Distinct Urinary Metabolic Profile in Rheumatoid Arthritis Patients: A Possible Link between Diet and Arthritis Phenotype

OBJECTIVE: We undertook this study to investigate the discriminant metabolites in urine from patients with established rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and from healthy individuals. METHODS: Urine samples were collected from 148 RA patients, 41 SLE patients and 104 healthy participants. The urinary metabolomic profiles were assessed using 1H nuclear magnetic resonance spectroscopy. The relationships between discriminant metabolites and clinical variables were assessed. Collagen-induced arthritis was induced in mice to determine if a choline-rich diet reduces arthritis progression. RESULTS: The urinary metabolic fingerprint of patients with established RA differs from that of healthy controls and SLE patients. Markers of altered gut microbiota (trimethylamine-N-oxide, TMAO), and oxidative stress (dimethylamine) were upregulated in patients with RA. In contrast, markers of mitochondrial dysfunction (citrate and succinate) and metabolic waste products (p-cresol sulfate, p-CS) were downregulated in patients with RA. TMAO and dimethylamine were negatively associated with serum inflammatory markers in RA patients. In particular, patients with lower p-CS levels exhibited a more rapid radiographic progression over two years than did those with higher p-CS levels. The in vivo functional study demonstrated that mice fed with 1% choline, a source of TMAO experienced a less severe form of collagen-induced arthritis than did those fed a control diet. CONCLUSION: Patients with RA showed a distinct urinary metabolomics pattern. Urinary metabolites can reflect a pattern indicative of inflammation and accelerated radiographic progression of RA. A choline-rich diet reduces experimentally-induced arthritis. This finding suggests that the interaction between diet and the intestinal microbiota contributes to the RA phenotype.

Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate in patients with active rheumatoid arthritis

BACKGROUND/AIMS: The objective of this study was to determine the efficacy and safety of add-on therapy with certolizumab pegol (CZP) in active rheumatoid arthritis (RA) patients of a single ethnicity. METHODS: In this 24-week, phase 3, randomized, double-blind, placebo-controlled trial, eligible patients (n = 127) were randomized 2:1 to subcutaneous CZP + methotrexate (MTX; 400 mg at week 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo + MTX. RESULTS: At week 24, the American College of Rheumatology criteria for 20% (ACR20) response rate was significantly greater with CZP + MTX than with placebo (66.7% vs. 27.5%, p < 0.001). Differences in ACR20 response rates for CZP vs. placebo were significant from week 1 (p < 0.05) and remained significant through week 24. The CZP group reported significant improvement in physical function and disability compared to the placebo group (p < 0.001) at week 24, as assessed by Korean Health Assessment Questionnaire-Disability Index (KHAQ-DI). Post hoc analysis indicated that the proportion of patients who had ACR70 responses, Disease Activity Score 28 (DAS28) low disease activity, and DAS28 remission at week 24 was greater in CZP + MTX-treated patients who achieved a decrease in DAS28 ≥ 1.2 (43.8%) at week 4 than in nonresponders. Among 18 (22.2%) and 14 patients (35.0%) in CZP and placebo groups who had latent tuberculosis (TB), none developed active TB. Most adverse events were mild or moderate. CONCLUSIONS: CZP treatment combined with MTX in active RA patients with moderate to severe disease activity and an inadequate response to MTX resulted in rapid onset of efficacy, which is associated with better clinical outcome at week 24 and has an acceptable safety profile, especially in an intermediate TB-burden population.

MicroRNA-143 and -145 modulate the phenotype of synovial fibroblasts in rheumatoid arthritis

Fibroblast-like synoviocytes (FLSs) constitute a major cell subset of rheumatoid arthritis (RA) synovia. Dysregulation of microRNAs (miRNAs) has been implicated in activation and proliferation of RA-FLSs. However, the functional association of various miRNAs with their targets that are characteristic of the RA-FLS phenotype has not been globally elucidated. In this study, we performed microarray analyses of miRNAs and mRNAs in RA-FLSs and osteoarthritis FLSs (OA-FLSs), simultaneously, to validate how dysregulated miRNAs may be associated with the RA-FLS phenotype. Global miRNA profiling revealed that miR-143 and miR-145 were differentially upregulated in RA-FLSs compared to OA-FLSs. miR-143 and miR-145 were highly expressed in independent RA-FLSs. The miRNA-target prediction and network model of the predicted targets identified insulin-like growth factor binding protein 5 (IGFBP5) and semaphorin 3A (SEMA3A) as potential target genes downregulated by miR-143 and miR-145, respectively. IGFBP5 level was inversely correlated with miR-143 expression, and its deficiency rendered RA-FLSs more sensitive to TNFα stimulation, promoting IL-6 production and NF-κB activity. Moreover, SEMA3A was a direct target of miR-145, as determined by a luciferase reporter assay, antagonizing VEGF165-induced increases in the survival, migration and invasion of RA-FLSs. Taken together, our data suggest that enhanced expression of miR-143 and miR-145 renders RA-FLSs susceptible to TNFα and VEGF165 stimuli by downregulating IGFBP5 and SEMA3A, respectively, and that these miRNAs could be therapeutic targets.

Identification of novel urinary biomarkers for assessing disease activity and prognosis of rheumatoid arthritis

To optimize treatment for rheumatoid arthritis (RA), it is ideal to monitor the disease activity on a daily basis because RA activity fluctuates over time. Urine can be collected routinely at home by patients. Recently, we identified four urinary biomarker candidates—gelsolin (GSN), orosomucoid (ORM)1, ORM2 and soluble CD14 (sCD14)—in RA patients through transcriptomic and proteomic studies. Here, we investigated the clinical significance of the aforementioned urinary biomarker candidates in a prospective manner. For the first time, we found that urinary ORM1, ORM2 and sCD14 levels, but not GSN, were elevated in RA patients and had a positive correlation with the status of the disease activity. In particular, urine tests for ORM 1, ORM 2 and sCD14 efficiently represented the presence of high RA activity without the need for measuring blood markers. In a parallel study, a more rapid radiographic progression over 3 years was observed in patients with higher ORM2 levels. Combined measurements of urinary ORM2 and serum C-reactive protein synergistically increased the predictability of the radiographic progression of RA (odds ratio: 46.5). Collectively, our data provide evidence that blood-free, urinary biomarkers are promising surrogates for assessing disease activity and prognosis of RA. We anticipate that our urinary biomarkers will provide novel candidates for patient-driven measurements of RA activity at home and can shift the paradigm from blood to urine testing in the assessment of RA activity and prognosis in hospitals.

Preventive Efficacy and Safety of Rebamipide in Nonsteroidal Anti-Inflammatory Drug-Induced Mucosal Toxicity

BACKGROUND/AIMS: The use of proton pump inhibitors or misoprostol is known to prevent the gastrointestinal complications of nonsteroidal anti-inflammatory drugs (NSAIDs). Rebamipide is known to increase the mucosal generation of prostaglandins and to eliminate free oxygen radicals, thus enhancing the protective function of the gastric mucosa. However, it is unknown whether rebamipide plays a role in preventing NSAID-induced gastropathy. The aim of this study was to determine the effectiveness of rebamipide compared to misoprostol in preventing NSAID-induced gastrointestinal complications in patients requiring continuous NSAID treatment. METHODS: We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 microg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy. RESULTS: Of the 479 patients in the study, 242 received rebamipide, and 237 received misoprostol. Ultimately, 44 patients (18.6%) withdrew from the misoprostol group and 25 patients (10.3%) withdrew from the rebamipide group. There was a significant difference in withdrawal rate between the two groups (p=0.0103). The per protocol analysis set was not valid because of the dropout rate of the misoprostol group; thus, the intention to treat (ITT) analysis set is the main set for the efficacy analysis in this study. After 12 weeks, the occurrence rate of gastric ulcers was similar in the rebamipide and misoprostol groups (20.3% vs 21.9%, p=0.6497) according to ITT analysis. In addition, the therapeutic failure rate was similar in the rebamipide and misoprostol groups (13.6% vs 13.1%, p=0.8580). The total severity score of the gastrointestinal symptoms was significantly lower in the rebamipide group than in the misoprostol group (p=0.0002). The amount of antacid used was significantly lower in the rebamipide group than in the misoprostol group (p=0.0258). CONCLUSIONS: Rebamipide can prevent gastric ulcers when used with NSAIDs and can decrease the gastrointestinal symptoms associated with NSAID administration. When the possibility of poor compliance and the potential adverse effects of misoprostol are considered, rebamipide appears to be a clinically effective and safe alternative.

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)

Spontaneous Remission of Hodgkin's Lymphoma in a Patient with Systemic Lupus Erythematosus after Withdrawal of Methotrexate

Methotrexate is often used in patients with systemic lupus erythematosus for effective disease controlsand steroid-sparing, and has been known to involve the development of lymphoproliferative disorders for patients with autoimmune diseases. We report a case of spontaneous regression of Epstein-Barr virus-positive methotrexate-associated Hodgkin's lymphoma in a 24-year-old woman with systemic lupus erythematosus. Following 6 months of treatment with low-dose methotrexate, the patient developed a neck mass in the right submandibular area. A computed tomography scan of the neck, chest and abdomen revealed multiple enlarged lymph nodes. Excisional biopsy of the neck masses confirmed infiltrations of malignant lymphoid cells that were positive for CD15, CD30, and Epstein-Barr virus-encoded RNA. Reduction of the mass was observed 3 weeks after withdrawing from the methotrexate treatment. At 7 months after initial presentation, computed tomography revealed near-complete regression of lymphadenopathy. After 30 months, the patient was still in complete clinical remission.

Reactive oxygen species regulate context-dependent inhibition of NFAT5 target genes

The activation of nuclear factor of activated T cells 5 (NFAT5), a well-known osmoprotective factor, can be induced by isotonic stimuli, such as activated Toll-like receptors (TLRs). It is unclear, however, how NFAT5 discriminates between isotonic and hypertonic stimuli. In this study we identified a novel context-dependent suppression of NFAT5 target gene expression in RAW 264.7 macrophages stimulated with lipopolysaccharide (LPS) or a high salt (NaCl) concentration. Although LPS and NaCl both used NFAT5 as a core transcription factor, these stimuli mutually inhibited distinct sets of NFAT5 targets within the cells. Although reactive oxygen species (ROS) are essential for this inhibition, the source of ROS differed depending on the context: mitochondria for high salt and xanthine oxidase for TLRs. Specifically, the high salt-induced suppression of interleukin-6 (IL-6) production was mediated through the ROS-induced inhibition of NFAT5 binding to the IL-6 promoter. The context-dependent inhibition of NFAT5 target gene expression was also confirmed in mouse spleen and kidney tissues that were cotreated with LPS and high salt. Taken together, our data suggest that ROS function as molecular sensors to discriminate between TLR ligation and osmotic stimuli in RAW 264.7 macrophages, directing NFAT5 activity toward proinflammatory or hypertonic responses in a context-dependent manner.

Role of placenta growth factor in cancer and inflammation

Accumulating evidences have documented that angiogenesis is closely linked to inflammation and regulators of angiogenesis play key roles in various inflammatory conditions. PlGF is an angiogenic protein belonging to the VEGF family and is upregulated mainly in pathologic conditions. Recently, PlGF was discovered having a proinflammatory role in inflammatory arthritis and its serum level drew attention not only as a useful surrogate biomarker but also a potential therapeutic target in atherosclerosis and various cancers. Particularly, PlGF has attractive clinical values because endogenous PlGF is redundant for vascular development and physiological vessel maintenance in healthy adults. However, there have been conflicting results about the efficacy of PlGF inhibition depending on the experimental and clinical settings. Further close investigations for resolving the puzzle of PlGF biology are required.

Diabetic Cheiroarthropathy / 대한류마티스학회지

No abstract available.

Intracranial Hypotension with Spontaneous CSF Leakage in a Patient with Systemic Lupus Erythematosus / 대한류마티스학회지

Headaches are not only one of the 19 different neuropsychiatric syndromes in SLE but also the most common chief complaint of patients with neuropsychiatric lupus. Approximately 50% of patients with SLE are presumed to have neuropsychiatric phenomena during their illness. There're no specific serological, radiological or histological biomarkers to confirm the clinical diagnosis of neuropsychiatric lupus. Therefore, physicians tend to try controlling lupus activity especially when the origins of the headache in patients with lupus are difficult to define. However, neuropsychiatric lupus can only be diagnosed after excluding other causes which is the point. A 47-year-old woman with lupus presented to the emergency department with the sudden onset of postural headache with nausea and vomiting. Through CSF tapping and CT myelography, intracranial hypotension with spontaneous CSF leakage was revealed. Her symptoms promptly improved after therapy using an epidural blood patch. Intracranial hypotension with spontaneous CSF leakage is rare disease, and it has never been reported in patients with SLE before. This case emphasizes the importance of finding out the origin of a headache in patients with lupus.

Cutaneous Leg Ulcer Mimicking Pyoderma Gangrenosum in Patient with Secondary Antiphospholipid Syndrome / 대한류마티스학회지

Antiphospholipid syndrome(APS) is characterized by vascular thrombosis in association with elevated titers of antiphospholipid antibodies. Leg ulcers are a considered to be a cutaneous manifestation of APS due to thrombosis of small to medium sized vessels. We report a case of necrotic non-healing, ankle ulcers mimicking pyoderma gangrenosum associated with APS in 50-year-old man. He had a past history of autoimmune thrombocytopenia and cerebral infarction. Laboratory findings showed a circulating lupus anticoagulant, positive anticardiolipin antibodies as well as anti-dsDNA and anti-Sm antibodies. Skin biopsy of ulcer lesions showed thrombotic vasculopathy of medium sized vessels with minimal leukocyte infiltration. Ulcers were successfully treated with surgical debridement and subsequent skin graft along with anticoagulation therapy.

A Case of Bronchioloalveolar Carcinoma Presenting Adult-onset Still's Disease-like Manifestations due to Paraneoplastic Syndrome / 대한류마티스학회지

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with the characteristics of high spiking fever, evanescent salmon-colored skin rash, arthralgia or arthritis, lymphadenopathy, hepato-splenomegaly, sore throat, leukocytosis, negative autoantibody and hyperferritinemia. There are reports that rheumatic diseases such as dermatomyositis, polymyositis, hypertrophic osteoarthropathy, and polymyalgia rheumatica are associated with neoplasms. And small cell lung cancer, thymoma, lymphoma, leukemia, and breast cancer are known to be more associated with paraneoplastic syndromes mimicking rheumatic diseases. We experienced a case with bronchioloalveolar carcinoma who developed clinical manifestations of AOSD. Although there are several reports that AOSD is associated with paraneoplastic syndrome, to our knowledge, this is the first case of bronchioloalveolar carcinoma mimicking AOSD reported in the world.

Clinical Characteristics of the Lung Involvement in Korean Patients with Inflammatory Myositis / 대한류마티스학회지

OBJECTIVE: To investigate the clinical manifestation and prognostic factors of interstitial lung disease (ILD) in Korean patients with idiopathic inflammatory myopathies include with polymyositis (PM) and dermatomyositis (DM). METHODS: Clinical and laboratory data of 110 patients with PM/DM in our rheumatology clinic were investigated. Clinical data including history, medication, pulmonary function tests (PFT) findings, radiologic findings, and labaratory findings were obtained from medical records at the first diagnosis of ILD with PM/DM. ILD was diagnosed on the basis of the imaging abnormalities defined above on definite findings of chest X-rays and high resolution computed tomography (HRCT), restrictive changes on PFT with respiratory symptoms. During the course of treatment, we assessed chest radiograph and HRCT findings. RESULTS: Forty-two PM/DM patients (38.2%) developed ILD. Anti-extracellular nuclear antigen (ENA) antibody, anti-Jo-1 antibody and ground glass opacity in HRCT were significantly high in PM-ILD. However honeycoomb appearance (53% : 22%) and fibrosis (41% : 6%) in HRCT were significantly high in DM-ILD. Interest in aspects of prognosis including initial steroid treatment response in HRCT were favorable in PM-ILD. There were statistically significant association between normal level of CPK and usual interstitial pneumonia (UIP) pattern in HRCT in DM-ILD. Such cases had resistance to steroid therapy. Overall interval between steroid and immunosuppressant therapy was significantly shorter in those with DM-ILD. CONCLUSION: The clinical manifestations between PM-ILD and DM-ILD in Korean patients were not significant different from those of other populations. DM-ILD is more refractory to steroid treatment, expecting in poor prognosis compared with PM-ILD. So immediate intensive immunosuppressive therapy should be considered in DM-ILD.

Expression of CCR2A, an isoform of MCP-1 receptor, is increased by MCP-1, CD40 ligand and TGF-beta in fibroblast like synoviocytes of patients with RA

Cytokine and chemokine receptors play a key role in inflammation caused by rheumatoid arthritis (RA). Two isoforms of human CC chemokine receptor R2 (CCR2), the receptor of monocyte chemoattractant protein 1 (MCP-1), have been identified but their relative expression in fibroblast-like synoviocytes (FLS) and their contribution to inflammatory responses mediated by MCP-1 or inflammatory cytokines in patients with RA remain uncertain. We examined the pattern of expression of two CCR2 isoforms upon stimulation by proinflammatory cytokines and CD40 ligation. FLS were prepared from the synovial tissues of RA patients and cultured in the presence of MCP-1, soluble CD40 ligand (sCD40L), TGF-beta, IL-1beta, IL-18, IL-15, and LPS. CCR2A and CCR2B expression was examined by immunohistochemistry, RT-PCR and western blot analysis. IL-15, TNF-alpha and MCP-1 production was determined by ELISA. Immunohistochemistry showed that CCR2A is highly expressed in RA synovium compared with OA synovium. Transcripts of both CCR2A and CCR2B were detected in FLS. Exogenous MCP-1, CD40L, TGF-beta, and IL-15 significantly increased the expression of CCR2A but not CCR2B. Exposure of FLS to sCD40L caused strong upregulation of CCR2A but not of CCR2B protein expression. MCP-1 increased the proliferation of FLS and the production of IL-15, TNF-alpha, and IL-18. Because CCR2A is the main target of regulation by cytokines and CD40 ligation, the relatively higher expression of CCR2A on the cell surface suggests that this isoform of MCP-1 receptor functions as the principal mediator of inflammatory signals in RA FLS.

Expression and Function of Plexin A1 in Rheumatoid Synoviocytes / 대한류마티스학회지

Objective: To investigate the expression and function of plexin A1, a transmembrane protein involving cell survival and cell-to cell interaction, in the rheumatoid synoviocytes. Methods: Immunohistochemical staining using anti-plexin A1 antibody was performed in the synovium of rheumatoid arthritis (RA) patients. The plexin A1 expression in cultured fibroblast-like synovioytes (FLS) was also examined by Western blot analysis and immunocytochemistry. Cell viability was determined by CCK-8 assay. Deficiency of plexin A1 was established by the method of short interfering RNA (siRNA). The productions of interleukin-6 (IL-6) and monocytes chemotactic protein-1 (MCP-1) were measured in culture supernatants by ELISA. Results: Plexin A1 was highly expressed in the lining layer of synovium and cultured FLS of RA patients. In RA FLS, basal expression of plexin A1 was higher than osteoarthritis FLS. On immunocytochemical staining, plexin A1 was co-expressed with neuropilin-1 in RA FLS. Semaphorin 3A (10 to 200 ng/mL), a specific ligand for neuropilin-1/plexin A1 complex, did not affect viability of RA FLS. The down regulation of plexin A1 mRNA by siRNA did not cause cell death, either. Co-culture of FLS with RA T cells, isolated from peripheral blood or synovial fluid, caused an increase in the productions of IL-6 and MCP-1 from FLS, but which were blocked by down-regulating plexin A1 transcripts using siRNA method. Conclusion: These data suggest that enhanced expression of plexin A1 in RA FLS may elicit over-production of IL-6 and MCP-1, and thereby contribute to perpetuation of chronic inflammation in RA.

Discrepancy between the Tuberculin Skin Test and the T-SPOT.TB for Detecting Latent Mycobacterium tuberculosis Infection in Patients with Rheumatoid Arthritis / 대한류마티스학회지

OBJECTIVE: To evaluate concordance rate between tuberculin skin test (TST) and T-SPOT.TB (T-SPOT) for detecting latent tuberculosis in patients with rheumatoid arthritis (RA) received disease modifying antirheumatic drugs (DMARDs) and/or immunosuppressant. METHODS: Fifty four patients with RA refractory to conventional DMARDs and planned ahead to be received tumor necrosis factor-alpha (TNF-alpha) blockade were enrolled in this study. The TST was performed by Mantoux method. Over 10 mm induration size was considered to be positive in the TST. The peripheral blood were collected from all patients and used for the T-SPOT. RESULTS: Only six patients (11.11%) had a positive TST, and 48 patients (88.89%) had a negative TST. The mean TST values were 13.51+/-3.51 mm (range: 10~19 mm) in TST (+) group and 2.50+/-3.12 mm (range: 0~9 mm) in TST (-) group, respectively. T-SPOT was indeterminate in 7 patients (12.96%). Twenty-five patients (53.19%) had a positive result, and 22 patients (46.81%) had a negative result in 47 patients determinated with T-SPOT. There was poor overall agreement between results of TST and T-SPOT (p=0.194). CONCLUSION: There was no concordance between TST and T-SPOT in patients with RA received DMARDs and/or immunosuppressant. Therefore, the results of TST should be interpreted with caution, taking into consideration of the result of T-SPOT in patients with RA who are prone to having false negative of TST.

Elevated Serum Osteoprotegerin Levels in Systemic Lupus Erythematosus / 대한류마티스학회지

OBJECTIVE: To determine the serum levels of soluble osteoprotegerin (OPG), decoy receptor of receptor activator of nuclear factor kB ligand (RANKL), in patients with systemic lupus erythematosus (SLE) and to assess the its relationships with certain clinical manifestations. METHODS: Serum levels of OPG in 60 patients with SLE and 30 healthy controls were determined by enzyme-linked immunosorbent assay. At the time of serum sampling, clinical manifestations and lupus disease activity index (SLEDAI) were assessed. RESULTS: Serum levels of OPG in 60 patients with SLE were significantly higher than in 30 healthy controls (1,058+/-699 versus 806+/-113 pg/mL, p=0.008). Patients with active disease had higher levels of OPG levels than those with inactive disease (1,355+/-837 versus 760+/-113 pg/mL, p<0.001). Serum OPG levels correlated with SLEDAI (gamma=0.588, p<0.0001), anti-dsDNA antibody titers (gamma=0.337, p=0.009) and serum MCP-1 levels (gamma=0.485, p<0.0001). In particular, serum OPG levels were found to be significantly increased in patients with neurological manifestation compared to those without (1,504+/-1,152 versus 918+/-376 pg/mL, p=0.004). CONCLUSION: The results of this study suggest that serum OPG levels are increased in patients with SLE. Serum OPG has a role as marker for disease activity and its increased levels reflect the involvement of neurological manifestation.

Expression and Function of Calcineurin in Inflammatory Arthritis

BACKGROUND: Calcineurin plays a crucial role in T cell activation, cell growth, apoptosis, and angiogenesis, and its over-expression has been implicated in the pathogenesis of cardiomyopathy and stroke. However, the expression and function of calcineurin in the pathologic lesion of chronic inflammatory diseases, like rheumatoid synovium, remain to be defined. This study was aimed to determine the role of calcineurin in inflammatory arthritis and investigate the expression and function of calcineurin in the rheumatoid synovium and synoviocytes, the actual site of chronic inflammation. METHODS: Immunohistochemical staining using specific antibody to calcineurin was perfomed in the synovium of rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients were isolated from RA and OA patients, and cultured with IL-1beta and TNF-alpha in the presence or absence of cyclosporin A, a calcineurin inhibitor. The calcineurin expression was assessed by phosphatase assay and Western blotting analysis. IL-6, -10, -17, matrix metalloproteinase (MMP)-1, -2, -3, and -9 released into the culture supernatants were measured by ELISA. After transfection with GFP-Cabin 1 gene into synoviocytes, the levels of IL-6 and MMPs were measured by ELISA. RESULTS: Calcineurin was highly expressed in the lining layer of synovium and cultured synoviocytes of RA patients. The elevated calcineurin activity in the rheumatoid synoviocytes was triggered by proinflammatory cytokines such as IL-1beta and TNF-alpha. In contrast, IL-10, an anti-inflammatory cytokine, failed to increase the calcineurin activity. The targeted inhibition of calcineurin by the over-expression of Cabin 1, a natural calcineurin antagonist, inhibited the production of IL-6 and MMP-2 by rheumatoid synoviocytes in a similar manner to the calcineurin inhibitor, cyclosporin A. CONCLUSION: These data suggest that abnormal activation of calcineurin in the synoviocytes may contribute to the pathogenesis of chronic arthritis, and thus provide a potential target for controlling inflammatory arthritis.

A Case of Systemic Sclerosis Developed after Autologous Hematopoietic Stem Cell Transplantation in the Patient with Multiple Sclerosis / 대한혈액학회지

Herein, the case of a 43-year-old woman, with a relapsing-remitting variant of multiple sclerosis (MS), which began when she was 34 years of age, and gave rise to severe neurological complications, including progressive paralysis in both legs and visual deterioration, is reported. Despite heavy immunomodulatory treatment, her condition relapsed and became aggravated. At this point, the decision was made to perform autologous hematopoietic stem cell transplantation (HSCT). The enrichment of CD34+ cells was followed by depletion of the peripheral T cells. The post-transplantation course was uneventful, and autoimmune thrombocytopenia developed within 7 months of the HSCT. The patient was treated with cyclosporine (CsA) and oral prednisolone, but subsequently developed systemic sclerosis (SSc). The administration of CsA following the syngeneic/autologous HSCT caused a T lymphocyte-dependent autoimmune disease, which resembled graft-versus-host disease (GVHD). It is quite probable the auto-reactive lymphocytes, which were paradoxically elicited by the CsA during the reconstitution of the immune system, partly contributed to the occurrence of the other autoimmune disease, SSc. To our knowledge, this is the first description of a MS patient, having undergone CD34+-selected autologous HSCT followed by the administration of CsA, who subsequently developed SSc.