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Roozbeh Sharif,
Marvin J Fritzler,
Maureen D Mayes,
Emilio B Gonzalez,
Terry A McNearney,
Hilda Draeger,
Murray Baron,
Daniel E Furst,
Dinesh K Khanna,
Deborah J del Junco, [......],
Richard M Silver,
Robert W Simms,
Marilyn Perry,
Carlos Rojo,
Julio Charles,
Xiaodong Zhou,
Sandeep K Agarwal,
John D Reveille,
Shervin Assassi,
Frank C Arnett
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ABSTRACT: Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival.
Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493).
Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.
The Journal of Rheumatology 05/2011; 38(8):1622-30. · 3.69 Impact Factor
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ABSTRACT: Peripheral blood cells (PBMCs) from some patients with systemic sclerosis (SSc) express an interferon-alpha (IFNalpha) signature. The aim of this study was to determine whether SSc patient sera could induce IFNalpha and whether IFNalpha induction was associated with specific autoantibodies and/or clinical features of the disease.
SSc sera containing autoantibodies against either topoisomerase I (anti-topo I; n = 12), nucleolar protein (ANoA; n = 12), or centromeric protein (ACA; n = 13) were cultured with a HeLa nuclear extract and normal PBMCs. In some experiments, different cell extracts or inhibitors of plasmacytoid dendritic cell (DC) activation, Fcgamma receptor II (FcgammaRII), endocytosis, or nucleases were used. IFNalpha was measured by enzyme-linked immunosorbent assay.
Topo I-containing sera induced significantly higher levels of IFNalpha as compared with all other groups. IFNalpha induction was inhibited by anti-blood dendritic cell antigen 2 (90%), anti-CD32 (76%), bafilomycin (99%), and RNase (82%). In contrast, ACAs induced low levels of IFNalpha even when necrotic, apoptotic, or demethylated extracts were used, despite the fact that CENP-B-binding oligonucleotide containing 2 CpG motifs effectively stimulated IFNalpha. IFNalpha production was significantly higher in patients with diffuse SSc (mean +/- SEM 641 +/- 174 pg/ml) than in those with limited SSc (215 +/- 66 pg/ml) as well as in patients with lung fibrosis than in those without.
Autoantibody subsets in SSc sera differentially induce IFNalpha and may explain the IFNalpha signature observed in SSc. IFNalpha is induced by plasmacytoid DCs and required uptake of immune complexes through FcgammaRII, endosomal transport, and the presence of RNA, presumably for interaction with Toll-like receptor 7. The higher IFNalpha induction in sera from patients with diffuse SSc than in those with limited SSc as well as in sera from patients with lung fibrosis suggests that IFNalpha may contribute to tissue injury.
Arthritis & Rheumatism 08/2008; 58(7):2163-73. · 7.87 Impact Factor
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Arnold E Postlethwaite,
Weng Kee Wong,
Philip Clements,
Soumya Chatterjee,
Barri J Fessler,
Andrew H Kang,
Joseph Korn,
Maureen Mayes,
Peter A Merkel, Jerry A Molitor,
Larry Moreland,
Naomi Rothfield,
Robert W Simms,
Edwin A Smith,
Robert Spiera,
Virginia Steen,
Kenneth Warrington,
Barbara White,
Frederick Wigley,
Daniel E Furst
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ABSTRACT: To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dcSSc; scleroderma) for <or=10 years.
One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 microg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed.
Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 -7.9 versus -2.9; P = 0.0063).
Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.
Arthritis & Rheumatism 07/2008; 58(6):1810-22. · 7.87 Impact Factor
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Hangjun Duan,
Jo Fleming,
David K Pritchard,
Lynn M Amon,
Jun Xue,
Heather A Arnett,
Guang Chen,
Patricia Breen,
Jane H Buckner, Jerry A Molitor,
Keith B Elkon,
Stephen M Schwartz
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ABSTRACT: We attempted to elucidate possible pathogenetic mechanisms in scleroderma by analysis of gene expression patterns of purified monocytes and lymphocytes, as well as protein profiles of cytokines and growth factors.
Expression analysis was performed on messenger RNA (mRNA) from cells that had been purified with magnetic beads. Plasma samples from the same patients were used for multiplex cytokine analysis. Potential sources of proteins were also examined by in situ hybridization of skin specimens.
A total of 1,800 genes from monocytes and 863 genes from CD4+ T cells were differentially expressed in scleroderma patients. As observed by other investigators using unfractionated peripheral blood cells from patients with autoimmune connective tissue diseases, the cell type-specific analyses of our scleroderma samples showed expression of genes suggesting the presence of interferon-alpha (IFNalpha), despite the apparent absence of this cytokine in plasma. IFNalpha RNA was, however, expressed at enhanced levels in vascular and perivascular cells in scleroderma skin samples. While levels of interleukin-1alpha (IL-1alpha) and IL-16 were among 10 proteins found to be significantly elevated in scleroderma patients, none of the large panel of plasma cytokines we analyzed correlated with the expression levels of putative IFN response genes.
The pattern of up-regulation of mRNA in both the monocytes and CD4 lymphocytes of scleroderma patients, together with the detection of IFNalpha RNA in the microvasculature, suggests that leukocytes respond to this cytokine locally in the vessels. Detection of high levels of IL-1alpha and IL-16 in plasma and the independence of these protein levels from the IFN signature, implicates an independent contribution of other cytokines to immune activation and/or inflammation in scleroderma.
Arthritis & Rheumatism 06/2008; 58(5):1465-74. · 7.87 Impact Factor
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Jo N Fleming,
Richard A Nash,
D O McLeod,
David F Fiorentino,
Howard M Shulman,
M Kari Connolly, Jerry A Molitor,
Gretchen Henstorf,
Robert Lafyatis,
David K Pritchard,
Lawrence D Adams,
Daniel E Furst,
Stephen M Schwartz
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ABSTRACT: Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.
We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue), antiangiogenic interferon alpha (overexpressed in the scleroderma dermis) and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.
These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have implications for other diseases characterized by loss of capillaries including hypertension, congestive heart failure and scar formation.
PLoS ONE 02/2008; 3(1):e1452. · 4.09 Impact Factor
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Jo N Fleming,
Richard A Nash,
D O McLeod,
David F Fiorentino,
Howard M Shulman,
M Kari Connolly, Jerry A Molitor,
Gretchen Henstorf,
Robert Lafyatis,
David K Pritchard,
Lawrence D Adams,
Daniel E Furst,
Stephen M Schwartz
PLoS ONE 02/2008; 3(8). · 4.09 Impact Factor
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Richard A Nash,
Peter A McSweeney,
Leslie J Crofford,
Muneer Abidi,
Chien-Shing Chen,
J David Godwin,
Theodore A Gooley,
Leona Holmberg,
Gretchen Henstorf,
C Fred LeMaistre, [......],
Bernadette McLaughlin, Jerry A Molitor,
J Lee Nelson,
Howard Shulman,
Rainer Storb,
Federico Viganego,
Mark H Wener,
James R Seibold,
Keith M Sullivan,
Daniel E Furst
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ABSTRACT: More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, -22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, -1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.
Blood 08/2007; 110(4):1388-96. · 9.90 Impact Factor
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Daniel O Clegg,
Domenic J Reda,
Crystal L Harris,
Marguerite A Klein,
James R O'Dell,
Michele M Hooper,
John D Bradley,
Clifton O Bingham,
Michael H Weisman,
Christopher G Jackson, [......],
Frederick Wolfe, Jerry A Molitor,
David E Yocum,
Thomas J Schnitzer,
Daniel E Furst,
Allen D Sawitzke,
Helen Shi,
Kenneth D Brandt,
Roland W Moskowitz,
H James Williams
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ABSTRACT: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis.
We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24.
The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups.
Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).
New England Journal of Medicine 03/2006; 354(8):795-808. · 53.30 Impact Factor
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ABSTRACT: Transcript array analysis is a novel technique that examines the expression of thousands of genes simultaneously. Transcript array analyses are being used to clarify the diagnosis and prognosis of malignancies, and to understand the underlying pathogenesis of complex human disorders such as the rheumatic diseases. In this review, the authors will outline the use of transcript arrays to simultaneously assess gene activation of hundreds or thousands of genes, and their potential use in understanding and managing rheumatic disorders. The authors focus on the use of transcript arrays to confirm and refine disease diagnoses, to generate new hypotheses regarding pathophysiology of rheumatic diseases, and to the possible profiling of patients with respect to their likely response to therapies.
Rheumatic Disease Clinics of North America 03/2002; 28(1):151-76, vii-viii. · 3.02 Impact Factor
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Jo N Fleming,
Richard A Nash,
D O McLeod,
David F Fiorentino,
Howard M Shulman,
M Kari Connolly, Jerry A Molitor,
Gretchen Henstorf,
Robert Lafyatis,
David K Pritchard,
Lawrence D Adams,
Daniel E Furst,
Stephen M Schwartz
