James C. Oates

Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus: The Randomized, Double-Blind, Phase II/III Systemic Lupus Erythematosus Evaluation of Rituximab Trial

OBJECTIVE B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE. METHODS Patients entered with >or=1 British Isles Lupus Assessment Group (BILAG) A score or >or=2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. RESULTS In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had >or=1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab. CONCLUSION The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.

Inhibition of Mesangial Cell Nitric Oxide in MRL/lpr Mice by Prostaglandin J2 and Proliferator Activation Receptor-γ Agonists

MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis similar to human lupus. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. PGJ2, a product of cyclooxygenase, is a potent in vitro inhibitor of macrophage inflammatory functions and is postulated to function as an in vivo inhibitor of macrophage-mediated inflammatory responses. We hypothesized that in lupus, a defect in PGJ2 production allows the inflammatory response to continue unchecked. To test this hypothesis, mesangial cells were isolated from MRL/lpr and BALB/c mice and stimulated with IL-1β or LPS plus IFN-γ. In contrast to the 2- to 3-fold increase in PGJ2 production by stimulated BALB/c mesangial cells, supernatant PGJ2 did not increase in MRL/lpr mesangial cell cultures. NO production in stimulated MRL/lpr and BALB/c mesangial cells, was blocked by PGJ2 and pioglitazone. These studies suggest that abnormalities in PGJ2 production are present in MRL/lpr mice and may be linked to the heightened activation state of mesangial cells in these mice.

Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the hyperaccumulation of fibrocytes in SSc-ILD may result from the altered phenotype and migratory activity of their monocyte precursors.

At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases

Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN‐α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody‐associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody‐associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN‐α production, measuring neutrophil extracellular traps may estimate IFN‐α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti‐IFN‐α therapies. In addition to anti‐IFN‐α therapies, other novel agents, such as N‐acetyl‐cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.

Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease

Objectives Reduced caveolin-1 levels in lung fibroblasts from patients with scleroderma and the lungs of bleomycin-treated mice promote collagen overexpression and lung fibrosis. This study was undertaken to determine whether caveolin-1 is deficient in leucocytes from bleomycin-treated mice and patients with scleroderma and to examine the consequences of this deficiency and its reversal. Methods Mice or cells received the caveolin-1 scaffolding domain (CSD) peptide to reverse the pathological effects of reduced caveolin-1 expression. In bleomycin-treated mice, the levels of caveolin-1 in leucocytes and the effect of CSD peptide on leucocyte accumulation in lung tissue were examined. To validate the results in human disease and to identify caveolin-1-regulated molecular mechanisms, monocytes and neutrophils were isolated from patients with scleroderma and control subjects and caveolin-1, extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, CXC chemokine receptor 4 (CXCR4) and matrix metalloproteinase 9 (MMP-9) expression/activation were evaluated. These parameters were also studied in monocytes treated with cytokines or CSD peptide. Results Leucocyte caveolin-1 is important in lung fibrosis. In bleomycin-treated mice, caveolin-1 expression was diminished in monocytes and CSD peptide inhibited leucocyte recruitment into the lungs. These observations are relevant to human disease. Monocytes and neutrophils from patients with scleroderma contained less caveolin-1 and more activated ERK, JNK and p38 than those from control subjects. Treatment with CSD peptide reversed ERK, JNK and p38 hyperactivation. Scleroderma monocytes also overexpressed CXCR4 and MMP-9, which was inhibited by the CSD peptide. Cytokine treatment of normal monocytes caused adoption of the scleroderma phenotype (low caveolin-1, high CXCR4 and MMP-9 and signalling molecule hyperactivation). Conclusions Caveolin-1 downregulation in leucocytes contributes to fibrotic lung disease, highlighting caveolin-1 as a promising therapeutic target in scleroderma.

Oral administration of a decaffeinated green tea (Camellia sinensis) extract did not alter urinary 8-epi-prostaglandin F2α, a biomarker for in-vivo lipid peroxidation

Oxidative stress is involved in the pathogenesis of numerous chronic human diseases. The objective of this study was to determine whether administration of a decaffeinated green tea extract providing 844 mg flavonoids daily reduced the urinary excretion of 8‐epi‐prostaglandin F2α (8‐epi‐PGF2α), a product of lipid peroxidation in cellular membranes and of low‐density lipoprotein (LDL). Nine healthy male and female subjects were studied at baseline and after 14 days of green tea supplementation. Analysis of urinary 8‐epi‐PGF2α was performed using immunoaffinity extraction‐gas chromatography‐negative ion chemical ionization‐mass spectrometry (GC‐NICI‐MS). Urinary 8‐epi‐PGF2α concentrations were 0.286±0.120 nmol (mmol creatinine)−1 at baseline and 0.244±0.177 nmol mmol−1 creatinine after green tea supplementation. There were no significant differences in the excretion of urinary 8‐epi‐PGF2α after treatment with green tea. We conclude that 14 days of green tea supplementation did not significantly alter in‐vivo lipid peroxidation.

Stress and Depression in Relation to Functional Health Behaviors in African American Patients with Systemic Lupus Erythematosus.

Objective While increased psychological distress in SLE has been clinically and empirically reported, the relationship between emotional distress, treatment adherence, and disease activity are complex and even more unclear in African American lupus patients. In an effort to elucidate this phenomenon in these patients, this exploratory study aimed to investigate relationships between stress, depression, and various health behaviors in this group. Methods Thirty patients invited to participate in this study were African American systemic lupus erythematosus (SLE) patients attending rheumatology clinics at the Medical University of South Carolina (MUSC). This study was part of a larger interventional pilot study, the Balancing Lupus Experiences with Stress Strategies (BLESS) study, that included a comprehensive battery of psychosocial, quality of life, and behavior change measures. Results When looking at the association between anxiety/stress and functionality, levels of reported stress had strong effects upon functionality, especially between health distress and functionality. When looking at the association between depressive symptoms and functionality, depressive symptoms had moderate effects upon social/role limitations and nights spent in the hospital. Conclusion Not only did the larger pilot project demonstrate significant reductions in stress and depression as a result of workshop participation; this nested study also showed that those improvements were positively associated with improved health behaviors. These results could have implications for developing interventions to improve disease experience and quality of life in SLE patients with stress and depression.

Rheumatology Informatics System for Effectiveness: A National Informatics-Enabled Registry for Quality Improvement

The Rheumatology Informatics System for Effectiveness (RISE) is a national electronic health record (EHR)–enabled registry. RISE passively collects data from EHRs of participating practices, provides advanced quality measurement and data analytic capacities, and fulfills national quality reporting requirements. Here we report the registrys architecture and initial data, and we demonstrate how RISE is being used to improve the quality of care.

The Place of William Osler in the Description of Systemic Lupus Erythematosus

In the pages of The American Journal of Medical Sciences more than 100 years ago (1,2) and reprinted in the present issue, famed internist and medical educator William Osler described 29 patients with skin disease without evident systemic or visceral involvement. Much has been written about the life of Osler (3) as well as the history of diseases called lupus or lupus erythematosus (4–11). These terms were originally applied to disease of the skin. Beginning in the middle of the nineteenth century with Kaposi, there was recognition that some patients with lupus erythematosus had involvement of organs other than the skin. Some have given a great deal of credit to Osler in the march towards an understanding of the disseminated nature of lupus erythematosus (6), while others have minimized his contribution (11). With the simultaneous reprinting of Osler’s classic article from 1904 (2), we attempt to put the contribution of William Osler into a perspective of the 21st century.

Word2Vec inversion and traditional text classifiers for phenotyping lupus

BackgroundIdentifying patients with certain clinical criteria based on manual chart review of doctors’ notes is a daunting task given the massive amounts of text notes in the electronic health records (EHR). This task can be automated using text classifiers based on Natural Language Processing (NLP) techniques along with pattern recognition machine learning (ML) algorithms. The aim of this research is to evaluate the performance of traditional classifiers for identifying patients with Systemic Lupus Erythematosus (SLE) in comparison with a newer Bayesian word vector method.MethodsWe obtained clinical notes for patients with SLE diagnosis along with controls from the Rheumatology Clinic (662 total patients). Sparse bag-of-words (BOWs) and Unified Medical Language System (UMLS) Concept Unique Identifiers (CUIs) matrices were produced using NLP pipelines. These matrices were subjected to several different NLP classifiers: neural networks, random forests, naïve Bayes, support vector machines, and Word2Vec inversion, a Bayesian inversion method. Performance was measured by calculating accuracy and area under the Receiver Operating Characteristic (ROC) curve (AUC) of a cross-validated (CV) set and a separate testing set.ResultsWe calculated the accuracy of the ICD-9 billing codes as a baseline to be 90.00% with an AUC of 0.900, the shallow neural network with CUIs to be 92.10% with an AUC of 0.970, the random forest with BOWs to be 95.25% with an AUC of 0.994, the random forest with CUIs to be 95.00% with an AUC of 0.979, and the Word2Vec inversion to be 90.03% with an AUC of 0.905.ConclusionsOur results suggest that a shallow neural network with CUIs and random forests with both CUIs and BOWs are the best classifiers for this lupus phenotyping task. The Word2Vec inversion method failed to significantly beat the ICD-9 code classification, but yielded promising results. This method does not require explicit features and is more adaptable to non-binary classification tasks. The Word2Vec inversion is hypothesized to become more powerful with access to more data. Therefore, currently, the shallow neural networks and random forests are the desirable classifiers.