Systemic Inflammatory Disorder Research Articles

Humoral Response to SARS-CoV-2 Antigen in Patients Treated with Monoclonal Anti-CD20 Antibodies: It Is Not All about B Cell Recovery.

Anti-CD20 therapies decrease the humoral response to SARS-CoV-2 immunization. We aimed to determine the extent of the humoral response to SARS-CoV-2 antigens in correlation with peripheral B-cell dynamics among patients with central nervous system inflammatory disorders treated with anti-CD20 medications. We retrospectively included patients receiving anti-CD20 therapy after antigen contact who were divided into responders (>7 binding antibody units (BAU)/mL) and non-responders (<7 BAU/mL). In participants with first antigen contact prior to therapy, we investigated the recall response elicited once under treatment. We included 80 patients (responders n = 34, non-responders n = 37, recall cohort n = 9). The B-cell counts among responders were significantly higher compared to non-responders (mean 1012 cells/µL ± SD 105 vs. mean 17 cells/µL ± SD 47; p < 0.001). Despite very low B-cell counts (mean 9 cells/µL ± SD 20), humoral response was preserved among the recall cohort (mean 1653 BAU/mL ± SD 2250.1) and did not differ significantly from responders (mean 735 BAU/mL ± SD 1529.9; p = 0.14). Our data suggest that peripheral B cells are required to generate antibodies to neo-antigens but not for a recall response during anti-CD20 therapy. Evaluation of B-cell counts and pre-existing SARS-CoV-2 antibodies might serve as biomarkers for estimating the immune competence to mount a humoral response to SARS-CoV-2 antigens.

Downregulation of UBA1 in Myelodysplastic Syndrome

Somatic loss-of-function mutations of major E1 ubiquitin activating enzyme gene UBA1 were identified in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) and myelodysplastic syndromes (MDS) recently, suggesting that impairment of UBA1 activity contributes to pathogenesis of these diseases that have systemic inflammatory disorders. We sought to determine whether abnormal expression of UBA1 also occurs in MDS and contributes to development of disease. We analyzed RNA sequencing results obtained from the CD34+ bone marrow hematopoietic stem and progenitor cells (BM HSPC) in a cohort containing treatment naive MDS (N=55), chronic myelomonocytic leukemia (CMML, N=22), and heathy donors (N=12). Since UBA1 is an X-chromosome linked gene that escapes X-chromosomal silencing in females, all donors in this cohort were males. Results indicated that the level of UBA1 RNA was significantly downregulated in MDS but not in CMML. In the subtypes of MDS-low blasts (N=23, including MDS with ring sideroblasts, multilineage dysplasia, and single lineage dysplasia), forty-eight percent (N=11) had an over 1.5-fold downregulation of UBA1 RNA expression. Based on gene set enrichment assay, the UBA1 downregulation in MDS-low blasts was associated with altered autophagy and innate immune signaling such as complement, IL6, and TNF signals. Moreover, we also identified that the UBA1 downregulation in BM CD34+ cells of MDS-low blasts co-occurred with SF3B1 mutations detected by targeted next generation sequencing in BM mononuclear cells: Among the 11 MDS-low blasts patients with downregulated UBA1 expression, six patients (55%) carried mutant SF3B1, whereas none of the 12 patients with normal UBA1 expression had SF3B1 mutation. In another word, all SF3B1 mutant patients with MDS-low blasts (N=6) presented decreased UBA1 RNA. To characterize whether impairment of UBA1 affects hematopoietic functions of BM HSPC, we applied TAK-243, an UBA1 specific inhibitor, to BM CD34+ cells isolated from healthy donors (N=5, all males) and cultured in vitro. Colony formation unit (CFU) assays were performed to evaluate hematopoietic repopulating activity. Results indicated the CFU in CD34+ cells treated by TAK-243 was significantly reduced compared with cells treated by vehicle control (P<0.05). Moreover, when hematopoietic colonies formed by CD34+ cells were collected from methylcellulose plates and characterized by flow cytometry analysis, the frequency of CD71-/ CD235+ erythroid cells in TAK-243 treated plates was significantly lower than that in control plates (P<0.05). These results implicated that impairment of UBA1 activity perturbed hematopoietic functions of BM HSPC, particularly the erythropoietic function. We next evaluated in vivo hematopoietic impact of UBA1 impairment by applying TAK-243 to wildtype male B6 mice. Compared to vehicle control treated mice (N=4), mice treated by TAK-243 (N=4) exhibited significant decreases in hemoglobin and white cell counts (P<0.05) in peripheral blood (PB) and splenomegaly. In BM compartment, TAK-243 treated mice had decreased CD71+ and Ter119+ erythroid populations and increased Gr1+/ CD11b+ myeloid population (P<0.05). TAK-243 treatment also altered BM HSPCs, including reduced megakaryocyte-erythroid progenitor (MEP) and increased granulocyte-monocyte progenitor (GMP) in BM, as well as reduced CD150+/ CD48- stem cells in the BM Lin-/ Sca1+/ cKit+ (LSK) population. Moreover, BM LSK isolated from TAK-243 treated mice (N=4) formed significantly reduced number of colonies compared to vehicle control treated mice (N=4) in CFU assay. Consistently, in competitive transplantation assay, repopulating activity of BM cells of TAK-243 treated mice was significantly impaired, as measured by the donor-derived CD45.2 chimerism in PB of the CD45.1 recipients. Moreover, we performed bulk RNA-Seq in BM LSK of drug treated mice, which revealed that the ribosomal function and cell cycle regulation signals in TAK-243 treated mice were significantly affected. In summary, our study indicated that, in addition to somatic mutations, there was also a significant downregulation of UBA1 expression in BM HSPC of MDS. Compromised UBA1 function impairs hematopoietic function of BM HSPC, which could be an important mechanism for pathogenesis of MDS.

Abstract 14569: Impact of Psoriasis on Inpatient Outcomes of Patients Admitted for Coronary Artery Bypass Graft: Analysis of the National Inpatient Sample

Introduction: Psoriasis is a systemic chronic inflammatory disorder with a global prevalence of 2-3%. Characterized by its skin manifestations and multiple comorbidities, it is notably associated with 50% increased likelihood of coronary artery, cerebrovascular and peripheral artery diseases. This study aims to assess the impact of psoriasis on inpatient outcomes of patients admitted for coronary artery bypass graft (CABG). Hypothesis: Co-existing psoriasis worsens hospital outcomes in patients admitted for CABG. Methods: We searched the National Inpatient Sample (NIS) 2016-17 database to identify adult hospitalizations with CABG as the principal diagnosis with and without psoriasis as a secondary diagnosis using ICD-10 codes. The primary outcome was inpatient mortality. Secondary outcomes were length of hospital stay (LOS) and total hospital charge (THC). Using Stata 17 software, multivariable logistic and linear regression analysis were applied to adjust for confounders. Results: There were over 71 million discharges included in the combined 2016-17 NIS database. Out of 477,389 CABG hospitalizations, 3,765 (0.8%) had psoriasis. The adjusted odds ratio (AOR) for inpatient mortality for CABG with co-existing psoriasis compared to those without psoriasis was 0.67 (95% CI 0.39-1.15, p=0.146). Hospitalizations for CABG with co-existing psoriasis had a decreased adjusted mean LOS by -0.44 days (95% CI {-0.85} - {-0.25}, p=0.037) and incurred a lower THC by -16,178.83 USD (95% CI {-27,541.02} - {4,816.63}, P=0.005) compared to those without psoriasis. Conclusions: In summary our study showed that CABG patients with psoriasis had a lower THC and LOS with no significant difference in mortality compared to CABG patients without psoriasis. It may be attributed to younger age group or immunosuppressive therapy and might warrant investigation into a more lenient CABG criteria for psoriasis patients.

Direct Action of Non-Digestible Oligosaccharides against a Leaky Gut.

The epithelial monolayer is the primary determinant of mucosal barrier function, and tight junction (TJ) complexes seal the paracellular space between the adjacent epithelial cells and represent the main "gate-keepers" of the paracellular route. Impaired TJ functionality results in increased permeation of the "pro-inflammatory" luminal contents to the circulation that induces local and systemic inflammatory and immune responses, ultimately triggering and/or perpetuating (chronic) systemic inflammatory disorders. Increased gut leakiness is associated with intestinal and systemic disease states such as inflammatory bowel disease and neurodegenerative diseases such as Parkinson's disease. Modulation of TJ dynamics is an appealing strategy aiming at inflammatory conditions associated with compromised intestinal epithelial function. Recently there has been a growing interest in nutraceuticals, particularly in non-digestible oligosaccharides (NDOs). NDOs confer innumerable health benefits via microbiome-shaping and gut microbiota-related immune responses, including enhancement of epithelial barrier integrity. Emerging evidence supports that NDOs also exert health-beneficial effects on microbiota independently via direct interactions with intestinal epithelial and immune cells. Among these valuable features, NDOs promote barrier function by directly regulating TJs via AMPK-, PKC-, MAPK-, and TLR-associated pathways. This review provides a comprehensive overview of the epithelial barrier-protective effects of different NDOs with a special focus on their microbiota-independent modulation of TJs.

Adult-Onset Still's Disease-A Complex Disease, a Challenging Treatment.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with an unknown cause characterized by high-spiking fever, lymphadenopathy, hepatosplenomegaly, hyperferritinemia, and leukocytosis. The clinical course can be divided into three significant patterns, each with a different prognosis: Self-limited or monophasic, intermittent or polycyclic systemic, and chronic articular. Two criteria sets have been validated. The Yamaguchi criteria are the most generally used, although the Fautrel criteria offer the benefit of adding ferritin and glycosylated ferritin values. AOSD's pathogenesis is not yet completely understood. Chemokines and pro-inflammatory cytokines, including interferon (IFN)-γ, tumor necrosis factor α (TNFα), interleukin (IL)-1, IL-6, IL-8, and IL-18, play a crucial role in the progression of illness, resulting in the development of innovative targeted therapeutics. There are no treatment guidelines for AOSD due to its rarity, absence of controlled research, and lack of a standard definition for remission and therapy objectives. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are used in AOSD treatment. Biological therapy, including IL-1, IL-6, IL-18, and IL-17 inhibitors, as well as TNFα or Janus-kinases (JAKs) inhibitors, is administered to patients who do not react to CS and csDMARDs or achieve an inadequate response.

Oral-gut bacterial profiles discriminate between periodontal health and diseases.

This investigation explored oral-gut microbial signatures with potential to distinguish among periodontal conditions. The interplay between the oral and gut microbiomes may be a critical pathway linking periodontal diseases and systemic inflammatory disorders. The mechanisms by which oral microorganisms translocate to the gut and cause microbial dysbiosis, favoring an inflammatory state, are still unknown. As a first approach, characterization of oral-gut microbial profiles associated with periodontal health and diseases can provide insights on such mechanisms of etiology and pathogenesis. Fecal and saliva samples from individuals with periodontal health (PH, 8), gingivitis (GG, 17), and periodontitis (PD, 24) were analyzed for their microbial composition by 16S rRNA gene sequencing. Microbial taxa were compared and correlated to periodontal parameters. Multivariate discriminant analysis (MDA) was carried out to identify profiles related to health and disease. Few significant differences in oral-gut taxa were detected among clinical groups, although increase in fecal Fusobacterium nucleatum ss vincentii and salivary Aggregatibacter actinomycetemcomitans, Parvimonas micra, and Fretibacterium sp. HMT358 were strongly correlated with deep pockets and inflammation (p < .01). Over 50% of the fecal microbiota comprised microorganisms shared between oral and gut sites, whereas oral taxa were detected in approximately 9%, particularly enriched in GG fecal samples (p=.04). Trends for lower fecal richness and higher salivary diversity in PD compared to PH were observed. MDA was able to classify correctly 82% of the patients into the clinical groups. Main classifiers of periodontitis were high BMI, older age, and enrichment of oral-fecal Leptotrichia sp. HMT4, Peptostreptococcus stomatis, Dialister invisus, and a novel Lautropia sp. HMTC89-like organism. Within the limitations of an exploratory investigation, specific profiles of oral-gut taxa, including known and potential novel organisms, combined with social-demographic features were able to discriminate individuals with periodontal diseases in this study population.

Inflammatory Disorders of the Central Nervous System Vessels: Narrative Review.

Inflammatory disorders of the central nervous system (CNS) vessels, also called CNS vasculitides, can cause substantial disability or even be fatal. Inflammation of the CNS vessels can be caused by primary angiitis of the CNS (PACNS), inflammatory cerebral amyloid angiopathy, or systemic inflammatory disorders. Clinical symptoms of these disorders are often non-specific, such as encephalopathy, cognitive and affective abnormalities, headache and focal neurological symptoms. Diagnostic workup includes a thorough neuropsychiatric examination, blood and cerebrospinal fluid analysis and magnetic resonance imaging (MRI) of the brain and its vessels. Biopsy of the brain remains the gold standard diagnostic test. Timely diagnosis and treatment initiation is of high importance, as it might prevent severe complications, such as ischemic and hemorrhagic stroke. In this review, we describe the specific characteristics of primary and secondary non-infectious CNS vasculitides which help to establish the diagnosis, discuss the peculiarities of the diagnostic workup and present current treatment recommendations.

Anemia and thrombocytosis associated with erythrodermic psoriasis successfully treated with ixekizumab: A case report

Introduction: Erythrodermic psoriasis is a rare and potentially life-threatening subtype of psoriasis. It can be accompanied by systemic inflammatory disorders such as arthritic, hematologic, hemodynamic, and metabolic disturbances. We herein report a case involving a woman with erythroderma, joint deformities, anemia, and thrombocytosis who was diagnosed with erythrodermic psoriasis and psoriasis arthritis that were successfully treated with interleukin-17A antibody. Case presentation: A 35-year-old woman presented with an almost 20-year history of recurrent erythema and desquamation. She was diagnosed with plaque psoriasis and psoriatic arthritis and treated with acitretin, etanercept combined with methotrexate, and etanercept combined with cyclosporin, respectively. However, at the time of consultation, she was experiencing an episode of severe skin and joint inflammation. Routine laboratory evaluation revealed moderate microcytic hypochromic anemia, thrombocytosis, and increased serum cytokine concentrations. The patient was given the standard dose of ixekizumab, which resulted in clearance of her skin lesions with a Psoriasis Area and Severity Index 90 response at week 12. Her arthritic symptoms, including arthralgia and joint dysfunction, also improved. Moreover, her hemoglobin concentration, platelet count, and inflammatory markers reached the normal ranges. Discussion: Multiple cytokines participate in the pathogenesis of erythrodermic psoriasis, including interleukin-17A, interleukin-6, interleukin-1β, and interleukin-8. In the present case, treatment targeting the interleukin-23/interleukin-17 axis showed great efficacy not only for the skin lesions but also for systemic inflammatory comorbidities, such as arthritis, anemia, and thrombocytosis. Conclusion: Patients with systemic inflammatory disorders related to psoriasis, such as anemia and thrombocytosis, may benefit from anti-IL-17A treatment.

Epicardial adipose tissue in patients with systemic sclerosis

Abstract Background Cardiac involvement is a major cause of death in patients with systemic sclerosis (SSc). Epicardial adipose tissue (EAT) has recently emerged as a mediator between systemic inflammatory disorders and cardiovascular disease, and may therefore play a role in the pathophysiology of cardiac involvement in SSc. Purpose To assess the correlation between EAT mass and left ventricular (LV) function, and to determine the prognostic value of EAT in patients with SSc. Methods Consecutive patients with SSc who underwent non-contrast thorax computed tomography and echocardiography were included. EAT mass was quantified using dedicated software (Figure A). The study endpoint was all-cause mortality. Results A total of 230 SSc patients [age 53±15 years, 14% male] were included. The median value of EAT mass was 67g (IQR: 45–101g). Patients with increased EAT mass (≥67g) showed specifically more impaired LV diastolic function as compared to patients with less EAT mass (&amp;lt;67g). After adjusting for age and comorbidities, EAT remained independently associated with LV diastolic function parameters including left atrial volume index (B=0.031, P=0.025), LV mass index (B=0.139, P=0.036), E/E$'$ (B=0.025, P&amp;lt;0.001) and E' (B=−0.012, P&amp;lt;0.001). During a median follow-up of 8 years 42 patients died, and by Kaplan-Meier analysis patients with increased EAT mass showed higher all-cause mortality rate as compared to patients with less EAT mass (log-rank p&amp;lt;0.001, Figure B). On multivariate analysis, EAT mass was independently associated with all-cause mortality (HR: 1.006; 95% CI: 1.001–1.010; p=0.010). Conclusion In patients with SSc, EAT mass is independently associated with LV diastolic dysfunction and higher mortality rate. Funding Acknowledgement Type of funding sources: None.

TAFRO Syndrome That Responded to Prednisolone-only Treatment: Evaluating Changes in IL-6.

Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is a systemic inflammatory disorder characterized by the above-mentioned symptoms. Because of the similarity in phenotypes between TAFRO syndrome and decompensated liver cirrhosis, an accurate diagnosis is often difficult. We herein report a 62-year-old Japanese patient with TAFRO syndrome who was misdiagnosed with intractable ascites associated with liver cirrhosis. Improvement of symptoms after treatment with prednisolone was associated with interleukin-6 rather than C-reactive protein. The pathogenesis of TAFRO syndrome, which has similar clinical manifestations to liver cirrhosis, remains unclear, and our findings may help elucidate the concept of this condition.

An uncommon case of complete AV block

BackgroundGranulomatosis with polyangiitis (GPA) is a rare systemic inflammatory disorder characterized by vasculitis of the small vessels, as well as necrotizing granulomatous lesions, affecting mainly upper and lower respiratory tracts, lungs and kidneys. Cardiac involvement has traditionally been a rare manifestation of GPA, with misleading clinical presentation until late stages. Cardiac conducting tissue involvement is a rare and potentially life-threatening complication.Case presentationWe report the case of a 45-year-old man diagnosed with GPA with typical symptoms, but also complete atrioventricular (AV) block at the onset of the disease. The echocardiogram was unremarkable but the cardiac magnetic resonance (CMR) showed evidence of inflammation of the basal and septal ventricle walls. Despite effective immunosuppressive therapy, a permanent pacemaker was required for recurring complete AV block.DiscussionConduction system abnormalities are a rare manifestation of GPA, due to granulomatous lesions within the conduction system, or arteritis of the atrioventricular nodal artery. Patients are often asymptomatic, so careful and regular screening for cardiac involvement in this multi-system condition is required, often with echocardiogram, electrocardiogram (ECG) monitoring and CMR. Early immunosuppressive treatment may reverse a complete AV block but a pacemaker implantation may sometimes be necessary.

Drug-related immune-mediated myelopathies.

Iatrogenic immune-mediated inflammatory disorders of the spinal cord are an uncommon but potentially severe complication of drug therapy for several human diseases. Particularly the introduction of novel biological agents in the treatment of systemic inflammatory disorders and cancer immunotherapy have led to a significant increase in immune-related adverse events of the central nervous system (CNS). The use of Tumor necrosis factor alpha (TNF-alpha) inhibitors in rheumatic and inflammatory bowel diseases has been associated with demyelinating and other inflammatory CNS conditions, including myelitis. The introduction of immune checkpoint inhibitors in the treatment of several human malignancies has led to an increase in drug-induced immune-related adverse events including in the CNS. Other drugs that have been associated with immune-mediated myelitis include tyrosine-kinase inhibitors and chimeric antigen receptor (CAR) T Cell therapy. A high degree of suspicion is necessary when diagnosing these conditions, as early diagnosis and treatment is crucial in preventing further neurological damage and disability. The treatment of drug-induced inflammatory myelitis typically involves administration of high-dose intravenous corticosteroids, however additional immunosuppressive agents may be required in severe or refractory cases. While most cases are monophasic and remit following discontinuation of the offending agent, chronic immunosuppressive therapy may be indicated in cases with a progressive or relapsing disease course or when a diagnosis of a specific underlying neuro-inflammatory disorder is made. Outcomes are generally favorable, however depend on the specific therapeutic agent used, the clinical presentation and patient factors. In this review we aim to describe the clinical characteristics, imaging findings and management for the most common forms of iatrogenic immune-mediated myelopathies.

Cytokine system in the patients with type 2 diabetes mellitus non-infected with SARS-CoV-2

Diabetes mellitus (DM) is a common chronic non-communicable disease, being the most significant comorbidity in SARS-CoV-2 viral infection. The proportion of DM patients among those with COVID-19 is up to 25.0% in the Russian Federation. In presence of DM, clinical course of COVID-19 is characterized by greater severity and persistence of pulmonary damage, an increased need for immunosuppressive, glucocorticoid and combined antiviral therapy in COVID-19 patients, and with prolonged rehabilitation period. Pathogenetic effects of DM on severe course of the SARS-CoV-2 viral infection are being actively studied. The following factors were considered, e.g., negative impact of hyperglycemia on the course of infection; direct cytotoxic and indirect damage to pancreatic -cells with further activation of pro-inflammatory mechanisms; cumulation and progression of generalized inflammation common to DM and COVID-19 including impaired production of cytokines; influence of SARS-CoV-2 virus on the renin-angiotensin-aldosterone system causing inhibition of insulin secretion and increased insulin resistance. Chronic inflammation and impaired immune response may be among the main mechanisms of association between type 2 DM (T2DM) and COVID-19. It is important to identify systemic inflammatory disorders in patients with type 2 diabetes, which may be associated with greater disease severity, being of negative prognostic value. The aim of the present work was to investigate concentrations of some serum cytokines in the patients with type 2 diabetes not infected with SARS-CoV-2.&#x0D; The study included 20 patients with type 2 diabetes; the control group consisted of 11 clinically healthy volunteers. The serum concentration of 13 cytokines was assessed by multiplex analysis on a MAGPIX-100 immunoanalyzer using a Merck multiplex analysis kit (Germany), in accordance with the manufacturers instructions.&#x0D; Increased serum concentrations in T2DM patients were found, as compared with the control group for some key pro-inflammatory cytokines: CX3CL1, TNF, IFN, IL-8, IL-17A, MIP-1, and MIP-1. We have also revealed a decrease in serum concentrations of IL-4. Serum immunoregulatory cytokines in the T2DM were found to be changed in different directions: a decrease in IL-5, along with increase of IL-12p70 and IL- 17, whereas the serum contents of IL-2, IL-13 did not change.&#x0D; A comprehensive analysis of serum cytokine concentrations may increase clinical significance of assessing serum cytokine concentrations as prognostic and diagnostic markers, as well as therapeutic targets in type 2 DM, like as in SARS-CoV-2 infection.

Antidepressant Effect of Ketamine on Inflammation-Mediated Cytokine Dysregulation in Adults with Treatment-Resistant Depression: Rapid Systematic Review.

Background Major depressive disorder (MDD) and treatment-resistant depression (TRD) represent a global source of societal and health burden. To advise proper management of inflammation-related depression among TRD patients, it is important to identify therapeutic clinical treatments. A key factor is related to proinflammatory cytokines such as interleukin- (IL-) 1β, IL-6, and tumor necrosis factor- (TNF-) α which have been implicated in the pathogenesis of depressive symptoms in MDD patients. Ketamine may provide an anti-inflammatory therapeutic strategy by targeting proinflammatory pathways associated with depressive disorders, which may be exacerbated in the ageing population with TRD. Objective Despite a burgeoning body of literature demonstrating that inflammation is linked to TRD, there is still a lack of comprehensive research on the relationship between proinflammatory biomarkers and ketamine's antidepressant effect on TRD patients. Method The Cochrane Library and PubMed/MEDLINE databases were systematically searched from inception up to February 1, 2022, adopting broad inclusion criteria to assess clinical topics related to the impact of ketamine on inflammatory cytokines in TRD patients. The present work is in compliance with the World Health Organization Rapid Review Guide. Results Five out of the seven studies examined in this review show that ketamine infusion may reduce depressive symptoms with a quick start of effect on TRD patients. Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D) scores, the overall response rate for ketamine was 56%; that is, 56% of those treated with ketamine had MADRS/HAM-D scores decreased by at least 50%. Conclusions While the anti-inflammatory effects of ketamine modulate specific proinflammatory cytokines, its rapid antidepressant effect on TRD patients remains inconsistent. However, our study findings can provide a reliable basis for future research on how to improve systemic inflammatory immune disorders and mental health. We suggest that ketamine infusion may be part of a comprehensive treatment approach in TRD patients with elevated levels of depression-specific inflammatory biomarkers.

32607 Risk of cardiovascular events and all cause mortality in patients with atopic dermatitis: A population-based cohort study

Atopic dermatitis (AD) is a systemic inflammatory disorder that may increase risk for cardiovascular (CV) events, but data are limited, particularly in children. We performed a population-based cohort study to quantify the risk of CV events and all-cause mortality in AD patients using a UK-based electronic medical records database from 1994 to 2015. 625,083 adults (≥18 y) and 409,431 children (<18 y) with AD were matched on age, practice, index date to 2,678,888 adult and 1,809,029 pediatric unaffected controls, respectively. In adults, we observed an association between AD and stroke (HR 1.04 [1.02-1.06]), particularly among those with severe AD (HR 1.21 [1.13-1.30]). Severe AD was associated with an increased risk of MI (HR 1.27 [1.15-1.39]) while no difference was detected for mild or moderate AD. Relative to non-AD controls, the risk of death was elevated among patients with mild AD (HR 1.13 [1.12-1.14]), but lower among those with moderate (HR 0.90 [0.89-0.91]) and at unity in severe AD (HR 0.99 [0.94-1.03]). In children, severe AD was associated with greater risk of stroke (HR 2.43 [1.13-5.22]). There was no association between pediatric AD and MI (HR 0.75 [0.28-1.99]). Compared with controls, the risk of death was lower among children with AD, particularly among those with mild or moderate disease (HRs 0.75 [0.66-0.85] and 0.48 [0.33-0.70], respectively). In conclusion, severe AD appeared to be associated with increased risk of several major CV events but not mortality, supporting the need for additional investigation into this relationship, as this is critical in understanding natural history of disease.

33257 Secukinumab effects on cardiovascular risk factors in patients with psoriasis, psoriatic arthritis and axial spondyloarthritis: Results from post hoc analyses of pooled data from 19 phase 3/4 clinical studies

Psoriasis (PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (AxSpA) are chronic systemic inflammatory disorders closely associated with cardiovascular (CV) disease. Here, we evaluated the effect of secukinumab on CV risk parameters in 9197 patients included in a post hoc analysis of 19 pooled phase 3/4 secukinumab studies in PsO (n = 4742), PsA (n = 2475), and AxSpA (n = 1980). Traditional (body mass index [BMI], fasting glucose, blood pressure, cholesterol, and lipids) and inflammatory CV risk parameters (high-sensitivity C-reactive protein [hsCRP] and neutrophil-lymphocyte ratio [NLR]) were assessed.

Molecular Modeling Guided Drug Designing for the Therapeutic Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that can cause destructive joint disease, significant disability, and increased mortality. RA is the most frequent of all chronic inflammatory joint diseases, and its prevalence frequency in Pakistan is 1.6 per thousand people. Different cytokines and receptors were involved in the triggering of RA, including interleukin-6 (ILR-6), major histocompatibility complex (MHC) antigen human leukocyte (HLA-DR) receptor, and CD20. Several studies illustrated RA as an inherent immune response and triggered due to the “shared epitope.” Therefore, the involvement of all these receptors (IL-6, HLA-DR, and CD20) leads to the neurological, ocular, respiratory, cardiac, skin, and hematological manifestations that have been considered a potential therapeutic target for drug design. Various herbal, natural, and synthetic source inhibitors of interleukin-6 (IL-6), human leukocyte (HLA-DR), and CD20 were studied and reported previously. Reported inhibitors are compared to elucidate the best inhibitor for clinical trials, leading to the orally active drug. In this study, a computer-aided drug designing approach disclosed the potential inhibitors for all receptors based on their distinct binding affinity. Moreover, drug suitability was carried out using Lipinski’s rule by considering the adsorption, distribution, metabolism, and excretion (ADME) of ligands. Results elucidated “calycosin 7-O-glucoside” and “angeliferulate” as putative ligands for IL-6 and HLA-DR, respectively. However, the pharmacokinetic properties (ADMET) revealed angeliferulate as an effete ligand for the biological system compared to calycosin 7-O-glucoside. Based on docking, drug toxicity profiling or pharmacokinetics, and MD simulation stability, this study highlights orally active therapeutic inhibitors to inhibit the activity of pivotal receptors (IL6, HLA-DR, and CD20) of RA in humans. After clinical trials, the resultant inhibitors could be potential therapeutic agents in the drug development against RA.

Activation mechanisms of monocytes/macrophages in adult-onset Still disease.

Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms. Thereafter, IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1β and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

The Role of Cutibacterium acnes in Sarcoidosis: From Antigen to Treatable Trait?

Cutibacterium acnes (C. acnes, formerly Propionibacterium acnes) is considered to be a non-pathogenic resident of the human skin, as well as mucosal surfaces. However, it also has been demonstrated that C. acnes plays a pathogenic role in diseases such as acne vulgaris or implant infections after orthopedic surgery. Besides a role in infectious disease, this bacterium also seems to harbor immunomodulatory effects demonstrated by studies using C. acnes to enhance anti-tumor activity in various cancers or vaccination response. Sarcoidosis is a systemic inflammatory disorder of unknown causes. Cultures of C. acnes in biopsy samples of sarcoidosis patients, its presence in BAL fluid, tissue samples as well as antibodies against this bacterium found in serum of patients with sarcoidosis suggest an etiological role in this disease. In this review we address the antigenic as well as immunomodulatory potential of C. acnes with a focus on sarcoidosis. Furthermore, a potential role for antibiotic treatment in patients with sarcoidosis will be explored.

COVID-19 Vaccination in Autoimmune Diseases (COVAD) study: Vaccine safety in idiopathic inflammatory myopathies.

Introduction/AimsIn this study we investigated COVID‐19 vaccination–related adverse events (ADEs) 7 days postvaccination in patients with idiopathic inflammatory myopathies (IIMs) and other systemic autoimmune and inflammatory disorders (SAIDs).MethodsSeven‐day vaccine ADEs were collected in an international patient self‐reported e‐survey. Descriptive statistics were obtained and multivariable regression was performed.ResultsTen thousand nine hundred respondents were analyzed (1227 IIM cases, 4640 SAID cases, and 5033 healthy controls [HCs]; median age, 42 [interquartile range, 30‐455] years; 74% female; 45% Caucasian; 69% completely vaccinated). Major ADEs were reported by 76.3% of the IIM patients and 4.6% reported major ADEs. Patients with active IIMs reported more frequent major (odds ratio [OR], 2.7; interquartile range [IQR], 1.04‐7.3) and minor (OR, 1.5; IQR, 1.1‐2.2) ADEs than patients with inactive IIMs. Rashes were more frequent in IIMs (OR, 2.3; IQR, 1.2‐4.2) than HCs. ADEs were not impacted by steroid dose, although hydroxychloroquine and intravenous/subcutaneous immunoglobulins were associated with a higher risk of minor ADEs (OR, 1.9; IQR, 1.1‐3.3; and OR, 2.2; IQR, 1.1‐4.3, respectively). Overall, ADEs were less frequent in inclusion‐body myositis (IBM) and BNT162b2 (Pfizer) vaccine recipients.DiscussionSeven‐day postvaccination ADEs were comparable in patients with IIMs, SAIDs, and HCs, except for a higher risk of rash in IIMs. Patients with dermatomyositis with active disease may be at higher risk, and IBM patients may be at lower risk of specific ADEs. Overall, the benefit of preventing severe COVID‐19 through vaccination likely outweighs the risk of vaccine‐related ADEs. Our results may inform future guidelines regarding COVID‐19 vaccination in patients with SAIDs, specifically in those with IIMs. Studies to evaluate long‐term outcomes and disease flares are needed to shed more light on developing future COVID‐19 vaccination guidelines.