A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations.

Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.

Immune and non-immune mechanisms that determine vasculitis and coronary artery aneurysm topography in Kawasaki disease and MIS-C.

The overlap between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) including coronary artery aneurysms (CAA) and broadly shared gastrointestinal and mucocutaneous disease is poorly defined. In this perspective, we highlight common age-related extravascular epicardial microanatomical and immunological factors that might culminate in CAA expression in both MIS-C and KD. Specifically, the coronary vasa vasorum originates outside the major coronary arteries. Widespread inflammation in the epicardial interstitial compartment in shared between KD and MIS-C. Age-related changes in the neonatal and immature coronary vasculature including the impact of coronary artery biomechanical factors including coronary vessel calibre, age-related vessel distensibility, flow, and vessel neurovascular innervation may explain the decreasing CAA frequency from neonates to older children and the virtual absence of CAA in young adults with the MIS-C phenotype. Other KD and MIS-C features including mucocutaneous disease with keratinocyte-related immunopathology corroborate that disease phenotypes are centrally influenced by inflammation originating outside vessel walls but a potential role for primary coronary artery vascular wall inflammation cannot be excluded. Hence, common extravascular originating tissue-specific responses to aetiologically diverse triggers including superantigens may lead to widespread interstitial tissue inflammation characteristically manifesting as CAA development, especially in younger subjects. Given that CAA is virtually absent in adults, further studies are needed to ascertain whether epicardial interstitial inflammation may impact on both coronary artery physiology and cardiac conduction tissue and contribute to cardiovascular disease- a hitherto unappreciated consideration.

A Large Cluster of New Onset Autoimmune Myositis in the Yorkshire Region Following SARS-CoV-2 Vaccination.

BACKGROUND: The novel SARS-CoV-2 vaccines partially exploit intrinsic DNA or RNA adjuvanticity, with dysregulation in the metabolism of both these nucleic acids independently linked to triggering experimental autoimmune diseases, including lupus and myositis. METHODS: Herein, we present 15 new onset autoimmune myositis temporally associated with SARS-CoV-2 RNA or DNA-based vaccines that occurred between February 2021 and April 2022. Musculoskeletal, pulmonary, cutaneous and cardiac manifestations, laboratory and imaging data were collected. RESULTS: In total, 15 cases of new onset myositis (11 polymyositis/necrotizing/overlap myositis; 4 dermatomyositis) were identified in the Yorkshire region of approximately 5.6 million people, between February 2021 and April 2022 (10 females/5 men; mean age was 66.1 years; range 37-83). New onset disease occurred after first vaccination (5 cases), second vaccination (7 cases) or after the third dose (3 cases), which was often a different vaccine. Of the cases, 6 had systemic complications including skin (3 cases), lung (3 cases), heart (2 cases) and 10/15 had myositis associated autoantibodies. All but 1 case had good therapy responses. Adverse event following immunization (AEFI) could not be explained based on the underlying disease/co-morbidities. CONCLUSION: Compared with our usual regional Rheumatology clinical experience, a surprisingly large number of new onset myositis cases presented during the period of observation. Given that antigen release inevitably follows muscle injury and given the role of nucleic acid adjuvanticity in autoimmunity and muscle disease, further longitudinal studies are required to explore potential links between novel coronavirus vaccines and myositis in comparison with more traditional vaccine methods.

T Helper 2 IL-4/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17‒Type Diseases, Including Seronegative Arthritis and Enthesitis/Enthesopathy, but Not to Humoral Autoimmune Diseases.

Dupilumab, an IL-4/IL-13 receptor blocker, has been linked to emergent seronegative inflammatory arthritis and psoriasis that form part of the spondyloarthropathy spectrum. We systematically investigated patterns of immune disorders, including predominantly T helper 17‒(spondyloarthropathy pattern) and T helper 2‒mediated disorders and humoral autoimmune pattern diseases, using VigiBase, the World Health Organization's global pharmacovigilance of adverse drug reactions. Several bioinformatics databases and repositories were mined to couple dupilumab-related immunopharmacovigilance with molecular cascades relevant to reported findings. A total of 37,848 dupilumab adverse drug reaction cases were reported, with skin, eye, and musculoskeletal systems most affected. Seronegative arthritis (OR = 9.61), psoriasis (OR = 1.48), enthesitis/enthesopathy (OR = 12.65), and iridocyclitis (OR = 3.77) were highly associated. However, ankylosing spondylitis and inflammatory bowel disease were not conclusively associated. Overall, classic polygenic humoral‒mediated autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus were not associated with dupilumab use. Pathway analysis identified several biological pathways potentially involved in dupilumab‒associated adverse drug reactions, including the fibroblast GF receptor (in particular, FGFR2) pathway. MicroRNAs analysis revealed the potential involvement of hsa-miR-21-5p and hsa-miR-335-5p. In conclusion, IL-4/IL-13 blockers are not unexpectedly protective against humoral autoimmune diseases but dynamically skew immune responses toward some IL-23/IL-17 cytokine pathway‒related diseases. IL-4/13 axis also plays a role in homeostatic tissue repair and we noted evidence for a link with ocular and arterial pathology.

COVID-19 Vasculitis and vasculopathy-Distinct immunopathology emerging from the close juxtaposition of Type II Pneumocytes and Pulmonary Endothelial Cells.

The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular immunopathology including reports of vasculitis. In this article, we critically review COVID-19 immunopathology from the vasculitis perspective and highlight the non-infectious nature of vascular endothelial involvement in severe COVID-19. Whilst COVID-19 lung disease pathological changes included juxta-capillary and vascular macrophage and lymphocytic infiltration typical of vasculitis, we review the evidence reflecting that such "vasculitis" reflects an extension of pneumonic inflammatory pathology to encompass these thin-walled vessels. Definitive, extrapulmonary clinically discernible vasculitis including cutaneous and cardiac vasculitis also emerged- namely a dysregulated interferon expression or "COVID toes" and an ill-defined systemic Kawasaki-like disease. These two latter genuine vasculitis pathologies were not associated with severe COVID-19 pneumonia. This was distinct from cutaneous vasculitis in severe COVID-19 that demonstrated pauci-immune infiltrates and prominent immunothrombosis that appears to represent a novel immunothrombotic vasculitis mimic contributed to by RNAaemia or potentially diffuse pulmonary venous tree thrombosis with systemic embolization with small arteriolar territory occlusion, although the latter remains unproven. Herein, we also performed a systematic literature review of COVID-19 vasculitis and reports of post-SARS-CoV-2 vaccination related vasculitis with respect to the commonly classified pre-COVID vasculitis groupings. Across the vasculitis spectrum, we noted that Goodpasture's syndrome was rarely linked to natural SARS-CoV-2 infection but not vaccines. Both the genuine vasculitis in the COVID-19 era and the proposed vasculitis mimic should advance the understanding of both pulmonary and systemic vascular immunopathology.

A role for neutrophils in early enthesitis in spondyloarthritis.

BACKGROUND: Neutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses. METHODS: Early inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant. RESULTS: Following fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils. CONCLUSION: Neutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.

Sex difference in the association between malnutrition and hypoglycemia in hospitalized patients.

BACKGROUND: The aim of this paper was to examine the difference between males and females regarding association between malnutrition risk and hypoglycemia through a sub-analysis of a cross-sectional study of newly admitted patients to internal medicine departments. METHODS: Malnutrition risk, assessed with Nutritional Risk Screening 2002 (NRS2002), and serum albumin were measured upon admission. Logistic regression was applied to men and women separately, to test the effect of malnutrition and hypoalbuminemia on incidence of hypoglycemia. RESULTS: Included were 1186 patients (50.4% males, 39.2% with positive NRS2002). Rate of positive NRS2002 was similar across sexes (36.5% vs. 41.2% in males and females respectively, P=0.204). Among females, NRS2002 was associated with higher incidence of hypoglycemia (9.5% vs. 2.4% in NRS2002 negative females, P<0.001). Among males, no such difference was noted (9.2% compared to 7.1% in NRS2002 positive and negative males respectively, P=0.520). The weight loss/decreased food intake criterion of the NRS2002 was significantly higher in the hypoglycemic group within females (P=0.03). Logistic regression showed that serum albumin was inversely associated with hypoglycemia in both females (OR 0.477, 95% CI 0.282-0.806, P=0.006) and males (OR 0.532, 95% CI 0.355-0.795, P=0.002). However, increased malnutrition risk was associated with hypoglycemia only among females (OR 2.007, 95% CI 1.058-3.809, P=0.033). Diabetes status was associated with hypoglycemia (OR 1.907, 95% CI 1.056-3.445, P=0.032) only in males; this association did not occur in females. CONCLUSIONS: Malnutrition risk, as measured by the NRS2002, is associated with significantly increased incidence of hypoglycemia in women alone. Females who lose weight prior to hospitalization have an increased risk to develop hypoglycemia.

Prediction of Hypoglycemia During Admission of Non-Critically Ill Patients: Results from the MENU Study.

The objective of the work was to study admission parameters associated with an increased incidence of hypoglycemia during hospitalization of non-critically ill patients. Included in this cross-sectional study were patients admitted to internal medicine units. The Nutritional Risk Screening 2002 (NRS2002) was used for nutritional screening. Data recorded included admission serum albumin (ASA) and all glucose measurements obtained by the institutional blood glucose monitoring system. Neither of these are included in the NRS2002 metrics. Hypoalbuminemia was defined as ASA<3.5 g/dl. Patients were categorized as hypoglycemic if they had at least one documented glucose≤70 mg/dl during the hospitalization period. Included were 1342 patients [median age 75 years (IQR 61-84), 51.3% male, 52.5% with diabetes mellitus, (DM)], who were screened during three distinct periods of time from 2011-2018. The incidence of hypoglycemia was 10.8% with higher rates among DM patients (14.6 vs. 6.6%, p<0.001). Hypoglycemia incidence was negatively associated with ASA regardless of DM status. Multivariable regression showed that ASA (OR 0.550 per g/dl, 95% CI 0.387-0.781, p=0.001) and positive NRS2002 (OR 1.625, 95% CI 1.072-2.465, p=0.022) were significantly associated with hypoglycemia. The addition of hypoalbuminemia status to the NRS2002 tool improved the overall sensitivity from 0.55 to 0.71, but reduced specificity from 0.63 to 0.46. The negative predictive value was 0.93. Our data suggest that the combination of positive malnutrition screen and hypoalbuminemia upon admission are independently associated with the incidence of hypoglycemia among non-critically ill patients, regardless of diabetes mellitus status.

Prediction of Chemotherapy-Induced Peripheral Neuropathy in Patients with Lymphoma and Myeloma: the Roles of Brain-Derived Neurotropic Factor Protein Levels and A Gene Polymorphism.

BACKGROUND AND PURPOSE: Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that plays an essential role in the maintenance of the nervous system. We have evaluated the peripheral blood protein levels of BDNF and the valine-to-methionine substitution at codon 66 (Val66Met) single-nucleotide polymorphism (SNP) as potential biomarkers for the early recognition of chemotherapy-induced peripheral neuropathy (CIPN) in non-Hodgkin lymphoma and multiple myeloma patients. METHODS: CIPN was assessed in 45 patients at the diagnosis and during vincristine or bortezomib-based therapy using objective [reduced version of the Total Neuropathy Score (TNSr)] and subjective (FACT-GOG-NTx) tools. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) questionnaire. BDNF protein levels and the Val66Met SNP were determined using ELISA and Sanger sequencing. RESULTS: The pretreatment BDNF protein level was inversely correlated with the maximum TNSr, FACT-GOG-NTx, and PHQ-9 scores in both genotypes. BDNF patients with the Val/Val genotype demonstrated significantly higher maximum FACT-GOG-NTx and PHQ-9 scores than those with the Val/Met and Met/Met genotypes (Met-BNDF carriers). Correlations between PHQ-9 and TNSr score were found only in Met-BDNF carriers, suggesting that peripheral neuropathy and depression coincide in Met-BDNF carriers. CONCLUSIONS: Determining the BDNF protein levels before initiating chemotherapy might be a useful tool for CIPN risk assessment and preemptive dose modification. The present data should be validated in larger studies that include other neurotoxic agents.

Malnutrition risk is associated with hypoglycemia among general population admitted to internal medicine units. Results from the MENU study.

BACKGROUND/OBJECTIVES: To examine the association between increased malnutrition risk upon admission, and the incidence of hypoglycemia among adult patients admitted to internal medicine units in Israel. SUBJECTS/METHODS: This was a cross-sectional study, and included were all adult patients admitted to internal medicine units, regardless of reason for admission. The NRS2002 was used to for nutritional screening. All glucose measurements were obtained using an institutional blood glucose-monitoring system, which consisted of a point of care, automated glucometer, and an interactive database. Patients were categorized as hypoglycemic if they had at least one documented hypoglycemia (= <70 mg/dL) event during the hospitalization period. Blood chemistry measured at admission was also recorded. RESULTS: Included were 876 patients (mean age 70.0 ± 17.3, 50.6% were males). Rate of positive malnutrition screen was 39.7% of the population. A total of 5.4% of the study population had at least one hypoglycemic event during hospitalization. Rate of diabetes mellitus did not differ between patients with or without hypoglycemia. A greater proportion of patients with hypoglycemia were at increased malnutrition risk compared to patients without documented hypoglycemic events (56.8% vs. 38.9%, p = 0.018). Patients who had hypoglycemia had higher NRS2002 scores for pre-hospitalization unintentional weight loss and reduced food consumed. In logistic regression analysis, increased malnutrition risk was associated with hypoglycemia occurrence (OR 1.982, 95% confidence interval 1.056-3.718, p = 0.033). Age, sex, and diabetes mellitus status did not affect the rate of hypoglycemia. CONCLUSIONS: Our data suggest increased malnutrition risk as measured by the NRS2002 almost doubled the risk for hypoglycemia during the hospitalization.

Severe Coagulation Disorder and Thrombocytopenia Associated with Tigecycline - Case Report and Review of Literature.

Herein, we report a 70-year-old male patient, with recurrent multiple hepatic abscesses, that was admitted to the internal medicine department for treatment of Carbapenem Resistant Escherichia Coli (CRE) bacteremia. The patient was treated with Tigecycline; few days later, he developed "Disseminated Intravascular Coagulation (DIC)" like coagulation study abnormality that seemed to be related to Tigecycline treatment. Upon discontinuing it, the DIC-like condition was resolved. Tigecycline should be considered as a possible etiological factor in patients with DIC-like, and this therapy should be withdrawn immediately in suspected cases.

MEasuring Nutrition risk in hospitalized patients: MENU, a hospital-based prevalence survey.

BACKGROUND: Depending on the definition used, malnutrition is prevalent among 20-50% of hospitalized patients. Routine nutritional screening is necessary to identify patients with or at increased risk for malnutrition. The Nutrition Risk Screening (NRS 2002) has been recommended as an efficient tool to identify the risk of malnutrition in adult inpatients. OBJECTIVES: To utilize the NRS 2002 to estimate the prevalence of malnutrition among newly hospitalized adult patients, and to identify risk factors for malnutrition. METHODS: During a 5 week period, all adult patients newly admitted to all inpatient departments (except Maternity and Emergency) at Wolfson Medical Center, Holon, were screened using the NRS 2002. An answer of "yes" recorded for any of the Step 1 questions triggered the Step 2 screen on which an age-adjusted total score > or = 3 indicated high malnutrition risk. RESULTS: Data were obtained from 504 newly hospitalized adult patients, of whom 159 (31.5%) were identified as being at high risk for malnutrition. Malnutrition was more prevalent in internal medicine than surgical departments: 38.6% vs. 19.1% (P < 0.001). Body mass index was within the normal range among subjects at high risk for malnutrition: 23.9 +/- 5.6 kg/m2 but significantly lower than in subjects at low malnutrition risk: 27.9 +/- 5.3 kg/m2 (P < 0.001). Malnutrition risk did not differ by gender or smoking status, but subjects at high malnutrition risk were significantly older (73.3 +/- 16.2 vs. 63.4 +/- 18.4 years, P < 0.001). Total protein, albumin, total cholesterol, low density lipoprotein-cholesterol, hemoglobin and % lymphocytes were all significantly lower, whereas urea, creatinine and % neutrophils were significantly higher in patients at high malnutrition risk. CONCLUSIONS: Use of the NRS 2002 identified a large proportion of newly hospitalized adults as being at high risk for malnutrition. These findings indicate the need to intervene on a system-wide level during hospitalization.