Prospective SARS-CoV-2 Booster Vaccination in Immunosuppressant-Treated Systemic Autoimmune Disease Patients in a Randomized Controlled Trial.

Background: Autoimmune disease patients on immunosuppressants exhibit reduced humoral responses to primary COVID-19 vaccination. Booster vaccine responses and the effects of holding immunosuppression around vaccination are less studied. We evaluated the efficacy and safety of additional vaccination in mycophenolate mofetil/mycophenolic acid (MMF/MPA)-, methotrexate (MTX)-, and B cell-depleting therapy (BCDT)-treated autoimmune disease patients, including the impact of withholding MMF/MPA and MTX.

Association of Autoantibody Concentrations and Trajectories With Lupus Nephritis Histologic Features and Treatment Response.

Objective: Autoantibodies are a hallmark of lupus nephritis (LN), but their association with LN classes and treatment response are not adequately known. In this study, we quantified circulating autoantibodies in the Accelerating Medicines Partnership LN longitudinal cohort to identify serological biomarkers of LN histologic classification and treatment response and how these biomarkers change over time based on treatment response.

Methods: Peripheral blood samples were collected from 279 patients with systemic lupus erythematosus undergoing diagnostic kidney biopsy based on proteinuria.

Neutrophils isolated from systemic lupus erythematosus patients exhibit a distinct functional phenotype.

Neutrophil dysregulation, particularly of a low-density subset, is associated with systemic lupus erythematosus (SLE); however, the exact role of normal-density neutrophils in SLE remains unknown. This study compares activation and functional phenotypes of neutrophils from SLE patients and healthy controls to determine potential contributions to SLE pathogenesis. Surface activation markers and release of neutrophil extracellular traps (NETs), granule proteins, and cytokines/chemokines were measured in resting and stimulated neutrophils from SLE patients (n=19) and healthy controls (n=10).

Ancestry-based differences in the immune phenotype are associated with lupus activity.

Systemic lupus erythematosus (SLE) affects 1 in 537 Black women, which is >2-fold more than White women. Black patients develop the disease at a younger age, have more severe symptoms, and have a greater chance of early mortality. We used a multiomics approach to uncover ancestry-associated immune alterations in patients with SLE and healthy controls that may contribute biologically to disease disparities.

Genetic load in incomplete lupus erythematosus.

Objective: Patients with incomplete lupus erythematosus (ILE) have lupus features but insufficient criteria for SLE classification. Some patients with ILE transition to SLE, but most avoid major organ involvement. This study tested whether the milder disease course in ILE is influenced by reduced SLE risk allele genetic load.

The promise of precision medicine in rheumatology.

Systemic autoimmune rheumatic diseases (SARDs) exhibit extensive heterogeneity in clinical presentation, disease course, and treatment response. Therefore, precision medicine - whereby treatment is tailored according to the underlying pathogenic mechanisms of an individual patient at a specific time - represents the 'holy grail' in SARD clinical care. Current strategies include treat-to-target therapies and autoantibody testing for patient stratification; however, these are far from optimal.

Serologic markers of Epstein-Barr virus reactivation are associated with increased disease activity, inflammation, and interferon pathway activation in patients with systemic lupus erythematosus.

SLE is a clinically heterogeneous disease characterized by an unpredictable relapsing-remitting disease course. Although the etiology and mechanisms of SLE flares remain elusive, Epstein-Barr virus (EBV) reactivation is implicated in SLE pathogenesis. This study examined the relationships between serological measures of EBV reactivation, disease activity, and interferon (IFN)-associated immune pathways in SLE patients.

The intersection of COVID-19 and autoimmunity.

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R.

Pathogenic T cell cytokines in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is believed to have an autoimmune etiology. As MS is the most common nontraumatic disease that causes disability in young adults, extensive research has been devoted to identifying therapeutic targets. In this review, we discuss the current understanding derived from studies of patients with MS and animal models of how specific cytokines produced by autoreactive CD4 T cells contribute to the pathogenesis of MS.

Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the CNS. Although CD4+ T cells are implicated in MS pathogenesis and have been the main focus of MS research using the animal model experimental autoimmune encephalomyelitis (EAE), substantial evidence from patients with MS points to a role for CD8+ T cells in disease pathogenesis. We previously showed that an MHC class I-restricted epitope of myelin basic protein (MBP) is presented in the CNS during CD4+ T cell-initiated EAE.

Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans.

Objectives: Cigarette smoking is a major risk factor for RA and has been associated with increased disease severity and lower rates of disease remission. We hypothesized that inflammation and disease activity would be associated with smoking status and this would be related to levels of ACPA.

Methods: RA patients from the Veterans Affairs RA registry were studied (n = 1466): 76.

The contribution of neutrophils to CNS autoimmunity.

Multiple sclerosis (MS) is believed to be initiated when myelin-specific T cells infiltrate the central nervous system (CNS), triggering subsequent recruitment of inflammatory leukocytes to the CNS. The contribution of neutrophils to CNS autoimmune disease has been underappreciated, but several studies in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, indicate that neutrophils have an important role in inflammation. Neutrophils are hypothesized to contribute to the pathogenesis of EAE by producing cytokines and promoting breakdown of the blood brain barrier.

CCL19 as a Chemokine Risk Factor for Posttreatment Lyme Disease Syndrome: a Prospective Clinical Cohort Study.

Approximately 10% to 20% of patients optimally treated for early Lyme disease develop persistent symptoms of unknown pathophysiology termed posttreatment Lyme disease syndrome (PTLDS). The objective of this study was to investigate associations between PTLDS and immune mediator levels during acute illness and at several time points following treatment. Seventy-six participants with physician-documented erythema migrans and 26 healthy controls with no history of Lyme disease were enrolled.

Cutting Edge: Integrin α4 Is Required for Regulatory B Cell Control of Experimental Autoimmune Encephalomyelitis.

The neutralization of integrin α4 (Itga4) is currently used as treatment in multiple sclerosis. Although most studies have focused on its function on lymphocyte migration to the CNS, we have uncovered the importance of Itga4 for the generation of regulatory B cells in peripheral immune organs and their control of pathogenic T cell response and CNS pathology. Our study underscores the importance of looking at the dual role of B cells in CNS autoimmunity and provides important perspectives regarding the efficacy and side effects associated with Itga4 neutralization and other B cell-targeting therapies.

Novel Insights and Therapeutics in Multiple Sclerosis.

The last twelve years have witnessed the development of new therapies for relapsing-remitting multiple sclerosis that demonstrate increased efficacy relative to previous therapies. Many of these new drugs target the inflammatory phase of disease by manipulating different aspects of the immune system. While these new treatments are promising, the development of therapies for patients with progressive multiple sclerosis remains a significant challenge.

Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis.

Objective: A hallmark of rheumatoid arthritis (RA) is the production of autoantibodies, including anti-citrullinated protein antibodies (ACPAs). Nevertheless, the specific targets of these autoantibodies remain incompletely defined. During an immune response, B cells specific for the inciting antigen(s) are activated and differentiate into plasmablasts, which are released into the blood.

Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.

Objective: The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation.

Serum inflammatory mediators as markers of human Lyme disease activity.

Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.

Peptidylarginine deiminase 4 contributes to tumor necrosis factor α-induced inflammatory arthritis.

Objective: Peptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that has multiple associations with inflammation. In rheumatoid arthritis, PAD4 and protein citrullination are increased in inflamed joints, and anti-citrullinated protein antibodies (ACPAs) form against citrullinated antigens are formed. ACPA immune complexes can deposit in the joint and induce the production of tumor necrosis factor α (TNFα), a critical inflammatory cytokine in the pathogenesis of rheumatoid arthritis.

Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.

Objective: We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA.

Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 'shared epitope' alleles.

Introduction: A hallmark of rheumatoid arthritis (RA) is the development of autoantibodies targeting proteins that contain citrulline. Anticitrullinated protein antibodies (ACPAs) are currently detected by the commercial cyclic citrullinated peptide (CCP) assay, which uses a mix of cyclised citrullinated peptides as an artificial mimic of the true antigen(s). To increase the sensitivity of ACPA detection and dissect ACPA specificities, we developed a multiplex assay that profiles ACPAs by measuring their reactivity to the citrullinated peptides and proteins derived from RA joint tissue.

Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case-control study.

Introduction: The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles.

Methods: We identified 192 women in the Nurses' Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use.