Placental growth factor regulates the generation of TH17 cells to link angiogenesis with autoimmunity.

Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.

Transcription Factor NFAT5 Promotes Migration and Invasion of Rheumatoid Synoviocytes via Coagulation Factor III and CCL2.

Fibroblast-like synoviocytes (FLSs) play a key role in the progression of rheumatoid arthritis (RA) as a primary component of invasive hypertrophied pannus. FLSs of RA patients (RA-FLSs) exhibit cancer-like features, including promigratory and proinvasive activities that largely contribute to joint cartilage and bone destruction. In this study, we hypothesized that the NF of activated T cell 5 (NFAT5), a transcription factor involving tumor invasiveness, would control the migration and invasion of RA-FLSs. Analyses of transcriptomes demonstrated the significant involvement of NFAT5 in locomotion of RA-FLSs and that tissue factor (TF; also known as coagulation factor III) and CCL2 were the major downstream target genes of NFAT5 involving FLS migration and invasion. In cultured RA-FLSs, IL-1ß and TGF-ß increased TF and CCL2 expression by upregulating NFAT5 expression via p38 MAPK. Functional assays demonstrated that NFAT5- or TF-deficient RA-FLSs displayed decreased lamellipodia formation, cell migration, and invasion under IL-1ß- or TGF-ß-stimulated conditions. Conversely, factor VIIa, a specific activator of TF, increased migration of RA-FLSs, which was blocked by NFAT5 knockdown. Recombinant CCL2 partially restored the decrease in migration and invasion of NFAT5-deficient RA-FLSs stimulated with IL-1ß. NFAT5-knockout mouse FLSs also showed decreased expressions of TF and CCL2 and reduced cell migration. Moreover, KRN2, a specific inhibitor of NFAT5, suppressed migration of FLSs stimulated with TGF-ß. Conclusively, to our knowledge, this is the first study to provide evidence of a functional link between osmoprotective NFAT5 and TF in the migration and invasion of RA-FLSs and supports a role for NFAT5 blockade in the treatment of RA.

MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis.

Fibroblast-like synoviocytes mediate joint destruction in rheumatoid arthritis and exhibit sustained proinflammatory and invasive properties. CD44 is a polymorphic transmembrane protein with defined roles in matrix interaction and tumor invasion that is also a signaling coreceptor for macrophage migration inhibitory factor (MIF), which engages cell surface CD74. High-expression MIF alleles (rs5844572) are associated with rheumatoid joint erosion, but whether MIF signaling through the CD74/CD44 receptor complex promotes upstream autoimmune responses or contributes directly to synovial joint destruction is unknown. We report here the functional regulation of CD44 by an autocrine pathway in synovial fibroblasts that is driven by high-expression MIF alleles to up-regulate an inflammatory and invasive phenotype. MIF increases CD44 expression, promotes its recruitment into a functional signal transduction complex, and stimulates alternative exon splicing, leading to expression of the CD44v3-v6 isoforms associated with oncogenic invasion. CD44 recruitment into the MIF receptor complex, downstream MAPK and RhoA signaling, and invasive phenotype require MIF and CD74 and are reduced by MIF pathway antagonists. These data support a functional role for high-MIF expression alleles and the two-component CD74/CD44 MIF receptor in rheumatoid arthritis and suggest that pharmacologic inhibition of this pathway may offer a specific means to interfere with progressive joint destruction.

Leukocyte-specific protein 1 regulates T-cell migration in rheumatoid arthritis.

Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel leukocyte-specific protein 1 (LSP1) deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 gene is significantly lower in patients with RA, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration by reducing ERK activation in vitro. In mice with T-cell-dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T-cell activation. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlight the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provide previously unidentified insights into the mechanisms underlying T-cell migration toward the inflamed synovium in RA.

Elevated levels of soluble CD40 ligand are associated with antiphospholipid antibodies in patients with systemic lupus erythematosus.

OBJECTIVES: The CD40L/CD40 pathway is involved in the pathophysiology of atherothrombotic disease, and elevated levels of soluble CD40L (sCD40L) were reported in SLE patients. However, the clinical implication of sCD40L in SLE remains elusive. METHODS: We measured levels of plasma sCD40L in 241 SLE patients and 37 healthy controls and investigated its association with clinical manifestation and laboratory parameters. RESULTS: Levels of plasma sCD40L in SLE patients were significantly elevated compared with healthy controls (p=0.013) and positively correlated with levels of soluble P-selectin (γ=0.336, p<0.001). SLE patients who experienced arterial thrombosis had a higher level of sCD40L than those who did not (p=0.029). Plasma sCD40L levels were positively correlated with the titers of anti-cardiolipin and anti-ß2 glycoprotein I antibodies (γ=0.338, p<0.001 and γ=0.364, p<0.001, respectively). Its levels were also significantly higher in patients with clinical antiphospholipid syndrome (APS) than in non-APS patients, irrespective of antiphospholipid antibody (aPL) positivity. Of those with arterial thrombosis, sCD40L levels were significantly elevated in patients with positive aPL, compared to those with negative aPL (p=0.011). Multiple regression analysis revealed that the presence of hypertension and positive aPL were independently associated with the occurrence of arterial thrombosis in SLE patients. A parallel analysis showed that sCD40L was also an independent variable for arterial thrombosis; however, this association disappeared when aPL, a strong variable, was included in the model because of collinearity between aPL and sCD40L. CONCLUSIONS: Plasma sCD40L levels were elevated in SLE patients who had positive aPL and experienced arterial thrombosis, suggesting that enhanced release of sCD40L through platelet activation presumably by aPL could contribute to the development of atherothrombotic disease.

Placental growth factor-1 and -2 induce hyperplasia and invasiveness of primary rheumatoid synoviocytes.

Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have promigratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. In this study, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with small interfering RNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and neuropilin-1, and upregulating the expression of antiapoptotic molecules, pErk and Bcl2. Knockdown of PlGF transcripts reduced RA-FLS proliferation in a xenotransplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy.

Identification of key regulators for the migration and invasion of rheumatoid synoviocytes through a systems approach.

Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLSs) and synovial macrophages (SMs), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLSs of RA patients (RA-FLSs) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone. RA-FLSs and SMs originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. We performed global transcriptome profiling of FLSs and SMs obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLSs and proinflammatory properties of RA-SMs, respectively. Interestingly, under the interleukin-1ß (IL-1ß)-stimulated condition, the RA-FLSs newly acquired proinflammatory signature dominant in RA-SMs without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including periostin, osteoblast-specific factor (POSTN) and twist basic helix-loop-helix transcription factor 1 (TWIST1), as key regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLSs and further instigated by IL-1ß. Functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLSs stimulated with IL-1ß. Together, our systems approach to rheumatoid synovitis provides a basis for identifying key regulators responsible for pathological features of RA-FLSs and -SMs, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.

A case of multicentric reticulohistiocytosis.

Multicentric reticulohistiocytosis (MRH) is a rare non-Langerhans histiocytosis of unknown etiology with a predilection for joint and skin. The characteristic clinical features are papulonodular skin eruptions and inflammatory polyarthritis, sometimes progressive to arthritis mutilans, a severe destructive arthropathy. Although these manifestations can present at the same time, it is more common that one feature precedes the others. Notably, these features are similar to those found in some rheumatic diseases, such as rheumatoid arthritis or dermatomyositis, and this can lead to a misdiagnosis, especially during periods where only one feature is present. Herein, we report a female patient with polyarthralgia and subsequent skin eruptions, who was eventually diagnosed with MRH. Her symptoms seemed to resemble those of some rheumatic diseases, but several features such as affected joints and the characteristic shape of the skin lesions did not correspond to that. The histological result of infiltration of histiocytes and multinucleated giant cells in the skin ultimately facilitated the correct diagnosis. In this paper, we review MRH briefly and highlight several differential points which enable us to increase the likelihood of correctly diagnosing MRH.

Interaction of mesenchymal stem cells with fibroblast-like synoviocytes via cadherin-11 promotes angiogenesis by enhanced secretion of placental growth factor.

Bone marrow-derived mesenchymal stem cells (MSC) exist in the synovium of patients with rheumatoid arthritis (RA), yet the role of MSC in RA is elusive. Placental growth factor (PlGF) expression is increased in RA synovial fluids, and blocking of PlGF attenuates progression of arthritis in mice. In this study, we observed that PlGF induced chemotaxis of MSC in a dose-dependent manner, which was blocked by anti-vascular endothelial growth factor receptor-1 peptide. MSC exposed to PlGF elicited increased phosphorylation of Akt and p38 MAPK. PlGF-mediated chemotaxis was inhibited by PI3K inhibitor (LY294002) and p38 MAPK inhibitor (SB203580), but not by ERK1/2 inhibitor (PD98059). Fibroblast-like synoviocytes (FLS) constitutively produced PlGF, but MSC released negligible amounts of PlGF. Of note, when FLS of RA patients and MSC were cocultured, PlGF production by FLS was significantly increased; such an increase was dependent on the number of added MSC. Moreover, coculture conditioned medium promoted chemotaxis of MSC and increased angiogenesis in Matrigel plugs assay, and these were suppressed by preincubation of the medium with anti-PlGF Ab. Transwell experiments revealed that MSC to FLS contact was required for the increase in PlGF production by coculture. Cadherin-11 was expressed both in FLS and MSC, and small interfering RNA knockdown of cadherin-11 in FLS significantly abrogated the enhanced PlGF production under coculture conditions. These data indicate that increased levels of PlGF in RA joints could induce the migration of MSC to the synovium, and interaction of migrated MSC with FLS via cadherin-11 may contribute to angiogenesis and chronic synovitis by enhancing the secretion of PlGF.

The xanthine oxidase-NFAT5 pathway regulates macrophage activation and TLR-induced inflammatory arthritis.

NFAT5 (nuclear factor of activated T cells), a well-known osmoprotective factor, can be activated by isotonic stimuli such as Toll-like receptor (TLR) triggering. However, it is unclear how NFAT5 discriminates between isotonic and hypertonic stimuli to produce different functional and molecular outcomes. Here, we identified a novel XO-ROS-p38 MAPK-NFAT5 pathway (XO is xanthine oxidase, ROS is reactive oxygen species) that is activated in RAW 264.7 macrophages upon isotonic TLR stimulation. Unlike what is seen under hypertonic conditions, XO-derived ROS were selectively required for the TLR-induced NFAT5 activation and NFAT5 binding to the IL-6 promoter in RAW 264.7 macrophages under isotonic conditions. In mouse peritoneal macrophages and human macrophages, TLR ligation also induced NFAT5 activation, which was dependent on XO and p38 kinase. The involvement of XO in NFAT5 activation by TLR was confirmed in RAW 264.7 macrophages implanted in BALB/c mice. Moreover, allopurinol, an XO inhibitor, suppressed arthritis severity and decreased the expression of NFAT5 and IL-6 in splenic macrophages in C57BL/6 mice. Collectively, these data support a novel function of the XO-NFAT5 axis in macrophage activation and TLR-induced arthritis, and suggest that XO inhibitor(s) could serve as a therapeutic agent for chronic inflammatory arthritis.

Urinary proteome profile predictive of disease activity in rheumatoid arthritis.

Current serum biomarkers for rheumatoid arthritis (RA) are not highly sensitive or specific to changes of disease activities. Thus, other complementary biomarkers have been needed to improve assessment of RA activities. In many diseases, urine has been studied as a window to provide complementary information to serum measures. Here, we conducted quantitative urinary proteome profiling using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and identified 134 differentially expressed proteins (DEPs) between RA and osteoarthritis (OA) urine samples. By integrating the DEPs with gene expression profiles in joints and mononuclear cells, we initially selected 12 biomarker candidates related to joint pathology and then tested their altered expression in independent RA and OA samples using enzyme-linked immunosorbent assay. Of the initial candidates, we selected four DEPs as final candidates that were abundant in RA patients and consistent with those observed in LC-MS/MS analysis. Among them, we further focused on urinary soluble CD14 (sCD14) and examined its diagnostic value and association with disease activity. Urinary sCD14 had a diagnostic value comparable to conventional serum measures and an even higher predictive power for disease activity when combined with serum C-reactive protein. Thus, our urinary proteome provides a diagnostic window complementary to current serum parameters for the disease activity of RA.

Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress.

OBJECTIVE: Elevated serum osteoprotegerin (OPG) levels represent an independent risk factor for atherosclerotic disease, although the underlying mechanism is not clear. The aim of this study was to investigate the association of serum OPG levels and circulating endothelial progenitor cell (EPC) numbers, and to explore the effect of OPG on EPC apoptosis and its underlying mechanisms. METHODS: Flow cytometry was used to enumerate EPCs in the peripheral blood of 91 patients with systemic lupus erythematosus (SLE). Cultured EPCs, isolated from peripheral blood, were challenged with OPG, and apoptosis was evaluated by TUNEL staining. Expression of apoptosis-related proteins was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Reactive oxygen species (ROS) were detected by flow cytometry, and the expression of NADPH oxidase (NOX) and MAP kinases (MAPK) was measured by qPCR and Western blotting. RESULTS: The serum OPG level was independently associated with reduced numbers of EPCs in patients with SLE. In vitro treatment with OPG significantly induced apoptosis of EPCs; this effect was mediated by syndecan 4. OPG-induced apoptosis was abolished by the ROS scavenger N-acetylcysteine and the NOX inhibitor diphenyleniodonium. OPG increased ROS production through activation of NOX-2 and NOX-4 and triggered phosphorylation of ERK-1/2 and p38 MAPK. Quenching of ROS by knockdown of NOX-2 or NOX-4 transcripts inhibited phosphorylation of ERK-1/2 and p38 MAPK. Moreover, inhibitors of ERK-1/2 and p38 MAPK decreased ROS production and subsequent EPC apoptosis, indicating a feed-forward loop between NOX and MAPK to amplify ROS production related to apoptosis. CONCLUSION: Elevated OPG levels increase apoptosis of EPCs by induction of oxidative stress.

Role of macrophage migration inhibitory factor in the regulatory T cell response of tumor-bearing mice.

Macrophage migration inhibitory factor (MIF) is involved in tumorigenesis by facilitating tumor proliferation and evasion of apoptosis; however, its role in tumor immunity is unclear. In this study, we investigated the effect of MIF on the progression of the syngenic, CT26 colon carcinoma and the generation of tumor regulatory T cells (Tregs). The results showed that the tumor growth rate was significantly lower in MIF knockout (MIF(-/-)) mice than in wild-type (MIF(+/+)) mice. Flow cytometric analysis of both spleen and tumor cells revealed that MIF(-/-) mice had significantly lower levels of tumor-associated CD4(+)Tregs than MIF(+/+) mice. The splenic cells of MIF(-/-) mice also showed a decrease in CD8(+)Tregs, which was accompanied by an increase in CD8-induced tumor cytotoxicity. Interestingly, the inducible Treg response in spleen cells to anti-CD3/CD28 plus IL-2 plus TGF-ß was greater in MIF(-/-) mice than in MIF(+/+) mice. Spleen cells of MIF(-/-) mice, stimulated with anti-CD3/CD28, produced lower levels of IL-2, but not TGF-ß, than those of MIF(+/+) mice, which was recovered by the addition of recombinant MIF. Conversely, a neutralizing anti-MIF Ab blocked anti-CD3-induced IL-2 production by splenocytes of MIF(+/+) mice and suppressed the inducible Treg generation. Moreover, the administration of IL-2 into tumor-bearing MIF(-/-) mice restored the generation of Tregs and tumor growth. Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers.

Prevalence of systemic lupus erythematosus in South Korea: an administrative database study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a rare autoimmune disease for which a population-based survey on the prevalence of the disease in South Korea has not yet been conducted. Our goal was to estimate the nationwide prevalence of SLE. METHODS: The International Classification of Diseases, Tenth Revision (ICD-10) code for SLE diagnosis-M32-was tentatively given when patients were suspected to have SLE before 2009. As such, the positive predictive value (PPV) of the M32 code shown in medical bills reflecting true SLE was uncertain. We attempted to estimate the prevalence of SLE in South Korea using national administrative database data from 2004-2006. We approximated the actual number of SLE patients by analyzing a list of SLE-coded patients provided by the National Health Insurance (NHI) and Health Insurance Review and Assessment Service. Prevalence was estimated by multiplying the PPV of the M32 diagnostic code by the number of patients receiving the code. The PPV was determined by three methods: direct investigation of the medical records of patients randomly selected from the SLE-coded patients list; assessment of all SLE patients treated at 56 selected hospitals in South Korea; and extrapolation from sub-groups at a single institute to the sub-groups of the national NHI data. RESULTS: The estimated number of national SLE cases was between 9000 and 11,000, depending on the method of ascertainment, corresponding to a prevalence of 18.8-21.7 per 100,000 people. CONCLUSIONS: This is the first report of a nationwide prevalence survey of SLE in South Korea. National databases may serve as a resource for epidemiologic studies of rare autoimmune diseases like SLE.

Comparison of the efficacy and safety profiles of a pelubiprofen versus celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, phase III, non-inferiority clinical trial.

BACKGROUND: Pelubiprofen is a prodrug of 2-arylpropionic acid with relatively selective effects on cyclooxygenase-2 activity. The aim of this study was to compare the efficacy and safety profiles of pelubiprofen with those of celecoxib in patients with rheumatoid arthritis. METHODS: This was a 6-week, multicenter, randomized, double-blind, double-dummy, parallel-group, phase III, non-inferiority clinical trial. The primary end point was non-inferiority of pain decrease from baseline to week-6 as determined using a 100 mm pain visual analog scale (VAS). Pelubiprofen was considered non-inferior to celecoxib if the lower limit of the 97.5% confidence interval for treatment difference [(pain reduction in pelubiprofen group) - (pain reduction in celecoxib group)] was more than -10 mm. The secondary end points were as follows: non-inferiority of (1) reduction of Korean health assessment questionnaire (KHAQ) score; (2) decreased duration of morning stiffness; and (3) decrease in the frequency and total dose of rescue drugs after 6 weeks of treatment. RESULTS: Seventy-seven patients in the pelubiprofen group and 68 patients in the celecoxib group started the study medication. Pelubiprofen was non-inferior to celecoxib with regard to reduction in VAS pain severity (difference, mean ± SD 5.0 ± 20.1; 97.5% CI, -2.3 to ∞). Pelubiprofen was also non-inferior to celecoxib in terms of the secondary end points, such as, decrease in KHAQ score (0.0 ± 0.5, 97.5% CI -0.2 to ∞), decrease in duration of morning stiffness (median 0.0 minute in both groups), and decrease in the frequency (0.7 ± 3.5, 97.5% CI -0.6 to ∞) and total amount (0.7 ± 3.6, 97.5% CI -0.6 to ∞) of rescue medication uses during the 6 week study period. Safety analysis revealed 31.2% patients in the pelubiprofen group and 20.6% patients in the celecoxib group experienced an adverse drug reaction (ADR). The frequency of gastrointestinal ADRs was 20.8 % and 8.8%, respectively. CONCLUSIONS: Pelubiprofen was found to be as effective as celecoxib at pain reduction and for relieving stiffness in RA patients. However, more patients in the pelubiprofen group experienced ADR and the frequency of gastrointestinal ADRs was higher in the pelubiprofen group. ClinialTrials.gov identifier: NCT01781702.

Efficacy and safety of intravenous belimumab in a subgroup of South Korean patients with systemic lupus erythematosus enrolled into a Phase 3, randomized, placebo-controlled trial in North East Asia.

AIM: This post hoc analysis evaluated the efficacy and safety of intravenous belimumab 10 mg/kg in the South Korean subgroup of patients with systemic lupus erythematosus (SLE) enrolled in the North East Asia (NEA) study (GSK Study BEL113750; NCT01345253). METHODS: NEA was a double-blind, placebo-controlled, randomized Phase 3 trial. Patients with active, autoantibody-positive SLE were randomized 2:1 to belimumab or placebo plus standard therapy administered on Days 0, 14, and 28, and then every 28 days up to Week 48. The primary efficacy endpoint in this analysis was SLE Responder Index 4 (SRI-4) response rate at Week 52, defined as the proportion of patients achieving a ≥4-point reduction in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, no worsening (<0.3 increase from baseline) in Physician Global Assessment, no new British Isles Lupus Assessment Group (BILAG) A domain and <2 new BILAG B domain scores. RESULTS: Among 100 South Korean patients enrolled in NEA, 54/66 (81.8%) belimumab- and 24/34 (70.6%) placebo-treated patients completed the double-blind phase. Significantly more belimumab- than placebo-treated patients achieved SRI-4 response at Week 52 (n = 35/66, 53.0% vs. n = 8/34, 23.5%; odds ratio [OR; 95% confidence interval (CI)]: 3.67 [1.45, 9.28]; p = .0061). The proportion of patients experiencing ≥1 adverse event was similar between groups (belimumab: n = 60/66, 90.9% vs. placebo: n = 31/34, 91.2%). No new safety signals emerged in this subgroup analysis. CONCLUSION: Belimumab was efficacious for the treatment of SLE and well tolerated among the South Korean subgroup of patients from the NEA study.

Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies.

Patients with immune thrombocytopenia (ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies (aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval (CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio (HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis.

The APOM polymorphism as a novel risk factor for dyslipidaemia in rheumatoid arthritis: a possible shared link between disease susceptibility and dyslipidaemia.

OBJECTIVES: A decrease in high-density lipoprotein (HDL) cholesterol during inflammation is common in many rheumatologic diseases, including rheumatoid arthritis (RA). Apolipoprotein M (apoM) is an apolipoprotein predominantly associated with HDL cholesterol. Recently, apoM polymorphisms have been related with RA susceptibility. We investigated the possible association between an APOM polymorphism and dyslipidaemia in Korean RA patients. METHODS: Two hundred and fifteen RA patients and 215 controls that provided complete genotyping were included. Genetic distribution, RA-associated phenotype, lipid profiles, and lipoproteins were evaluated. RESULTS: RA patients had increased frequencies of the APOM C-1065A A allele compared to the controls. RA patients with A/A genotypes had lower levels of HDL cholesterol than those with C/C genotypes. After adjustment for confounding factors, the A/A genotype was a risk factor for low HDL cholesterolaemia (OR=1.070, p=0.001). Subgroup analyses according to disease activity showed that the association between APOM genotype and HDL cholesterol levels was still significant in all subgroups, indicating that this APOM polymorphism may increase the dyslipidaemia risk, independently of RA disease activity. CONCLUSIONS: These data support that the APOM C-1065A polymorphism is associated with increased risk for developing RA and dyslipidaemia in RA patients. Reduced HDL cholesterol levels are independent of disease activity but are significantly influenced by APOM genotype. These findings suggest that a specific genetic factor for RA could be linked to dyslipidaemia and this could increase the risk of atherosclerosis in RA patients.

A clinical trial and extension study of infliximab in Korean patients with active rheumatoid arthritis despite methotrexate treatment.

Currently, infliximab is given for disease control for active rheumatoid arthritis (RA) patients despite methotrexate treatment. However, the efficacy and safety of infliximab in Korean patients has not been assessed appropriately. Therefore, we performed placebo-controlled, double-blind, randomized study and extension study. One-hundred forty-three patients with active RA were randomized to receive placebo or infliximab 3 mg/kg intravenously at week 0, 2, 6, 14, and 22 with methotrexate maintenance. Primary endpoint was American College of Rheumatology 20% improvement criteria (ACR20) at 30 week. After the clinical trial, patients on placebo (Group 1) and patients on infliximab who showed ACR20 response (Group 2) were treated with infliximab through another 84 week for evaluation of safety. During clinical trial, patients in infliximab group showed higher ACR20 at week 30 than patients in placebo group (50.1% vs 30.6%, P=0.014). A total of 92 patients participated in the extension study. The maintenance rate of infliximab was 62.0% at 84 weeks of extension study. The overall rate of adverse events was not different between Group 1 and Group 2. In Korean patients with active RA despite methotrexate treatment, infliximab in combination with methotrexate is effective and the long-term treatment with infliximab is well tolerated. (ClinicalTrials.gov No. NCT00202852, NCT00732875).

Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis.

Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal α1-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered.