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The use of magnetic resonance imaging (MRI) and positron emission tomography (PET) in rheumatology allows a better understanding of the pathophysiology of the disease as well as early diagnosis and appropriate evaluation of the disease status and treatment responses. Despite the limited availability because of the high cost, there is growing evidence for the advantages and clinical application of these modalities to various rheumatic diseases. This review discusses the basic mechanisms and clinical applications of MRI and PET in certain rheumatic diseases, including rheumatoid arthritis, axial spondyloarthritis, idiopathic inflammatory myopathies, large vessel vasculitis, central nervous system disease associated with rheumatic diseases, polymyalgia rheumatica, adult-onset Still’s disease, and immunoglobulin G4-related disease. (J Rheum Dis 2020;27:136-151)

Background/aims To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. Methods A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values ± standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. Results The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. Conclusion We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program.

Background There is increasing interest in the quality of health care and considerable efforts are being made to improve it. Rheumatoid arthritis (RA) is a disease that can result in favorable outcomes when appropriate diagnosis and treatment are provided. However, several studies have shown that RA is often managed inappropriately. Therefore, the Korean College of Rheumatology aimed to develop quality indicators (QIs) to evaluate and improve the health care of patients with RA. Methods Preliminary QIs were derived based on the existing guidelines and QIs for RA. The final QIs were determined through two separate consensus meetings of experts. The consensus was achieved through a panel of experts who voted using the modified Delphi method. Results Fourteen final QIs were selected among 70 preliminary QIs. These included early referral to and regular follow-up with a rheumatologist, radiographs of the hands and feet, early initiation and maintenance of disease-modifying anti-rheumatic drug (DMARD) therapy, periodic assessment of disease activity, screening for drug safety and comorbidities, including viral hepatitis and tuberculosis before biologic DMARD therapy, periodic laboratory testing, supplementation with folic acid, assessment of the risk for cervical spine instability before general anesthesia, patient education, and specialized nurse. Conclusion These QIs can be used to assess and improve the quality of health care for patients with RA., Graphical Abstract

Objectives This study is aimed to investigate the role of nuclear factor of activated T cells 5 (NFAT5), originally known as the osmosensitive mammalian transcription factor, in the pathogenesis of osteoarthritis (OA) in mice. Methods OA was induced in male C57BL/6 (wild-type) and NFAT5 haplo-insufficient (NFAT5+/–) mice via destabilization of the medial meniscus (DMM) surgery. OA severity and synovial inflammation were histologically assessed. Expression of CCL2, inflammatory cytokines, cartilage degrading enzymes was determined in the knee joints and cultured chondrocytes from wild-type and NFAT5+/− mice. Results NFAT5 expression was significantly upregulated in the knee joint of a mouse after DMM surgery. NFAT5 deficiency decreased the severity of synovial inflammation and osteoarthritic changes in cartilage and subchondral bone. Moreover, NFAT5 deficiency also decreased the expression of CCL2, IL-1β, MMP-13, ADMATS-5, and macrophage infiltration in the joint. In cultured chondrocytes, hyperosmolar or IL-1β stimulation significantly enhanced the expression of NFAT5, CCL2, IL-1β, IL-6, and MMP-13, and this effect was abolished in chondrocytes from NFAT5+/− mice. Hyperosmolarity or IL-1β-induced NFAT5 and CCL2 downregulated by inhibiting p38 MAPK, JNK, and ERK pathways. Conclusions Our results indicate that NFAT5 is a crucial regulator of OA pathogenesis by upregulating CCL2 expression and macrophage recruitment. In chondrocyte, NFAT5 plays an important role in the response to hyperosmolar or IL-1β stimulation. Thus, NFAT5 could be an attractive therapeutic target for OA treatment.

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.

Antimicrobial, antifungal and anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa (EOCO) have previously been reported. In the present study, the anti-inflammatory effects of EOCO were investigated in two murine models of inflammation: Carrageenan-induced paw edema and thioglycollate-induced peritonitis, and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The expression levels of proinflammatory cytokines were analyzed by ELISA, the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. In mice with carrageenan-induced edema, paw thickness and the expression levels of interleukin (IL)‑1β and IL-6 in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group, as compared with the control group. In mice with thioglycollate-induced peritonitis, treatment with EOCO (5 and 10 mg/kg) reduced the number of total cells and suppressed tumor necrosis factor‑α (TNF‑α), IL‑1β and IL‑6 levels in peritoneal fluid. In addition, EOCO reduced nitric oxide, TNF‑α and IL‑6 production, and suppressed iNOS and COX‑2 expression in LPS‑stimulated RAW 264.7 cells. These results suggest that EOCO may exert anti‑inflammatory effects in vivo and in vitro, and that these effects may be associated with the inhibition of inflammatory mediators. Therefore, EOCO may be considered an effective therapeutic agent for the treatment of inflammatory diseases.

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 T

Objective The proportion of elderly patients with rheumatoid arthritis (RA) is continuously growing as a result of the increasing aging population. We compared disease activity between different age groups, and evaluated the clinical factors associated with high disease activity. Methods This cross-sectional study analyzed the data of RA patients enrolled in the Korean College of Rheumatology Biologics registry (KOBIO-RA) between 2012 and 2014. Disease activity between elderly (age ≥ 65 years) and non-elderly patients (age < 65 years) was compared, and the association of clinical factors with high disease activity was assessed using a multivariate logistic regression model. Results Of 1,227 patients in KOBIO-RA, 244 patients with RA were aged 65 years or over. In elderly patients, the proportion of men was higher (P = 0.012), and the duration of disease was longer (P < 0.001) compared with non-elderly patients. The elderly group showed a higher incidence of comorbidity (P < 0.001), and less use of methotrexate (P = 0.004). Assessment of disease activity using various composite measures showed a higher proportion of high disease activity in elderly patients than non-elderly patients. Longer disease duration, presence of comorbidity, and non-use of methotrexate were independently associated with high disease activity (P = 0.002, P < 0.001, and P = 0.029, respectively). Conclusions At enrollment of KOBIO-RA, elderly patients showed higher disease activity compared with non-elderly patients. Disease duration, use of methotrexate, and comorbidity are associated with disease activity control in Korean patients with RA.

Ultrasonography (US) is a valuable imaging modality used to assess joint and periarticular abnormalities in patients with osteoarthritis (OA). US can detect articular cartilage damage, bony changes, joint effusion, synovitis, and adjacent soft tissue lesions. In addition, US facilitates the monitoring of disease progression and effects of treatments. US is a safe and accessible bedside procedure that can improve diagnosis and management of patients. The objective of this article was to describe the clinical applications of US for patients with OA. (Korean J Med 2015;89:616-619)

Objectives Glycogen synthase kinase (GSK)-3β, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3β inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA). Method FLS from RA patients were treated with selective GSK-3β inhibitors, including lithium chloride, 6-bromoindirubin-3′-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3β inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3β inhibitors were examined in mice with CIA. Results Treatment of RA FLS with GSK-3β inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-κB, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3β inhibitors. GSK-3β inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3β inhibitors treatment. Serum levels of IL-1β, IL-6, TNF-α and IFN-γ in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3β inhibitors. Conclusion Treatment with GSK-3β inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3β can be used as an effective therapeutic agent for RA.

The purpose of this study is to investigate the frequency of the subclinical synovitis in hand or wrist joints of the SLE patients using ultrasonography (US) and to correlate them with clinical parameters. Forty-eight systemic lupus erythematosus (SLE) patients without musculoskeletal (MS) involvement were enrolled and underwent clinical and laboratory examinations. Gray-scale and power Doppler (PD) US was performed for imaging the wrist, second and third metacarpophalangeal (MCP) joints, and flexor tendons on non-dominant sides of the individuals. US synovitis index (USSI) and PD index were calculated as sum of the synovitis and PD semiquantitative scores, respectively, obtained from each joint. Subclinical synovitis was found by US in 28 (58.3 %) out of 48 patients. US revealed synovitis of the wrist in 16 (33.3 %) patients, of the second MCP joint in 14 (29.2 %) and of the third MCP joint in 15 (31.3 %). PD signals in three (6.3 %) patients and tenosynovitis in two (4.2 %) were also detected. USSI scores showed significant positive correlation with erythrocyte sedimentation rate (ESR) levels (r = 0.30, p < 0.05) or anti-dsDNA Ab titers (r = 0.34, p < 0.05). Within 6 months after US examination, new MS symptoms were developed in 11 (22.9 %) patients. Older age at diagnosis (OR 1.283, 95 % CI 1.029–1.601, p = 0.027) or higher USSI scores (OR 12.93, 95 % CI 1.023–163.503, p = 0.048) were independently associated with development of new MS symptoms. Subclinical synovitis is common in SLE patients who do not suffer from MS symptoms. US is useful to detect joint abnormalities before symptoms appear in SLE patients.

Aim To estimate the point prevalence of pulmonary hypertension (PH) and determine the associated factors for PH in patients with systemic lupus erythematosus (SLE). Methods A prospective cross-sectional study of 114 patients with SLE was conducted in a single tertiary center. Transthoracic echocardiography was performed to estimate the pulmonary arterial pressures. PH was defined as resting systolic pulmonary artery pressure (sPAP) ≥ 40 mmHg, in the absence of left heart disease. Results PH was identified in nine patients (7.9%) who had few cardiopulmonary symptoms. SLE patients with PH had higher SLE disease activity index score. In particular, serum uric acid (UA) was significantly higher in patients with PH than in those without PH. In multivariate analysis, UA remained significant for the presence of PH. Moreover, serum UA level correlated significantly with plasma NT-pro-B-type natriuretic peptide level as well as sPAP. At the cutoff level of 6.5 mg/dL, serum UA had reasonable accuracy for predicting the presence of PH in SLE patients (sensitivity 66.7% and specificity 96.2%). Conclusion A significant number of SLE patients in rheumatology practice have undiagnosed PH with few discernible symptoms. Serum UA level may be useful as a surrogate marker for screening of PH in patients with SLE.

Resume Objectifs Evaluer si l’acide gallique (acide 3, 4, 5-trihydroxybenzoique), acide polyphenolique naturel retrouve dans les noix de Galle, le sumac, l’ecorce de chene, les feuilles de the, de raisin et dans le vin, a des proprietes pro-apoptotiques et anti-inflammatoires sur les synoviocytes fibroblastiques (SFL) provenant de patients atteints de polyarthrite rhumatoide (PR). Methodes La viabilite des SFL de PR a ete evaluee en utilisant un test MTT apres traitement par l’acide gallique. L’apoptose a ete evaluee par un test TUNEL et l’activite caspase-3 a ete determinee par un test colorimetrique. Les taux des proteines liees a l’apoptose incluant Bcl-2, pAkt, p53, et Bax ont ete determines en utilisant des analyses par Western blot, et l’expression de l’ARNm des differents mediateurs pro-inflammatoires a ete mesuree en utilisant la technique quantitative de PCR en temps reel. Resultats La viabilite cellulaire des SFL PR a ete significativement diminuee par le traitement avec une dose d’au moins 10 μM d’acide gallique. Le traitement par l’acide gallique a des concentrations n’affectant pas la viabilite cellulaire (0,1 et 1 μM) a induit l’apoptose cellulaire des SFL PR. Le traitement par les doses de 0,1 et 1 μM d’acide gallique a induit aussi une augmentation de l’activite caspase-3 et a regule la production de Bcl-2, Bax, p53 et de pAkt. L’expression ARNm des cytokines pro-inflammatoires (IL-1β, IL-6), des chimiokines (CCL-2/MCP-1, CCL-7/MCP-3), de la cyclo-oxygenase-2, et de la metalloprotease matricielle-9 de SFL a ete supprimee par l’acide gallique de facon dose-dependante. Conclusion Le traitement par l’acide gallique semble induire l’apoptose des SFL rhumatoides par une regulation de l’expression des proteines de l’apoptose et par une reduction de l’expression des genes pro-inflammatoires dans ces cellules isolees. Ces donnees suggerent que l’activite pro-apoptotique et anti-inflammatoire de l’acide gallique pourrait etre exploitee comme option therapeutique dans la PR.

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.We measured levels of plasma sCD40L in 241 SLE patients and 37 healthy controls and investigated its association with clinical manifestation and laboratory parameters.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, p0.001). 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-β2 glycoprotein I antibodies (γ=0.338, p0.001 and γ=0.364, p0.001, 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.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.

This study aimed to investigate the effects of a two-day forest therapy program on individuals with chronic widespread pain. Sixty one employees of a public organization providing building and facilities management services within the Seoul Metropolitan area participated in the study. Participants were assigned to an experimental group (n = 33) who participated in a forest therapy program or a control group (n = 28) on a non-random basis. Pre- and post-measures of heart rate variability (HRV), Natural Killer cell (NK cell) activity, self-reported pain using the visual analog scale (VAS), depression level using the Beck Depression Inventory (BDI), and health-related quality of life measures using the EuroQol Visual Analog Scale (EQ-VAS) were collected in both groups. The results showed that participants in the forest therapy group, as compared to the control group, showed physiological improvement as indicated by a significant increase in some measures of HRV and an increase in immune competence as indicated by NK cell activity. Participants in the forest therapy group also reported significant decreases in pain and depression, and a significant improvement in health-related quality of life. These results support the hypothesis that forest therapy is an effective intervention to relieve pain and associated psychological and physiological symptoms in individuals with chronic widespread pain.

The aim of this study is to clarify the association between serum leptin levels and the presence of syndesmophytes in male patients with ankylosing spondylitis (AS). Seventy-two male patients with AS and 20 age-matched healthy male controls were included. Patients were stratified by the presence of syndesmophytes. Serum leptin levels were measured and adjusted for body mass index (BMI). In addition, bone-specific alkaline phosphatase (BALP), osteocalcin, and telopeptide of type I collagen were determined. Patients with syndesmophytes were associated with older age (p < 0.001), longer disease duration (p = 0.003), and higher BMI (p = 0.038). Serum leptin levels and leptin per BMI (leptin/BMI) ratio were not different between AS patients and healthy controls. However, serum leptin/BMI ratio was significantly higher in patients with syndesmophytes compared to those without (p = 0.010). In multivariate analysis, higher serum leptin/BMI ratio remained significantly associated with the presence of syndesmophytes (p = 0.029). Moreover, serum leptin/BMI ratio was positively correlated with serum BALP (γ = 0.279, p = 0.039). However, there was no significant association between serum leptin/BMI ratio and bone mineral density. Serum leptin levels are elevated in male AS patients with syndesmophytes and were found to be correlated with bone formation marker, suggesting a potential role of leptin in new bone formation in AS.

Objective To investigate the role of NF-AT5, an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in patients with rheumatoid arthritis (RA). Methods The expression of NF-AT5 in synovial tissue and synoviocytes from RA patients was examined by immunohistochemistry and Western blot analysis, respectively. Messenger RNA (mRNA) in RA synoviocytes and human umbilical vein endothelial cells (HUVECs) transfected with dummy small interfering RNA (siRNA) or NF-AT5 siRNA were profiled using microarray technology. Assays to determine synoviocyte apoptosis and proliferation were performed in the presence of NF-AT5 siRNA. VEGF165-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wound migration of HUVECs. Experimental arthritis was induced in mice by injection of anti–type II collagen antibody. Results NF-AT5 was highly expressed in rheumatoid synovium, and its activity was increased by proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. The mRNA profiling of synoviocytes and HUVECs transfected with NF-AT5–targeted siRNA revealed 3 major changes in cellular processes associated with the pathogenesis of RA: cell cycle and survival, angiogenesis, and cell migration. Consistent with these results, NF-AT5 knockdown in RA synoviocytes and HUVECs inhibited their proliferation/survival and impeded angiogenic processes in HUVECs. Mice with NF-AT5 haploinsufficiency (NF-AT5+/–) developed a very limited degree of synovial proliferation, as seen on histologic analysis, and decreased angiogenesis, and they exhibited a nearly complete suppression of experimentally induced arthritis. Conclusion NF-AT5 regulates synovial proliferation and angiogenesis in chronic arthritis.

Lupus mesenteric vasculitis (LMV) is a unique clinical entity found in patients who present with gastrointestinal manifestations of systemic lupus erythematosus, and is the main cause of acute abdominal pain in these patients. LMV usually presents as acute abdominal pain with sudden onset, severe intensity and diffuse localization. Other causes of abdominal pain, such as acute gastroenteritis, peptic ulcers, acute pancreatitis, peritonitis, and other reasons for abdominal surgery should be ruled out. Prompt and accurate diagnosis of LMV is critical to ensure implementation of appropriate immunosuppressive therapy and avoidance of unnecessary surgical intervention. The pathology of LMV comprises immune-complex deposition and complement activation, with subsequent submucosal edema, leukocytoclastic vasculitis and thrombus formation; most of these changes are confined to small mesenteric vessels. Abdominal CT is the most useful tool for diagnosing LMV, which is characterized by the presence of target signs, comb signs, and other associated findings. The presence of autoantibodies against phospholipids and endothelial cells might provide information about the likelihood of recurrence of LMV. Immediate, high-dose, intravenous steroid therapy can lead to a favorable outcome and prevent serious complications such as bowel ischemia, necrosis and perforation.

IL-23, a clinically novel cytokine, targets CD4+ T cells. Recent IL-1Ra−/− mouse studies have demonstrated that IL-23 indirectly stimulates the differentiation of osteoclast precursors by enhancing IL-17 release from CD4+ T cells. IL-17, in turn, stimulates osteoclastogenesis in osteoclast precursor cells. In this study, we found that IL-23 up-regulates receptor activator of NF-κB ligand expression by CD4+ T cells, and thus contributes to osteoclastogenesis. This indirect pathway is mediated by NF-κB and STAT3. We have also demonstrated that IL-23 can influence osteoclastogenesis positively under the special conditions in the IL-1-dominant milieu of IL-1Ra−/− mice. We propose that IL-23-enhanced osteoclastogenesis is mediated mainly by CD4+ T cells. The results of this study show that IL-23 is a promising therapeutic target for the treatment of arthritis-associated bone destruction.

The receptor activator of nuclear factor kappaB ligand (RANKL) is an osteoclastogenic mediator, which is mainly expressed by stromal cells and osteoblast. However, T cells can also be an important provider for RANKL in special condition such as autoimmune arthritis. We examined the RANKL expression of hyporesponsive CD4+ T cells induced by oral feeding with type II collagen in collagen-induced arthritis (CIA) mice. The potential of RANKL expression in CD4+ T cells was downregulated in tolerance, as compared with CIA. One of possible explanations for this phenomenon is that CII-specific T cell activation was intrinsically impaired in oral tolerance, which caused suppression of RANKL expression of CD4+ T cells. We also investigated the extrinsic role of cytokine in this process. IL-17, well-known pro-inflammatory cytokine was upregulated in CIA and downregulated in tolerance. IL-17 had a potential to stimulate T cells to express RANKL in dose-dependent manner. IL-17-associated RANKL expression of CD4+ T cells was downregulated in oral tolerance, suggesting that the induction of tolerance ameliorates IL-17-induced RANKL expression of T cells in murine CIA. We also discovered that CIA - T cells could enhance osteoclastogenesis but not oral tolerance - T cells. Oral tolerance might be promising therapeutic option in viewpoints of modulating autoreactivity of CII which can induce not only IL-17 production but also RANKL expression in CD4+ T cells.

Macrophage activation syndrome (MAS) is one of the serious complications of juvenile rheumatoid arthritis (JRA) and recently, cyclosporine A has been found to be effective in patients with corticosteroid-resistant MAS. A 29-yr-old male was admitted with high fever and jaundice for one month. He was diagnosed as juvenile arthritis 16 yr ago. Physical and laboratory results showed hepatosplenomegaly, high fever, pancytopenia and impaired liver and renal function tests, elevated triglyceride and serum ferritin levels. Bone marrow biopsy showed hyperplasia of histiocytes with active hemophagocytosis. He was diagnosed as MAS associated with juvenile rheumatoid arthritis and managed with high-dose corticosteroids initially, but clinical symptoms and laboratory findings did not improve immediately. Finally, he completely recovered after treatment with cyclosporine A (3 mg/kg/day).

Tumour necrosis factor-α is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF-α is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF-α blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF-α inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti-TNF-α therapy in various autoimmune diseases.

Interleukin-18 (IL-18) is a novel pro-inflammatory cytokine which has been implicated to play a pathogenic role in rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In present study, we examined the effect of IL-18 on VEGF production in fibroblast-like synoviocytes (FLS) isolated from the patients with RA. FLS were prepared from the synovial tissues of patients with RA and osteoarthritis (OA) and cultured in the presence of IL-18. The production of VEGF from FLS was measured in culture supernatants by enzyme-linked immunosorbent assay (ELISA). The VEGF messenger RNA (mRNA) expression and AP-1 binding activity of VEGF transcript were determined by reverse transcription-polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA). IL-18 and VEGF levels of sera and synovial fluids (SF) of RA patients (n=30) were significantly higher than those of OA patients (n=20). IL-18 dose-dependently increased the production of VEGF. The effect of IL-18 on VEGF production appeared to be as potent as IL-1beta, whereas tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma showed little effects on VEGF production. AP-1-specific inhibitor Curcumin dose-dependently abrogated the effect of IL-18 on VEGF production. The VEGF enhancement of IL-18 was associated with increased AP-1 binding activity to the VEGF promoter site. These findings suggest IL-18 as an angiogenic factor in RA and down-regulation of IL-18 activity or AP-1 signal pathway can be potential therapeutic targets for RA.

Objective Although oral tolerance is a well-known phenomenon, the role of dendritic cells (DCs) is not well characterized. This study was conducted to better understand the differential role played by each Peyer's patch DC subset in the induction of oral tolerance to type II collagen (CII) in murine collagen-induced arthritis (CIA). Methods CII was fed 6 times to DBA/1 mice beginning 2 weeks before immunization, and the effect on arthritis was assessed. We compared the proportion of CD11c+,CD11b+ DCs and CD11c+,CD8α+ DCs in the Peyer's patches of CII-fed tolerized and phosphate buffered saline–fed nontolerized mice after the induction of CIA. The immunosuppressive properties of each DC subset were determined using fluorescence-activated cell sorter analysis for intracellular interleukin-10 (IL-10) and IL-12 and mixed lymphocyte culture. The ability of each DC subset to induce CD4+,CD25+ T regulatory cells was also examined. Mice were injected with CII-pulsed CD11c+,CD11b+ DCs isolated from Peyer's patches of tolerized mice, and the effect on CIA was examined. Results The severity of arthritis was significantly lower in tolerized mice. The proportion of CD11c+,CD11b+ DCs was increased in the Peyer's patches of tolerized mice and those DCs exhibited immunosuppressive characteristics, such as increased IL-10 production, inhibition of T cell proliferative responses to CII, and CD4+,CD25+ regulatory T cell induction. Furthermore, the CD11c+,CD11b+ DCs suppressed the severity of arthritis upon adoptive transfer. Conclusion Our observations demonstrate that CD11c+,CD11b+ DCs, which are abundant in Peyer's patches during the induction of oral tolerance to CII, are crucial for the suppression of CIA and could be exploited for immunotherapy of autoimmune diseases.

Objective To investigate the effector function exerted by type II collagen (CII)-stimulated T cells on rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and to determine their contribution to RA pathogenesis. Methods We used enzyme-linked immunosorbent assays to measure the levels of interleukin-15 (IL-15), tumor necrosis factor alpha (TNFalpha), and IL-18 production by FLS that were cocultured with antigen-activated T cells. Likewise, we analyzed the levels of interferon-gamma (IFN gamma) and IL-17 production by RA T cells coincubated with FLS. To investigate the cross-talk between CII-stimulated T cells and RA FLS, we examined the effect of using a transwell membrane to separate T cells and FLS in a culture chamber, as well as the effect of adding an antibody to block CD40 ligation. Results The levels of IL-15, TNF alpha, IFN gamma, and IL-17 were all significantly increased in the serum of RA patients compared with normal control serum. Among the patients, the group with a stronger T cell proliferation response to CII showed higher levels of these inflammatory mediators. When coincubated with RA FLS, these T cells induced the production of IL-15, TNF alpha, and IL-18 by FLS with an intensity that increased in proportion to the duration of CII stimulation. T cells, in turn, responded to FLS stimulation by secreting higher amounts of IL-17 and IFN gamma in coculture. Interestingly, T cells that were activated by CII for longer periods of time showed stronger induction of these cytokines. The cross-talk between T cells and FLS appeared to require direct cell-cell contact as well as CD40 ligation, at least in part. Conclusion Through repeated stimulation by CII, RA synovial T cells became trained effector cells that induced the production of proinflammatory mediators by FLS, while in the process the T cells becoming more sensitized to the activation signal from FLS.

Fasciitis, one of the presentations of chronic skin graft-versus-host disease (GVHD), is characterized by symmetrical inflammatory swelling of extremities with or without eosinophilia, but it is rarely reported. This article describes a patient with the clinical and histologic features of fasciitis, as the only form of chronic GVHD that developed 20 months after HLA-matched allogeneic peripheral hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). She reported tightness of the skin and pain in both wrists and elbows on motion, with edema of the limbs. A deep cutaneous biopsy showed thickening of the subcutaneous fascia with inflammatory infiltrates. The patient was treated with cyclosporine and prednisone, which resulted in much improvement of her symptoms and signs related to the fasciitis. The authors recommend that clinicians maintain a high index of suspicion for fasciitis because fasciitis is a distinct entity among the chronic GVHD that may lead to a functional disability.

Pulmonary arterial hypertension (PAH) is a rare but serious complication of systemic lupus erythematosus (SLE). Chronic hypoxia is known to cause PAH resulting from pulmonary vascular remodeling. We investigated the association between anemic hypoxia and PAH in SLE patients.Systolic pulmonary artery pressure (PAP) was measured in 132 SLE patients by echocardiography. Increased PAP was defined as resting PAP40 mm Hg. Oxygen delivery (DO2) was estimated as the product of cardiac output and arterial oxygen content.Of 132 patients, 17 (12.9%) had increased PAP, and these patients had significantly lower DO2 values than patients with normal PAP (P = 0.002). The DO2 values inversely correlated with PAP values (γ = -0.308, P0.001) and plasma N-terminal pro-brain natriuretic peptide levels (γ = -0.323, P = 0.001), but positively correlated with hemoglobin levels (γ = 0.402, P0.001). Compared to those with normal PAP, patients with increased PAP had significantly longer durations of anemia over the preceding 6-24 months. Patients with anemia of longer durations (≥3 months) in the preceding 6 months had a higher risk of increased PAP compared to those with shorter durations (P0.001). When SLE patients were divided into 3 groups according to hemoglobin and PAP, serum interleukin-6 (IL-6) levels increased across groups with higher PAP (P = 0.001 for trend), but decreased across tertiles of hemoglobin levels (P = 0.008 for trend).Our data indicate an association between chronic anemic hypoxia and increased PAP in SLE patients and suggest that increased IL-6 might participate in this process.

Ultrasonography is a useful imaging modality for the diagnosis of pathologic conditions in the biceps tendon. We describe a 64-year old man with rheumatoid arthritis (RA) who suddenly developed a painless lump in the antecubital region of the right arm. The bulging was prominent when he flexed his forearm. Proximal loss of the long head in biceps tendon could be demonstrated by ultrasonography. The ultrasonographic features of spontaneous isolated biceps tendon rupture occurring in a patient with RA are described.

There is no consensus on whether it is safe to re-administer tumor necrosis factor-alpha (TNFα) inhibitors in patients with rheumatoid arthritis (RA) or ankylosing spondylitis (AS) flared after withdrawal of TNFα inhibitors due to active tuberculosis (TB). We evaluated the safety of restarting anti-TNFα therapy in patients with TNFα-associated TB. We used data of 1,012 patients with RA or AS treated with TNFα inhibitors at Seoul St. Mary's Hospital between January 2003 and July 2013 to identify patients who developed active TB. Demographic and clinical data including the results of tuberculin skin tests (TST) and interferon-γ releasing assays (IGRA) were collected. Fifteen patients developed active TB. Five cases were occurred in RA and 10 cases in AS. Nine of 15 patients had a negative TST or IGRA and 6 TST-positive patients had received prophylaxis prior to initiating anti-TNFα therapy. All patients discontinued TNFα inhibitors with starting the treatment of TB. Eight patients were re-administered TNFα inhibitors due to disease flares and promptly improved without recurrence of TB. TNFα inhibitors could be safely resumed after starting anti-TB regimen in patients with RA or AS.

Objective. The aim of this study was to examine and compare the gastrointestinal (GI) risk factors and treatment patterns of rheumatoid arthritis (RA) and osteoarthritis (OA) patients in Korea. Methods. This was a cross-sectional, observational study on RA and OA patients taking non-steroidal anti-inflammatory drugs (NSAIDs) for at least 1 month. A total of 1,896 patients (981 RA patients, 915 OA patients) were recruited from 20 university hospitals. Data were collected through medical records and patient surveys. GI risk factors included age, prolonged (over 3 months) or high-dose use of NSAIDs, alcohol drinking, smoking, use of aspirin, anticoagulants or glucocorticoids, comorbidities, and history of Helicobacter pylori infection or other GI complications. Treatment patterns were classified according to groups using, selective cyclooxygenase (COX)-2 inhibitors± gastro-protective agents, non-selective COX-2 inhibitors+proton pump inhibitor, or non-selective COX-2 inhibitors±other gastro-protective agents. Results. GI risk factors were highly present in both RA and OA patients. The proportion of prolonged use of NSAIDs, smoking, and glucocorticoid use were higher in RA patients (p＜0.001). The proportion of comorbidities and use of aspirin were higher in OA patients (p＜0.001). The remaining GI risk factors were present in similar proportions in both groups. Use of selective COX-2 inhibitors or gastro-protective agents was higher in RA patients. Conclusion. Prolonged use of NSAIDs and concomitant glucocorticoid use were higher in RA patients, while comorbidities and concomitant aspirin use were predominant in OA patients. These results will provide insights for use in development of future guidelines for proper selection of NSAIDs and effective prevention of GI complications in arthritis patients. (J Rheum Dis 2016;23:47-54)

Summary 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.

Objectives To investigate whether gallic acid (3, 4, 5-trihydroxybenzoic acid), a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, has pro-apoptotic and anti-inflammatory effects on fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Methods Viability of RA FLS was assessed using a MTT assay after gallic acid treatment. Apoptosis was assessed by TUNEL assay and caspase-3 activity was determined by a colorimetric assay. The levels of apoptosis-related proteins including Bcl-2, p-Akt, p53, and Bax were determined using western blot analyses, and the mRNA expressions of various pro-inflammatory mediators were measured using quantitative real-time PCR. Results Cell viability of RA FLS was significantly decreased by treatment with 10 or more μM of gallic acid. Gallic acid treatment at the concentrations that do not affect cell viability (0.1 and 1 μM) induced cellular apoptosis of RA FLS. Treatment with 0.1 and 1 μM of gallic acid also resulted in a significant increase in caspase-3 activity and regulated the productions of Bcl-2, Bax, p53 and pAkt. The mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6), chemokines (CCL-2/MCP-1, CCL-7/MCP-3), cyclooxygenase-2, and matrix metalloproteinase-9 from RA FLS were suppressed by the gallic acid treatment in dose-dependent manners. Conclusion Gallic acid treatment was found to induce apoptosis of RA FLS through regulation of apoptosis-related protein expressions and to reduce the expression of pro-inflammatory genes in RA FLS. These data suggest that pro-apoptotic and anti-inflammatory activities of gallic acid may be used as a possible therapeutic option for RA.

We compared the validity of the sonographic longitudinal sagittal image with the suprapatellar transverse axial image for assessment of thickness of femoral cartilage in osteoarthritis (OA) patients. Fifty-one patients with knee OA were enrolled in this study. Cartilage thicknesses of medial and lateral femoral condyles were measured with longitudinal sagittal and suprapatellar transverse axial image using sonography. Fat-suppressed 3D spoiled gradient-echo magnetic resonance imaging (MRI) was also used to get the reference value. The joint space width (JSW) and Kellgren and Lawrence (K-L) grade were measured in weight-bearing anteroposterior knee radiograph. The kappa and intraclass correlation coefficient (ICC) were used to determine inter- and intra-observer agreement of the ultrasound sonography (US) measurements. In medial femoral condyle, the opportunity to obtain cartilage thickness was increased significantly using the longitudinal US scan as compared with tansverse scan (48 cases vs. 36 cases, p < 0.05). There was a good correlation between longitudinal US scan and MRI in the maximum and minimum cartilage thicknesses of medial condyle (r = 0.568; r = 0.844, respectively, p < 0.01). However, there was no correlation between suprapatellar transverse US scan and MRI in medial condyle. In lateral condyle, both US scans showed good correlations with MRI. In Bland-Altman analysis, longitudinal US scan showed good agreement with MRI except in the minimal cartilage thickness of lateral condyle. There was high overall intra- and inter-observer agreement in US scan. US scan in the longitudinal plane is a more feasible method than suprapatellar transverse scan for measuring cartilage thickness of medial femoral condyle in knee OA patient.

To investigate the relationship between macrophage migration inhibitory factor (MIF) levels and clinical measures in rheumatoid arthritis (RA), and the potential for regulation of angiogenesis in RA.Serum and synovial fluid (SF) levels of MIF and vascular endothelial growth factor (VEGF) in patients with RA were determined by sandwich ELISA, and the relationships among MIF, VEGF, and RA clinical measures were analyzed. RA synovial fibroblasts were cultured with recombinant human MIF (rhMIF) and the production of VEGF and interleukin 8 (IL-8) were measured in the conditioned media. The angiogenic effect of MIF was examined using established measures of angiogenesis in vitro.Erythrocyte sedimentation rate, C-reactive protein, and the daily dosage of oral prednisolone were correlated with SF levels of MIF. The SF levels of MIF were found to be higher in patients with bony erosion than in those without (69.2 +/- 11.4 ng/ml vs 44.0 +/- 6.2 ng/ml; p = 0.045). MIF levels had good correlation with VEGF levels (r = 0.52, p0.001 in sera, and r = 0.6, p0.001 in SF). Production of the angiogenic factors VEGF and IL-8 was enhanced in cultured RA synovial fibroblasts stimulated by rhMIF. Endothelial tube formation was augmented when the endothelial cells were cultured with the conditioned media from rhMIF-pretreated SF mononuclear cells, and this phenomenon was reversed by anti-VEGF antibody.SF MIF may reflect the clinical activity in patients with RA, and rhMIF induces the angiogenic factors in RA synovial fibroblasts. These results suggest that MIF may be an important cytokine in the perpetuation of the angiogenic and inflammatory processes in patients with RA.

Although the biological activities of essential oil extracted from Chamaecyparis obtusa (EOCO) are not yet fully understood, antimicrobial, antifungal and anti-inflammatory effects have been reported. In this study, we investigated the anti-inflammatory effects of EOCO in two inflammatory models of mice, carrageenan-induced paw edema and thioglycollate-induced peritonitis, and lipopolysaccharide (LPS)-stimulated Raw 264.7 macrophage cells. Levels of pro-inflammatory cytokines were analyzed by ELISA, expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. The thicknesses of mice paw edema induced by carrageenan and interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group as compared with control group. In mice with thioglycollate-induced peritonitis, EOCO (5 and 10 mg/kg) treatment reduced the numbers of total cells and suppressed tumor necrosis factor (TNF)-α, IL-1β, and IL-6 levels in peritoneal fluid. EOCO also decreased nitric oxide (NO), TNF-α and IL-6 production and inhibited iNOS and COX-2 expressions in LPS-stimulated Raw 264.7 cells. These data showed that EOCO has anti-inflammatory effect both in vivo and in vitro, and this effect may be related with inhibition of inflammatory mediators. In conclusion, EOCO could be an effective therapeutic agent in inflammatory diseases.

Relapsing polychondritis (RP) is a rare systemic disease characterized by an inflammatory process involving predominantly cartilaginous structures. Pneumatosis cystoides intestinalis (PCI) in RP has not been reported previously. We report a case of PCI in RP that was successfully treated with high oxygen and antibiotics.

Behçet's disease is a chronic, relapsing, multisystem inflammatory disorder characterized predominantly by recurrent orogenital ulcers, skin involvement, and uveitis. Recurrent mucocutaneous lesions may be the only symptom in mild cases, but ocular, gastrointestinal, and central nervous system involvement may occur in severe cases. We report in this study the successful treatment with infliximab of severe life-threatening GI bleeding caused by an ileal ulcer in a patient with Behçet's disease. Antitumor necrosis factor (TNF) therapy could be an emergency therapeutic option in patients with massively bleeding Behçet's disease and unstable patients or those with acute bleeding with other TNF-alpha-mediated autoimmune diseases. Another option for anti-TNF therapy could be as bridging management between conservative and surgical treatment.

Cyclosporine A (CSA) has various biological effects on T cells, including inhibition of interleukin (IL)-15-induced IL-17 production in CD4+ T cells from patients with rheumatoid arthritis (RA). However, the mechanism underlying this effect is not fully understood. Here, we tried to investigate the mechanism of CSA to inhibit IL-17 production induced by IL-15 in CD4+ T cells. Synovial fluid and serum levels of IL-15 and IL-17 were determined by ELISA. CD4+ T cells from RA patients were treated with IL-15 in the presence of CSA or several signal inhibitors. The concentration of IL-17 in culture supernatants was measured by ELISA and IL-17 mRNA expression was determined by RT-PCR. NF-kappaB binding activity for IL-17 transcription was assessed by electrophoretic mobility shift assay. IL-15 induced IL-17 production by CD4+ T cells in dose- and time-dependent manner. IL-15-stimulated IL-17 production and mRNA expression were inhibited by CSA in CD4+ T cells. Moreover PI3K/Akt inhibitor, NF-kappaB inhibitor, and FK506 significantly inhibited IL-15-induced IL-17 production in CD4+ T cells. Inhibition studies revealed the requirement of PI3K/Akt and NF-kappaB signal pathway for IL-15-induced IL-17 production. CSA down-regulated the phosphorylation of Akt and IkappaB. CSA inhibited binding of NF-kappaB to IL-17 promoter. The inhibitory effect of CSA on IL-15 induced IL-17 production partially depended on the increase in IL-10, since neutralizing anti-IL-10 antibodies were able to partially reverse this inhibition. CSA inhibits IL-17 production by CD4+ T cells and this effect is mediated by IL-15-activated NF-kappaB pathway in CD4+ T cells, which is possible mechanism of CSA in treating RA as NF-kappaB targeting strategy.

IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4+ T cells and stimulating the proliferation of memory CD4+ T cells. We investigated the pathogenic role of IL-23 in CD4+ T cells in mice lacking the IL-1R antagonist (IL-1Ra−/−), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra−/− mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1β further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4+ T cells of IL-1Ra−/− mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4+ T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-κB, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra−/− model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.

To investigate type II collagen (CII)-specific CD4+ T cell receptors involving in Collagen-induced arthritis (CIA) in DBA/1J mice as a model of rheumatoid arthritis in humans, TCR Vbeta usage in draining lymph nodes (dLNs) was assessed by flow cytometric analysis at 3, 5, and 8 weeks after bovine CII immunizations. In the early stage of CIA, the draining lymph node CD4+ T cells from CIA mice showed a higher proportion of CD4+ Vbeta3+ subsets compared with those from control mice. The CD4+ Vbeta3+ T cells were specifically and primarily expanded by antigen-specific stimulation in in vitro culture of dLNs lymphocytes and splenocytes from CIA mice. In addition, CII-reactive response was observed when CD4+ Vbeta3+ T cells were added to a non-responding T cell population. The adoptive transfer of CD4+ Vbeta3+ T cells produced exaggerated arthritis compared with that in the control group. Our results indicate that CD4+ Vbeta3+ T cells, which were selectively expanded in dLN of CIA mice, play a pivotal role in CIA pathogenesis.

We report a case of rapidly-progressive glomerulonephritis complicating Behcet's disease (BD). A 44-year-old male has suffered from recurrent oral ulcers and retinal vasculitis developed 2 years ago. He complained of abdominal pain and papulopustular skin lesions. Multiple ulcers were seen on the colon on colonoscopy. Routine renal work-up revealed heavy proteinuria and hematuria. Renal biopsy demonstrated crescentic glomerulonephritis. Most symptoms improved after steroid therapy, except for urinary abnormalities. At this point, intravenous monthly cyclophosphamide pulse therapy was undergone. After the sixth pulse therapy, proteinuria and hematuria were dramatically improved and renal function was well preserved.

Inflammatory mediators have been recognized as being important in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-17 is an important regulator of immune and inflammatory responses, including the induction of proinflammatory cytokines and osteoclastic bone resorption. Evidence for the expression and proinflammatory activity of IL-17 has been demonstrated in RA synovium and in animal models of RA. Although some cytokines (IL-15 and IL-23) have been reported to regulate IL-17 production, the intracellular signaling pathways that regulate IL-17 production remain unknown. In the present study, we investigated the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the regulation of IL-17 production in RA. Peripheral blood mononuclear cells (PBMC) from patients with RA (n = 24) were separated, then stimulated with various agents including anti-CD3, anti-CD28, phytohemagglutinin (PHA) and several inflammatory cytokines and chemokines. IL-17 levels were determined by sandwich enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction. The production of IL-17 was significantly increased in cells treated with anti-CD3 antibody with or without anti-CD28 and PHA (P0.05). Among tested cytokines and chemokines, IL-15, monocyte chemoattractant protein-1 and IL-6 upregulated IL-17 production (P0.05), whereas tumor necrosis factor-alpha, IL-1beta, IL-18 or transforming growth factor-beta did not. IL-17 was also detected in the PBMC of patients with osteoarthritis, but their expression levels were much lower than those of RA PBMC. Anti-CD3 antibody activated the PI3K/Akt pathway; activation of this pathway resulted in a pronounced augmentation of nuclear factor kappaB (NF-kappaB) DNA-binding activity. IL-17 production by activated RA PBMC is completely or partly blocked in the presence of the NF-kappaB inhibitor pyrrolidine dithiocarbamate and the PI3K/Akt inhibitor wortmannin and LY294002, respectively. However, inhibition of activator protein-1 and extracellular signal-regulated kinase 1/2 did not affect IL-17 production. These results suggest that signal transduction pathways dependent on PI3K/Akt and NF-kappaB are involved in the overproduction of the key inflammatory cytokine IL-17 in RA.

To the Editor: We found an error in our published article. Safe Re-administration of Tumor Necrosis Factor-alpha (TNFα) Inhibitors in Patients with Rheumatoid Arthritis or Ankylosing Spondylitis Who Developed Active Tuberculosis on Previous Anti-TNFα Therapy. J Korean Med Sci 2014; 29: 38-42. Corrected Notes of the Above Article. This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health and Welfare, Republic of Korea. (Grant No. HI10C2020) The authors have no conflicts of interest to disclose.