of the vaccine such as aluminum, among others. Accordingly, the introduction of ASIA enabled better understanding, proper diagnosis, and early treatment of the disorder. Furthermore, ASIA was shown to be associated with almost all body systems and various rheumatic and autoimmune diseases such as systemic lupus erythematosus, antiphospholipid syndrome, and systemic sclerosis. In addition, the correlation between COVID-19 and ASIA was noticed during the pandemic. In this review, we summarized the reported effects of adjuvants and medical literature before and after ASIA was defined, the several ways ASIA can manifest and impact different systems of the body, and the incidences of ASIA during the COVID-19 pandemic. It is important to clarify, that vaccines are among, if not the, most effective means of fighting infectious diseases however, we believe that vaccines manufacturing is not above criticism, particularly when it comes to added substances possessing a risk of side effects.

Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial.

OBJECTIVE: To investigate whether vitamin D and marine derived long chain omega 3 fatty acids reduce autoimmune disease risk. DESIGN: Vitamin D and omega 3 trial (VITAL), a nationwide, randomized, double blind, placebo controlled trial with a two-by-two factorial design. SETTING: Nationwide in the United States. PARTICIPANTS: 25 871 participants, consisting of 12 786 men ≥50 years and 13 085 women ≥55 years at enrollment. INTERVENTIONS: Vitamin D (2000 IU/day) or matched placebo, and omega 3 fatty acids (1000 mg/day) or matched placebo. Participants self-reported all incident autoimmune diseases from baseline to a median of 5.3 years of follow-up; these diseases were confirmed by extensive medical record review. Cox proportional hazard models were used to test the effects of vitamin D and omega 3 fatty acids on autoimmune disease incidence. MAIN OUTCOME MEASURES: The primary endpoint was all incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others. RESULTS: 25 871 participants were enrolled and followed for a median of 5.3 years. 18 046 self-identified as non-Hispanic white, 5106 as black, and 2152 as other racial and ethnic groups. The mean age was 67.1 years. For the vitamin D arm, 123 participants in the treatment group and 155 in the placebo group had a confirmed autoimmune disease (hazard ratio 0.78, 95% confidence interval 0.61 to 0.99, P=0.05). In the omega 3 fatty acids arm, 130 participants in the treatment group and 148 in the placebo group had a confirmed autoimmune disease (0.85, 0.67 to 1.08, P=0.19). Compared with the reference arm (vitamin D placebo and omega 3 fatty acid placebo; 88 with confirmed autoimmune disease), 63 participants who received vitamin D and omega 3 fatty acids (0.69, 0.49 to 0.96), 60 who received only vitamin D (0.68, 0.48 to 0.94), and 67 who received only omega 3 fatty acids (0.74, 0.54 to 1.03) had confirmed autoimmune disease. CONCLUSIONS: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo). STUDY REGISTRATION: ClinicalTrials.gov NCT01351805 and NCT01169259.

Vitamin D status in patients with autoimmune bullous dermatoses: a meta-analysis.

BACKGROUND: The association between autoimmune bullous dermatoses (AIBD) and serum vitamin D levels has been revealed by some studies, however, inconsistent. OBJECTIVES: We aimed to evaluate the difference in vitamin D status between AIBD patients and controls. METHODS: We searched the studies about the vitamin D status of AIBD patients in electronic databases published before January 2020. Mean difference (MD) and 95% confidence intervals (CI) of eligible studies were calculated in meta-analyses of 25(OH)D levels. Pooled odds ratio (OR) and 95%CI were used in analyses of the prevalence of hypovitaminosis D. Different subgroup analyses, sensitivity analyses and publication bias assessment were conducted. RESULTS: We included nine case-control studies in the meta-analysis. Vitamin D level was significantly lower in both pemphigus (MD: -7.02, 95%CI: -10.30 to -3.74) and bullous pemphigoid (BP) (MD: -6.37, 95%CI: -12.15 to -0.58) patients than that in controls. Active pemphigus patients were at higher risk of presenting hypovitaminosis D (OR: 6.95, 95%CI: 1.37-35.25). CONCLUSIONS: Abnormal vitamin D status are more common in AIBD patients than that in general population. Therefore, regular monitoring of vitamin D levels and vitamin D supplementation should be considered as part of the management strategy for AIBD.

Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome.

CONTEXT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized. OBJECTIVE: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients. METHODS: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated. RESULTS: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients). CONCLUSION: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Iodoprophylaxis and thyroid autoimmunity: an update.

Adequate iodine intake is necessary for normal thyroid function. Iodine deficiency is associated with serious complications, but also iodine excess can lead to thyroid dysfunction, and iodine supplementation aimed to prevent iodine deficiency disorders has been associated with development of thyroid autoimmunity. The epidemiology of thyroid diseases has undergone profound changes since the implementation of iodoprophylaxis, notably by means of iodine-enriched salt, specifically resulting in decreased prevalence of goiter and neonatal hypothyroidism, improved cognitive function development in infancy, and reduced incidence of more aggressive forms of thyroid cancer. The main question we address with this review is the clinical relevance of the possible effect on autoimmunity exerted by the use of iodine-enriched salt to correct iodine deficiency. In animal models, exogenous iodine is able to trigger or exacerbate thyroid autoimmunity, but it is still not clear whether the observed immunological changes are due to a direct effect of iodine on immune response, or whether they represent a secondary response to a toxic effect of iodine on thyroid tissue. Previous iodine status of a population seems to influence the functional thyroid response to increased iodine intake and possibly the development of thyroid autoimmunity. Moreover, the prevalence of thyroid antibodies, regarded as hallmark of autoimmune thyroid disease, varies between populations under the influence of genetic and environmental factors, and the presence of thyroid antibodies does not always coincide with the presence of thyroid disease or its future development. In addition, the incidence of autoimmune diseases shows a general increasing trend in the last decades. For all these reasons, available data are quite heterogeneous and difficult to analyze and compare. In conclusion, available data from long-term population surveys show that a higher than adequate population iodine intake due to a poorly controlled program of iodine prophylaxis could induce thyroid dysfunction, including thyroid autoimmunity mostly represented by euthyroid or subclinical hypothyroid autoimmune thyroiditis. Close monitoring iodine prophylaxis is therefore advised to ensure that effects of both iodine deficiency and iodine excess are avoided.

Antibodies Against Hypothalamus and Pituitary Gland in Childhood-Onset Brain Tumors and Pituitary Dysfunction.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

[Generalized granuloma annulare: A clinicopathological study]. / Granulome annulaire généralisé : étude anatomoclinique.

BACKGROUND: Granuloma annulare (GA) is a benign granulomatous skin disorder that is generalized (GGA) in 15 % of cases. Although many case reports describe a relationship between GGA and systemic diseases, few large series have been published, and their association is debated. We present herein a series of GGA in order to describe their clinical and histological features. PATIENTS AND METHODS: We included all biopsy-proven cases of GA presenting at the dermatopathology laboratory of Strasbourg where generalized (i.e. over 10 lesions). Clinical features were obtained from patients' medical files. RESULTS: We included 35 GGA, with a sex ratio of 0.5. The mean age was 54 years. Lesions were annular or non-annular in equal measure and were symptomatic in 25 % of cases. Most patients (77 %) had an associated disease, already known in 60 % of cases, including dyslipidemia (27 %), diabetes mellitus (20 %), immunosuppressive drugs (17 %), atopy (17 %), auto-immune disease (17 %), hematological disease (14 %), and cancer (9 %). Histological analysis revealed the predominant pattern to be interstitial (54 %) rather than palisading (20 %), having no correlation with clinical type. Eosinophils were frequent (46 %) in GA but were not correlated with systemic disease or drug taking. Among the 40 % of patients treated, 50 % had a successful outcome on topical corticosteroids, doxycycline, antimalarial drugs or phototherapy. DISCUSSION: GGA differs from localized GA, which is mostly associated with an already known systemic disease, whether metabolic, infectious or neoplastic, uncorrelated with clinical or histological features, and screening is necessary.

News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments.

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure. There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy. Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

Risk of major autoimmune diseases in female breast cancer patients: A nationwide, population-based cohort study.

BACKGROUND: Breast cancer is one of the most common malignancies among women. However, there remains no consensus in current literature on the incidence of autoimmune diseases among breast cancer patients. The purpose of this study was to evaluate the risks of major autoimmune diseases (MAD) including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and dermatomyositis (DMtis)/polymyositis (PM) in female breast cancer patients. METHODS: Using the Taiwanese National Health Insurance Research Database (NHIRD) records from 2003 to 2013, we identified newly-diagnosed female breast cancer patients and randomly selected females without breast cancer in the period 2007 to 2013 into a control group. We matched the two cohorts using a 1:4 ratio based on age, and the year of index date for comparison of the risk of major autoimmune diseases. We estimated and compared the relative risks of autoimmune diseases in female breast cancer patients and females without breast cancer. RESULTS: A total of 54,311 females with breast cancer and 217,244 matched females without breast cancer were included in this study. For SLE, the incidence rates were 2.3 (breast cancer group) vs. 10.0 (control group) per 100,000 women years; for RA rates were 19.3 (breast cancer group) vs. 42.7 (control group) per 100,000 women years; and for SS rates were 20.5 (breast cancer group) vs. 38.2 (control group) per 100,000 women years. After adjusting for potential confounders, the hazard ratios (95% confidence intervals) for female breast cancer patients vs. control group were 0.04 (0.01-0.24) for SLE; 0.03 (0.02-0.04) for RA; and 0.21 (0.09-0.48) for SS. CONCLUSION: Female breast cancer patients had lower risks of SLE, RA and SS when compared to female individuals without breast cancer. However, there was no significant difference in the risk of developing DMtis/PM between both groups.

Early Probiotic Supplementation and the Risk of Celiac Disease in Children at Genetic Risk.

Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk.

Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications.

Vitamin D plays a key role in in calcium homeostasis and, thus, provides an important support in bone growth by aiding in the mineralization of the collagen matrix. However, vitamin D performs various immunomodulatory, anti-inflammatory, antioxidant and anti-fibrotic actions. Autoimmune diseases result from an aberrant activation of the immune system, whereby the immune response is directed against harmless self-antigens. Does vitamin D play a role in the pathophysiology of autoimmune diseases? And, if so, what is its role? In the last decade, researchers' interest in vitamin D and its correlations with autoimmune diseases has considerably increased. We conducted a literature review, covering the period January 1, 2009 through March 30, 2019, in PubMed. We analyzed more than 130 studies in order to find a correlation between vitamin D levels and its effect upon several autoimmune diseases. The analysis demonstrated an inverse association between vitamin D and the development of several autoimmune diseases, such as SLE, thyrotoxicosis, type 1 DM, MS, iridocyclitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, seropositive RA, polymyalgia rheumatica. International multicenter study could allow us to confirm the data already present in the literature in the single clinical studies and to evaluate when to effectively supplement vitamin D in patients who do not take corticosteroids.

Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) demonstrates distinct autoimmune and autoinflammatory disease associations according to the adjuvant subtype: Insights from an analysis of 500 cases.

BACKGROUND: We investigated the pattern of reported immune diseases in the international ASIA syndrome registry. METHODS: Data from 500 subjects exposed to adjuvants from the ASIA syndrome international registry were analysed. RESULTS: The patient mean age was 43 ±â€¯17 years and 89% were female. Within the reported immune diseases, 69% were well-defined immune diseases (autoimmune, autoinflammation, and mixed pattern diseases). Among the well-defined immune diseases following the exposure to adjuvants, polygenic autoimmune diseases were significantly higher than autoinflammatory disorders (92.7% vs 5.8%, respectively, p < 0.001). Polygenic autoimmune diseases such as connective tissue diseases were significantly linked to the exposure to HBV vaccine (OR 3.15 [95%CI 1.08-9.23], p = 0.036). Polygenic autoinflammatory diseases were significantly associated with the exposure to influenza vaccination (OR 10.98 [95%CI 3.81-31.67], p < 0.0001). CONCLUSIONS: Immune conditions following vaccination are rare, and among these, polygenic autoimmune diseases represent the vast majority of the well-defined immune diseases reported under the umbrella ASIA syndrome. However, vaccines benefit outweighs their autoimmune side effects.

Low yield for routine laboratory checks in follow-up of coeliac disease.

AIM: To evaluate the yield of routine laboratory tests and Dual Energy X-ray Absorptiometry (DEXA) scans in coeliac disease. METHODS: A retrospective analysis of medical files of all followed-up patients with coeliac disease attending Rijnstate Hospital in 2016 was conducted with respect to blood tests of hemoglobin, vitamin B12, folate acid, iron status, calcium, vitamin D, glucose, thyroid function, DEXA-scans and related symptoms or signs of abnormalities. All patients had positive coeliac serology and/or biopsy-proven coeliac disease and attended regular visits after diagnosis. The chi-square test for trend was used for statistical analysis: a two-tailed probability of p < 0.05 was considered significant. RESULTS: We analyzed 250 patients with a median follow-up of 7.8 (1-22) years. At diagnosis, we found anemia in 24.4%, iron deficiency in 38%, folic acid deficiency in 22.6% and vitamin B12 deficiency in 15.9%. All deficiencies recovered within 1-2 years with or without supplements. Deficiencies or autoimmune diseases occurred in 50 patients (37 possibly coeliac-related) during follow-up. Twelve cases of coeliac-related deficiencies or autoimmune diseases occurred in patients with normal values at diagnosis of whom 10 were asymptomatic (incidence 10/1000 patient years). Osteoporosis and osteopenia were present in 23.3% and 35% at diagnosis. In most patients bone mineral density (BMD) improved or stabilized during follow up (p < 0.05), 8% deteriorated. CONCLUSIONS: The incidence of asymptomatic coeliac-related deficiencies or autoimmune diseases is low in patients with normal values at diagnosis. Therefore, routine laboratory screening is not necessary in this group: attending regular follow-up visits should be sufficient. DEXA scans are recommended.

Autoimmune diseases are associated with an increased risk of schizophrenia: A nationwide population-based cohort study.

OBJECTIVES: Studies have suggested a possible autoimmune contribution in a subset of patients with schizophrenia. The purpose of this study was to determine if a history of autoimmune diseases (AD) is associated with an increased risk of later onset of schizophrenia. METHODS: Taiwan's National Health Insurance Research Database was used to identify a total of 64,817 AD patients and an equal number of age-matched control patients. The incidence rates of schizophrenia with a maximum follow-up period of 10 years between patients with and without AD were compared using a Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence interval (95% CI). RESULTS: The main finding was the discovery of a higher incidence of subsequent schizophrenia in patients with AD (HR: 1.72, 95% CI: 1.23-2.4) after adjustment for other demographic characteristics. Specifically, the risk of schizophrenia was observed to be a significant increase in systemic lupus erythematosus (3.73, 2.07-6.72), rheumatoid arthritis (2.89, 1.97-4.23), dermatomyositis (5.85, 1.32-25.94) and autoimmune vasculitis (2.44, 1.17-5.06). Also, this study revealed some potential risk factors for developing schizophrenia, including younger age (less than or equal to 50 years) and some comorbidities (hypertension, chronic obstructive pulmonary disease, and alcohol use disorder). Conversely, this study found that steroid use was a potential protective factor for the development of schizophrenia. CONCLUSIONS: This study found that AD were associated with an increased risk of developing schizophrenia, suggesting that the abnormal autoimmune process was associated with an increase in the expression of psychiatric disturbances.

Diet during pregnancy and infancy and risk of allergic or autoimmune disease: A systematic review and meta-analysis.

BACKGROUND: There is uncertainty about the influence of diet during pregnancy and infancy on a child's immune development. We assessed whether variations in maternal or infant diet can influence risk of allergic or autoimmune disease. METHODS AND FINDINGS: Two authors selected studies, extracted data, and assessed risk of bias. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. We searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Web of Science, Central Register of Controlled Trials (CENTRAL), and Literatura Latino Americana em Ciências da Saúde (LILACS) between January 1946 and July 2013 for observational studies and until December 2017 for intervention studies that evaluated the relationship between diet during pregnancy, lactation, or the first year of life and future risk of allergic or autoimmune disease. We identified 260 original studies (964,143 participants) of milk feeding, including 1 intervention trial of breastfeeding promotion, and 173 original studies (542,672 participants) of other maternal or infant dietary exposures, including 80 trials of maternal (n = 26), infant (n = 32), or combined (n = 22) interventions. Risk of bias was high in 125 (48%) milk feeding studies and 44 (25%) studies of other dietary exposures. Evidence from 19 intervention trials suggests that oral supplementation with nonpathogenic micro-organisms (probiotics) during late pregnancy and lactation may reduce risk of eczema (Risk Ratio [RR] 0.78; 95% CI 0.68-0.90; I2 = 61%; Absolute Risk Reduction 44 cases per 1,000; 95% CI 20-64), and 6 trials suggest that fish oil supplementation during pregnancy and lactation may reduce risk of allergic sensitisation to egg (RR 0.69, 95% CI 0.53-0.90; I2 = 15%; Absolute Risk Reduction 31 cases per 1,000; 95% CI 10-47). GRADE certainty of these findings was moderate. We found weaker support for the hypotheses that breastfeeding promotion reduces risk of eczema during infancy (1 intervention trial), that longer exclusive breastfeeding is associated with reduced type 1 diabetes mellitus (28 observational studies), and that probiotics reduce risk of allergic sensitisation to cow's milk (9 intervention trials), where GRADE certainty of findings was low. We did not find that other dietary exposures-including prebiotic supplements, maternal allergenic food avoidance, and vitamin, mineral, fruit, and vegetable intake-influence risk of allergic or autoimmune disease. For many dietary exposures, data were inconclusive or inconsistent, such that we were unable to exclude the possibility of important beneficial or harmful effects. In this comprehensive systematic review, we were not able to include more recent observational studies or verify data via direct contact with authors, and we did not evaluate measures of food diversity during infancy. CONCLUSIONS: Our findings support a relationship between maternal diet and risk of immune-mediated diseases in the child. Maternal probiotic and fish oil supplementation may reduce risk of eczema and allergic sensitisation to food, respectively.

Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy.

The development of immune checkpoint inhibitors [monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1)] represents a major breakthrough in cancer therapy. Although they present a favorable risk/benefit ratio, immune checkpoint blockade therapies have a very specific safety profile. Due to their unique mechanism of action, they entail a new spectrum of adverse events that are mostly immune related [immune-related adverse events (irAEs)], notably mediated by the triggering of cytotoxic CD4+/CD8+ T cell activation. Cutaneous toxicities appear to be one of the most prevalent irAEs, both with anti-PD-1 and anti-CTLA-4 agents or with the newly developed anti-PD-L1 agents, which corresponds to a class effect. They are observed in more than one-third of the treated patients, mainly in the form of a maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. A wide range of other dermatologic manifestations can also occur, including lichenoid reactions, psoriasis, acneiform rashes, vitiligo-like lesions, autoimmune skin diseases (e.g., bullous pemphigoid, dermatomyositis, alopecia areata), sarcoidosis or nail and oral mucosal changes. In addition, the use of anti-CTLA-4 and anti-PD-1 therapies in combination is associated with the development of more frequent, more severe and earlier cutaneous irAEs compared to single agents. In most cases, these dysimmune dermatologic adverse events remain self-limiting and readily manageable. Early recognition and adequate management, however, are critical to prevent exacerbation of the lesions, to limit treatment interruption and to minimize quality of life impairment. This review describes the variable clinical and histopathologic aspects of dermatologic irAEs induced by immune checkpoint inhibitors. Appropriate treatment and counseling are also proposed, with a step-by-step approach for optimized management by both practicing oncologists and dermatologists.