Seropositivity For Autoantibodies Research Articles

Staging of operative link on gastritis assessment and operative link on gastric intestinal metaplasia systems for risk assessment of early gastric cancer: a case–control study

AimsOperative link on gastritis assessment (OLGA) and operative link on gastric intestinal metaplasia assessment (OLGIM) systems are histological staging systems of gastritis for gastric cancer (GC) risk estimation. Intermediate OLGA/OLGIM...

Abstract 12535: Spontaneous Coronary Artery Dissection in Women: A New Role for Autoimmunity?

Introduction: Spontaneous coronary artery dissection (SCAD) is an uncommon cause of myocardial infarction (MI) in women, with a still unclear pathophysiology. Autoantibodies targeting angiotensin-II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) (AT1R-AAs and ETAR-AAs, respectively) lead to endothelial dysfunction and have already been associated with aortic dissection. Hypothesis: We hypothesized that titers of AT1R-AAs and ETAR-AAs are higher in patients with SCAD compared to controls. Methods: Our case-control study was conducted at Padua University Hospital between January 2022 and June 2022. Female patients diagnosed at coronary angiography with MI and SCAD were consecutively enrolled. Ten women with SCAD and 20 age-matched controls (10 women with ST-elevation MI (STEMI) and 10 healthy women) were included. Serum levels for AT1R-AAs and ETAR-AAs were determined for each participant. Absolute autoantibody titers and seropositivity prevalence were compared between SCAD patients, STEMI patients, and healthy women. Seropositivity was defined according to the threshold value suggested by the manufacturer (>10 U/mL). Results: Six out of 10 (60%) women with MI and SCAD were seropositive for AT1R-AAs and ETAR-AAs. In contrast, only one (10%) healthy woman and one (10%) STEMI patient were seropositive for AT1R-AAs (p=0.03 and p=0.03, respectively). One STEMI patient was seropositive for ETAR-AAs, while none of the healthy women was found to be seropositive (p=0.03 and p=0.01, respectively). The median autoantibody titer was significantly higher in SCAD patients than in healthy women (p=0.01 for AT1R-AAs; p=0.02 for ETAR-AAs) and STEMI patients (p<0.001 for AT1R-AAs; p=0.002 for ETAR-AAs). Conclusions: AT1R-AAs and ETAR-AAs seropositivity is significantly higher in SCAD women than in healthy women or female patients with STEMI. Our findings suggest a possible role for AT1R-AAs and ETAR-AAs in the pathophysiology of SCAD in women with MI.

Aberrant B-cell activation and B-cell subpopulations in rheumatoid arthritis: analysis by clinical activity, autoantibody seropositivity, and treatment.

Few studies analyze the role of B-cell subpopulations in rheumatoid arthritis (RA) pathophysiology. Therefore, this study aimed to analyze the differences in B-cell subpopulations and B-cell activation according to disease activity, RA subtype, and absence of disease-modifying antirheumatic drugs (DMARDs) therapy. These subgroups were compared with control subjects (CS). One hundred and thirty-nine subjects were included, of which 114 were RA patients, and 25 were controls. Patients were divided into 99 with seropositive RA, 6 with seronegative RA, and 9 without DMARDs. The patients with seropositive RA were subclassified based on the DAS28 index. A seven-color multicolor flow cytometry panel was used to identify B-cell immunophenotypes and cell activation markers. There were no changes in total B-cell frequencies between RA patients and controls. However, a lower frequency of memory B cells and pre-plasmablasts was observed in seropositive RA compared to controls (P < 0.0001; P = 0.0043, respectively). In contrast, a higher frequency of mature B cells was observed in RA than in controls (P = 0.0002). Among patients with RA, those with moderate activity had a higher percentage of B cells (P = 0.0021). The CD69+ marker was increased (P < 0.0001) in RA compared to controls, while the CD40+ frequency was decreased in patients (P < 0.0001). Transitional, naïve, and double-negative B-cell subpopulations were higher in seronegative RA than in seropositive (P < 0.01). In conclusion, in seropositive and seronegative RA patients, there are alterations in B-cell activation and B-cell subpopulations, independently of clinical activity and DMARDs therapy.

Is Isolated Autoantibody Seropositivity a Risk Factor in the Development of Diabetic Nephropathy in Type 1 Diabetic Children?

Is Isolated Autoantibody Seropositivity a Risk Factor in the Development of Diabetic Nephropathy in Type 1 Diabetic Children?

Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis

BackgroundLymphocyte activation gene-3 (LAG-3) inhibits T cell activation and interferes with the immune response by binding to MHC-II. As antigen presentation is central in rheumatoid arthritis (RA) pathogenesis, we studied aspects of LAG-3 as a serological marker and mediator in the pathogenesis of RA. Since Galectin-3 (Gal-3) is described as an additional binding partner for LAG-3, we also aimed to study the functional importance of this interaction.MethodsPlasma levels of soluble (s) LAG-3 were measured in early RA patients (eRA, n = 99) at baseline and after 12 months on a treat-to-target protocol, in self-reportedly healthy controls (HC, n = 32), and in paired plasma and synovial fluid (SF) from chronic RA patients (cRA, n = 38). Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were examined for LAG-3 expression by flow cytometry. The binding and functional outcomes of LAG-3 and Gal-3 interaction were assessed with surface plasmon resonance (SPR) and in cell cultures using rh-LAG3, an antagonistic LAG-3 antibody and a Gal-3 inhibitor.ResultsBaseline sLAG-3 in the plasma was increased in eRA compared to HC and remained significantly elevated throughout 12 months of treatment. A high level of sLAG-3 at baseline was associated with the presence of IgM-RF and anti-CCP as well as radiographic progression. In cRA, sLAG-3 was significantly increased in SF compared with plasma, and LAG-3 was primarily expressed by activated T cells in SFMCs compared to PBMCs. Adding recombinant human LAG-3 to RA cell cultures resulted in decreased cytokine secretion, whereas blocking LAG-3 with an antagonistic antibody resulted in increased cytokine secretion. By SPR, we found a dose-dependent binding between LAG-3 and Gal-3. However, inhibiting Gal-3 in cultures did not further change cytokine production.ConclusionssLAG-3 in the plasma and synovial fluid is increased in both early and chronic RA patients, particularly in the inflamed joint. High levels of sLAG-3 are associated with autoantibody seropositivity and radiographic progression in eRA, and LAG-3 plays a biologically active role in cRA by decreasing inflammatory cytokine production. This functional outcome is not affected by Gal-3 interference. Our results suggest that LAG-3 is a faceted regulator of inflammation in early and chronic RA.

Silencing of aryl hydrocarbon receptor repressor modulates Th17-cell immunity in human autoimmune hepatitis

Abstract Th17-cells play a key role in the pathogenesis of autoimmune hepatitis (AIH), a severe hepatopathy characterized by hypergammaglobulinemia, seropositivity for autoantibodies and interface hepatitis on histology. Aberrant Th17-cell response in AIH is linked to alterations of aryl-hydrocarbon-receptor (AHR) signaling. These result in Th17-cell inability to respond to AHR activation. Since AHR can be regulated upon binding to aryl-hydrocarbon-receptor-repressor (AHRR), we investigated whether defective Th17-cell response to AHR derives from aberrant AHRR regulation in AIH. Th17-cells obtained from AIH patients and healthy controls (HC) were exposed to the AHR endogenous ligands unconjugated bilirubin and L-kynurenine (L-kyn), with or without AHRR siRNA. Levels of AHRRmRNA were similar in AIH and HC Th17-cells. Silencing of AHRRby siRNA boosted Th17-cell response to L-kyn, as reflected by increased CYP1A1, this effect being noted in AIH but not in HC-derived Th17-cells. AHRRblockade did not change the levels of AHR-regulated genes like CD39, IL10, IL17, and IL22, but decreased the levels of IL1b, in the absence and presence of L-kyn in AIH Th17-cells. Silencing of AHRRlimited the differentiation of naïve CD4-cells into Th17-cells and modulated Th17-cell transcriptome by downregulating SOCS2, CISHand IL2RA. Overall, these data indicate that blockade of AHRRrestores Th17-cell response to AHR activation and modulates Th17-cell differentiation by decreasing IL1b along with genes involved in cell activation and linked to JAK/STAT signaling. Silencing of AHRRmight represent a novel therapeutic strategy to modulate effector Th17-cell immunity and restore immune homeostasis in AIH. Supported by grants from NIH (R01DK124408 and R01DK108894)

Atrophic Gastritis and Autoimmunity: Results from a Prospective, Multicenter Study.

Despite a global decrease, gastric cancer (GC) incidence appears to be increasing recently in young, particularly female, patients. The causal mechanism for this "new" type of GC is unknown, but a role for autoimmunity is suggested. A cascade of gastric precancerous lesions, beginning with chronic atrophic gastritis (CAG), precedes GC. To test the possible existence of autoimmunity in patients with CAG, we aimed to analyze the prevalence of several autoantibodies in patients with CAG as compared to control patients. Sera of 355 patients included in our previous prospective, multicenter study were tested for 19 autoantibodies (anti-nuclear antibodies, ANA, anti-parietal cell antibody, APCA, anti-intrinsic factor antibody, AIFA, and 16 myositis-associated antibodies). The results were compared between CAG patients (n = 154), including autoimmune gastritis patients (AIG, n = 45), non-autoimmune gastritis patients (NAIG, n = 109), and control patients (n = 201). ANA positivity was significantly higher in AIG than in NAIG or control patients (46.7%, 29%, and 27%, respectively, p = 0.04). Female gender was positively associated with ANA positivity (OR 0.51 (0.31-0.81), p = 0.005), while age and H. pylori infection status were not. Myositis-associated antibodies were found in 8.9% of AIG, 5.5% of NAIG, and 4.4% of control patients, without significant differences among the groups (p = 0.8). Higher APCA and AIFA positivity was confirmed in AIG, and was not associated with H. pylori infection, age, or gender in the multivariate analysis. ANA antibodies are significantly more prevalent in AIG than in control patients, but the clinical significance of this finding remains to be established. H. pylori infection does not affect autoantibody seropositivity (ANA, APCA, AIFA). The positivity of myositis-associated antibodies is not increased in patients with CAG as compared to control patients. Overall, our results do not support an overrepresentation of common autoantibodies in patients with CAG.

Presymptomatic Aquaporin-4 (AQP4) Autoantibody Seropositivity in NMOSD: Analysis of the Department of Defense Serum Repository (DoDSR) (S50.005)

Presymptomatic Aquaporin-4 (AQP4) Autoantibody Seropositivity in NMOSD: Analysis of the Department of Defense Serum Repository (DoDSR) (S50.005)

Prevalence and Significance of Autoantibody Seropositivity in Children with Wilson's Disease.

Autoantibodies occur in healthy subjects as well as in children with Wilson's disease (WD), but their prevalence and significance are unknown. Thus, we aimed to assess the prevalence of autoantibodies and autoimmune markers, and their relationship to liver injury in WD children. The study included 74 WD and 75 healthy children as a control group. Patients with WD underwent transient elastography (TE) examinations, as well as determination of liver function tests, copper metabolism markers, and serum immunoglobulins (Ig). In the sera of the WD patients and controls, anti-nuclear (ANA), anti-smooth muscle, anti-mitochondrial, anti-parietal cell, anti-liver/kidney microsomal, anti-neutrophil cytoplasmic autoantibodies, and specific celiac antibodies were determined. Among the autoantibodies, only the prevalence of ANA in children with WD was higher than in the controls. There was no significant relationship between the presence of autoantibodies and liver steatosis or stiffness after TE. However, advanced liver stiffness (E > 8.2 kPa) was related to IgA, IgG, and gamma globulin production. The type of treatment did not influence the prevalence of autoantibodies. Our results suggest that autoimmune disturbances in WD might not be directly related to liver damage as expressed by steatosis and/or liver stiffness after TE.

Anti-Integrin αvβ6 Autoantibodies Are a Novel Biomarker That Antedate Ulcerative Colitis

Better biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin αvβ6 (anti-αvβ6) autoantibodies have been described in patients with UC. We tested for the presence of anti-αvβ6 antibodies in the preclinical phase of UC and studied their association with disease-related outcomes after diagnosis. Anti-αvβ6 autoantibodies were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense preclinical cohort (PREDICTS [Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects]). In a distinct, external validation cohort (Crohn's and Colitis Canada Genetic Environmental Microbial project cohort), we tested 12 pre-UC subjects and 49 matched controls. Furthermore, anti-αvβ6 autoantibodies were measured in 2 incident UC cohorts (COMPASS [Comprehensive Care for the Recently Diagnosed IBD Patients], n= 55 and OSCCAR [Ocean State Crohn's and Colitis Area Registry], n= 104) and associations between anti-αvβ6 autoantibodies and UC-related outcomes were defined using Cox proportional hazards model. Anti-αvβ6 autoantibodies were significantly higher among individuals who developed UC compared with controls up to 10 years before diagnosis in PREDICTS. The anti-αvβ6 autoantibody seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 time points. Anti-αvβ6 autoantibodies predicted UC development with an area under the curve of at least 0.8 up to 10 years before diagnosis. The presence of anti-αvβ6 autoantibodies in preclinical UC samples was validated in the GEM cohort. Finally, high anti-αvβ6 autoantibodies was associated with a composite of adverse UC outcomes, including hospitalization, disease extension, colectomy, systemic steroid use, and/or escalation to biologic therapy in recently diagnosed UC. Anti-integrin αvβ6 autoantibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

Characterization of Clinical and Paraclinical Features Associated With TS-HDS Autoantibody Seropositivity

Objective To evaluate neuropathy phenotypes and clinical outcomes associated with trisulfated heparin disaccharide (TS-HDS) autoantibodies. Background TS-HDS autoantibody has been reported as a biomarker of immune-mediated neuropathy. However, studies evaluating the clinical associations of this autoantibody are limited. Design/Methods Electronic medical records were reviewed to identify TS-HDS autoantibody seropositive patients and characterize their clinical and electrodiagnostic findings. Results Seventy-seven TS-HDS-IgM seropositive (titer range 9000-350,000) patients were identified (50 females; median age of onset was 48 years (range 9-83 years). Eleven patients were also positive for FGFR3-IgG (titer range 4000-19,000). 70% (54/77) had clinical/paraclinical evidence of neuropathy (54/77, 70% of TS-HDS-IgM alone; 10/11, 91% of TS-HDS-IgM with coexisting FGFR3-IgG). The managing physician characterized an immune-mediated neuropathy in 30% (23/77) and 54% (6/11) of the TS-HDS-IgM only and TS-HDS-IgM with coexisting FGFR3-IgG seropositive patients, respectively. Small fiber neuropathy presented in 58% (45/77) and 63% (7/11) of TS-HDS-IgM only, and both antibodies seropositive patients, respectively. Length-dependent neuropathy was the most common neuropathy phenotype amongst TS-HDS IgM (43/54, 80%) and dual seropositive cases (7/11, 63%). Forty-one (53%) patients received immunotherapy, predominantly: IVIG (n = 37), IV solumedrol (n = 7), oral prednisone (n = 14), and mycophenolate mofetil (n = 12). Among these, 43% (15/35) with TS-HDS-IgM seropositivity alone had improvement in inflammatory neuropathy cause and treatment (INCAT) disability score or modified Rankin Scale (mRS), while 33% (2/6) of patients with dual seropositivity had INCAT and mRS improvement. TS-HDS-IgM titers had low discriminative ability to identify immunotherapy response with an AUC of 0.621. Conclusions Neuropathy associations and clinical phenotypes amongst TS-HDS-IgM seropositive cases are variable. Furthermore, only a minority of cases are immunotherapy responsive, limiting the value of this biomarker in identifying immune-mediated neuropathies.

Post-COVID-19 Syndrome: Retinal Microcirculation as a Potential Marker for Chronic Fatigue.

Post-COVID-19 syndrome (PCS) is characterized by persisting sequelae after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PCS can affect patients with all COVID-19 disease severities. As previous studies have revealed impaired blood flow as a provoking factor triggering PCS, it was the aim of the present study to investigate the potential association between self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker. A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT angiography (OCT-A) and quantified using the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic fatigue (CF) was assessed according to the variables of Bell's score, age and gender. VDs in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed, considering the repetitions (12 times). Seropositivity for autoantibodies targeting G protein-coupled receptors (GPCR-AAbs) was determined by an established cardiomyocyte bioassay. Taking account of the repetitions, a mixed model was performed to detect possible differences in the least square means between the different groups included in the analysis. An age effect in relation to VD was observed between patients and controls (p &lt; 0.0001). Gender analysis showed that women with PCS showed lower VD levels in the SVP compared to male patients (p = 0.0015). The PCS patients showed significantly lower VDs in the ICP as compared to the controls (p = 0.0001 (CI: 0.32; 1)). Moreover, considering PCS patients, the mixed model revealed a significant difference between those with chronic fatigue (CF) and those without CF with respect to VDs in the SVP (p = 0.0033 (CI: -4.5; -0.92)). The model included variables of age, gender and Bell's score, representing a subjective marker for CF. Consequently, retinal microcirculation might serve as an objective biomarker in subjectively reported chronic fatigue in patients with PCS.

Comparative analysis of the repertoire of insulin-reactive B cells in type 1 diabetes-prone and resistant mice.

Seropositivity for autoantibodies against multiple islet antigens is associated with development of autoimmune type 1 diabetes (T1D), suggesting a role for B cells in disease. The importance of B cells in T1D is indicated by the effectiveness of B cell-therapies in mouse models and patients. B cells contribute to T1D by presenting islet antigens, including insulin, to diabetogenic T cells that kill pancreatic beta cells. The role of B cell receptor (BCR) affinity in T1D development is unclear. Here, we employed single cell RNA sequencing to define the relationship between BCR affinity for insulin and B cell phenotype during disease development. We utilized immunoglobulin (Ig) heavy chain (VH125) mouse models in which high-affinity insulin-reactive B cells (IBCs) were previously shown to be anergic in diabetes-resistant VH125.C57BL/6-H2g7 and activated in VH125. NOD mice developing disease. Here, high-affinity IBCs were found in the spleen of prediabetic VH125. NOD mice and exhibited marginal zone or follicular phenotypes. Ig light chains expressed by these B cells are unmutated and biased toward Vκ4-74 and Vκ4-57 usage. Receptors expressed by anergic high-affinity IBCs of diabetes-resistant VH125.C57BL/6-H2g7 are also unmutated; however, in this genetic background light chains are polymorphic relative to those of NOD. Light chains derived from NOD and C57BL/6-H2g7 genetic backgrounds conferred divergent kinetics of binding to insulin when paired with the VH125 heavy chain. These findings suggest that relaxation of tolerance mechanisms in the NOD mouse leads to accumulation and partial activation of B cells expressing germline encoded high-affinity BCRs that support development of autoimmunity.

CLINICAL, EPIDEMIOLOGICAL AND IMMUNOLOGICAL ASPECTS IN AUTOIMMUNE HEPATITIS

"The typical phenotype of autoimmune hepatitis (AIH) is well recognized, but special subforms such as AIH with sero-negativity for autoantibodies, severe and acute forms of AIH, forms that have concomitant features of primary biliary cirrhosis or occur in the context of other liver diseases, making diagnosis and therapy a challenge for the clinician. The objective of this study was the complex analysis in terms of clinical and phenotypic characteristics of patients with AIH diagnosed at the County Clinical Emergency Hospital of Craiova, between November 2015 and September 2019. In order to carry out this study, we set the following specific objectives: • Determining the demographic and clinical characteristics of patients diagnosed with AIH compared to a group of patients diagnosed with chronic viral hepatitis C (CHC), in terms of age of onset, location, severity of inflammatory lesions and intestinal and extra-intestinal complications; • Evaluation of the biochemical profile in the studied groups by dosing the serum levels of liver enzymes such as transaminases [Aspartate-amino-transferase (AST), Alanine-amino-transferase (ALT), total bilirubin (TBIL), γ-glutamyl-transpeptidase (γ-GT), alkaline phosphatase (ALP)], and total γ-globulins (IgG, IgM, IgA)]; • Evaluation of the serological profile of patients with AIH by determining the presence of autoantibodies [ANA, anti-SMA, anti-soluble-liver-antigen (anti-SLA) antibodies, anti-liver kidney microsomal type 1 (anti-LKM-1) antibodies, anti-liver cytosol antigen type 1 (anti-LC1) antibodies, anti-mitochondrial antibodies (AMA)]. In our study we obtained the following patient profile: female patient, from an urban areas, aged at the time of diagnosis in the decade of age 45-55 years, with sero-positivity for antinuclear autoantibodies (ANA), with elevated levels of liver enzymes, accompanied by polyclonal hyper-gamaglobulinemia (IgG)."

Cell-based flow cytometry assay for simultaneous detection of multiple autoantibodies in a single serum sample

Accurate serologic evaluation of autoantibodies in patients with autoimmune diseases is critical. In the present study, we established a live cell-based assay for simultaneous detection of multiple autoantibodies in a single serum sample. Autoantibody seropositivity was determined by 3-color flow cytometry using live Chinese hamster ovary cells transiently expressing a target protein of interest fused to enhanced green fluorescent protein and labeled with Alexa Fluor 647 and Hoechst 33342. As a representative example, we applied the strategy for simultaneous detection of 2 recently established biomarkers for central nervous system autoimmune inflammatory demyelinating disorders, anti-aquaporin-4 autoantibody and anti-myelin oligodendrocyte glycoprotein autoantibody, in a single serum sample. This analysis revealed the coexistence of these 2 autoantibodies. We demonstrated that this assay can simultaneously detect 3 different autoantibodies. We propose a quadrant gating strategy of flow cytometry contour plots to clearly distinguish seropositive sera from seronegative sera regardless of the extent of the background signal level or the autoantibody titer. This novel and practical method using a combination of fluorescent proteins and fluorochromes to simultaneously detect multiple autoantibodies improves the efficiency of evaluating serum samples, and therefore provides significant benefits to both the patient and the healthcare professionals performing autoantibody testing.

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a condition caused by self-perpetuating immune response towards hepatocytes in liver. In children, AIH may progressed more rapidly compared to adults. Thus, early diagnosis and prompt treatment are the key for successful management of AIH. Five main characteristics of AIH include female predominance, increased IgG or hypergammaglobulinemia, circulatory autoantibody seropositivity, and hepatitis interface from the histological finding. Liver biopsy is needed to evaluate the degree of damage and to confirm the diagnosis. The standard regiment for AIH include prednisone (or prednisolone) and azathioprine. Other alternative treatments available for non-responder, such as mycophenolate mofetil, tacrolimus, cyclosporine, budesonide, rituximab, and infliximab. AIH treatment is recommended to be taken minimally for 2-3 years before attempting treatment termination.

Elevations in adipocytokines and mortality in rheumatoid arthritis.

This study assessed whether circulating levels of adiponectin and leptin are associated with higher mortality in patients with RA. Participants were adults from the Veterans Affairs RA Registry. Adipokines and inflammatory cytokines were measured as part of a multi-analyte panel on banked serum at enrolment. Dates and causes of death were derived from the Corporate Data Warehouse and the National Death Index. Covariates were derived from medical record, biorepository and registry databases. Multivariable Cox proportional hazard models evaluated associations between biomarkers and all-cause and cause-specific mortality. A total of 2583 participants were included. Higher adiponectin levels were associated with older age, male sex, white race, lower BMI, autoantibody seropositivity, radiographic damage, longer disease duration, prednisone use and osteoporosis. Higher adiponectin concentrations were also associated with higher levels of inflammatory cytokines but not higher disease activity at enrolment. Leptin was primarily associated with greater BMI and comorbidity. The highest quartile of adiponectin (vs lowest quartile) was associated with higher all-cause mortality [hazard ratio (HR): 1.46 (95% CI: 1.11, 1.93), P = 0.009] and higher cardiovascular mortality [HR: 1.85 (95% CI: 1.24, 2.75), P = 0.003], after accounting for covariates. Higher leptin levels were also associated with greater all-cause and cancer mortality. Elevations in adipokines are associated with age, BMI, comorbidity and severe disease features in RA and independently predict early death. Associations between adiponectin and inflammatory cytokines support the hypothesis that chronic subclinical inflammation promotes metabolic changes that drive elevations in adipokines and yield adverse health outcomes.

Risk of COVID-19 in Rheumatoid Arthritis: A National Veterans Affairs Matched Cohort Study in At-Risk Individuals.

ObjectiveRheumatoid arthritis (RA) and its treatments are associated with an increased risk of infection, but it remains unclear whether these factors have an impact on the risk or severity of COVID‐19. The present study was undertaken to assess the risk and severity of COVID‐19 in a US Department of Veterans Affairs (VA) cohort of patients with RA and those without RA.MethodsA matched cohort study using national VA data was conducted. Patients diagnosed as having RA were identified among nondeceased individuals who were active in the VA health care system as of January 1, 2020 and who had received care in a VA medical center in 2019; patients for whom no RA diagnostic code was indicated were matched to the RA patients (1:1) by age, sex, and VA site (non‐RA controls). Patients diagnosed as having COVID‐19 and those with severe COVID‐19 (defined as requiring hospitalization or leading to death) were ascertained from a national VA COVID‐19 surveillance database through December 10, 2020. Multivariable Cox models were used to compare the risk of COVID‐19 and COVID‐19 hospitalization or death between RA patients and non‐RA controls, after adjusting for demographic characteristics, comorbidities, health care utilization and access, and county‐level COVID‐19 incidence rates.ResultsThis VA cohort of RA patients and non‐RA controls (n = 33,886 subjects per group) predominantly comprised male patients (84.5%), and the mean age was 67.8 years. During follow‐up, 1,503 patients in the cohort were diagnosed as having COVID‐19; among them, 388 patients had severe COVID‐19 (hospitalization or death), while in 228 patients, the deaths were not related to COVID‐19. In the multivariable model, RA was associated with a higher risk of COVID‐19 (adjusted hazard ratio [HR] 1.25 [95% confidence interval (95% CI) 1.13–1.39]) and a higher risk of COVID‐19 hospitalization or death (adjusted HR 1.35 [95% CI 1.10–1.66]) as compared to non‐RA controls. Use of disease‐modifying antirheumatic drugs and prednisone, as well as self‐reported Black race, self‐reported Hispanic ethnicity, and presence of several chronic conditions, but not seropositivity for RA autoantibodies, were each associated with risk of COVID‐19 and severe COVID‐19 (hospitalization or death).ConclusionPatients with RA are at higher risk of developing COVID‐19 and severe COVID‐19 (leading to hospitalization or death) compared to those without RA. With a risk of COVID‐19 that approaches that of other recognized chronic conditions, these findings suggest that RA patients should be prioritized for COVID‐19 prevention and management strategies.

Value and risk of percutaneous liver biopsy in patients with cirrhosis and clinical suspicion of autoimmune hepatitis

ObjectiveThe decision regarding whether to perform a liver biopsy in patients with cirrhosis and clinically suspected autoimmune hepatitis (AIH) remains a challenge. This study aimed to assess the utility and...

Circulating and Synovial Pentraxin-3 (PTX3) Expression Levels Correlate With Rheumatoid Arthritis Severity and Tissue Infiltration Independently of Conventional Treatments Response.

AimsTo determine the relationship between PTX3 systemic and synovial levels and the clinical features of rheumatoid arthritis (RA) in a cohort of early, treatment naïve patients and to explore the relevance of PTX3 expression in predicting response to conventional-synthetic (cs) Disease-Modifying-Anti-Rheumatic-Drugs (DMARDs) treatment.MethodsPTX3 expression was analyzed in 119 baseline serum samples from early naïve RA patients, 95 paired samples obtained 6-months following the initiation of cs-DMARDs treatment and 43 healthy donors. RNA-sequencing analysis and immunohistochemistry for PTX3 were performed on a subpopulation of 79 and 58 synovial samples, respectively, to assess PTX3 gene and protein expression. Immunofluorescence staining was performed to characterize PTX3 expressing cells within the synovium.ResultsCirculating levels of PTX3 were significantly higher in early RA compared to healthy donors and correlated with disease activity at baseline and with the degree of structural damages at 12-months. Six-months after commencing cs-DMARDs, a high level of PTX3, proportional to the baseline value, was still detectable in the serum of patients, regardless of their response status. RNA-seq analysis confirmed that synovial transcript levels of PTX3 correlated with disease activity and the presence of mediators of inflammation, tissue remodeling and bone destruction at baseline. PTX3 expression in the synovium was strongly linked to the degree of immune cell infiltration, the presence of ectopic lymphoid structures and seropositivity for autoantibodies. Accordingly, PTX3 was found to be expressed by numerous synovial cell types such as plasma cells, fibroblasts, vascular and lymphatic endothelial cells, macrophages, and neutrophils. The percentage of PTX3-positive synovial cells, although significantly reduced at 6-months post-treatment as a result of global decreased cellularity, was similar in cs-DMARDs responders and non-responders.ConclusionThis study demonstrates that, early in the disease and prior to treatment modification, the level of circulating PTX3 is a reliable marker of RA activity and predicts a high degree of structural damages at 12-months. In the joint, PTX3 associates with immune cell infiltration and the presence of ectopic lymphoid structures. High synovial and peripheral blood levels of PTX3 are associated with chronic inflammation characteristic of RA. Additional studies to determine the mechanistic link are required.