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1.
Vitamin D and Autoimmune Rheumatic Diseases.
Athanassiou, L, Kostoglou-Athanassiou, I, Koutsilieris, M, Shoenfeld, Y
Biomolecules. 2023;(4)
Abstract
Vitamin D is a steroid hormone with potent immune-modulating properties. It has been shown to stimulate innate immunity and induce immune tolerance. Extensive research efforts have shown that vitamin D deficiency may be related to the development of autoimmune diseases. Vitamin D deficiency has been observed in patients with rheumatoid arthritis (RA) and has been shown to be inversely related to disease activity. Moreover, vitamin D deficiency may be implicated in the pathogenesis of the disease. Vitamin D deficiency has also been observed in patients with systemic lupus erythematosus (SLE). It has been found to be inversely related to disease activity and renal involvement. In addition, vitamin D receptor polymorphisms have been studied in SLE. Vitamin D levels have been studied in patients with Sjogren's syndrome, and vitamin D deficiency may be related to neuropathy and the development of lymphoma in the context of Sjogren's syndrome. Vitamin D deficiency has been observed in ankylosing spondylitis, psoriatic arthritis (PsA), and idiopathic inflammatory myopathies. Vitamin D deficiency has also been observed in systemic sclerosis. Vitamin D deficiency may be implicated in the pathogenesis of autoimmunity, and it may be administered to prevent autoimmune disease and reduce pain in the context of autoimmune rheumatic disorders.
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2.
Modifiable contributing factors to COVID-19: A comprehensive review.
Kostoff, RN, Briggs, MB, Kanduc, D, Dewanjee, S, Kandimalla, R, Shoenfeld, Y, Porter, AL, Tsatsakis, A
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2023;:113511
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Abstract
The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. The current study identifies eighty immune system dysfunction-enabling toxic stressors and behaviors (hereafter called modifiable contributing factors (CFs)) that also link directly to COVID-19. Each CF is assigned to one of the five categories in the CF taxonomy shown in Section 3.3.: Lifestyle (e.g., diet, substance abuse); Iatrogenic (e.g., drugs, surgery); Biotoxins (e.g., micro-organisms, mycotoxins); Occupational/Environmental (e.g., heavy metals, pesticides); Psychosocial/Socioeconomic (e.g., chronic stress, lower education). The current study shows how each modifiable factor contributes to decreased immune system capability, increased inflammation and coagulation, and increased neural damage and neurodegeneration. It is unclear how real progress can be made in combatting COVID-19 and other similar diseases caused by viral variants without addressing and eliminating these modifiable CFs.
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Sexual dimorphism in COVID-19: potential clinical and public health implications.
Bechmann, N, Barthel, A, Schedl, A, Herzig, S, Varga, Z, Gebhard, C, Mayr, M, Hantel, C, Beuschlein, F, Wolfrum, C, et al
The lancet. Diabetes & endocrinology. 2022;(3):221-230
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Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.
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Gluten-free diet can ameliorate the symptoms of non-celiac autoimmune diseases.
Lerner, A, Freire de Carvalho, J, Kotrova, A, Shoenfeld, Y
Nutrition reviews. 2022;(3):525-543
Abstract
CONTEXT A gluten-free diet (GFD) is the recommended treatment for gluten-dependent disease. In addition, gluten withdrawal is popular and occasionally is suggested as a treatment for other autoimmune diseases (ADs). OBJECTIVE The current systematic review summarizes those entities and discusses the logic behind using a GFD in classical non-gluten-dependentADs. DATA SOURCES A search for medical articles in PubMed/MEDLINE, Web of Sciences, LILACS, and Scielo published between 1960 and 2020 was conducted, using the key words for various ADs and GFDs. DATA EXXTRACTION Eight-three articles were included in the systematic review (using PRISMA guidelines). DATA ANALYSIS Reduction in symptoms of ADs after observance of a GFD was observed in 911 out of 1408 patients (64.7%) and in 66 out of the 83 selected studies (79.5%). The age of the patients ranged from 9 months to 69 years. The duration of the GFD varied from 1 month to 9 years. A GFD can suppress several harmful intraluminal intestinal events. Potential mechanisms and pathways for the action of GFD in the gut - remote organs' axis have been suggested. CONCLUSION A GFD might represent a novel nutritional therapeutic strategy for classical non-gluten-dependent autoimmune conditions.
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Ferritin - from iron, through inflammation and autoimmunity, to COVID-19.
Mahroum, N, Alghory, A, Kiyak, Z, Alwani, A, Seida, R, Alrais, M, Shoenfeld, Y
Journal of autoimmunity. 2022;:102778
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Abstract
While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.
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Outcomes of ICU patients treated with intravenous immunoglobulin for sepsis or autoimmune diseases.
Tocut, M, Kolitz, T, Shovman, O, Haviv, Y, Boaz, M, Laviel, S, Debi, S, Nama, M, Akria, A, Shoenfeld, Y, et al
Autoimmunity reviews. 2022;(12):103205
Abstract
OBJECTIVES To evaluate the outcomes of hospitalized patients in two intensive care units (ICU) treated with intravenous immunoglobulin (IVIg) added to standard-of-care therapy. The indications for IVIg therapy were sepsis or autoimmune disease. METHODS We conducted a retrospective study involving adult patients with sepsis and autoimmune diseases, who received IVIg in the ICU at Wolfson and Sheba Medical Centers. A predefined chart was compiled on Excel to include a complete demographic collection, patient comorbidities, chronic medication use, disease severity scores (Charlson Comorbidity Index; SOFA and APACHE II index scores), indication and dosage of IVIg administration, duration of hospitalization and mortality rates. RESULTS Patients (n - 111) were divided into 2 groups: patients with sepsis only (n-67) and patients with autoimmune disease only (n-44). Septic patients had a shorter ICU stay, received IVIg early, and had reduced mortality if treated with high dose IVIg. Patients with autoimmune diseases did not have a favorable outcome despite IVIg treatment. In this group, IVIg was administered later than in the sepsis group. CONCLUSIONS IVIg therapy improved the outcomes for ICU patients with sepsis.
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Graves' disease: Clinical manifestations, immune pathogenesis (cytokines and chemokines) and therapy.
Antonelli, A, Fallahi, P, Elia, G, Ragusa, F, Paparo, SR, Ruffilli, I, Patrizio, A, Gonnella, D, Giusti, C, Virili, C, et al
Best practice & research. Clinical endocrinology & metabolism. 2020;(1):101388
Abstract
Graves' disease (GD) is characterized by thyrotoxicosis, caused by the presence of circulating thyroid stimulating antibodies (TSAb), that are determinant also in the pathogenesis of its extrathyroidal manifestations [Graves' ophthalmopathy (GO), pretibial myxedema]. T helper (Th)1 immune response prevails in the immune-pathogenesis of GD and GO, during the active phase, when Th1 chemokines, and their (C-X-C)R3 receptor, play a key role. In GD, the existing treatments are not ideal for hyperthyroidism (long-term remission with anti-thyroid-drugs only in 50% of patients; while radioiodine and surgery cause hypothyroidism). In GD, antigen-specific therapy has been recently published, with the induction of T cell tolerance via an immunization by TSH-R peptides. In GO, rituximab and drugs targeting cytokines have been evaluated. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) showed to be very effective in GO patients. Further researches are necessary to identify novel effective therapies targeting GD, or GO.
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Graves' disease: Epidemiology, genetic and environmental risk factors and viruses.
Antonelli, A, Ferrari, SM, Ragusa, F, Elia, G, Paparo, SR, Ruffilli, I, Patrizio, A, Giusti, C, Gonnella, D, Cristaudo, A, et al
Best practice & research. Clinical endocrinology & metabolism. 2020;(1):101387
Abstract
Graves' disease (GD) is the most common cause of hyperthyroidism in developed Countries. It is more common between 30 and 60 years; 5-10 times more frequent in women. The genetic predisposition accounts for 79% of the risk for GD, while environmental factors for 21%. About 70% of genes associated with autoimmune thyroid disorders (AITD) are implicated in T-cell function. Among GD endogenous factors, estrogens, X-inactivation and microchimerism are important. Among environmental risk factors, smoking, iodine excess, selenium and vitamin D deficiency, and the occupational exposure to Agent Orange have been associated with GD. Many studies showed that HCV is associated with thyroid autoimmunity and hypothyroidism, in patients with chronic HCV hepatitis (CHC); a significant link has been shown also between HCV-related mixed cryoglobulinemia and risk for GD. Moreover, IFN-α-treated CHC patients develop GD more frequently. Novel studies are needed about possible risk factors to reduce the occurence of GD in West Countries.
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COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy.
Perricone, C, Bartoloni, E, Bursi, R, Cafaro, G, Guidelli, GM, Shoenfeld, Y, Gerli, R
Immunologic research. 2020;(4):213-224
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Abstract
SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.
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Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm.
Ruscitti, P, Berardicurti, O, Di Benedetto, P, Cipriani, P, Iagnocco, A, Shoenfeld, Y, Giacomelli, R
Frontiers in immunology. 2020;:1130
Abstract
The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.