B- and T-Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis.

B- and T-lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression in the pathogenesis of systemic lupus erythematosus (SLE), a multisystem autoimmune disease.

Laser Capture Microscopy RNA Sequencing for Topological Mapping of Synovial Pathology During Rheumatoid Arthritis.

Objective: Rheumatoid arthritis (RA) is an autoimmune disease in which the joint lining or synovium becomes highly inflamed and majorly contributes to disease progression. Understanding pathogenic processes in RA synovium is critical for identifying therapeutic targets. We performed laser capture microscopy (LCM) followed by RNA sequencing (LCM-RNAseq) to study regional transcriptomes throughout RA synovium.

A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases.

B cells contribute to multiple aspects of autoimmune disorders, and B cell-targeting therapies, including B cell depletion, have been proven to be efficacious in treatment of multiple autoimmune diseases. However, the development of novel therapies targeting B cells with higher efficacy and a nondepleting mechanism of action is highly desirable. Here we describe a nondepleting, high-affinity anti-human CD19 antibody LY3541860 that exhibits potent B cell inhibitory activities.

Target modulation and pharmacokinetics/pharmacodynamics translation of the BTK inhibitor poseltinib for model-informed phase II dose selection.

The selective Bruton tyrosine kinase (BTK) inhibitor poseltinib has been shown to inhibit the BCR signal transduction pathway and cytokine production in B cells (Park et al. Arthritis Res. Ther.

Sub-setting systemic lupus erythematosus by combined molecular phenotypes defines divergent populations in two phase III randomized trials.

Objectives: Heterogeneity of SLE patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity.

Methods: Combinations of IFN (high/low), anti-dsDNA (+/-) and C3 and C4 (low/normal) were used to subset n = 1747 patients from two randomized phase III trials.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial.

Background: Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus.

Methods: In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries.

Clinical trial parameters that influence outcomes in lupus trials that use the systemic lupus erythematosus responder index.

Objective: The SLE Responder Index (SRI) is a composite endpoint used in SLE trials. This investigation examined the clinical trial elements that drive response measured by the SRI.

Methods: Analyses are based on data from two phase 3 trials (n = 2262) that evaluated the impact of an anti-B-cell activating factor antibody on disease activity using SRI-5 as the primary endpoint (ClinicalTrials.

Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab.

Objective: To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52-week, randomized, placebo-controlled, double-blind studies in which patients were treated with the BAFF-blocking IgG4 monoclonal antibody tabalumab.

Methods: Patient samples were obtained from SLE patients from the ILLUMINATE-1 and ILLUMINATE-2 studies, and control samples were obtained from healthy donors. Blood was collected in Tempus tubes at baseline, week 16, and week 52.

Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial.

Objective: To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA).

Methods: Adult patients with active RA (≥ 5 swollen and ≥ 5 tender joints) receiving a stable dose of MTX (10-25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥ 12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥ 1 serious infection through week 24.

Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial.

Objective: To investigate whether treatment with abetimus delays renal flare in patients with lupus nephritis. Secondary objectives included evaluation of the effect of abetimus on C3 levels, anti-double-stranded DNA (anti-dsDNA) antibody levels, use of high-dose corticosteroids and/or cyclophosphamide, and major systemic lupus erythematosus (SLE) flare.

Methods: We conducted a randomized, placebo-controlled study of treatment with abetimus at 100 mg/week for up to 22 months in SLE patients.

Pharmacokinetics of high-dose abetimus sodium in normal subjects with specific assessment of effect on coagulation.

Abetimus sodium is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-double-stranded DNA antibody levels. The safety and pharmacokinetics of abetimus were evaluated in 24 healthy volunteers at intravenous doses of 600 mg, 1200 mg, and 2400 mg. The mean half-life ranged from 0.

Anti-inflammatory effects of LJP 1586 [Z-3-fluoro-2-(4-methoxybenzyl)allylamine hydrochloride], an amine-based inhibitor of semicarbazide-sensitive amine oxidase activity.

Semicarbazide-sensitive amine oxidase (SSAO, amine oxidase, copper-containing 3, and vascular adhesion protein-1) is a copper-containing enzyme that catalyzes the oxidative deamination of primary amines to an aldehyde, ammonia, and hydrogen peroxide. SSAO is also involved in leukocyte migration to sites of inflammation, and the enzymatic activity of SSAO is essential to this role. Thus, inhibition of SSAO enzyme activity represents a target for the development of small molecule anti-inflammatory compounds.

Anti-beta2-glycoprotein I antibodies in complex with beta2-glycoprotein I can activate platelets in a dysregulated manner via glycoprotein Ib-IX-V.

Objective: Results of previous studies suggest that anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in complex with beta2GPI activate platelets in a dysregulated manner, potentially contributing to the prothrombotic tendency associated with the antiphospholipid syndrome (APS). We undertook this study to investigate the possible contribution of the GPIb-IX-V receptor to platelet activation mediated by the anti-beta2GPI antibody-beta2GPI complex.

Methods: In vitro methods were used in the present study.

Design, synthesis, and biological evaluation of semicarbazide-sensitive amine oxidase (SSAO) inhibitors with anti-inflammatory activity.

In an attempt to examine the effect of inhibition of semicarbazide-sensitive amine oxidase (SSAO; EC 1.4.3.

Vascular adhesion protein-1 plays an important role in postischemic inflammation and neuropathology in diabetic, estrogen-treated ovariectomized female rats subjected to transient forebrain ischemia.

Endothelial vascular adhesion protein-1 (VAP-1) facilitates leukocyte adhesion and infiltration. This relates partly to the function of VAP-1 as a semicarbazide-sensitive amine oxidase (SSAO). We examined the effects of VAP-1/SSAO inhibition [via LJP-1207 (N'-(2-phenyl-allyl)-hydrazine hydrochloride)] on pial venular leukocyte adhesion and infiltration (at 2-10 h of reperfusion) and neuropathology (at 72 h of reperfusion) after transient forebrain ischemia (TFI).

Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase.

Human semicarbazide-sensitive amine oxidase (SSAO) or vascular adhesion protein-1 (VAP-1) is a copper-containing amine oxidase (AOC3, EC 1.4.3.

Relationship between anti-double-stranded DNA antibodies and exacerbation of renal disease in patients with systemic lupus erythematosus.

Objective: To examine the relationship between changes in anti-double-stranded DNA (anti-dsDNA) antibody levels and the risk of renal flare in patients with systemic lupus erythematosus (SLE), using data from 2 randomized, controlled trials.

Methods: Analyses were based on 487 patients with SLE and a history of lupus nephritis who had an anti-dsDNA antibody titer >/=15 IU/ml at baseline, as measured by Farr assay. Results are presented for the combined population of patients, the placebo arms, and the drug treatment arms in which a dsDNA-based bioconjugate (abetimus sodium; LJP 394) was used.

Domain V of beta2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318.

The fifth domain (DV) of beta2-glycoprotein I (beta2GPI) is important for binding a number of ligands including phospholipids and factor XI (FXI). Beta2GPI is proteolytically cleaved in DV by plasmin but not by thrombin, VIIa, tissue plasminogen activator, or uPA. Following proteolytic cleavage of DV by plasmin, beta2GPI retains binding to FXI but not to phospholipids.

Therapeutic potential of toleragens in the management of antiphospholipid syndrome.

Autoantibodies to beta2-glycoprotein I (beta2GPI) are believed to be the primary cause of coagulation abnormalities in patients with antiphospholipid syndrome (APS). Clinical features include a range of life-threatening thrombotic events and microangiopathies affecting multiple organ systems. Current standard of care relies on long-term, high-intensity anticoagulation and is associated with a high risk for serious bleeding events.

Detection and characterization of B cell epitopes on beta2-glycoprotein I.

Autoantibodies in antiphospholipid syndrome react predominantly with the plasma protein beta2-glycoprotein I (beta2GPI). Work by a large number of investigators has led to considerable progress in detecting and understanding beta2GPI reactivity with autoantibodies. Characterization of B cell epitopes on beta2GPI has benefited from an appreciation of its interactions with anionic phospholipids and a variety of microplate surfaces.

Advances in understanding what we measure when detecting anticardiolipin autoantibodies.

Understanding so-called anticardiolipin autoantibodies has been the focus of significant interest due to their accepted role in the pathology of antiphospholipid syndrome (APS). How these antibodies contribute to thrombosis, stroke and recurrent fetal loss is not clearly understood. A precise determination of the antigenic epitope(s) recognized by anticardiolipin autoantibodies will contribute to an understanding of their role in this complex disease; however, there have been many conflicting reports regarding these epitope(s), and many of the apparent contradictions arise from the assay systems that have been used.

Beta 2-Glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped beta 2-glycoprotein I.

Activation of factor XI (FXI) by thrombin in vivo plays a role in coagulation by providing an important positive feedback mechanism for additional thrombin generation. FXI is activated in vitro by thrombin, or FXIIa in the presence of dextran sulfate. In this report, we investigated the effect of beta(2)-glycoprotein I (beta(2)GPI) on the activation of FXI.

In vivo characterization of bioconjugate B cell toleragens with specificity for autoantibodies in antiphospholipid syndrome.

This study investigated the use of well-defined bioconjugate molecules to suppress antigen-specific B cell responses to domain I (DI) of human beta(2)-glycoprotein I (beta(2)GPI) in rats. DI is the dominant target of pathogenic autoimmune antibodies in patients with antiphospholipid syndrome (APS), a disease characterized by antibody-mediated thromboembolic events. Rats primed with DI conjugated to keyhole limpet hemocyanin (DI-KLH) were rendered tolerant to subsequent antigen challenge by treatment with multivalent conjugates of DI.

LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: results from a randomized, double-blind, placebo-controlled study.

Objective: To determine whether LJP 394 delays or prevents renal flare in patients with systemic lupus erythematosus (SLE) and a history of renal disease.

Methods: In a 76-week, double-blind, placebo-controlled study, 230 SLE patients were randomized to receive 16 weekly doses of 100 mg of LJP 394 or placebo, followed by alternating 8-week drug holidays and 12 weekly doses of 50 mg of LJP 394 or placebo. An assay measuring the affinity of the serum IgG fraction for the DNA epitope of LJP 394 identified a high-affinity population of patients (189 of 213 patients; 89% taking LJP 394 and 90% taking placebo).

Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies.

Autoantibodies against beta(2)-glycoprotein I (beta(2)GPI) appear to be a critical feature of the antiphospholipid syndrome (APS). As determined using domain deletion mutants, human autoantibodies bind to the first of five domains present in beta(2)GPI. In this study the fine detail of the domain I epitope has been examined using 10 selected mutants of whole beta(2)GPI containing single point mutations in the first domain.