RNA Therapeutics: A Healthcare Paradigm Shift.

COVID-19 brought about the mRNA vaccine and a paradigm shift to a new mode of treating and preventing diseases. Synthetic RNA products are a low-cost solution based on a novel method of using nucleosides to act as an innate medicine factory with unlimited therapeutic possibilities. In addition to the common perception of vaccines preventing infections, the newer applications of RNA therapies include preventing autoimmune disorders, such as diabetes, Parkinson's disease, Alzheimer's disease, and Down syndrome; now, we can deliver monoclonal antibodies, hormones, cytokines, and other complex proteins, reducing the manufacturing hurdles associated with these products. Newer PCR technology removes the need for the bacterial expression of DNA, making mRNA a truly synthetic product. AI-driven product design expands the applications of mRNA technology to repurpose therapeutic proteins and test their safety and efficacy quickly. As the industry focuses on mRNA, many novel opportunities will arise, as hundreds of products under development will bring new perspectives based on this significant paradigm shift-finding newer solutions to existing challenges in healthcare.

Corrigendum: Can vitamin D status influence seroconversion to SARS-COV2 vaccines?

[This corrects the article DOI: 10.3389/fimmu.2022.1038316.].

Vitamin D: Physiology, clinical applications, dietary sources, and requirements

Vitamin D, the sunshine vitamin, is essential for bone health and reducing risk of acute and chronic diseases, including autoimmune diseases, cancers, heart disease, type II diabetes, neurocognitive dysfunction and infectious diseases including COVID-19. Vitamin D deficiency is one of the most common nutritional deficiencies worldwide. Vitamin D status is determined by measuring 25-hydroxyvitamin D in the blood. To maintain a normal level of at least 30ngmL−1 (75nmolL−1) as recommended by the Endocrine Society Guidelines on Vitamin D, infants up to 1 year need 400–1000IUs, children 600IU–1000IU, adults 1500–2000IU of vitamin D daily. Obese adults require 2–3 times more vitamin D to satisfy their requirement because of the vitamin D being diluted in the body fat and not available. This can be accomplished by receiving sensible sun exposure in combination with ingesting foods that either naturally contain or are fortified with vitamin D along with a vitamin D supplement. © 2023 Elsevier Ltd. All rights reserved

The post-COVID syndrome

Post-COVID syndrome is a multifactorial condition characterized by a combination of neurological, autoimmune, cardiovascular factors as well as psychological stress and neuro-endocrine dysfunction. The most common complaints include shortness of breath, pain syndrome, tachycardia, flu-like syndrome, chronic fatigue, impaired attention, memory, and sleep. These symptoms can develop within 2-4 weeks after acute novel coronavirus infection and persist for many months. The principles of therapy include, first of all, a multidisciplinary approach, and treatment of autoimmune disorders, which can play a key role in the pathogenesis of post-COVID syndrome. Intravenous immunoglobulins in combination with other immunomodulatory techniques can enable millions of patients around the world to improve their quality of life and return to normal activities. © 2023 Elsevier Inc. All rights reserved.

Can vitamin D status influence seroconversion to SARS-COV2 vaccines?

Existing data indicate an association between vitamin D deficiency and increased severity of respiratory distress due to COVID-19 infection, especially in high-risk populations. To date, the effect of vitamin D on immunogenicity to SARS-CoV-2 vaccines has been investigated solely in young healthcare workers in a few studies, yielding conflicting findings, yet highlighting that the response to immunization is inversely related to age. Vitamin D status can potentially influence the antibody titers in people with a previous (or naïve) SARS-CoV-2 infection and vaccination, given its role in immune regulatory functions. From this standpoint, vitamin D supplementation can help reduce the risk of SARS-CoV-2 infection, COVID-19 severity/mortality and rebalance immunological function, particularly in subjects with vigorous T lymphocyte responses to COVID-19. However, more research is needed to establish a correlation between vitamin D status and the generation of protective serological responses to SARS-CoV-2 vaccination.

GLOBAL RESEARCH: THE JOURNAL OF THE HEALTH VISITORS' ASSOCIATION

The study could help policymakers amend interventions that improve vaccine confidence, as well as help public health organisations better tailor their communications. bit.ly/JSTP_behaviour_ vaccine_hesitancy ITALY AIR POLLUTION LINKED TO HEIGHTENED RISK OF AUTOIMMUNE DISEASE Long-term exposure to air pollution may be linked to an increased risk of autoimmune disease, including rheumatoid arthritis, research published in RMD Open has found. Long-term exposure to traffic and industrial air pollutants was associated with an approximately 40% higher risk of rheumatoid arthritis, a 20% higher risk of inflammatory bowel disease, and a 15% higher risk of connective tissue diseases. bit.ly/RMDO_pollution_autoimmune_disease NORWAY FAMILY-BASED TREATMENT OF CHILDREN WITH SEVERE OBESITY IMPROVES WEIGHT LOSS Family-based behavioural social facilitation treatment (FBSFT), delivered at an obesity outpatient clinic, improved weight-related outcomes significantly more than treatment as usual (TAU) among children aged six to 18 years with severe obesity, a study has found. Children receiving FBSFT reduced their body mass index standard deviation score and percentage above the International Obesity Task Force cut-off for overweight significantly more than children enrolled in TAU. bit.ly/CO_family_children_obesity NORWAY WOMEN EXPOSED TO ADVERSE CHILDHOOD EXPERIENCES MORE LIKELY TO DEVELOP MS Childhood trauma could be linked to an increased risk of women developing multiple sclerosis (MS) later in life, research suggests.

A Case of Chronic Myelomonocytic Leukemia Unmasked After Receiving J&J COVID-19 Vaccine.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disease that comes under the overlap syndrome (myelodysplastic and myeloproliferative disorders). CMML is characterized by peripheral blood monocytosis and bone marrow dysplasia. The pathogenesis of CMML is poorly understood. Although cytogenetic and molecular abnormalities are common, they are not diagnostic. Herein, we present a rare case of CMML after receiving the J&J COVID-19 vaccine with the rare association of limited scleroderma. Based on the Surveillance, Epidemiology, and End Result (SEER) cancer statistics review 2014-2018, the five-year age-adjusted incidence rate of CMML in both sexes is 0.5/100,000, with greater incidence in males (0.7/100,000) compared to females (0.3/100,000). We emphasize the fact that, based on the previous studies reported, the association of scleroderma with CMML is very rare. Our patient had concomitant CMML and scleroderma, which were unmasked after the patient received the COVID-19 vaccine. Our case suggests the possibility of developing CMML after receiving the J&J COVID vaccine. Immunization has always been a life-saving intervention in history. As the world is foreseeing getting the COVID-19 vaccine, it is essential to report all the possible adverse events for safety monitoring. Physicians should be aware of this unusual complication of the vaccine, and more cases are needed to confirm the association between them.

Epigenetic mechanisms regulate sex-specific bias in disease manifestations.

Sex presents a vital determinant of a person's physiology, anatomy, and development. Recent clinical studies indicate that sex is also involved in the differential manifestation of various diseases, affecting both clinical outcome as well as response to therapy. Genetic and epigenetic changes are implicated in sex bias and regulate disease onset, including the inactivation of the X chromosome as well as sex chromosome aneuploidy. The differential expression of X-linked genes, along with the presence of sex-specific hormones, exhibits a significant impact on immune system function. Several studies have revealed differences between the two sexes in response to infections, including respiratory diseases and COVID-19 infection, autoimmune disorders, liver fibrosis, neuropsychiatric diseases, and cancer susceptibility, which can be explained by sex-biased immune responses. In the present review, we explore the input of genetic and epigenetic interplay in the sex bias underlying disease manifestation and discuss their effects along with sex hormones on disease development and progression, aiming to reveal potential new therapeutic targets. KEY MESSAGES: Sex is involved in the differential manifestation of various diseases. Epigenetic modifications influence X-linked gene expression, affecting immune response to infections, including COVID-19. Epigenetic mechanisms are responsible for the sex bias observed in several respiratory and autoimmune disorders, liver fibrosis, neuropsychiatric diseases, and cancer.

A CASE OF AUTOIMMUNE NECROTISING MYOSITIS

Introduction An 88-year-old previously independent lady presented with progressive proximal weakness of all limbs and multiple falls for 10 months. Her swallowing got difficult lately. She lost weight gradually in that duration but denied any other symptoms suggestive of malignancy. PMH—Hypothyroid, Mild cognitive impairment Drg History—Atorvastatin for years. Stopped in this admission. On examination, she showed signs of proximal muscle weakness and areflexia in both upper and lower limbs without muscle tenderness. She had no facial nor eye muscle weakness. Sensory functions were intact. There were no rashes. Investigations CK 2000 TSH 24 Inflammatory markers, white cell counts—non-significant Vitamin D—18 CT-Chest Abdomen Pelvis, CT-colonography—No evidence of malignancy Paraneoplastic antibodies—Negative Anti-OJ and anti-Ro52 Antibodies—positive ENA profile—negative Anti-RNP—equivocal HMG-CoA reductase antibodies (HMCR)—Positive. Progress Prednisolone was commenced and gradually increased to 60 mg once a day but there is no significant improvement clinically though creatinine kinase level had improved. She was unfortunately infected with COVID-19 infection in the stay which delayed the plan for muscle biopsy and EMG. It affected the plan for Intravenous Immunoglobulins and was later decided to be non-beneficial due to high risks of thromboembolic events and superimposed infections. Steroid was later switched to methotrexate. She was discharged to a rehab unit. Conclusion Necrotising Autoimmune Myopathy is a rare form of idiopathic inflammatory myopathy. Risk factors include statins, cancer, connective tissue diseases, autoimmune diseases, and infections such as HIV2. Diagnosis includes clinical features, serum creatine kinase, HMG CoA reductase antibody (HMGCR-Ab), electromyography, and muscle biopsy. The first-line treatment options are steroids and immunosuppressive agents. Early use of immunoglobulin achieves good outcome. It is still under investigation for the recommended choice for immunosuppressive therapy and the duration of the therapy.

Characteristics, treatment, and outcomes of Myasthenia Gravis in COVID-19 patients: A systematic review.

OBJECTIVE: Recent studies suggest that the clinical course and outcomes of patients with coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG) are highly variable. We performed a systematic review of the relevant literature with a key aim to assess the outcomes of invasive ventilation, mortality, and hospital length of stay (HLoS) for patients presenting with MG and COVID-19. METHODS: We searched the PubMed, Scopus, Web of Science, and MedRxiv databases for original articles that reported patients with MG and COVID-19. We included all clinical studies that reported MG in patients with confirmed COVID-19 cases via RT-PCR tests. We collected data on patient background characteristics, symptoms, time between MG and COVID-19 diagnosis, MG and COVID-19 treatments, HLoS, and mortality at last available follow-up. We reported summary statistics as counts and percentages or mean±SD. When necessary, inverse variance weighting was used to aggregate patient-level data and summary statistics. RESULTS: Nineteen studies with 152 patients (mean age 54.4 ± 12.7 years; 79/152 [52.0%] female) were included. Hypertension (62/141, 44.0%) and diabetes (30/141, 21.3%) were the most common comorbidities. The mean time between the diagnosis of MG and COVID-19 was7.0 ± 6.3 years. Diagnosis of COVID-19 was confirmed in all patients via RT-PCR tests. Fever (40/59, 67.8%) and ptosis (9/55, 16.4%) were the most frequent COVID-19 and MG symptoms, respectively. Azithromycin and ceftriaxone were the most common COVID-19 treatments, while prednisone and intravenous immunoglobulin were the most common MG treatments. Invasive ventilation treatment was required for 25/59 (42.4%) of patients. The mean HLoS was 18.2 ± 9.9 days. The mortality rate was 18/152 (11.8%). CONCLUSION: This report provides an overview of the characteristics, treatment, and outcomes of MG in COVID-19 patients. Although COVID-19 may exaggerate the neurological symptoms and worsens the outcome in MG patients, we did not find enough evidence to support this notion. Further studies with larger numbers of patients with MG and COVID-19 are needed to better assess the clinical outcomes in these patients.

Platelet Activation Mechanisms and Consequences of Immune Thrombocytopenia.

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

Clinical characteristics and COVID-19 outcomes in a regional cohort of pediatric patients with rheumatic diseases.

BACKGROUND: This study aimed to assess the baseline characteristics and clinical outcomes of coronavirus disease 2019 (COVID-19) in pediatric patients with rheumatic and musculoskeletal diseases (RMD) and identify the risk factors associated with symptomatic or severe disease defined as hospital admission, intensive care admission or death. METHODS: An observational longitudinal study was conducted during the first year of the SARS-CoV-2 pandemic (March 2020-March 2021). All pediatric patients attended at the rheumatology outpatient clinics of six tertiary referral hospitals in Madrid, Spain, with a diagnosis of RMD and COVID-19 were included. Main outcomes were symptomatic disease and hospital admission. The covariates were sociodemographic and clinical characteristics and treatment regimens. We ran a multivariable logistic regression model to assess associated factors for outcomes. RESULTS: The study population included 77 pediatric patients. Mean age was 11.88 (4.04) years Of these, 30 patients (38.96%) were asymptomatic, 41 (53.25%) had a mild-moderate COVID-19 and 6 patients (7.79%) required hospital admission. The median length of hospital admission was 5 (2-20) days, one patient required intensive care and there were no deaths. Previous comorbidities increased the risk for symptomatic disease and hospital admission. Compared with outpatients, the factor independently associated with hospital admission was previous use of glucocorticoids (OR 3.51; p = 0.00). No statistically significant risk factors for symptomatic COVID-19 were found in the final model. CONCLUSION: No differences in COVID-19 outcomes according to childhood-onset rheumatic disease types were found. Results suggest that associated comorbidities and treatment with glucocorticoids increase the risk of hospital admission.

Fatal Case of Rhabdomyolysis Post-COVID-19 Vaccine.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 pandemic has taken away the lives of many people (>4 million per WHO) around the world as of July 2021. With the advancement of the vaccine against COVID-19, in less than a year since the start of the pandemic, the infection rate has come under control in certain regions but is still rising in many more. However, with time, we are also learning a lot more about the adverse events related to the vaccine. This report documents the first fatal case of rhabdomyolysis potentially associated with the COVID-19 vaccine and supports the possibility that autoimmunity is a major risk factor for covid vaccine-related rhabdomyolysis.

Pharyngeal-Cervical-Brachial Variant of Guillain-Barré Syndrome in a Patient of COVID-19 Infection.

Guillain-Barré syndrome (GBS) has an annual incidence rate ranging from 0.4 to 1.7 cases per 1,00,000 population. Pharyngeal-cervical-brachial (PCB) variant is an extremely rare variant of GBS (3%), which presents with muscle weakness initially involving the neck, oropharynx, and upper extremities. GBS often has an infectious inciting event leading to an autoimmune response. There has been an increase in the incidence of GBS during the COVID-19 pandemic, and several case studies have shown an association between the development of GBS and COVID-19 infection. High clinical suspicion is needed to reach a diagnosis. As PCB variant of GBS can have fatal outcomes, a good clinical knowledge of its presentation can allow timely life-saving interventions. Here, we report a case of GBS with acute onset of neck and respiratory muscle weakness that progressed to upper limb weakness. The patient developed these symptoms two weeks after the onset of cough, fever, and malaise. PCB variant of GBS should always be considered as an important differential diagnosis in any patient presenting with limb weakness and bulbar palsy.

Recombinant CD137-Fc, its synthesis, and applications for improving the immune system functions, such as tumor immunotherapy and to reduce the inflammation due to the novel coronavirus.

CD137 (ILA/4-1BB), a member of tumor necrosis factor receptor superfamily, is one of the most important T cell costimulatory molecules. Interaction of this molecule with its ligand transmits a two-way signal that activates both T lymphocyte and antigen presenting cells. The soluble form of CD137 (sCD137) reduces the activity of its membrane isoform and is associated with T lymphocyte activation-induced cell death. Recombinant CD137-Fc may be used to treat cancers, autoimmune disorders and viral infections. It may also be useful for management of coronavirus infection. The 1276 bp DNA sequence encoded CD137-Fc recombinant protein was prepared and subcloned into lentiviral vector and expressed in transduced CHO-K1 eukaryotic cells. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot analysis, and enzyme-linked immunosorbent assay analysis results demonstrated that the expression of the 70-kDa CD137-Fc molecule was detectable without any degradation. This study helps to confirm previous research suggesting the use of this recombinant protein as a promising solution for the treatment of virus infections. CD137-Fc fusion protein could also make immunotherapy more effective for some diseases. This product is widely used in novel medical treatments, including cell-based immunotherapy such as dendritic cell, CAR T and CAR NK therapy. Its production and usage in research and treatment is noticeable also in current coronavirus disease 2019 pandemic.

Ophthalmological Considerations for COVID-19 Vaccination in Patients with Inflammatory Eye Diseases and Autoimmune Disorders.

The global impact imposed by the coronavirus disease 2019 (COVID-19) pandemic may be soon alleviated by the introduction and worldwide dissemination of safe and effective vaccines. This expedited timetable for development and approval of COVID-19 vaccines is an unprecedented extraordinary, concerted achievement by the scientific community. With the pending global rollout of vaccines, each with different mechanisms of action, physicians of various specialties will need to identify vulnerable patient groups for special considerations or advice. In this commentary, we analyse the important considerations for COVID-19 vaccines in patients with inflammatory eye diseases. Scrutiny of immunogenicity and adverse effects, particularly antibody-dependent enhancement, would better help in counselling these patients undergoing vaccination. More research on pharmacovigilance would allow for tailored guidelines and personalised management strategies.

Hematologic autoimmune disorders in the course of COVID-19: a systematic review of reported cases.

OBJECTIVE: As COVID-19 is a new emerging disease, the hematological/immunological changes that develop in the infected patients remain unknown. This study aims to systematically review the hematologic autoimmune complications in these patients. METHOD: Data from three online databases including Medline (via PubMed), Scopus and Web of Science were searched on 19 December 2020, and after excluding duplicate, irrelevant and inappropriate records, eligible documents were identified. Afterwards, information such as patients' history, presentations, paraclinical data, treatment course and outcome were extracted from the records. RESULTS: A total of 58 documents were considered to be eligible for data extraction which described 94 patients with COVID-19 who developed hematologic autoimmune disorder in their course of infection. Of these patients with COVID-19, the most common hematologic autoimmune disorder was immune thrombocytopenic purpura (55 cases) followed by autoimmune hemolytic anemia (22 cases). Other hematologic autoimmune disorders include antiphospholipid syndrome, thrombotic thrombocytopenic purpura, Evans syndrome and autoimmune neutropenia. CONCLUSION: The current study would help us to always consider an autoimmune etiology for cases with abnormal hematologic finding which further lead to an appropriate treatment of the patients, especially when the symptoms present in about 1-2 weeks after the first manifestation of the infection symptoms. Maybe, at least in this pandemic, it should be recommended to evaluate patients with unexpected and unexplained decrease in their hemoglobulin or platelet count for COVID-19. Another challenging issue is the treatment options. Given the multiorgan involvement and multifaceted nature of the infection, an individualized approach should be taken for each patient.