Single-Nucleotide Variants in PADI2 and PADI4 and Ancestry Informative Markers in Interstitial Lung Disease and Rheumatoid Arthritis among a Mexican Mestizo Population (preprint)

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease -ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms, PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with rheumatoid arthritis, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variations (SNV) and a haplotype were identified as susceptibility factors for ILD-RA development. Elevated levels of PAD4 were found in ILD-RA cases, while PADI2 showed an association with RA susceptibility. This document presents the data obtained from the conducted research, which has been published.

The Correlation between Cigarette Smoking and Rheumatoid Arthritis: An Eight-Year, Prospective, Clinical, Observational, Cohort Study (preprint)

Background: Cardiovascular disease (CVD) increases the risk of mortality and morbidity in patients with rheumatoid arthritis (RA). Patients with RA have a 50-60% increased risk for CVD compared with the general population. Cardiovascular risk is commonly meas-ured using the Systemic Coronary Risk Estimation 2 calculator modified for patients with RA. Traditional modifiable risk factors for CVD include arterial hypertension, dyslipidemia, insulin resistance, diabetes, cigarette smoking, and low physical activity. In this study, we analyzed the effects of smoking and the risk of CVD in patients with RA. Methods: This was a prospective, clinical, cohort study with an eight-year follow-up pe-riod. A total of 201 patients, 124 with RA (study group) and 77 with osteoarthritis (OA) (control group), were included in this study. However, only 137 patients (82 with RA and 55 with OA) completed the study. Fifty-eight patients (41 with RA and 17 with OA) died during the study period. We compared the prevalence of smoking and its association with the risk for CVD and RA. Results: The prevalence of smoking in the RA group was higher than that in the OA group (p<0.0001). Trends in the prevalence of smoking in both groups did not change signifi-cantly during the follow-up period. In the RA group, smoking was associated with the in-cidence of CVD in current smokers (p=0.028) and in patients with a history of smoking (p=0.016). These results suggest that smokers have an increased risk for RA. The trend of continued smoking in patients with RA may be attributed to attempts to reduce stress caused by RA symptoms. Conclusions: Previous studies have shown that current and former smokers with RA have more severe symptoms, more joint damage, and poorer response to therapy than those who have never smoked. However, the reason underlying the trend of continued cigarette smoking in patients with RA remains unclear. Further studies are needed to clarify the trend of continued smoking in patients with RA.

Cardiovascular Disease in Patients with Rheumatoid Arthritis (RA) (preprint)

The risk of developing cardiovascular diseases (CVD) in patients suffering from rheumatoid arthritis (RA) is 1.5 times higher compared to the general population. The objective of this retrospective study was to determine the type of cardiovascular complications that can appear in patients with rheumatoid arthritis. Reducing the cardiovascular risk, through an aggressive management of the traditional and non-traditional risk factors, is another objective of this study. Early diagnosis and initiation of therapeutic measures to reduce the progression rate of rheumatoid arthritis, while also maintaining an active lifestyle, are the most important problems in young patients. We included a number of 200 patients with rheumatoid arthritis, presenting various stages of disease, concomitant with cardiovascular complications. The incidence by gender was higher in women, while men presented a higher incidence of traditional and non-traditional cardiovascular risk factors. All the patients presented an atherogenic coefficient over 2, indicating a significant risk of atherogenesis. An increased incidence of coronary artery disease was found in men. The patients presented cardiac arrhythmias, especially in the active stage of the condition, while the incidence of atrial fibrillation was higher in women. The active stage of the disease was evaluated using inflammatory biomarkers (ESR, PCR). ESR is not a specific tool for diagnosing the disease, but its important role in monitoring the activity of RA should not be ignored. Moreover, ESR has a significant role in monitoring the evolution and determining the prognostic of congestive heart failure. A target treatment prescribed a target treatment to reduce inflammation and prevent exacerbations was prescribed for all patients. However, in daily clinical practice, the screening for RA is poorly done. Thus, patients are often undiagnosed, while the risk factors are not assessed. In conclusion, even nowadays, RA patients continue to present an increased risk of developing CVD.

An AI Approach to Identifying Novel Therapeutics for Rheumatoid Arthritis (preprint)

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that has significant impact on quality of life and work capacity. Treatment of RA aims to control inflammation and alleviate pain, however achieving remission with minimal toxicity is frequently not possible with the current suite of drugs. This review aims to summarise current treatment practices and highlight the urgent need for alternative pharmacogenomic approaches to novel drug discovery. These approaches can elucidate new relationships between drugs, genes, and diseases to identify additional effective and safe therapeutic options. This review discusses how computational approaches such as connectivity mapping offers the ability to repurpose FDA approved drugs beyond their original treatment indication. This review also explores the concept of drug sensitisation, to predict co-prescribed drugs with synergistic effects that produce enhanced anti-disease efficacy by involving multiple disease pathways. Challenges of this computational approach are discussed including the availability of suitable high-quality datasets for comprehensive analysis and other data curation issues. The potential benefits include accelerated identification of novel drug combinations, and ability to trial and implement established treatments in a new index disease. This review underlines the huge opportunity to incorporate disease-related data and drug-related data to develop methods and algorithms which have strong potential to determine novel and effective treatment regimens.

Ozone as Redox Bioregulator in Preventive Medicine. The Molecular and Pharmacological Basis of the Low-Dose Ozone Concept (preprint)

The best form of prevention against human infection through bacteria, viruses and other parasites is ozone disinfection of wastewater and drinking water as a highly effective, well-known method. As a therapeutic measure, various preclinical studies showed promising results, which are being revisited and reconsidered in times of pandemics and led to interesting results in recent clinical trials and reports, as presented by the example of protective measures against covid-19 in particularly vulnerable clinical personnel. In patients with rheumatoid arthritis, repeated ozone treatments have led to new findings in the "immunomodulation" through ozone. The more effective immune response is discussed as the response of innate immune memory and opens interesting aspects for complementary treatment of autoimmune diseases.

Immunotherapy Strategy for Systemic Autoimmune Diseases: Betting on CAR-T (preprint)

Systemic autoimmune diseases (SAIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA) are fully related to the unregulated innate and adaptive immune systems involved in their pathogenesis. They have similar pathogenic characteristics including the interferon signature, loss of tolerance to self-nuclear antigens, and enhanced tissue damage like necrosis and fibrosis. Glucocorticoids and immunosuppressants, which have limited specificity and are prone to tolerance, are used as the first-line therapy. A plethora of novel immunotherapies have been developed including monoclonal and bispecific antibodies, and other biological agents to target cellular and soluble factors involved in disease pathogenesis such as B cells, co-stimulatory molecules, cytokines or their receptors, and signalling molecules. Many of these have shown encouraging results in clinical trials. CAR-T cell therapy is considered the most promising technique for curing autoimmune diseases, with recent successes in the treatment of SLE and SSc.

Radial Artery Deviation and Reimplantation (RADAR) to Accelerate the Maturation of Radial-Cephalic Fistulas for Hemodialysis (preprint)

Background: The most common form of vascular access for hemodialysis is a native arteriovenous fistula, which connects site of the artery to the end of the vein. The maturation process of the fistula plays a crucial role in the establishment of a functional vascular access. Radial artery stenosis is among others a potential cause of maturation failure. In these cases, improving the fistula's blood flow may be difficult, as traditional surgical reanastomosis and endovascular intervention frequently fail. Radial artery deviation and reimplantation (RADAR) is a novel, effective technique for creating primary fistulas with a high patency rate. The main disadvantage of this procedure is the ligation of the radial artery and the subsequent known consequences. Methods: In order to accelerate maturation, we used RADAR as a secondary fistula in three patients with radial artery stenosis and maturation failure. In all patients after surgery we observed significant increase in fistula blood flow. Two patients used fistula for hemodialysis after surgery. We describe the image diagnosis, procedure, and benefits of this method based on a single case. Conclusion: The RADAR technique may be successfully used as a secondary access in patients with maturation failure, due to RA stenosis to accelerate fistula maturation.

Bone Involvement in Rheumatoid Arthritis and Spondyloartritis: An Updated Review (preprint)

Several rheumatologic diseases are primarily distinguished by their involvement of bone tissue, where it not only serves as a mere target of the condition but often plays a pivotal role in its pathogenesis. This scenario is particularly prominent in chronic inflammatory arthritis such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). Given the immunological and systemic nature of these diseases, in this review, we report an overview of the pathogenic mechanisms underlying the specific bone involvement, focusing on the complex interactions that occur between bone tissue's own cells and the molecular and cellular actors of the immune system, a recent and fascinating field of interest defined osteoimmunology. Specifically, we have comprehensively elaborated on the distinct pathogenic mechanisms of bone erosion seen in both rheumatoid arthritis and spondyloarthritis, as well as the characteristic process of aberrant bone formation observed in spondyloarthritis. Lastly, chronic inflammatory arthritis lead to systemic bone involvement, resulting in systemic bone loss and consequent osteoporosis, along with increased skeletal fragility.

Determinants of SARS-CoV-2 IgG response and decay in Canadian healthcare workers: a prospective cohort study. (preprint)

Introduction Healthcare workers (HCWs) from an interprovincial Canadian cohort were asked to give serial blood samples to identify factors associated with anti-receptor binding domain (anti-RBD) IgG response to the SARS-CoV-2 virus. Methods Members of the HCW cohort donated blood samples four months after their first SARS-CoV-2 immunization and again at 7, 10 and 13 months. Date and type of immunizations and dates of SARS-CoV-2 infection were collected at each of four contacts, together with information on immunologically-compromising conditions and current therapies. Blood samples were analyzed centrally for anti-RBD IgG and anti-nucleocapsid IgG (Abbott Architect, Abbott Diagnostics). Records of immunization and SARS-CoV-2 testing from public health agencies were used to assess the impact of reporting errors on estimates from the random-effects multivariable model fitted to the data. Results 2752 of 4567 vaccinated cohort participants agreed to donate at least one blood sample. Modelling of anti-RBD IgG titer from 8903 samples showed an increase in IgG with each vaccine dose and with first infection. A decrease in IgG titer was found with the number of months since vaccination or infection, with the sharpest decline after the third dose. An immunization regime that included mRNA1273 (Moderna) resulted in higher anti-RBD IgG. Participants reporting multiple sclerosis, rheumatoid arthritis or taking selective immunosuppressants, tumor necrosis factor inhibitors, calcineurin inhibitors and antineoplastic agents had lower anti-RBD IgG. Supplementary analyses showed higher anti-RBD IgG in those reporting side-effects of vaccination, no relation of anti-RBD IgG to obesity and lower titers in women immunized early in pregnancy. Sensitivity analysis results suggested no important bias in the self-report data. Conclusion Creation of a prospective cohort was central to the credibility of results presented here. Serial serology assessments, with longitudinal analysis, provided effect estimates with enhanced accuracy and a clearer understanding of medical and other factors affecting response to vaccination.

Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease (preprint)

Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheu-matoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and eth-nicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the his-topathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.

COVID-19 vaccines and autoimmune disorders: A scoping review protocol (preprint)

Background - Two years into the global vaccination program, important questions about the association between COVID-19 vaccines and autoimmune diseases have arisen. A growing number of reports have documented associations between COVID-19 vaccination and autoimmunity, suggesting, for example, a causal link between vaccination and new-onset and/or relapsing autoimmune disorders such as type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, Graves disease, and Hashimoto s thyroiditis. These autoimmune phenomena have occurred with various COVID-19 vaccines and research is required to elucidate the underlying mechanisms and causal directions, for example, whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events post-vaccination. Methods and analysis - Specific objectives of this scoping review will address the following questions: Can COVID-19 vaccination trigger and/or exacerbate autoimmune disorders? Are persons with autoimmune disorders at higher risk of experiencing additional autoimmune disorders? What are the mechanisms connecting autoimmune disorders with COVID-19 vaccination? Can COVID-19 vaccination interact with immunosuppressive therapy in persons with autoimmune disorders? Does the risk of autoimmune disorders following COVID-19 vaccination differ by vaccine type, age, gender, or other still unidentified characteristics (e.g., SES)? What is the consensus of care concerning COVID-19 vaccination in persons with autoimmune disorders and what evidence informs it? Our review will follow Arksey and O Malley s (2005) framework, enhanced by Levac et al. s team-based approach (2010), and adhering to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. To capture the broadest range of perspectives on the phenomenon of interest, data will be synthesized through numerical summaries describing general characteristics of included studies and thematic analysis. Subgroup analysis of primary outcomes will be performed to compare findings according to 1) the previous existence of autoimmune disorder, 2) the presence of relevant co-morbidities, 3) vaccine type; and other relevant factors that we may encounter as the research proceeds. Significance - COVID-19 has triggered the largest vaccination campaign in history, targeting literally the global human community. Drug safety is a crucial aspect of any medical intervention, critical to a proper assessment of the balance of risks and benefits. Our investigation should yield information useful to improve medical and public health practice in multiple ways, including assisting in clinical decision-making, policy development, and ethical medical practice.

Effectiveness of Oral Versus Injectable Semaglutide in Adults with Type 2 Diabetes: Results from a Retrospective Observational Study in Croatia (preprint)

Background: The number of people with type 2 diabetes is increasing daily, and therefore effective therapy is needed to successfully regulate glycemia and reduce the risk of associated complications. Recently, an oral formulation of the glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide has become available. Therefore, the aim of our study was to compare the effectiveness of the new oral formulation and the existing injectable formulation of semaglutide in terms of glycemic and body weight control in a real-world setting. Patients and methods: This was a single-center retrospective observational study conducted at the Rijeka Clinical Hospital Centre. A total of 106 patients with inadequately controlled type 2 diabetes (HbA1 ≥ 7%) on different oral or basal insulin supported oral therapy were recruited from the diabetes outpatient clinic, and data from electronic medical records were retrospectively collected and analyzed from May 2021 to November 2022. All subjects were GLP-1 RA naive and consequently prescribed 0.5 or 1.0 mg once weekly injectable semaglutide (IS) or 7 mg or 14 mg once daily oral semaglutide (OS) for at least 6 months. Glycated hemoglo-bin (HbA1c), body weight, and body mass index (BMI) were assessed prior to semaglutide administration and after a 6-month follow-up period. The primary endpoint was the change from baseline in HbA1c, and sec-ondary endpoints were the change in body weight and the proportion of participants with a reduction in body weight of ≥ 5% and ≥ 10%, respectively, 6 months after the initiation of semaglutide treatment. Results: At 6-month follow-up, no significant difference was observed between the two formulations in terms of HbA1c reduction (IS -1.1% vs OS -1.4%, p=0.126) and weight loss (IS -6.50 kg vs OS -5.90 kg, p=0.714). Exactly the same proportion of participants in both groups achieved a weight loss of ≥ 5% (56.7%, n=30). A weight loss ≥ 10% was observed in 20.7% (n=11) of participants administered IS and 15.1% (n=8) of participants adminis-tered OS, respectively (p=0.454). Conclusion: In a real-world setting, oral semaglutide as add-on therapy to ongoing antihyperglycemic treatment in patients with inadequately controlled type 2 diabetes who had not previously received GLP-1 RA demonstrated the same effectiveness as injectable semaglutide in terms of gly-cemic control and weight loss after 6 months of treatment.

Visceral adipose macrophage content does not associate with body mass index or systemic inflammation in COVID-19: an autopsy study (preprint)

Introduction: Adiposity, especially visceral adiposity with elevated body mass index (BMI), is associated with a hyperinflammatory syndrome and poor outcomes in patients with COVID-19. In other diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, systemic inflammation is driven directly by visceral adipose macrophages which release pro-inflammatory cytokines. Currently it is unknown whether visceral adipose tissue macrophage content may similarly explain the observation that COVID-19 patients with elevated BMI are at risk for a hyperinflammatory syndrome and death. Methods: This was a retrospective study of hospitalized adults who died of COVID-19 between March 2020 and June 2020 and underwent autopsy. Visceral adipose tissue macrophage content was quantified by histological staining of visceral adipose tissue samples with CD68, using pericolic fat gathered at autopsy from each subject. Clinical data including inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive Protein (CRP), Troponin, D-dimer, Interleukin-6 (IL-6), and ferritin as well as BMI were collected from electronic medical records. Results: A total of 39 subjects were included in this study. There was no association between BMI and visceral adipose tissue macrophage content (Spearman R=0.025, p=0.88). Additionally, there was no association between adipose tissue macrophage content and any of the systemic markers of inflammation measured including ESR, CRP, Troponin, D-dimer, IL-6, and Ferritin (p>0.05 for all markers). Conclusion: Unlike chronic diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, elevated BMI is not associated with increased visceral adipose tissue macrophage content in patients who died of COVID-19. Additionally, among patients who died of COVID-19, visceral adipose tissue macrophage content is not associated with markers of systemic inflammation. These results suggest that the elevations in systemic markers of inflammation-and the hyperinflammatory syndrome often observed during acute COVID-19-does not directly originate from visceral adipose macrophages as it seems to in chronic disease states.

Expression and Activation of the NF-κB Pathway Correlates with Methotrexate Resistance and Cell Proliferation in Acute Lymphoblastic Leukemia (preprint)

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Immunogenicity and safety of mixed COVID-19 vaccine regimens in patients with immune-mediated inflammatory diseases: a single-centre prospective cohort study.

OBJECTIVE: Among persons with immune-mediated inflammatory diseases (IMIDs) who received SARS-CoV-2 vaccines, we compared postvaccine antibody responses and IMID disease activity/states. DESIGN: Single-centre prospective cohort study. SETTING: Specialty ambulatory clinics in central Canada. PARTICIPANTS: People with inflammatory arthritis (n=78; 77% rheumatoid arthritis), systemic autoimmune rheumatic diseases (n=84; 57% lupus), inflammatory bowel disease (n=93; 43% Crohn's) and multiple sclerosis (n=72; 71% relapsing-remitting) (female 79.4%, white 84.7%, mean (SD) age 56.0 (14.3) years) received COVID-19 vaccinations between March 2021 and September 2022. PRIMARY OUTCOME: Postvaccination anti-spike, anti-receptor binding domain (anti-RBD) and anti-nucleocapsid (anti-NC) IgG antibodies tested by multiplex immunoassays compared across vaccine regimens and with responses in 370 age-matched and sex-matched vaccinated controls. SECONDARY OUTCOMES: COVID-19 infection and self-reported IMID disease activity/state. RESULTS: Most (216/327, 66.1%) received homologous messenger RNA (mRNA) (BNT162b2 or mRNA1273) vaccines, 2.4% received homologous ChAdOx1 and 30.6% received heterologous vaccines (23.9% ChAdOx1/mRNA, 6.4% heterologous mRNA) for their first two vaccines (V1, V2). Seroconversion rates were 52.0% (91/175) for post-V1 anti-spike and 58.9% (103/175) for anti-RBD; 91.5% (214/234) for post-V2 anti-spike and 90.2% (211/234) for anti-RBD; and were lower than controls (post-V2 anti-spike 98.1% (360/370), p<0.0001). Antibody titres decreased 3 months after V2 but increased 1 month after the third vaccine (V3) and 1 month after the fourth vaccine (V4) (BAU/mL median (IQR), anti-spike 1835 (2448) 1 month post-V2, 629.1 (883.4) 3 months post-V2, 4757.5 (7033.1) 1 month post-V3 and 4356.0 (9393.4) 1 month post-V4; anti-RBD 1686.8 (2199.44) 1 month post-V2, 555.8 (809.3) 3 months post-V2, 4280.3 (6380.6) 1 month post-V3 and 4792.2 (11 673.78) 1 month post-V4). If primed with a vector vaccine, an mRNA vaccine increased antibody titres to those comparable to homologous mRNA vaccines. Anti-RBD and anti-spike titres were higher in anti-NC seropositive (n=31; 25 participants) versus seronegative samples (BAU/mL median (IQR) anti-RBD 11 755.3 (20 373.1) vs 1248.0 (53 278.7); anti-spike 11 254.4 (15 352.6) vs 1313.1 (3106.6); both p<0.001). IMID disease activity/state and rates of self-reported moderate or severe IMID flare were similar across vaccinations. CONCLUSION: Heterologous COVID-19 vaccination improves seroconversion rates following a vector vaccine and does not lead to IMID disease flare. IMIDs benefit from at least three vaccines.

Immunogenicity of COVID-19 vaccines in adult patients with autoimmune inflammatory rheumatic diseases: A systematic review and meta-analysis.

COVID-19 vaccines approved by the Food and Drug Administration have been studied mainly in healthy individuals and there is limited information on their immunogenicity in patients with autoimmune diseases. Therefore, the current systematic review and meta-analysis study, aimed to comprehensively investigate the immunogenicity of these vaccines in patients with autoimmune inflammatory rheumatoid diseases (AIRDs). A comprehensive literature search was performed on various databases, including Google Scholar, PubMed, Web of Science, EMBASE, and Cochrane Library, to select cohort and randomized clinical trial (RCT) studies up to January 2022. Also, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist protocol and the I2 statistic were used for quality assessment and heterogeneity tests of the selected studies. Fixed and random-effects models were estimated based on the heterogeneity tests, and pooled data were determined as the ratio of mean (ROM) with a 95% confidence interval (CI). As a result, we found that vaccines can cause favorable immunogenicity and antibody response in vaccinated AIRD patients; however, older age and the concomitant consumption of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biologic DMARDs (bDMARDs) could significantly reduce the vaccine immunogenicity. Consequently, our findings revealed significant humoral responses (seropositive) in AIRD patients following the administration of COVID-19 vaccines.

Mapping current status and emerging trends in NETosis: A bibliometric study.

BACKGROUND: NETosis is a critical innate immune mechanism of neutrophils that contributes to the accelerated progression of autoimmune diseases, thrombosis, cancer, and coronavirus disease 2019 (COVID-19). This study qualitatively and quantitatively analyzed the relevant literature by bibliometric methods in order to provide a more comprehensive and objective view of the knowledge dynamics in the field. METHODS: The literature on NETosis was downloaded from the Web of Science Core Collection, analyzed with VOSviewer, CiteSpace, and Microsoft for co-authorship, co-occurrence, and co-citation analysis. RESULTS: In the field of NETosis, the United States was the most influential countries. Harvard University was the most active institutions. Mariana J. Kaplan and Brinkmann V were, respectively, the most prolific and most co-cited authors. Frontiers in Immunology, Journal of Immunology, Plos One, Blood, Science, Journal of Cell Biology, and Nature Medicine were the most influential journals. The top 15 keywords are associated with immunological and NETosis formation mechanisms. The keywords with the strongest burst detection were mainly related to COVID-19 (coronavirus, ACE2, SARS coronavirus, cytokine storm, pneumonia, neutrophil to lymphocyte ratio), and cancer (circulating tumor cell). CONCLUSION: Research on NETosis is currently booming. The mechanism of NETosis and its role in innate immunity, autoimmune diseases, especially systemic lupus erythematosus and rheumatoid arthritis, and thrombosis are the focus of research in the field of NETosis. A future study will concentrate on the function of NETosis in COVID-19 and recurrent metastasis of cancer.

Low-dose radiation therapy suppresses viral pneumonia by enhancing broad-spectrum anti-inflammatory responses via transforming growth factor-ß production.

Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-ß (TGF-ß) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-ß reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-ß production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-ß may be an alternative therapy for viral pneumonia.