Development Of Autoantibodies Research Articles

Acquired hemophilia A in a case of purple urine bag syndrome

The rare hemorrhagic disorder known as acquired hemophilia A (AHA) is brought on by the spontaneous development of autoantibodies against coagulation factor VIII (FVIII). It may be secondary to autoimmune diseases or cancers, or it may be idiopathic. Less than 10% of cases may have an infection as a secondary cause. We present the case of a 90-year-old anemic woman who was admitted to the hospital. She contracted a urinary tract infection (UTI) while in the hospital, and her urine took on a distinct purple hue. She had poor hemorrhagic manifestations and a prolonged partial thromboplastin time. After ruling out autoimmune and neoplastic causes, we diagnosed AHA as a result of a UTI caused by Enterococcus faecalis.

Concurrent congenital hemophilia B and acquired hemophilia A: a unique case report.

Congenital hemophilia B is a rare X-linked recessive bleeding disorder caused by factor IX deficiency. Acquired hemophilia A is a rare, acquired bleeding disorder that presents with new-onset bleeding, especially in older adults, due to the development of auto-antibodies against factor VIII (FVIII). This case report presents the medical management of a patient with congenital hemophilia B and acquired hemophilia A. We highlight the limitations of maintaining factor levels with factor replacement therapy alone, particularly in hemophilia patients who have developed factor inhibitors. In addition, we draw attention to the need for dose escalation, the cost, and the need for immune-tolerance induction therapy. This case illustrates that when the current diagnosis does not explain the full clinical picture and laboratory data are inadequate, it is important to continue to seek alternative diagnoses and cost-effective treatment.

Autoimmune Nodopathy

Autoimmune nodopathy (AN), a newly established category of autoimmune disease, refers to an immune-mediated neuropathy associated with development of autoantibodies against membrane proteins, including neurofascin 186, neurofascin 155, contactin-1, and contactin-associated protein 1 located in the nodes of Ranvier or paranodes. Subclass analysis of these autoantibodies reveals predominant elevation of immunoglobulin (G4. Patients with AN show clinical and laboratory characteristics such as distal-predominant sensorimotor disturbance, sensory ataxia, poor response to intravenous immunoglobulin, and highly elevated cerebrospinal fluid protein levels. B cell-depletion therapy using an anti-CD20 monoclonal antibody is effective for patients with AN. Autoantibody measurement is beneficial not only for diagnosis but also for deciding treatment strategies for AN.

The development of anticyclic citrullinated peptide (anti-CCP) antibody following severe COVID-19.

The dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID-19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID-19. The serum samples obtained from 176 hospitalized COVID-19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID-19. Also, the serum samples collected from healthy subjects before the COVID-19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble-stranded DNA (anti-dsDNA), cytoplasmic-anti neutrophil cytoplasmic antibody (c-ANCA), perinuclear ANCA (p-ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti-CCP) occurrence was evaluated using a solid-phase enzyme-linked immunosorbent assay (ELISA). The results showed that the occurrence of ANAs, anti-dsDNA, anti-CCP, c-ANCA, and p-ANCA was significantly higher in the COVID-19 patients compared to serum obtained from healthy subjects (p < .0001, p < .0001, p < .0001, p < .05, and p < .001, respectively). The positive number of anti-CCP tests increased significantly in severe COVID-19 compared to the moderate group (p < .01). Our study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti-CCP in a severe form of COVID-19.

JMJD6 Autoantibodies as a Potential Biomarker for Inflammation-Related Diseases.

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima-media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC.

Redox Pathogenesis in Rheumatic Diseases.

Despite being some of the most anecdotally well-known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end-organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

Machine learning-based prediction of rheumatoid arthritis with development of ACPA autoantibodies in the presence of non-HLA genes polymorphisms.

Machine learning (ML) algorithms can handle complex genomic data and identify predictive patterns that may not be apparent through traditional statistical methods. They become popular tools for medical applications including prediction, diagnosis or treatment of complex diseases like rheumatoid arthritis (RA). RA is an autoimmune disease in which genetic factors play a major role. Among the most important genetic factors predisposing to the development of this disease and serving as genetic markers are HLA-DRB and non-HLA genes single nucleotide polymorphisms (SNPs). Another marker of RA is the presence of anticitrullinated peptide antibodies (ACPA) which is correlated with severity of RA. We use genetic data of SNPs in four non-HLA genes (PTPN22, STAT4, TRAF1, CD40 and PADI4) to predict the occurrence of ACPA positive RA in the Polish population. This work is a comprehensive comparative analysis, wherein we assess and juxtapose various ML classifiers. Our evaluation encompasses a range of models, including logistic regression, k-nearest neighbors, naïve Bayes, decision tree, boosted trees, multilayer perceptron, and support vector machines. The top-performing models demonstrated closely matched levels of accuracy, each distinguished by its particular strengths. Among these, we highly recommend the use of a decision tree as the foremost choice, given its exceptional performance and interpretability. The sensitivity and specificity of the ML models is about 70% that are satisfying. In addition, we introduce a novel feature importance estimation method characterized by its transparent interpretability and global optimality. This method allows us to thoroughly explore all conceivable combinations of polymorphisms, enabling us to pinpoint those possessing the highest predictive power. Taken together, these findings suggest that non-HLA SNPs allow to determine the group of individuals more prone to develop RA rheumatoid arthritis and further implement more precise preventive approach.

Clinical care advice for monitoring of islet autoantibody positive individuals with presymptomatic type 1 diabetes.

Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.

Diagnosis and management of autoimmune diseases in the ICU.

Autoimmune diseases encompass a broad spectrum of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, resulting in inflammation and multiple organ involvement. A distinction should be made between connective tissue diseases (mainly systemic lupus erythematosus, systemic scleroderma, inflammatory muscle diseases, and rheumatoid arthritis) and vasculitides (mainly small-vessel vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and immune-complex mediated vasculitis). Admission of patients with autoimmune diseases to the intensive care unit (ICU) is often triggered by disease flare-ups, infections, and organ failure and is associated with high mortality rates. Management of these patients is complex, including prompt disease identification, immunosuppressive treatment initiation, and life-sustaining therapies, and requires multi-disciplinary involvement. Data about autoimmune diseases in the ICU are limited and there is a need for multicenter, international collaboration to improve patients' diagnosis, management, and outcomes. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe systemic autoimmune diseases.

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist in Development for the Treatment of Autoimmune Cytopenias, Suppresses Disease in a Mouse Model of Autoimmune Hemolytic Anemia

Introduction: B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) play key roles in B cell development, survival, and differentiation into antibody-secreting cells (ASC). Given their importance in ASC survival and antibody production, inhibition of BAFF and/or APRIL (particularly in combination) is a promising approach for the treatment of a variety of autoimmune or autoantibody-related diseases including autoimmune cytopenias like warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), and cold agglutinin disease (CAD). Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with AIHA and ITP compared to healthy subjects, and polymorphisms in BAFF and TACI have been associated with ITP [Abdel-Hamid et al., Am J Med, 2011; Xu et al., Int J Hematol., 2015; Emmerich, et al., Br J Haematol, 2007; Peng, et al., J Thromb Haemost, 2017; Yu, et al., Blood Adv, 2021]. Belimumab, an anti-BAFF antibody, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus [De Marchi, et al., Clin Exp Rheumatol, 2017] and in combination with rituximab in patients with ITP [Mahévas, et al., Haematologica, 2021]. Currently, there are no BAFF and/or APRIL inhibitors approved to treat AIHA or ITP. Povetacicept (ALPN-303) is an engineered, potent dual BAFF/APRIL antagonist. We previously evaluated the impact of BAFF/APRIL co-inhibition preclinically in the accelerated HODxOTII transgenic mouse model of AIHA, in which povetacicept treatment significantly suppressed plasma cells in the spleen and bone marrow, reduced pathogenic anti-RBC autoantibodies, and significantly increased hematocrit [Dillon et al., ASH 2022 abstract #3763]. Here, we have evaluated povetacicept in a second preclinical model of AIHA, a rat red blood cell (RRBC)-to-mouse model of erythrocyte autoimmunity. Methods: In the RRBC model, C57BL/6NJ mice were immunized weekly with 2 x 10 8 Wistar rat RBC for 10 weeks, leading to development of anti-mouse RBC autoantibodies. Groups of mice were treated twice weekly via intraperitoneal injection with povetacicept or a matched Fc isotype control. Analyses included anti-RRBC alloantibodies and autoantibodies bound to mouse erythrocytes (measured via direct anti-globulin test [DAT]). While significant anemia does not occur in this model, serum lactate dehydrogenase (LDH) was also measured as an index measure of subclinical hemolysis. Immune cell subset analysis of splenocytes by flow cytometry was also performed. Results: As compared to Fc control, povetacicept treatment significantly reduced levels of anti-RRBC and DAT of IgM and IgG isotypes and significantly limited serum LDH elevations at various timepoints during the study ( Figure 1). Furthermore, at 10 weeks, numbers of T follicular helper (Tfh) cells, total B cells, germinal center (GC) B cells, and plasma cells were significantly lower in spleens of povetacicept-treated mice ( Figure 2). Conclusions: Povetacicept effectively reduced pathogenic autoantibodies and key B cell populations (e.g., ASC) and limited serum LDH elevations in this mouse model of erythrocyte autoimmunity. These data suggest that povetacicept may reduce multiple pathogenic inflammatory processes including autoantibody production and may be an effective treatment for AIHA and other autoimmune cytopenias. Povetacicept is currently being evaluated in an open-label study (RUBY-4; NCT05757570) of adults with autoimmune cytopenias (ITP, AIHA, and CAD).

Management of Acquired Hemophilia: A Real-World Experience, 2007-2023

Introduction.Acquired hemophilia A (AH) is a rare, potentially life-threatening, bleeding disorder caused by the development of autoantibodies directed against coagulation factor VIII (FVIII). Incidence is 1-1.5 per million people per year with a morality rate as high as 22% and is especially dangerous in the elderly. Since autoantibodies rarely resolve spontaneously, initial management involves controlling acute bleeding episodes, and immunosuppressive treatment (IST) to eradicate the autoantibodies to restore hemostasis. There are no evidence-based guidelines for the management of AH and treatment decisions rely on the clinical judgement and expertise of the treating provider, which impacts overall health outcomes. There is a dearth of prospective, controlled clinical trials to guide management of AH and much of the reported data come from observational studies and extrapolation from studies on patients with congenital hemophilia complicated by inhibitors. Methods.Retrospective chart review of AH patients treated by a single provider at Jackson Memorial Hospital from 2007 through May 2023 utilizing in-house medical record systems and supplemental external health records from transferring facilities. Partial remission (PR) was defined as FVIII activity &amp;gt;50 IU/dL and no active bleeding after stopping hemostatic drugs &amp;gt;24 hours. Complete remission (CR) was defined as PR plus negative inhibitor, prednisone tapered to &amp;lt;15 mg/day, and cessation of other IST. Results.We identified 17 patients with first episode of AH with laboratory evidence of acquired FVIII inhibitor (aFVIIIi) (see Table 1). The majority were male (76%), Hispanic (53%) and White (88%). The median age at diagnosis was 72 (range 31-88). While 65% of cases were idiopathic, other associated conditions included malignancy and trauma. The median aFVIIIi was 23.2 BU/mL (range 2.2-400) and median FVIII activity was 1% (range 0-12) at presentation. The most common presenting symptom was hematoma (59%) followed by mucocutaneous bleeding (41%). Hematuria was also seen frequently and initially attributed to another cause. To control bleeding, 47% received activated prothrombin complex concentrate (aPCC), 17% received recombinant factor VIIa, and 12% received emicizumab. Emicizumab was initiated at an outside facility lacking bypassing agents for one patient, while the other had bleeding with neutropenic sepsis. All patients received IST with glucocorticoids; cyclophosphamide was used in 82%, rituximab in 41%, and IVIG in 12%. For patients with appropriate follow-up (median follow-up 707 days), 7/9 (78%) achieved a CR to IST and 2/9 (22%) developed PR. The median time to PR was 41 days and median time to CR was 168 days in patients who achieved those respective responses. Five patients (29%) responses were not assessable due to lack of appropriate follow-up. Three patients (17%) had a clinically evident relapse requiring retreatment at 617, 730, and 1427 days after initial response. Ultimately, three patients (17%) died or were discharged to hospice within a median of 8 days, but only one death was directly related to bleeding (which was prior to receiving any appropriate hemostatic agents). Discussion.We report a single-provider experience on patients treated for AH, with focus on acute management and CR due to its impact on health outcomes. Our experience confirms the importance of initiating IST early in diagnosis and tapering as FVIII levels recover, finding the lowest effective dose to eradicate the inhibitor. It should be noted that bypassing agents are not always required if bleeding is not significant. While no one who received hemostatic agents died of hemorrhage, several patients required dozens of doses of these expensive medications. Recent reports using emicizumab off-label for AH suggest effective hemostasis in the acute phase, which was successful in two patients described here. Monitoring the response to emicizumab is more challenging due to lab interference with PTT and single-stage factor assays, and therefore requires bovine assays that are costly, untimely, and not widely available. A large proportion of patients referred from outside lacked appropriate follow-up after initial diagnosis for acute management. For optimal long-term outcomes, patients with AH should have ongoing follow up with periodic lab monitoring as relapses may occur several years after initial response in 17% or more of patients.

Impact of Anticoagulation in Acquired Hemophilia a

Background Acquired Hemophilia A (AHA) is a rare autoimmune disorder that occurs due to the development of autoantibodies against factor VIII which leads to inhibition of the coagulation cascade and results in a propensity for hemorrhage. The estimated incidence is approximately 1.5 per million per year. It carries an exceptionally high morbidity and mortality rate, with severe or life-threatening hemorrhagic events occurring in 70-90% of cases, with 5-10% of these cases resulting in mortality. Several underlying conditions are associated with AHA, including autoimmune disorders, obstetrical and oncologic disease, and various medications, such as direct oral anticoagulants (DOACs) and antiplatelet therapy (APT), both of whose usage has increased significantly over the past decade. Objectives We aimed to evaluate whether patients prescribed an antiplatelet or anticoagulant at the time of diagnosis of AHA experienced more severe bleeding and worse clinical outcomes compared to those with AHA not prescribed an antiplatelet or anticoagulant. Methods This is a single-center retrospective study examining 16 individuals with AHA from April 2013 to April 2023. These individuals were categorized by the presence or absence of a prescribed anticoagulant and then further divided into class of anticoagulant (APT, DOAC or other oral anticoagulant (OAC), or exposure to both). Primary end points included the number of blood product transfusions received, hospital length of stay (LOS), need for intervention or procedure, and degree of hemoglobin (Hgb) drop from baseline. Continuous variables were compared using t-test or Wilcoxon rank-sum test while categorical variables were compared using the chi-square test or Fisher's exact test. Results Of the 16 individuals in our cohort, 9 were without prior exposure to anticoagulation or antiplatelet agents before the diagnosis of AHA while 7 were prescribed either an anticoagulant, antiplatelet agent, or both. Of those taking one of these classes of medications, 2 were prescribed OACs, 3 were prescribed APTs, and 2 were prescribed both classes. The mean baseline Hgb was similar in both groups, 12.84 for the non-exposed group and 12.92 for the exposed group, while mean Hgb at diagnosis was 9.55 and 8.81 for the non-exposed group and exposed group respectively (p-value 0.638). Median factor VIII titer inhibitors at diagnosis were 3.30 and 38.10 (p-value 0.124) for non-exposed and exposed groups, respectively. Mean hospitalization rates for non-exposed individuals versus exposed individuals were 5.0 and 7.0 (p-value 2.00) with a mean hospital LOS of 10.20 and 12.57 days (p-value 0.624) in the non-exposed and exposed group, respectively. The mean number of packed red blood cell (pRBC) transfusions needed during the index hospitalization was 1.6 and 3.0 (p-value 0.333) in the non-exposed group and exposed group respectively while the mean number of platelet transfusions were 4 and 6 in the non-exposed and exposed groups respectively. There was a statistically significant increase in intramuscular bleeding with a mean of 1.0 and 5.0 (p-value 0.035) in the non-exposed and exposed groups respectively. In each group there was only one individual who required procedural intervention. There was one death due to hemorrhage which occurred in the exposed group (p-value 0.467). Conclusions The increased rates of intramuscular bleeding in patients exposed to prior anticoagulation was statistically significant. Intramuscular hemorrhage is associated with increased morbidity due to the risk for compartment syndrome requiring surgical intervention. Our data demonstrates a trend towards the need for a longer hospitalization and more pRBC transfusions in individuals with prior exposure though notably, there is not an apparent increased trend for an increased rate of platelet transfusions. There is also a trend towards significance for higher factor VIII titer inhibitor levels in patients on anticoagulation at the time of diagnosis. While this study is limited in power by the sample size, there are no comparable studies to date examining the impact of anticoagulation on individuals with AHA. With the increasing rates of anticoagulation therapy, further investigation is needed on the impact of therapeutic anticoagulant or antiplatelet use prior to the diagnosis of AHA and subsequent clinical outcomes.

Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection

Although the genetic basis and pathogenesis of type 1 diabetes have been studied extensively, how host responses to environmental factors might contribute to autoantibody development remains largely unknown. Here, we use longitudinal blood transcriptome sequencing data to characterize host responses in children within 12 months prior to the appearance of type 1 diabetes-linked islet autoantibodies, as well as matched control children. We report that children who present with insulin-specific autoantibodies first have distinct transcriptional profiles from those who develop GADA autoantibodies first. In particular, gene dosage-driven expression of GSTM1 is associated with GADA autoantibody positivity. Moreover, compared with controls, we observe increased monocyte and decreased B cell proportions 9-12 months prior to autoantibody positivity, especially in children who developed antibodies against insulin first. Lastly, we show that control children present transcriptional signatures consistent with robust immune responses to enterovirus infection, whereas children who later developed islet autoimmunity do not. These findings highlight distinct immune-related transcriptomic differences between case and control children prior to case progression to islet autoimmunity and uncover deficient antiviral response in children who later develop islet autoimmunity.

Increased development of T-bet+CD11c+ B cells predisposes to lupus in females: Analysis in BXD2 mouse and genetic crosses

Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. We quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6J) x BXD2. Sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies. The percentage of T-bet+CD11c+ IgD+ activated naive B cells (aNAV) was higher in females and was associated with increased T-bet+CD11c+ IgD− age-related B cells, Fas+GL7+ germinal center B cells, Cxcr5−Icos+ peripheral T-helper cells, and Cxcr5+Icos+ follicular T-helper cells. IFN-β was elevated in females. Variation in aNAV cells was mapped to Chr 7 in a locus that shows significant interactions between the female sex and heterozygous B/D variant. Our results suggest that activation of naive B cells forms the basis for the female-predominant development of autoantibodies in lupus-susceptible BXD2 mice.

The effect of proprotein convertase subtilisin/kexin type 9 inhibition on the plasma proteome: a SPIRE sub-study

Abstract Background The plasma proteome is an intermediate phenotype for disease and is a tool to inform on pharmacological mechanisms of effect. For selective low-density lipoprotein cholesterol (LDL-C) lowering by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, multiple studies have demonstrated that its potent LDL-C lowering effect coincides with marked reductions in both cellular and arterial plaque inflammation, despite unaltered high-sensitivity C-reactive protein (hs-CRP) levels. Purpose In the present study, we set out to investigate potential anti-inflammatory effects of PCSK9 inhibition using plasma proteomics. Methods In 190 patients participating in the SPIRE-1/2 trials, 184 targeted proteins were measured at baseline and after 12 months of bococizumab treatment using the Cardiovascular II and III panels (Sweden). Of the included patients, 96 patients received placebo and 94 received 150mg of bococizumab, once every two weeks. Considering the development of auto-antibodies in some patients, patients with LDL-C reduction below 15% were excluded. The primary outcome was the fold change in protein levels after 12 months compared to baseline. The Benjamini-Hochberg method was used to adjust for multiple comparisons with a false discovery rate (FDR) of 5%. The findings were compared to the LoDoCo2 sub-study which used the same proteomic panels. Results In the placebo group, there was no significant change in any of the proteins. In the bococizumab group (n=77, mean age 62.2±9.7 years and 70 [91%] male), LDL-C levels were reduced from 114±41 mg/dL to 47±34 mg/dL (mean reduction 66±29 mg/dL) on top of statin therapy while there was a neutral effect on hs-CRP (median change 0.0 mg/L IQR [-0.8,1.1]). PCSK9 was the only protein with change upon treatment with bococizumab (24.4±11.0 vs. 15.0±10.7; PFDR=0.033; Figure 1A). In comparison, treatment of colchicine in the LoDoCo2 sub-study was associated with a significant change in 60 proteins (Figure 1B). Conclusion Here, we show that PCSK9 inhibition with bococizumab resulted in a highly selective reduction of PCSK9 plasma levels without robustly affecting other circulating proteins in the measured panels, implying PCSK9 inhibition lowers ASCVD risk via pure lipid lowering pathways. Our study reinforces the neutral systemic inflammatory effect of PCSK9 inhibition on top of statin therapy. The local effects on cellular and vascular inflammation by PCSK9 inhibition observed in earlier studies most likely reflect a direct consequence of a reduced cholesterol content in inflammatory cells and plaques, subsequently leading to a local anti-inflammatory effect. These findings support the combination of targeted anti-inflammatory therapies on top of potent LDL-C lowering in order to further reduce the residual inflammatory risk.

The Interaction between the Host Genome, Epigenome, and the Gut-Skin Axis Microbiome in Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that occurs in genetically predisposed individuals. It involves complex interactions among the host immune system, environmental factors (such as skin barrier dysfunction), and microbial dysbiosis. Genome-wide association studies (GWAS) have identified AD risk alleles; however, the associated environmental factors remain largely unknown. Recent evidence suggests that altered microbiota composition (dysbiosis) in the skin and gut may contribute to the pathogenesis of AD. Examples of environmental factors that contribute to skin barrier dysfunction and microbial dysbiosis in AD include allergens, irritants, pollution, and microbial exposure. Studies have reported alterations in the gut microbiome structure in patients with AD compared to control subjects, characterized by increased abundance of Clostridium difficile and decreased abundance of short-chain fatty acid (SCFA)-producing bacteria such as Bifidobacterium. SCFAs play a critical role in maintaining host health, and reduced SCFA production may lead to intestinal inflammation in AD patients. The specific mechanisms through which dysbiotic bacteria and their metabolites interact with the host genome and epigenome to cause autoimmunity in AD are still unknown. By understanding the combination of environmental factors, such as gut microbiota, the genetic and epigenetic determinants that are associated with the development of autoantibodies may help unravel the pathophysiology of the disease. This review aims to elucidate the interactions between the immune system, susceptibility genes, epigenetic factors, and the gut microbiome in the development of AD.

SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood

The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.

Distinct subsets of anti-pulmonary autoantibodies correlate with disease severity and survival in severe COVID-19 patients.

Autoantibodies targeting the lung tissue were identified in severe COVID-19 patients in this retrospective study. Fifty-three percent of 104 patients developed anti-pulmonary antibodies, the majority of which were IgM class, suggesting that they developed upon infection with SARS-CoV-2. Anti-pulmonary antibodies correlated with worse pulmonary function and a higher risk of multiorgan failure that was further aggravated if 3 or more autoantibody clones were simultaneously present (multi-producers). Multi-producer patients were older than the patients with less or no autoantibodies. One of the identified autoantibodies (targeting a pulmonary protein of ~ 50kDa) associated with worse clinical outcomes, including mortality. In summary, severe COVID-19 is associated with the development of lung-specific autoantibodies, which may worsen the clinical outcome. Tissue proteome-wide tests, such as the ones applied here, can be used to detect autoimmunity in the post-COVID state to identify the cause of symptoms and to reveal a new target for treatment.

Acquired Postpartum Hemophilia A Presentation of Severe Hematuria: A Case Report

BACKGROUND: Acquired hemophilia A (AHA) is a rare, severe bleeding disorder caused by the development of autoantibodies against FVIII that may be idiopathic or secondary to medical conditions. Postpartum AHA can occur as early as 1–4 months after delivery or as late as 1-year postpartum. CASE REPORT: A 20-year-old female presented with vaginal bleeding 20 days after delivery, then ecchymotic patches developed 2 months later, followed by hematuria 2 months after that. Laboratory investigation revealed isolated, prolonged partial thromboplastin time that was not corrected by mixing 50:50 with fresh normal plasma. FVIII activity was markedly deficient, with a high titer of immediate-acting FVIII inhibitor antibodies. CONCLUSION: The case was diagnosed as postpartum AHA with a good response to the combined steroids and cyclophosphamide treatment.

Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study.

To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior [1.41-2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54-3.02]). Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.