S100A8 and S100A9 are major leukocyte proteins, known as damage-associated molecular patterns, found at high concentrations in the synovial fluid of patients with rheumatoid arthritis (RA). A heterodimeric complex of S100A8/A9 is secreted by activated leukocytes and binds to Toll-like receptor 4, which mediates downstream signaling and promotes inflammation and autoimmunity. Serum and synovial fluid levels of S100A8/A9 are markedly higher in patients with RA than in patients with osteoarthritis or miscellaneous inflammatory arthritis. Serum levels of S100A8/A9 are significantly correlated with clinical and laboratory markers of inflammation, such as C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, and the Disease Activity Score for 28 joints. Significant correlations have also been found between S100A8/A9 and radiographic and clinical assessments of joint damage, such as hand radiographs and the Rheumatoid Arthritis Articular Damage score. In addition, among known inflammatory markers, S100A8/A9 has the strongest correlation with total sum scores of ultrasonography assessment. Furthermore, baseline levels of S100A8/A9 are independently associated with progression of joint destruction in longitudinal studies and are responsive to change during conventional and biologic treatments. These findings suggest S100A8/A9 to be a valuable diagnostic and prognostic biomarker for RA.
Arthritis, Rheumatoid/*blood/pathology/radiography ; Arthrography ; Biological Markers/blood ; Calgranulin A/*blood ; Calgranulin B/*blood ; Humans ; Joints/pathology ; Synovial Fluid/metabolism

OBJECTIVES: To analyze arthritic manifestations in Behcet disease, which is one of the most common manifestations of Behcet disease. METHODS: Among the patients who visited the Rheumatology Division, Keimyung University Dongsan Medical Center, Taegu, Korea from March 1997 to February 1998, 35 patients, with more than 3 months follow-up, were compatible for the diagnosis of Behcet disease according to the Shimizu criteria, after exclusion of uncertain or possible Behcet cases. The presence of various manifestations was evaluated. Regarding the joint manifestations, the involved joint, signs and the pattern of the articular symptoms were examined. Basic laboratory tests, HLA studies and simple radiologic studies were done. RESULTS: All 35 patients had evident, recurrent, painful oral ulcers by the study definition. Genital ulcers were found in 29%, skin lesions in 77%, uveitis in 9%, gastrointestinal ulcerations in 6% and vascular manifestations in 6%. Joint manifestations appeared in 97%. Knee(91%), proximal interphalangeal (53%) and metacarpophalangeal joints(21%) were the main sites. Tenderness was prominent in 91% and swelling in 44%. Polyarticular presentation was found in 47%. In most cases (76.4%), the articular symptom was short-lasting. C-reactive protein was likely to be positive in active Behcet disease. HLA B51 was positive in 46%. CONCLUSIONS: In Behcet disease, various manifestations can be found. The arthritic manifestation seems quite common. It may present as seronegative rheumatoid arthritis. Otherwise, it may present as palindromic rheumatism.
Adult ; Arthritis, Rheumatoid/diagnosis* ; Arthritis, Rheumatoid/blood ; Behcet's Syndrome/diagnosis* ; Behcet's Syndrome/blood ; C-Reactive Protein/metabolism ; Comparative Study ; Diagnosis, Differential ; Female ; Human ; Joints/pathology ; Male ; Middle Age ; Rheumatic Diseases/diagnosis* ; Rheumatic Diseases/blood

BACKGROUND: Interleukin-17 (IL-17)-producing T helper (Th) 17 cells are considered as a new subset of cells critical to the development of rheumatoid arthritis (RA). We aimed to investigate the distribution of Th1 and Th17 cells and their association with disease activity, and determine the Th17-related cytokine levels in the peripheral blood of RA patients. METHODS: Peripheral blood mononuclear cells from 55 RA and 20 osteoarthritis (OA) patients were stimulated with mitogen, and the distributions of CD4+Interferon (INF)+IL-17- (Th1 cells) and CD4+INF-IL-17+ (Th17 cells) were examined by flow cytometry. Serum levels of IL-6, IL-17, IL-21, IL-23, and tumor necrosis factor (TNF)-alpha were measured by ELISA. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were recorded. The 28-joint disease activity score (DAS28) was also assessed. RESULTS: The median percentage of Th17 cells was higher in RA patients than in OA patients (P=0.04), and in active than in inactive RA (P=0.03), whereas that of Th1 cells was similar in both groups. Similarly, the levels of IL-17, IL-21, and IL-23 were detected in a significantly higher proportion of RA patients than OA patients and the frequencies of detectable IL-6, IL-17, and IL-21 were higher in active RA than in inactive RA group. The percentage of Th17 cells positively correlated with the DAS28, ESR, and CRP levels. CONCLUSIONS: These observations suggest that Th17 cells and Th17-related cytokines play an important role in RA pathogenesis and that the level of Th17 cells in peripheral blood is associated with disease activity in RA.
Adult ; Aged ; Arthritis, Rheumatoid/blood/metabolism/*pathology ; Blood Sedimentation ; C-Reactive Protein/analysis ; Cytokines/blood ; Female ; Humans ; Male ; Middle Aged ; Osteoarthritis/blood/metabolism/pathology ; Severity of Illness Index ; Th1 Cells/cytology/immunology/metabolism ; Th17 Cells/*cytology/immunology/metabolism

OBJECTIVETo determine the levels of CC chemokine ligand 5 (CCL5) in serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and their relations with disease activity and medication.

METHODSCCL5 in serum and SF was quantified by enzyme-linked immunosorbent assay (ELISA) in 28 RA patients and 21 osteoarthritis (OA) patients. In RA patients, the correlations of CCL5 levels in serum and SF with disease activity were analyzed. Meanwhile, the serum CCL5 levels among RA patients treated with disease-modifying antirheumatic drugs (DMARDs), Tripterygium Glucosides, and other Chinese herbs without disease-modifying effects were also compared.

RESULTSCCL5 levels in both serum and SF of RA patients were significantly higher than those of OA patients (P < 0.05). Moreover, the level of CCL5 was higher in SF than that in serum of RA patients (P < 0.01). Serum CCL5 level was correlated significantly with the number of swollen joints (r = 0.3329, P < 0.05), erythrocyte sedimentation rate (r = 0.4001, P < 0.05), and C reactive protein (r = 0.3735, P < 0.01). In addition, the level of CCL5 had a trend of lower in patients treated with DMARDs or Tripterygium Glucosides than those treated with other Chinese herbs, although the difference was not significant among those patients due to the small number of patients in each group.

CONCLUSIONSIn RA patients, the expression of CCL5 increases and correlates with some clinical and laboratory parameters of RA, which indicate that CCL5 plays an important role in RA and may serve as a useful marker of disease activity. DMARDs and Tripterygium Glucosides might exert their clinical effects through reducing CCL5 production in RA.

Adult ; Aged ; Arthritis, Rheumatoid ; blood ; drug therapy ; metabolism ; pathology ; Blood Sedimentation ; C-Reactive Protein ; metabolism ; Chemokine CCL5 ; analysis ; blood ; Female ; Humans ; Joints ; pathology ; Male ; Middle Aged ; Osteoarthritis ; blood ; metabolism ; Synovial Fluid ; metabolism ; Young Adult

Oxidative stress such as reactive oxygen species (ROS) within the inflamed joint have been indicated as being involved as inflammatory mediators in the induction of arthritis. Correlations between extracellular-superoxide dismutase (EC-SOD) and inflammatory arthritis have been shown in several animal models of RA. However, there is a question whether the over-expression of EC-SOD on arthritic joint also could suppress the progression of disease or not. In the present study, the effect on the synovial tissue of experimental arthritis was investigated using EC-SOD over-expressing transgenic mice. The over-expression of EC-SOD in joint tissue was confirmed by RT-PCR and immunohistochemistry. The degree of the inflammation in EC-SOD transgenic mice was suppressed in the collagen-induced arthritis model. In a cytokine assay, the production of pro-inflammatory cytokines such as, IL-1beta, TNFalpha, and matrix metalloproteinases (MMPs) was decreased in fibroblast-like synoviocyte (FLS) but not in peripheral blood. Histological examination also showed repressed cartilage destruction and bone in EC-SOD transgenic mice. In conclusion, these data suggest that the over-expression of EC-SOD in FLS contributes to the activation of FLS and protection from joint destruction by depressing the production of the pro-inflammatory cytokines and MMPs. These results provide EC-SOD transgenic mice with a useful animal model for inflammatory arthritis research.
Animals ; Arthritis, Experimental/blood/*enzymology/metabolism ; *Arthritis, Rheumatoid/enzymology/pathology ; Fibroblasts/metabolism ; Gene Expression Regulation ; Inflammation/pathology ; Interleukin-1beta/blood/metabolism ; Joints/enzymology/pathology ; Matrix Metalloproteinases/blood/metabolism ; Mice ; Mice, Transgenic ; Reactive Oxygen Species/metabolism ; *Superoxide Dismutase/genetics/metabolism ; Synovial Fluid/*enzymology ; Synovial Membrane/pathology

OBJECTIVETo observe the effect of electro-acupuncture (EA) on tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in peripheral blood and joint synovia in patients with rheumatoid arthritis (RA) to verify the clinical efficacy of EA.

METHODSAdopting randomized controlled principle, the 63 RA patients enrolled were assigned to two groups, the 32 patients in the EA group were treated with EA, and the 31 patients in the simple needling (SN) group treated with simple needling. According to the integral-local combining method, the acupoints were selected mainly from yang-meridian and local Ashi points (pain-point). EA or SN was applied every other day, 10 times as a course, and each patient received a total of 3 courses of treatment.

RESULTSBlood and synovial levels of TNF-α and VEGF were reduced significantly after treatment in both groups. The lowering (absolute value and difference value) of TNF-α as well as the absolute value of VEGF, either in blood or in synovia, were similar in the two groups (P>0.05); but the lowering of VEGF after treatment was more significant in the EA group than that in the SN group (P<0.05).

CONCLUSIONEA could effectively lower the contents of TNF-α and VEGF in peripheral blood and joint synovia to improve the internal environment for genesis and development of RA, so as to enhance the clinical therapeutic effectiveness.

Adolescent ; Adult ; Aged ; Arthritis, Rheumatoid ; blood ; therapy ; Electroacupuncture ; adverse effects ; methods ; Female ; Humans ; Joints ; pathology ; Male ; Synovial Fluid ; metabolism ; Treatment Outcome ; Tumor Necrosis Factor-alpha ; blood ; metabolism ; Vascular Endothelial Growth Factor A ; blood ; metabolism ; Young Adult

Rheumatoid arthritis (RA) is an autoimmune disease involving the synovial membrane of peripheral joints. T cells specific for self antigens may play a critical role. Identification of T cell receptors (TCR) of such specific T cell clones is very important for treatment, prevention and identification of relevant autoantigens. To identify specific T cells, TCR V beta family repertoire and the clonal expansion of T cells were analyzed in this study. The percentage of V beta 5+ or V beta 8+ cells in the synovial fluid mononuclear cells (SFMCs) was similar to that in the peripheral blood mononuclear cells (PBMCs). However, the percentage of DR+ T cells in the SFMCs was higher (p< 0.01). Analyzing the clonality of T cells in 8 V beta families (V beta 1, V beta 5, V beta 8, V beta 14, V beta 16, V beta 17, V beta 18, V beta 20), clonal expansions in CD8+ T cells from the SFMCs were found more frequently than in the PBMCs. The patterns of clonal expansions were discrepant between the SFMCs and the PBMCs even in the same patient, which suggests several inflamed tissue specific T cell clonal expansions in the SFMCs. These T cell clones might be activated by autoantigens which are not identified yet and responsible for the RA pathogenesis.
Arthritis, Rheumatoid/*metabolism/pathology ; Base Sequence ; Blood Cells/*metabolism ; Clone Cells ; Female ; Human ; Male ; Molecular Probes ; Molecular Sequence Data ; Polymerase Chain Reaction ; Receptors, Antigen, T-Cell/genetics/*metabolism ; Support, Non-U.S. Gov't ; Synovial Fluid/cytology/*metabolism ; T-Lymphocytes/*metabolism

PURPOSE: The function of regulatory B lymphocytes is known to be abnormal in inflammatory diseases. However, a recent study indicates that IL-10+ B cells seem to be expanded in rheumatoid arthritis (RA). Therefore, the state of IL-10+ B cells in the peripheral blood from RA patients and healthy controls were investigated. MATERIALS AND METHODS: CD19+ cells in peripheral blood mononuclear cells were purified from blood samples of RA patients and age and gender-matched healthy controls, and stimulated with CD40 ligand and CpG for 48 hours. Then, intracellular IL-10 in CD19+ cells was analyzed using flow cytometry. RESULTS: There was no significant difference in the proportion of IL-10+ B cells between 10 RA patients and 10 healthy controls (RA, 0.300+/-0.07 vs. healthy control 0.459+/-0.07, p=0.114). The proportion of induced IL-10+ B cells to total B cells in RA patients was significantly higher than those in controls (RA, 4.44+/-3.44% vs. healthy control 2.44+/-1.64%, p=0.033). However, the proportion of IL-10+ B cells to total B cells correlated negatively with disease activity in RA patients (r=-0.398, p=0.040). Erythrocyte sedimentation rate or C-reactive protein or medication was not associated with the proportion of IL-10+ B cells. CONCLUSION: The proportion of induced IL-10+ B cell increased in RA patients compared to healthy control, however, negatively correlated with disease activity in RA.
Adult ; Aged ; Antigens, CD19/metabolism ; Arthritis, Rheumatoid/blood/*immunology/pathology ; B-Lymphocytes, Regulatory/metabolism/*physiology ; Biological Markers/blood ; Female ; Humans ; Interleukin-10/metabolism ; Male ; Middle Aged ; Severity of Illness Index

OBJECTIVETo investigate the changes in the circulating levels of Treg cells in patients with rheumatoid arthritis (RA) and their associations with the disease activity.

METHODSThe fraction of circulating CD4+CD25+FOXP3+ Treg cells in 40 active RA patients and 40 healthy controls were determined by flow cytometry. The serum levels of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) were measured using enzyme-linked immunosorbent assay, and the expression of Foxp3 mRNA was detected with real-time PCR. The correlation of the changes in the fraction of Treg cells and the disease activity of RA was analyzed.

RESULTSRA patients showed a significantly lower level of circulating Treg cells than the control subjects [(5.36∓1.55)% vs (7.49∓1.46)%, P<0.01]. The expression of Foxp3 mRNA (P<0.01) and serum IL-10 level (P=0.000) were significantly lower, whereas TGF-β1 significantly higher (P=0.000) in RA patients than in the controls. Spearman analysis showed that serum level of IL-10 but not TGF-β1 was correlated to the fraction of Treg cells and Foxp3 mRNA expression, but the fraction of Treg cells was not correlated to such indices of disease activity as tender joint counts, swollen joint counts, visual analog scale, HAQ, disease activity score in 28 joints, ESR, or CRP, nor to RA self-antibodies (including RF and anti-CCP antibodies).

CONCLUSIONA lower fraction and dysfunction of circulating Treg cells might be involved in the pathologies of RA, and a higher disease activity is associated with a greater reduction of Treg cells.

Adult ; Aged ; Arthritis, Rheumatoid ; blood ; pathology ; physiopathology ; Blood Sedimentation ; CD4 Lymphocyte Count ; Case-Control Studies ; Female ; Flow Cytometry ; Forkhead Transcription Factors ; metabolism ; Humans ; Interleukin-10 ; blood ; Male ; Middle Aged ; T-Lymphocytes, Regulatory ; cytology ; Transforming Growth Factor beta1 ; blood

Macrophage activation syndrome (MAS) is a rare and potentially fatal complication of rheumatic disorders in children. We describe a 13-month-old boy in whom MAS developed as a complication of systemic juvenile rheumatoid arthritis (S-JRA). He suffered from fever and generalized rash followed by multiple joints swelling for four months before admission. Physical examination revealed cervical lymphadenopathy and hepatosplenomegaly. Laboratory findings were: abnormal liver enzymes, increased triglyceride and ferritin levels, coagulopathies resembling disseminated intravascular coagulation, anemia and thrombocytopenia. Hyperplasia of hemophagocytic macrophages was remarkable in his bone marrow. Methylprednisolone and cyclosporin therapy resulted in clinical and laboratory improvements. This is the third case of MAS associated with S-JRA in Koreans, and the first one, in which hemophagocytic macrophages were proven in bone marrow.
Alanine Transaminase/metabolism ; Alkaline Phosphatase/metabolism ; Antigens, CD/blood ; Antigens, Differentiation, Myelomonocytic/blood ; Arthritis, Juvenile Rheumatoid/blood/*complications/pathology ; Aspartate Aminotransferases/metabolism ; Blood Cell Count ; Hepatomegaly/*etiology/pathology ; Humans ; Infant ; Liver/enzymology/pathology ; *Macrophage Activation ; Male ; Partial Thromboplastin Time ; Prothrombin Time ; Splenomegaly/*etiology/pathology ; Syndrome ; gamma-Glutamyltransferase/metabolism