Kyung-Su Park

Catholic University of Korea, Seoul, Seoul, South Korea

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Publications (48)180.33 Total impact

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    ABSTRACT: IL-6-mediated STAT3 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis. To investigate the molecular mechanism underlying the antirheumatic effects and T cell regulatory effects of STAT3 inhibition, we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell/regulatory T cell (Treg) balance and osteoclastogenesis. AG490 was administered to mice with collagen-induced arthritis (CIA) via i.p. injection, and its in vivo effects were determined. Differential expression of proinflammatory cytokines, including IL-17A, IL-1β, and IL-6, was analyzed by immunohistochemistry. Levels of phosphorylated STAT3 and STAT5 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining. In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real-time PCR. AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3(+) Tregs. In contrast, the proportion of IL-17A-producing T cells and levels of inflammatory markers were reduced in AG490-treated mice. Numbers of p-STAT3(+) CD4(+) T cells and p-STAT5(+) CD4(+) T cells were reduced and elevated, respectively, after treatment with AG490. Furthermore, AG490 markedly increased the expression of molecules associated with Treg development (ICOS, programmed cell death protein 1, ICAM-1, and CD103). The development and function of osteoclasts were suppressed by AG490 treatment. Our results suggest that AG490, specifically regulating the JAK2/STAT3 pathway, may be a promising treatment for rheumatoid arthritis.
    The Journal of Immunology 03/2014; · 5.52 Impact Factor
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    ABSTRACT: [This corrects the article on p. 38 in vol. 29, PMID: 24431903.].
    Journal of Korean medical science 03/2014; 29(3):460. · 0.84 Impact Factor
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease in which abnormal immune responses are mediated by tissue-binding autoantibodies and immune complex deposition. Because most SLE patients are women of child-bearing age, estrogen has been suggested to play an important role in SLE pathogenesis. One proposed role is to induce B-cell activation, culminating in increased autoantibody production. Interleukin-21 (IL-21) has been shown to be crucial in the differentiation of activated B cells into plasma cells. We therefore hypothesized that estrogen upregulates IL-21 production and induces subsequent B-cell activation in SLE patients. Peripheral blood was obtained from 22 SLE patients and 16 healthy controls. Expression levels of IL-21 and its receptor in serum, peripheral blood mononuclear cells (PBMCs), and CD4+ T cells were higher in SLE patients than in healthy controls. Exposure of CD4+ T cells from SLE patients to 17-β estradiol led to a dose- and time-dependent increase in IL-21 expression, which was abolished in the presence of mitogen-activated protein kinase (MAPK; MEK, p38, JNK) inhibitors. B cells from healthy controls showed increased antibody production when they were co-cultured with estrogen-treated CD4+ T cells from SLE patients. Treatment with IL-21 antibody abrogated the increased antibody production of the co-culture systems. This study revealed the association between estrogen and IL-21 in SLE patients. Estrogen upregulates IL-21 expression of CD4+ T cells via MAPK-dependent pathways in SLE patients, which in turn induces increased antibody production by B cells. This article is protected by copyright. All rights reserved.
    Immunology 02/2014; · 3.71 Impact Factor
  • Modern Rheumatology 01/2014; · 1.72 Impact Factor
  • International Journal of Rheumatic Diseases 01/2014; 17(1):125-6. · 1.65 Impact Factor
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    Jennifer Lee, Sung-Hwan Park, Kyung-Su Park
    The Korean Journal of Internal Medicine 01/2014; 29(1):131.
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    ABSTRACT: Interleukin (IL)-33 is an important mediator of innate immunity. Behcet's disease (BD) is an autoinflammatory disorder characterized by hyperactivity of the innate immune response. We measured serum levels of IL-33 and its receptor soluble ST2 (sST2) in patients with BD to investigate their association with disease activity. Serum levels of both IL-33 and sST2 were higher in patients with BD compared with those in normal controls (IL-33: 594.48±175.04 pg/mL in BD and 224.23±56.64 pg/mL in normal controls [P=0.048], sST2: 99.01±15.92 pg/mL in BD and 23.56±3.25 pg/mL in normal controls [P<0.001]). IL-33 and sST2 expression in skin tissue, as shown by immunohistochemistry, was higher in patients with BD compared with that in the normal controls. Serum sST2 level correlated significantly with the BD currently active form (BDCAF), Iranian BD dynamic activity measure (IBDDAM), erythrocyte sedimentation rate and C-reactive protein. Multiple linear regression showed that serum sST2 was an independent factor associated with IBBDAM (regression coefficient, 0.374; P=0.004), and BDCAF (regression coefficient, 0.236; P=0.047). These results demonstrate that IL-33 and sST2 are highly expressed in patients with BD and that serum sST2 is an independent factor associated with IBDDAM and BDCAF, suggesting a potential role for sST2 as a surrogate marker of disease activity in patients with BD.
    Journal of Korean medical science 08/2013; 28(8):1145-53. · 0.84 Impact Factor
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    ABSTRACT: Bone destruction is critical in the functional disability of patients with rheumatoid arthritis (RA). Osteoclasts, specialized bone-resorbing cells regulated by cytokines, such as receptor activator of NF-κB ligand (RANKL), are primarily implicated in bone destruction in RA. The aim of the study was to examine whether tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, has osteoclastogenic activity in patients with RA and in animal models, including mice with collagen-induced arthritis (CIA mice) and IL-1 receptor antagonist knockout (IL-1RaKO) mice. TWEAK was increased in the synovium, synovial fluid, and serum of patients with RA and in the synovium of CIA mice and IL-1RaKO mice. TWEAK induced RANKL expression in mixed joint cells and splenocytes from CIA mice, IL-1RaKO mice, and fibroblast-like synoviocytes from patients with RA. Both osteoclast precursor cells and osteoclasts express TWEAK receptor fibroblast growth factor-inducible 14. In addition, TWEAK enhanced in vitro osteoclastogenesis without the presence of RANKL-providing cells and by inducing RANKL expression in fibroblast-like synoviocytes. Moreover, treatment with fibroblast growth factor-inducible 14-Fc inhibited RANKL-induced osteoclastogenesis, indicating that endogenous TWEAK also has osteoclastogenic activity. Our data demonstrated that TWEAK promotes osteoclastogenesis in RA, suggesting that therapeutic strategies targeting TWEAK could be effective for treatment of patients with RA, especially in preventing bone destruction.
    American Journal Of Pathology 07/2013; · 4.52 Impact Factor
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    ABSTRACT: Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The 'early' effect of each cytokine was investigated at the time of first RANKL treatment, whereas the 'late' effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.
    International Journal of Molecular Medicine 04/2013; 31(4):769-77. · 1.96 Impact Factor
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    ABSTRACT: Abstract Purpose: To determine whether the frequencies of specific killer cell immunoglobulin-like receptors (KIR) genotypes are associated with the incidence of uveitis in ankylosing spondylitis (AS) and Behçet disease (BD). Methods: The authors analyzed the frequency of 16 KIR genes in Koreans with either AS (110 patients, all HLA-B27-positive) or BD (86 patients), using polymerase chain reaction sequence-specific oligonucleotide probing. Results: The frequency of the inhibitory receptor KIR3DL1 was lower in AS patients affected by uveitis than that in the general population (p < 0.05). The frequency of the KIR3DL1(-)/2DS3(-) was significantly higher in AS patients with uveitis (odds ratio = 9.306, p = 0.007). Conclusions: The study suggests that KIR3DL1 might associate with the resistance to AS-associated uveitis by influencing natural killer cell activity.
    Ocular immunology and inflammation 04/2013; 21(2):135-143. · 0.72 Impact Factor
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    ABSTRACT: The aim of this study was to determine the influence of HLA-DRB1 and HLA-DQB1 genes on the disease susceptibility and the disease severity in elderly onset rheumatoid arthritis (EORA) compared with young onset rheumatoid arthritis (YORA) in Korean patients. Genetic analysis of HLA-DRB1 and HLA-DQB1 alleles was performed in three groups. Group 1 included 63 patients who were diagnosed with (rheumatoid arthritis) RA after the age of 60 (EORA). Group 2 consisted of 109 patients who were diagnosed with RA before the age of 60 (YORA). Group 3 involved 133 normal controls. The shared-epitope-coding alleles included the members of the HLA-DRB1*04 allele group (*0401, *0404, *0405, *0408, *0410), HLA-DRB1*01 allele group (*0101,*0102), HLA-DRB1*1001, and HLA-DRB1*1402. The disease severity was assessed by the modified total sharp score (mTSS). The shared-epitope-coding alleles were more frequently observed in the RA patients than in the normal controls. The shared-epitope-coding alleles were less frequently found in EORA group than YORA group (31/63 (49.2 %) in group 1, 72/109 (66.1 %) in group 2, 45/133 (33.8 %) group 3, p = 0.02). Although the mTSS of the group 1 was higher than group 2 at symptom onset, the overall mean mTSS of the group 1 was lower than that of group 2 (26.8 vs. 57.5, p < 0.05). HLA-DQ*04 showed the higher frequency in the patients group than in normal controls (p < 0.001). And HLA-DQ*04 was less commonly found in the patients with EORA than YORA (p < 0.05). The influence of shared epitope and HLA-DQ*04 alleles may be less significant on disease susceptibility in EORA. The presence of shared-epitope-coding alleles did not appear to influence on disease severity in EORA patients as well as in YORA patients. Radiologic deterioration in EORA group was less severe than in YORA group. The presence of shared epitope and radiologic progression are less prominent in EORA patients than YORA patients.
    Rheumatology International 02/2013; · 2.21 Impact Factor
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    ABSTRACT: We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (ĸ = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration ≤ 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.
    Journal of Korean medical science 02/2013; 28(2):287-94. · 0.84 Impact Factor
  • Arthritis & Rheumatology 07/2012; · 7.48 Impact Factor
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    ABSTRACT: In oral tolerance, locally instigated tolerance in the gut propagate to systemic tolerance. In order to investigate the mechanism, we analyzed indoleamine 2,3-dioxygenase (IDO) expression in splenic dendritic cell (DC) subsets and tested whether DCs suppress collagen-induced arthritis (CIA) by inducing regulatory T cells (Tregs). The proportion of IDO-expressing cells was higher in the CD11b(+) subset of splenic DCs from orally tolerized CIA mice. These DCs suppressed type II collagen-specific T cell proliferation and promoted Treg induction from CD4(+)CD25(-) T cells using transforming growth factor-β. These DCs also increased the expression of cytotoxic T lymphocyte antigen-4 and programmed death-1 on Tregs. When adoptively transferred, spenic IDO-expressing CD11b(+) DCs from tolerized animals suppressed the development of arthritis, increased the Treg/Th17 cell ratio, and decreased the production of inflammatory cytokines in the spleen. Taken together, a distinct subset of splenic IDO(+)CD11b(+)DCs is responsible for the systemic immune regulation in oral tolerance.
    Cellular Immunology 07/2012; 278(1-2):45-54. · 1.74 Impact Factor
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    ABSTRACT: OBJECTIVE.: To investigate the impact of STAT3-mediated regulation on Th17 differentiation in patients with rheumatoid arthritis (RA). METHODS.: CD4(+) T cells isolated from peripheral blood (PB) and synovial fluid (SF) were stimulated to differentiate into Th17 or regulatory T cells (Tregs). The activity of STAT3 was knocked down by transfecting small interfering RNA (siRNA) into CD4(+) T cells. After 3 days in culture, the proportions of Th17 cells and Tregs were measured by flow cytometry, and the production of IL-17 was measured by RT-PCR and ELISA. RESULTS.: The levels of interleukin-17 (IL-17), IL-6, IL-23, and IL-1, and tumor necrosis factor-α were significantly higher in RA SF and synovial tissue (ST) than in SF and ST from osteoarthritis patients. In RAST, the expression of STAT3 increased in proportion to the severity of synovitis, as shown by stromal cellularity, intimal hyperplasia, and inflammatory infiltration. The degree of Th17 differentiation decreased in the order RASF > RAPB > normal. In CD4(+) T cells, transfection with STAT3 siRNA prevented Th17 differentiation of mononuclear cells from RA PB and SF but increased the proportion of Tregs. By contrast, inhibition of STAT5, the transcription factor for Tregs, increased the proportion of Th17 cells and reduced that of Tregs. CONCLUSION.: Modulation of STAT3 in CD4(+) T cells affected the differentiation of Th17 cells and Tregs in patients with RA. This role of STAT3 in RA synovial T cells may provide a new therapeutic target for the management of RA.
    Arthritis & Rheumatology 06/2012; · 7.48 Impact Factor
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    ABSTRACT: The study was undertaken to investigate the interrelation of toll-like receptor (TLR) and interleukin (IL)-17 in the salivary glands of patients with primary Sjogren's syndrome (pSS) and to determine the role of TLR and IL-17 in the pathophysiology of pSS. The expressions of various TLRs, IL-17 and the cytokines involved in Th17 cell differentiation including IL-6, IL-23, tumor necrosis factor-alpha (TNF-α) and IL-1β were examined by immunohistochemistry in salivary glands of pSS patients. The IL-17 producing CD4+ T cells (Th17 cells) were examined by flow cytometry and confocal staining in peripheral mononuclear blood cells (PMBCs) and salivary glands of pSS patients. After PBMCs were treated with TLR specific ligands, the induction of IL-17 and IL-23 was determined using real-time PCR and ELISA. The signaling pathway that mediates the TLR2 stimulated production of IL-17 and IL-23 was investigated by using treatment with specific signaling inhibitors. We showed that TLR2, TLR4, TLR6, IL-17 and the cytokines associated with Th17 cells were highly expressed in salivary glands of pSS patients but not in controls. The expressions of TLR2, TLR4 and TLR6 were observed in the infiltrating mononuclear cells and ductal epithelial cells, whereas IL-17 was mainly observed in infiltrating CD4+ T cells. The number of IL-17 producing CD4+ T cells was significantly higher in pSS patients both in PBMCs and minor salivary glands. The stimulation of TLR2, TLR4 and TLR6 additively induced the production of IL-17 and IL-23 from the PBMCs of pSS patients especially in the presence of TLR2 stimulation. IL-6, signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappaB (NF-kB) pathways were implicated in the TLR2 stimulated IL-17 and IL-23. Our data demonstrate that TLR2 ligation induces the production of IL-23/IL-17 via IL-6, STAT3 and NF-kB pathway in pSS. Therefore, therapeutic strategies that target TLR/IL-17 pathway might be strong candidates for treatment modalities of pSS.
    Arthritis research & therapy 03/2012; 14(2):R64. · 4.27 Impact Factor
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    ABSTRACT: Interleukin (IL)-21 is a cytokine that controls the functional activity of effector T helper cells and the differentiation of Th17 cells, and promotes B-cell differentiation. To test whether IL-21 participates in the pathogenesis of primary Sjögren's syndrome (SS), serum IL-21 level was measured and IL-21 expression in the labial salivary glands (LSG) was examined. Serum IL-21 levels in 40 primary SS, 40 rheumatoid arthritis (RA), and 38 systemic lupus erythematosus (SLE) patients and 20 healthy controls were measured. Serum IL-21 levels of SS patients were assessed for correlations with laboratory data, including anti-nuclear antibody, anti-Ro/La antibodies, globulin, immunoglobulin (Ig) class, and IgG subclass. LSGs from 16 primary SS and 4 controls with sicca symptoms were evaluated for IL-21 and IL-21 receptor (IL-21R) expression by immunohistochemistry. Confocal microscopy was performed to further characterize the IL-21 positive cells. Primary SS patients had significantly higher serum IL-21 levels than controls, and these increments correlated positively with levels of IgG, IgG1. Serum IgG1 levels correlated with anti-Ro antibody titers. Immunohistochemical analyses showed that lymphocytic foci and the periductal area of the LSGs from SS patients expressed high levels of IL-21 and lower levels of IL-21R, whereas the control LSGs showed minimal expression of both antigens. The more the lymphocyte infiltrated, IL-21 expression in LSGs showed a tendency to increase. Confocal microscopic analyses revealed that IL-21 expressing infiltrating lymphocytes in the LSGs of SS patients also expressed CXCR5. Primary SS is associated with high serum IL-21 levels that correlate positively with serum IgG, especially IgG1, levels. The expression of IL-21 is increased as more lymphocytes infiltrated in LSGs. These observations suggest that IL-21 may play an important role in primary SS pathogenesis.
    Arthritis research & therapy 10/2011; 13(5):R179. · 4.27 Impact Factor
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    ABSTRACT: Since chronic kidney disease (CKD) is closely associated with cardiovascular disease and mortality as well as endstage renal disease, prediction of progressive CKD is a clinically important issue. We investigated the independent risk factors for the development of CKD in patients with lupus nephritis (LN). The cohort included 322 Korean patients diagnosed with LN between 1985 and 2010. We retrospectively analyzed the clinical and laboratory indices, treatment response, the final renal function, and the biopsy findings. The timing and cumulative risk of developing CKD were identified by Kaplan-Meier methods. The independent risk factors for developing CKD were examined by univariate and multivariate Cox proportional hazards regression analyses. The median followup time after the diagnosis of LN was 84 months. CKD occurs in 22% of the patients within 10 years after the diagnosis of LN. The probability of developing CKD was significantly associated with the onset time of LN (delayed-onset LN vs initial-onset LN; HR 2.904, p = 0.003), deteriorated renal function [an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2) body surface area] at the onset of LN (HR 7.458, p < 0.001), relapse of LN after achieving remission (HR 2.806, p = 0.029), and resistance to induction therapy (HR 8.120, p < 0.001). Our results demonstrate that delayed-onset LN, a decreased eGFR at the time of LN onset, and the failure to achieve a sustained remission are predictors for the development of CKD in Korean patients with LN.
    The Journal of Rheumatology 10/2011; 38(12):2588-97. · 3.26 Impact Factor
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    ABSTRACT: The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] ≥5) despite at least 4 weeks' NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS <4) were randomized to receive either tramadol/APAP or NSAID for 8 weeks. On days 29 and 57, Western Ontario and McMaster Universities (WOMAC) OA index score was measured. Secondary measures included pain intensity (NRS), pain relief score, and subjects' and investigators' overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs.
    Clinical Rheumatology 08/2011; 31(2):317-23. · 2.04 Impact Factor
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    ABSTRACT: We report an 18-year old female patient with systemic lupus erythematosus (SLE), who developed fever, pancytopenia, abdominal pain, and watery diarrhea. Computed tomography (CT) and bone marrow aspirate revealed lupus mesenteric vasculitis (LMV) and hemophagocytic syndrome (HPS). Serologic tests for Epstein-Barr virus (EBV) indicated its reactivation. This case demonstrates that HPS and concomitant LMV associated with viral reactivation can occur as clinical manifestations of SLE flare.
    Modern Rheumatology 01/2011; 21(3):330-3. · 1.72 Impact Factor

Publication Stats

432 Citations
180.33 Total Impact Points


  • 2002–2012
    • Catholic University of Korea
      • • Department of Internal Medicine
      • • College of Medicine
      • • Rheumatism Research Center
      Seoul, Seoul, South Korea
  • 2011
    • Chungbuk National University
      • Department of Internal Medicine
      Tyundyu, North Chungcheong, South Korea
  • 2010
    • Incheon St. Mary’s Hospital, Catholic Medical Center
      Bucheon, Gyeonggi Province, South Korea