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1.  Cell-bound complement activation products in systemic lupus erythematosus: comparison with anti-double-stranded DNA and standard complement measurements 
Lupus Science & Medicine  2014;1(1):e000056.
Objective
To compare the performance characteristics of cell-bound complement (C4d) activation products (CBCAPS) on erythrocyte (EC4d) and B cells (BC4d) with antibodies to double-stranded DNA (anti-dsDNA) and complement C3 and C4 in systemic lupus erythematosus (SLE).
Methods
The study enrolled 794 subjects consisting of 304 SLE and a control group consisting of 285 patients with other rheumatic diseases and 205 normal individuals. Anti-dsDNA and other autoantibodies were measured using solid-phase immunoassays while EC4d and BC4d were determined using flow cytometry. Complement proteins were determined using immunoturbidimetry. Disease activity in SLE was determined using a non-serological Systemic Lupus Erythematosus Disease Activity Index SELENA Modification. A two-tiered methodology combining CBCAPS with autoantibodies to cellular and citrullinated antigens was also developed. Statistical analyses used area under receiver operating characteristic curves and calculations of area under the curve (AUC), sensitivity and specificity.
Results
AUC for EC4d (0.82±0.02) and BC4d (0.84±0.02) was higher than those yielded by C3 (0.73±0.02) and C4 (0.72±0.02) (p<0.01). AUC for CBCAPS was also higher than the AUC yielded by anti-dsDNA (0.79±0.02), but significance was only achieved for BC4d (p<0.01). The combination of EC4d and BC4d in multivariate testing methodology with anti-dsDNA and autoantibodies to cellular and citrullinated antigens yielded 80% sensitivity for SLE and specificity ranging from 70% (Sjogren's syndrome) to 92% (rheumatoid arthritis) (98% vs. normal). A higher proportion of patients with SLE with higher levels of disease activity tested positive for elevated CBCAPS, reduced complement and anti-dsDNA (p<0.03).
Conclusions
CBCAPS have higher sensitivity than standard complement and anti-dsDNA measurements, and may help with the differential diagnosis of SLE in combination with other autoantibodies.
doi:10.1136/lupus-2014-000056
PMCID: PMC4225732  PMID: 25396070
Autoimmune Diseases; Systemic Lupus Erythematosus; Autoantibodies
3.  Enhanced ROCK Activation in Patients with Systemic Lupus Erythematosus 
Arthritis and rheumatism  2013;65(6):1592-1602.
Objective
Rho-kinases (ROCKs) have been implicated in the pathogenesis of cardiovascular and renal disorders. We recently showed that ROCKs could regulate the differentiation of murine TH17 cells and production of IL-17 and IL-21, two cytokines associated with SLE. The goal of this study was to assess ROCK activation in human TH17 cells and evaluate ROCK activity in SLE patients.
Methods
An ELISA-based ROCK activity assay was employed to evaluate ROCK activity in human cord blood CD4+ T cells differentiated under TH0 or TH17 conditions. We then performed a cross-sectional analysis of 28 SLE patients and 25 healthy matched controls. ROCK activity in peripheral blood mononuclear cell (PBMC) lysates was assessed by ELISA. Cytokine and chemokine profiles were analyzed via ELISA.
Results
Human cord blood CD4+ T cells differentiated under TH17 conditions expressed higher levels of ROCK activity than CD4+ T cells stimulated under TH0 conditions. Production of IL-17 and IL-21 was furthermore inhibited by addition of a ROCK inhibitor. SLE PBMCs expressed significantly higher levels of ROCK activity as compared to healthy controls, 1.25 vs. 0.56, respectively (p=0.0015). Sixteen (57%) SLE patients expressed high ROCK levels (OD450>1). Disease duration, lymphocyte count, and azathioprine use were significant independent predictors of ROCK activity in multivariable analyses.
Conclusions
Consistent with previous results in the murine system, increased ROCK activation was associated with TH17 differentiation. Enhanced ROCK activity was furthermore observed in a subgroup of SLE patients. These data support the concept that the ROCK pathway could represent an important therapeutic target for SLE.
doi:10.1002/art.37934
PMCID: PMC3672311  PMID: 23508371
4.  Increased Serum Type I Interferon Activity in Organ-Specific Autoimmune Disorders: Clinical, Imaging, and Serological Associations 
Background: Activation of the type I interferon (IFN) pathway has been implicated in the pathogenesis of systemic autoimmune disorders but its role in the pathogenesis of organ-specific autoimmunity is limited. We tested the hypothesis that endogenous expression of type I IFN functional activity contributes to the pathogenesis of autoimmune thyroid disease (ATD) and type I diabetes (T1DM).
Methods: We studied 39 patients with ATD and 39 age and sex matched controls along with 88 T1DM patients and 46 healthy matched controls respectively. Available clinical and serological parameters were recorded by chart review, and thyroid ultrasound was performed in 17 ATD patients. Type I IFN serum activity was determined in all subjects using a reporter cell assay. The rs1990760 SNP of the interferon-induced helicase 1 gene was genotyped in ATD patients.
Results: Serum type I IFN activity was increased in patients with ATD and T1DM compared to controls (p-values: 0.002 and 0.04, respectively). ATD patients with high type I IFN serum activity had increased prevalence of antibodies against thyroglobulin (anti-Tg) and cardiopulmonary manifestations compared to those with low IFN activity. Additionally, the presence of micronodules on thyroid ultrasound was associated with higher type I IFN levels. In patients with T1DM, high IFN levels were associated with increased apolipoprotein-B levels.
Conclusion: Serum type I IFN activity is increased in ATD and T1DM and is associated with specific clinical, serological, and imaging features. These findings may implicate type I IFN pathway in the pathogenesis of specific features of organ-specific autoimmunity.
doi:10.3389/fimmu.2013.00238
PMCID: PMC3746787  PMID: 23966997
type I interferon; autoimmune thyroid disease; organ-specific autoimmunity; type I diabetes
5.  Autoimmune Disease Risk Variant of IFIH1 Is Associated with Increased Sensitivity to IFN-α and Serologic Autoimmunity in Lupus Patients 
Increased IFN-α signaling is a heritable risk factor for systemic lupus erythematosus (SLE). IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-α pathway signaling. We studied the impact of the autoimmune-disease–associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism upon IFN-α signaling in SLE patients in vivo. We studied 563 SLE patients (278 African-American, 179 European-American, and 106 Hispanic-American). Logistic regression models were used to detect genetic associations with autoantibody traits, and multiple linear regression was used to analyze IFN-α–induced gene expression in PBMCs in the context of serum IFN-α in the same blood sample. We found that the rs1990760 T allele was associated with anti-dsDNA Abs across all of the studied ancestral backgrounds (meta-analysis odds ratio = 1.34, p = 0.026). This allele also was associated with lower serum IFN-α levels in subjects who had anti-dsDNA Abs (p = 0.0026). When we studied simultaneous serum and PBMC samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased IFN-induced gene expression in PBMCs in response to a given amount of serum IFN-α in anti-dsDNA–positive patients. This effect was independent of the STAT4 genotype, which modulates sensitivity to IFN-α in a similar way. Thus, the IFIH1 rs1990760 Tallele was associated with dsDNA Abs, and in patients with anti-dsDNA Abs this risk allele increased sensitivity to IFN-α signaling. These studies suggest a role for the IFIH1 risk allele in SLE in vivo.
doi:10.4049/jimmunol.1100857
PMCID: PMC3304466  PMID: 21705624
6.  Cyclophosphamide Responsive Interstitial Lung Disease in “Overlap Syndrome” 
HSS Journal  2010;7(1):99-105.
doi:10.1007/s11420-010-9186-8
PMCID: PMC3026100  PMID: 22294966
interstitial lung disease; systemic sclerosis; overlap syndrome; cyclophosphamide
7.  Belimumab in systemic lupus erythematosus: an update for clinicians 
Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that is driven by autoantibodies that target multiple organ systems. B-lymphocyte stimulator (BLyS) and its receptors on B-cell subsets play an important role in autoimmune B-cell development and SLE pathogenesis. Targeted therapy with belimumab, the monoclonal antibody against BLyS, has shown clinical benefit in two large-scale, multicenter phase III trials leading to US Food and Drug Administration approval for patients with serologically positive SLE who have active disease despite standard therapy. This review will discuss the challenges in lupus drug development and clinical trials, the basics of B-cell pathogenesis in SLE, the recent lupus clinical trials of B-cell targeted treatments, and other potential targeted therapies under investigation for patients with lupus.
doi:10.1177/2040622311424806
PMCID: PMC3513897  PMID: 23251765
belimumab; B-lymphocyte stimulator; systemic lupus erythematosus
8.  Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial 
Annals of the Rheumatic Diseases  2011;70(6):1003-1009.
Objective
To assess the safety and effectiveness of imatinib mesylate in the treatment of diffuse cutaneous systemic sclerosis (dcSSc).
Methods
In this phase IIa, open-label, single-arm clinical trial, 30 patients with dcSSc were treated with imatinib 400 mg daily. Patients were monitored monthly for safety assessments. Modified Rodnan skin scores (MRSS) were assessed every 3 months. Pulmonary function testing, chest radiography, echocardiography and skin biopsies were performed at baseline and after 12 months of treatment.
Results
Twenty-four patients completed 12 months of therapy. 171 adverse events (AE) with possible relation to imatinib were identified; 97.6% were grade 1 or 2. Twenty-four serious AE were identified, two of which were attributed to study medication. MRSS decreased by 6.6 points or 22.4% at 12 months (p=0.001). This change was evident starting at the 6-month time point (Δ=−4.5; p<0.001) and was seen in patients with both early and late-stage disease. Forced vital capacity (FVC) improved by 6.4% predicted (p=0.008), and the diffusion capacity remained stable. The improvement in FVC was significantly greater in patients without interstitial lung disease. Health-related quality of life measures improved or remained stable. Blinded dermatopathological analysis confirmed a significant decrease in skin thickness and improvement in skin morphology.
Conclusions
Treatment with imatinib was tolerated by most patients in this cohort. Although AE were common, most were mild to moderate. In this open-label experience, improvements in skin thickening and FVC were observed. Further investigation of tyrosine kinase inhibition for dcSSc in a double-blind randomised placebo controlled trial is warranted.
ClinicalTrials.gov, NCT00555581
doi:10.1136/ard.2010.143974
PMCID: PMC3086082  PMID: 21398330
9.  A new tool for detection of type I interferon activation in systemic lupus erythematosus 
The IFN-I pathway is activated in systemic lupus erythematosus (SLE) and appears to be important in the pathogenesis of the disease. As a result, several clinical trials of anti-IFN monoclonal antibodies, which hold promise to control the disease, have been launched. Additionally, activation of IFN-I might be important in the prognosis and activity assessment of the disease. Therefore, new biomarkers that reflect activity of the IFN-I pathway and are simple to measure, such as the monocyte CD64 receptor, are expected to have a great impact on the management of SLE, if properly validated.
doi:10.1186/ar3114
PMCID: PMC2945060  PMID: 20815919
10.  Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN-α in Lupus Patients In Vivo1 
Increased IFN-α signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-α signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-α activity and simultaneous IFN-α-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-α activity and greater IFN-α-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-α signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-α activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-α. These data provide biologic relevance for the risk variant of STAT4 in the IFN-α pathway in vivo.
PMCID: PMC2716754  PMID: 19109131
11.  Anti-neutrophil Cytoplasmic Antibody (c-ANCA) Positive Recurrent Eosinophilic Fasciitis Responsive to Cyclophosphamide 
HSS Journal  2007;4(1):81-86.
doi:10.1007/s11420-007-9067-y
PMCID: PMC2504280  PMID: 18751869
eosinophilic fasciitis; cyclophosphamide; necrotizing vasculitis
12.  Interferon-induced versus chemokine transcripts as lupus biomarkers 
Compelling support for a central role for interferon-alpha in lupus pathogenesis has led to a new focus on the role of innate immune system activation in the generation of pathogenic mediators. These insights have been extended in translational studies of patients with well-characterized disease activity and clinical manifestations in order to identify informative molecular biomarkers. Chemokines are among the interferon-inducible genes, and new data support an association between the expression of chemokines and both lupus disease activity and organ damage. Longitudinal studies that relate molecular biomarkers to disease activity will be needed to validate these promising data and establish a sensitive measure of change for interventional studies and patient care.
doi:10.1186/ar2559
PMCID: PMC2656240  PMID: 19183425

Results 1-12 (12)