Elevated interleukin-10: a new cause of dyslipidemia leading to severe HDL deficiency.

Background: Low high-density lipoprotein cholesterol (HDL-C) is a risk factor for coronary artery disease. Investigating mechanisms underlying acquired severe HDL deficiency in noncritically ill patients ("disappearing HDL syndrome") could provide new insights into HDL metabolism.

Objective: To determine the cause of low HDL-C in patients with severe acquired HDL deficiency.

Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus.

Background: Circulating plasmablasts/plasma cells and activated B and T cells are increased in systemic lupus erythematosus (SLE). Interleukin (IL)-6 induces differentiation of B cells into antibody-forming cells and of T cells into effector cells.

Objective: To examine the hypothesis that blocking IL-6 would reverse some of the immune abnormalities present in SLE.

Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study.

Objective: To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Methods: Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary.

Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study.

Objective: To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).

Methods: In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.

Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis.

Objectives: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis.

Methods: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.

Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus.

CD4(+)CD25(+) T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4(+)CD25(high) Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE.

Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus.

Objective: To assess the association of cognitive dysfunction and depression with serum antibodies to N-methyl-D-aspartate (NMDA) receptor (anti-NR2) and analyze clinical and neuroimaging correlates in patients with systemic lupus erythematosus (SLE).

Methods: Sixty patients underwent neurocognitive assessment, evaluation for depression with the Beck Depression Inventory II (BDI-II) and psychiatric interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), brain magnetic resonance imaging, and proton magnetic resonance spectroscopy imaging (1H-MRSI). Cognition was assessed in 5 domains: memory, attention/executive, visuospatial, motor, and psychomotor, and adjusted to each individual's best level of prior cognitive functioning estimated from the reading subtest of the Wide Range Achievement Test-3 (WRAT-3).

Abnormal differentiation of memory T cells in systemic lupus erythematosus.

Objective: The chemokine receptor CCR7 and the tumor necrosis factor receptor family member CD27 define 3 distinct, progressively more differentiated maturational stages of CD4 memory subpopulations in healthy individuals: the CCR7+, CD27+, the CCR7-, CD27+, and the CCR7-, CD27- populations. The goal of this study was to examine maturational disturbances in CD4 T cell differentiation in systemic lupus erythematosus (SLE), using these phenotypic markers.

Methods: Phenotypic analysis by flow cytometry, in vitro stimulation experiments, telomere length measurement, and determination of inducible telomerase were carried out.

Use of computerized assessment to predict neuropsychological functioning and emotional distress in patients with systemic lupus erythematosus.

Objective: Cognitive dysfunction and neuropsychiatric disturbance are common in systemic lupus erythematosus (SLE). This study addressed the ability of the Automated Neuropsychological Assessment Metrics (ANAM), a computerized cognitive testing battery consisting of cognitive subtests, a sleepiness rating scale, and a mood scale, to predict neuropsychological status in patients with SLE.

Methods: Sixty individuals with SLE and no overt neuropsychiatric symptoms were administered ANAM to determine its validity as a screening measure of cognitive dysfunction and emotional distress in SLE.

ICF core sets: how to specify impairment and function in systemic lupus erythematosus.

The World Health Organization's International Classification of Function (ICF) is a tool to characterize and illuminate better the full of array of problems a patient faces when affected by disease. Specifying these problems is a particular challenge in a disease like systemic lupus erythematosus (SLE) because of the wide variety in organ systems involved, its variable activity and severity, and considerable ethnic and local differences. The authors of this manuscript believe, however, that a broader understanding will prove essential for optimal patient care, and that there is sufficient experience now in defining ICF Core Sets to successfully complete core sets for SLE.

The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus.

Background: A common functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) was previously associated with diminished episodic memory performance in healthy people. As cognitive function is commonly impaired in patients with systemic lupus erythematosus (SLE), the association of the BDNF Val66Met with neurocognitive function was studied.

Objective: To study the association of the BDNF Val66Met with neurocognitive function in a cohort of patients with SLE.

Identification and characterization of circulating human transitional B cells.

Murine B-cell development begins in bone marrow and results in the generation of immature transitional B cells that transit to the spleen to complete their maturation. It remains unclear whether the same developmental pathway takes place in humans. Using markers characteristic of human bone marrow immature B cells, we have identified a population of circulating human B cells with a phenotype most similar to mouse transitional type I (T1) B cells, although these human counterparts express CD5.

Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis.

Objective: Pulse cyclophosphamide is the treatment of choice for severe lupus nephritis. However, not all patients respond to this therapy, and gonadal toxicity is of particular concern. Cyclophosphamide is a prodrug that requires activation by cytochrome P450 (CYP) enzymes.

A pilot study of the use of 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography to assess the distribution of activated lymphocytes in patients with systemic lupus erythematosus.

Objective: The 2-[(18)F]-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) technique provides information on uptake and metabolism of glucose in various tissues. Compared with resting cells, activated lymphocytes take up radioactively labeled glucose analog at a higher rate, which makes it possible to identify lymphoid organs with higher concentrations of activated lymphocytes. This study was undertaken to compare the pattern of PET images and quantitative FDG uptake in lymphoid organs of patients with active systemic lupus erythematosus (SLE) versus patients with inactive SLE and to correlate these findings with peripheral blood lymphocyte phenotypes.

Number of active joints, not diagnosis, is the primary determinant of function and performance in early synovitis.

Objective: A substudy within a larger study of patients with inflammatory arthritis of less than one year, to analyze baseline measures or joint counts, laboratory values, patient questionnaires and ARA diagnostic criteria for rheumatoid arthritis, as predictors of one year performance and functional status.

Methods: 229 patients with synovitis of less than one year were enrolled and evaluated at baseline and one year. Measures included the number of swollen or tender joints [active joint counts]; biological indices of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)]; and patient questionnaire measures of pain [Wisconsin Brief Pain Inventory], fatigue [multi-dimensional assessment of fatigue], depression [Center for Epidemiologic Studies--Depression Scale], sleep [Sleep Quality Index], performance [Human Activity Profile], and function [Sickness Impact Profile ambulation subscale and Health Assessment Questionnaire].

Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions.

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period.

Lymphocyte depletion with fludarabine in patients with psoriatic arthritis: clinical and immunological effects.

Objective: To obtain preliminary information on the safety and efficacy of fludarabine in PsA and analyse its immunomodulatory effects in peripheral blood and synovial tissue.

Methods: 15 patients with active PsA who did not respond to DMARDs were randomly allocated to receive fludarabine every four weeks or placebo. Primary outcomes were the proportion of patients who met the ACR20 and the psoriatic arthritis response criteria (PsARC) at 16 weeks.

Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis.

Advanced glycation end-product (AGE)-damaged IgG occurs as a result of hyperglycemia and/or oxidative stress. Autoantibodies to IgG-AGE were previously demonstrated in patients with severe, longstanding rheumatoid arthritis (RA). We investigated whether IgG-AGE and anti-IgG-AGE antibodies were present early in the course of RA and other inflammatory arthropathies.

Response of peripheral blood mononuclear cells from lupus patients to stimulation by CpG oligodeoxynucleotides.

Objectives: Increased levels of hypomethylated CpG-containing DNA in sera from patients with systemic lupus erythematosus (SLE) may contribute to the initiation and/or perpetuation of the disease. This study characterizes the in vitro response of peripheral blood mononuclear cells (PBMC) from SLE patients to CpG DNA.

Methods: Secretion of cytokines and IgM, cell proliferation and up-regulation of co-stimulatory molecules were evaluated in PBMC from SLE patients (n=24) and normal controls (n=24) after stimulation with synthetic oligodeoxynucleotides (ODN) containing CpG motifs.

Pilot clinical trial of intravenous doxycycline versus placebo for rheumatoid arthritis.

Objective: To screen for potential efficacy and assess the feasibility of intravenous (IV) doxycycline as a treatment for rheumatoid arthritis (RA).

Methods: The study was a (stratified, block) randomized, double blind, 12 week, pilot trial of IV doxycycline 300 mg/day versus identical appearing IV placebo given over 2 h for 14 days. The primary comparison was to a hypothesized placebo rate of 20% as described by Paulus.

Renal flares are common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies.

Objective: Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares.

Methods: Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both.

IL-10 improves skin disease and modulates endothelial activation and leukocyte effector function in patients with psoriatic arthritis.

Psoriatic arthritis (PsA) provides an ideal disease model in which to investigate the bioactivities of potentially therapeutic cytokines at multiple sites of tissue inflammation. We investigated the effects of IL-10, an antiinflammatory cytokine, given s.c.

Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis.

Background: Controlled trials in lupus nephritis have demonstrated that cyclophosphamide therapy is superior to corticosteroid therapy alone. The long-term effectiveness and side-effect profiles of pulse immunosuppressive regimens warrant further study.

Objective: To define the long-term risk and benefit of monthly treatment with boluses of methylprednisolone, cyclophosphamide, or both.

Fludarabine pharmacokinetics after subcutaneous and intravenous administration in patients with lupus nephritis.

Study Objective: To compare the pharmacokinetics of subcutaneous and intravenous fludarabine in patients with lupus nephritis.

Design: Open-label, randomized, crossover trial conducted with a phase I-II trial.

Setting: Government research hospital.

Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis.

Introduction: In cancer the gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] have been shown to be associated with tissue invasion and metastatic disease. In patients with inflammatory arthritis the gelatinases are expressed in the synovial membrane, and have been implicated in synovial tissue invasion into adjacent cartilage and bone. It is hypothesized that an imbalance between the activators and inhibitors of the gelatinases results in higher levels of activity, enhanced local proteolysis, and bone erosion.