INTRODUCTION: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are used in the diagnosis and prognostication of rheumatoid arthritis (RA). We wanted to determine the specific contributions of RF and ACPA to the biological nature of RA and whether they act synergistically. METHODS: We identified 731 patients from our prospective multi-ethnic RA cohort and categorised them into four groups: ACPA-positive, RF-positive, doubly positive and doubly negative. We compared the demographics, Disease Activity Score-28, Health Assessment Questionnaire score, quality of life using Short Form 36 and the use of prednisolone and disease-modifying antirheumatic drugs (DMARDs) of these patient groups. RESULTS: Four hundred and ninety-one patients (67.2%) were ACPA+RF+, 54 (7.4%) were ACPA+RF-, 82 (11.2%) were ACPA-RF+ and 104 (14.2%) were ACPA-RF-. Mean disease duration before the study entry was not different in the four groups. Patients with older age of onset were less likely to be positive for RF and ACPA. Fewer ACPA+RF+ patients were in remission compared to those in the other groups ( P < 0.05). Erythrocyte sedimentation rate (ESR) was higher at study entry in the ACPA+RF+ group (40.4 mm/h vs. 30.6-30.9 mm/h, P < 0.05). Prednisolone and number of DMARDs used were higher in the ACPA+RF+ group compared to the doubly negative group. There were no differences in the functional status and quality of life. CONCLUSIONS RA patients who were positive for both ACPA and RF had lower remission rate, higher baseline ESR and required more corticosteroid and DMARD treatment compared to those who were singly positive or doubly negative. Being doubly positive confers a worse outcome to RA patients.
Humans ; Arthritis, Rheumatoid/diagnosis* ; Male ; Female ; Middle Aged ; Rheumatoid Factor/blood* ; Anti-Citrullinated Protein Antibodies/blood* ; Adult ; Quality of Life ; Prospective Studies ; Antirheumatic Agents/therapeutic use* ; Aged ; Peptides, Cyclic/immunology* ; Prednisolone/therapeutic use* ; Surveys and Questionnaires ; Severity of Illness Index ; Prognosis

Objective To investigate the effects of hyaluronic acid and proteoglycan-linked protein 1 (HAPLN1) secreted by synovial fibroblasts (FLS) on the polarization of macrophages (Mϕ) in rheumatoid arthritis (RA). Methods Human monocytic leukemia cells (THP-1) were differentiated into Mϕ, which were subsequently exposed to recombinant HAPLN1 (rHAPLN1). RA-FLS were transfected separately with HAPLN1 overexpression plasmid (HAPLN1^OE) or small interfering RNA targeting HAPLN1 (si-HAPLN1), and then co-cultured with Mϕ to establish a co-culture model. The viability of Mϕ was assessed using the CCK-8 assay, and the proportions of pro-inflammatory M1-type and anti-inflammatory M2-type Mϕ were analyzed by flow cytometry. Additionally, the expression levels of inflammatory markers, including interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS), were quantified using quantitative real-time PCR and Western blot analysis. Results The viability of Mϕ was increased in the rHAPLN1 group compared to the control group. Furthermore, both the M1/Mϕ ratio and inflammatory factor levels were elevated in the rHAPLN1 and HAPLN1^OE groups. In contrast, the si-HAPLN1 group exhibited a decrease in the M1/Mϕ ratio and inflammatory factor expression. Notably, the introduction of rHAPLN1 in rescue experiments further promoted Mϕ polarization towards the M1 phenotype. Conclusion HAPLN1, secreted by RA fibroblast-like synoviocytes (RA-FLS), enhances Mϕ polarization towards the M1 phenotype.
Humans ; Arthritis, Rheumatoid/genetics* ; Macrophages/immunology* ; Fibroblasts/metabolism* ; Phenotype ; Extracellular Matrix Proteins/genetics* ; Proteoglycans/genetics* ; Synovial Membrane/cytology* ; Tumor Necrosis Factor-alpha/genetics* ; Interleukin-1beta/genetics* ; Nitric Oxide Synthase Type II/genetics* ; Cell Differentiation ; Coculture Techniques ; THP-1 Cells

OBJECTIVE: To investigate the serum level of lumican (LUM) and its clinical correlation with disease and immune activities in patients with rheumatoid arthritis (RA). METHODS: The serum LUM levels in both RA patients and health controls (HCs) were detected by enzyme-linked immunosorbent assay (ELISA). The clinical and laboratory data of the patients were collected. The LUM levels in the patients with different clinical features were analyzed. The correlation between the clinical data, laboratory parameters, and serum LUM levels were also analyzed. Independent samples t test, Spearman correlation were used for statistical analysis. Analysis of variance and Kruskal-Wallis test, the least significant difference (LSD)-t test and Bonferroni correction were used for statistical analysis. The Pearson Chi-square test was used for comparison of the rates between the groups. Statistical significance was set at P < 0.05. RESULTS: The levels of LUM were elevated in the RA patients than in the HCs (P < 0.000 1). Serum LUM levels were correlated with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), immunoglobulin A (IgA), titers of platelet (PLT) and 28-joint disease activity score (DAS28, all P < 0.05). Next, we compared the serum LUM levels in the RA patients with different characteristics, and no difference was found in serum LUM levels between early-RA and RA, the same to RA with different gender (P>0.05). The levels of serum LUM were elevated in the RF positive patients (P < 0.000 1), and in the RF and anti-CCP positive patients (P < 0.05) than in the RA patients with negative RF whether the anti-CCP was positive. In addition, no differences were found between the RA patients with negative RF whether the anti-CCP was positive (P>0.05). All the levels of serum LUM were elevated in the RA patients with different CRP or ESR than in the HCs (P < 0.05), and the serum LUM levels in the RA patients with elevated ESR and CRP were significantly elevated in those with normal ESR and CRP (P < 0.05). Additionally, the results demonstrated that serum LUM levels were positively associated with RA disease activity, and they were declined in RA sustained remission than those in middle or high disease activity (P < 0.05). Furthermore, no difference was found between the RA patients in remission and HCs (P>0.05). No differences were found in the RA patients with and without complications including interstitial pneumonia disease, Sjögren's syndrome, thyroid gland diseases and osteoporosis (P>0.05). The LUM positivity rates were significantly elevated in the RF positive patients than the RF negative patients in RA (P < 0.05). CONCLUSION LUM, a cyclocitrullinated protein, might be a promising biomarker which could reflect both disease activity and immune activity in RA.
Humans ; Arthritis, Rheumatoid/immunology* ; Lumican/blood* ; C-Reactive Protein/metabolism* ; Female ; Male ; Rheumatoid Factor/blood* ; Middle Aged ; Adult ; Chondroitin Sulfate Proteoglycans/blood* ; Blood Sedimentation ; Keratan Sulfate/blood* ; Enzyme-Linked Immunosorbent Assay ; Aged

OBJECTIVE: To investigate the clinical characteristics of rheumatoid arthritis (RA) patients with malignant tumor. METHODS: Retrospective summary was made of 1 562 in patients of RA from January 2011 to June 2017. In the study, 74 RA patients with malignant tumor were reviewed and analyzed, and the general conditions, tumor types, RA and tumor onset sequence, and the medication situation were analyzed. RESULTS: The incidence of malignant tumor in the patients with rheumatoid arthritis in our center was 4.16%. The 74 patients were complicated with malignant tumor, of whom 53 were female, and 21 male. The age of RA at presentation was (52.6±17.8) years. The average disease duration of malignant tumor was (63.4 ± 12.7) years. The onset time of rheumatoid arthritis was earlier than that of malignant tumors in 51 cases (51/74), with an average of (17.2±14.2) years between 2 and 60 years. The incidence of malignant tumor was earlier than that of rheumatoid arthritis in 16 cases (16/74), with an average of (6.2±5.9) years between 1 and 21 years, of which 10 cases were sex hormone related tumors. Seven cases (7/74) were diagnosed with RA at the same time, and the time interval between the two diseases was within 1 year. All the patients were over 60 years old with digestive tract tumors. All the 7 patients showed polyarthritis, significantly increased erythrocyte sedimentation rate and C-reactive protein, including 4 rheumatoid factor positive cases and 2 anti-CCP antibody positive cases. The effect of non-steroidal anti-inflammatory drugs and traditional drugs to improve the condition of the disease was poor in the 7 patients, and the condition was relieved after using low-dose glucocorticoids. Gastrointestinal tumors, breast and reproductive system tumors were the most common, followed by respiratory, urological and blood system tumors. CONCLUSION The risk in patients of rheumatoid arthritis complicated with malignant tumor is higher than that of the general population. A variety of factors play an important role in cancer risk of RA, including disease activity, some estrogen metabolites, the use of drugs and so on. Therefore, all RA patients should be screened for malignant tumor during diagnosis, and malignant tumor surveillance is mandatory for all rheumatoid arthritis patients after diagnosis.
Adult ; Aged ; Arthritis, Rheumatoid/complications* ; Autoantibodies ; C-Reactive Protein/analysis* ; Female ; Humans ; Male ; Middle Aged ; Neoplasms/immunology* ; Peptides, Cyclic ; Retrospective Studies ; Rheumatoid Factor/blood*

In this study, we evaluated the performance of a recently developed immunoassay analyser, the VISTA 500 (Siemens, Germany). Precision, linearity, and comparison studies were performed according to the Clinical and Laboratory Standards Institute guidelines. The test items evaluated included IgG, IgA, IgM, C3, C4, ceruloplasmin, prealbumin, transferrin, haptoglobin, rheumatoid factor, anti-streptolysin O, and cystatin C. Commercial control materials (BioRad Laboratories, USA), commercial linearity validation materials (Maine Standards, USA), and patient samples were used for the evaluation. For the correlation study, analysis with a BN-II nephelometer (Siemens) was used as a comparative method. Total coefficients of variation of analytes were found to be between 1.9% and 5.5%. Results of the linearity evaluation were also acceptable for the range tested. Correlations with comparative methods were acceptable. The VISTA 500 analyser showed satisfactory analytical performance with respect to precision, linearity, and comparison. We conclude that the VISTA 500 is likely a good candidate as an immunology analyser.
Allergy and Immunology ; Ceruloplasmin ; Cystatin C ; Evaluation Studies as Topic ; Haptoglobins ; Humans ; Immunoassay ; Immunoglobulin A ; Immunoglobulin G ; Immunoglobulin M ; Prealbumin ; Rheumatoid Factor ; Statistics as Topic ; Transferrin

BACKGROUND/AIMS: To evaluate the impact on mortality of anti-tumor necrosis factor (anti-TNF) treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: We retrospectively reviewed the medical records of 100 RA-ILD patients who visited our tertiary care medical center between 2004 and 2011, identified those treated with an anti-TNF agent, divided patients into non-survivor and survivor groups and evaluated their clinical characteristics and causes of death. RESULTS: A total of 24 RA-ILD patients received anti-TNF therapy, of whom six died (25%). Mean age at initiation of anti-TNF therapy was significantly higher in the nonsurvivor versus survivor group (76 years [range, 66 to 85] vs. 64 years [range, 50 to 81], respectively; p = 0.043). The mean duration of anti-TNF treatment in the non-survivor group was shorter (7 months [range, 2 to 14] vs. 23 months [range, 2 to 58], respectively; p = 0.030). The duration of anti-TNF therapy in all nonsurviving patients was < 12 months. Pulmonary function test results at ILD diagnosis, and cumulative doses of disease-modifying drugs and steroids, did not differ between groups. Five of the six deaths (83%) were related to lung disease, including two diffuse alveolar hemorrhages, two cases of acute exacerbation of ILD, and one of pneumonia. The sixth patient died of septic shock following septic arthritis of the knee. CONCLUSIONS: Lung complications can occur within months of initial anti-TNF treatment in older RA-ILD patients; therefore, anti-TNF therapy should be used with caution in these patients.
Adult ; Aged ; Aged, 80 and over ; Antirheumatic Agents/adverse effects/*therapeutic use ; Arthritis, Rheumatoid/complications/diagnosis/*drug therapy/immunology/mortality ; Female ; Humans ; Lung Diseases, Interstitial/diagnosis/etiology/*mortality ; Male ; Middle Aged ; Republic of Korea ; Retrospective Studies ; Risk Assessment ; Risk Factors ; Tertiary Care Centers ; Time Factors ; Treatment Outcome ; Tumor Necrosis Factor-alpha/*antagonists & inhibitors

Rheumatoid arthritis (RA) and osteoarthritis (OA), two common types of arthritis, affect the joints mainly by targeting the synovium and cartilage. Increasing evidence indicates that a significant network connects synovitis and cartilage destruction during the progression of arthritis. We recently demonstrated that hypoxia-inducible factor (HIF)-2alpha causes RA and OA by regulating the expression of catabolic factors in fibroblast-like synoviocytes (FLS) or chondrocytes. To address the reciprocal influences of HIF-2alpha on FLS and chondrocytes, we applied an in vitro co-culture system using a transwell apparatus. When co-cultured with HIF-2alpha-overexpressing chondrocytes, FLS exhibited increased expression of matrix metalloproteinases and inflammatory mediators, similar to the effects induced by tumor-necrosis factor (TNF)-alpha treatment of FLS. Moreover, chondrocytes co-cultured with HIF-2alpha-overexpressing FLS exhibited upregulation of Mmp3 and Mmp13, which is similar to the effects induced by interleukin (IL)-6 treatment of chondrocytes. We confirmed these differential HIF-2alpha-induced effects via distinct secretory mediators using Il6-knockout cells and a TNF-alpha-blocking antibody. The FLS-co-culture-induced gene expression changes in chondrocytes were significantly abrogated by IL-6 deficiency, whereas TNF-alpha neutralization blocked the alterations in gene expression associated with co-culture of FLS with chondrocytes. Our results further suggested that the observed changes might reflect the HIF-2alpha-induced upregulation of specific receptors for TNF-alpha (in FLS) and IL-6 (in chondrocytes). This study broadens our understanding of the possible regulatory mechanisms underlying the crosstalk between the synovium and cartilage in the presence of HIF-2alpha, and may suggest potential new anti-arthritis therapies.
Animals ; Arthritis/genetics/*immunology/pathology ; Arthritis, Rheumatoid/genetics/immunology/pathology ; Basic Helix-Loop-Helix Transcription Factors/genetics/*immunology ; Cells, Cultured ; Chondrocytes/immunology/metabolism/*pathology ; Coculture Techniques ; Fibroblasts/immunology/metabolism/*pathology ; Gene Expression Regulation ; Interleukin-6/genetics/*immunology ; Male ; Mice ; Mice, Inbred C57BL ; Osteoarthritis/genetics/immunology/pathology ; Synovial Membrane/immunology/metabolism/*pathology ; Tumor Necrosis Factor-alpha/genetics/*immunology ; Up-Regulation

OBJECTIVETo compare the diagnostic value of antibodies to mutated citrullinated vimentin (MCV) and some associated autoantibodies in juvenile idiopathic arthritis and to further analyze the relation between antibodies and inflammatory markers.

METHODAntibodies to cyclic citrullinated peptides (CCP) and anti-MCV antibodies were detected by enzyme-linked immunosorbent assay (ELISA), antiperinuclear factor (APF) and antikeratin antibody (AKA) by indirect immunofluorescent assay, as well as rheumatoid factor (RF) by latex agglutination test in serum samples from 113 patients with JIA and 56 children without rheumatoid arthritis.

RESULT(1) The positive rate of anti-MCV antibodies, anti-CCP antibodies, and RF was 16.8%, 14.2%, and 21.2% in the JIA. In the other group, the positive rate was 2.2%, 2.2%, and 6.5%. There was a significant difference between the two groups (χ(2)=8.105, 6.337, 7.036, P<0.05). The positive rate of AKA and APF were not significantly different. The area under the ROC curve of anti-MCV antibodies, anti-CCP antibodies, RF, AKA, APF was 0.579, 0.561, 0.578, 0.539, 0.505. (2) The positive rate of anti-MCV antibodies and anti-CCP antibodies were higher than other antibodies. In the RF-positive polyarticular disease patients, they were higher than those in the other subtypes (P<0.05). Antibody levels were not significantly different (P>0.05) from other subtypes. (3) The swollen joint counts and tender joint counts had a low correlation to anti-MCV antibodies, anti-CCP antibodies, RF, AKA and APF. No correlation was found between ESR, CRP and anti-MCV antibodies, anti-CCP antibodies, RF, AKA and APF.

CONCLUSIONThe diagnostic value of anti-MCV antibodies is low for JIA. The positive rate of anti-MCV antibodies was higher than the other antibodies in the classification of JIA. There was a low correlation between anti-MCV antibodies, anti-CCP antibodies, RF, AKA, APF and swollen joint counts, tender joint counts.

Antibodies, Antinuclear ; blood ; Arthritis, Juvenile ; blood ; Arthritis, Rheumatoid ; Autoantibodies ; blood ; Biomarkers ; blood ; Child ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique, Indirect ; Humans ; Peptides, Cyclic ; immunology ; ROC Curve ; Rheumatoid Factor ; blood ; Vimentin ; immunology

Eupatilin is the main active component of DA-9601, an extract from Artemisia. Recently, eupatilin was reported to have anti-inflammatory properties. We investigated the anti-arthritic effect of eupatilin in a murine arthritis model and human rheumatoid synoviocytes. DA-9601 was injected into collagen-induced arthritis (CIA) mice. Arthritis score was regularly evaluated. Mouse monocytes were differentiated into osteoclasts when eupatilin was added simultaneously. Osteoclasts were stained with tartrate-resistant acid phosphatase and then manually counted. Rheumatoid synoviocytes were stimulated with TNF-alpha and then treated with eupatilin, and the levels of IL-6 and IL-1beta mRNA expression in synoviocytes were measured by RT-PCR. Intraperitoneal injection of DA-9601 reduced arthritis scores in CIA mice. TNF-alpha treatment of synoviocytes increased the expression of IL-6 and IL-1beta mRNAs, which was inhibited by eupatilin. Eupatilin decreased the number of osteoclasts in a concentration dependent manner. These findings, showing that eupatilin and DA-9601 inhibited the expression of inflammatory cytokines and the differentiation of osteoclasts, suggest that eupatilin and DA-9601 is a candidate anti-inflammatory agent.
Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Arthritis, Experimental/chemically induced/*drug therapy ; Arthritis, Rheumatoid/drug therapy/pathology ; Cell Differentiation/*drug effects ; Cells, Cultured ; Collagen Type II ; Cytokines/biosynthesis ; Disease Models, Animal ; Drugs, Chinese Herbal/therapeutic use ; Female ; Flavonoids/pharmacology/*therapeutic use ; Humans ; Inflammation/drug therapy/immunology ; Interleukin-1beta/genetics/metabolism ; Interleukin-6/genetics/metabolism ; Lymph Nodes/cytology ; Mice ; Mice, Inbred DBA ; Monocytes/cytology ; Osteoclasts/*cytology ; Plant Extracts/pharmacology ; RNA, Messenger/biosynthesis ; Synovial Membrane/cytology ; T-Lymphocytes, Regulatory/cytology/immunology ; Tumor Necrosis Factor-alpha/pharmacology

BACKGROUND/AIMS: Increased resting energy expenditure (REE) in rheumatoid arthritis (RA) patients is thought to be caused by hypermetabolism associated with production of proinflammatory cytokines. Our aim in the present study was to explore the possible association between REE and disease activity in females with RA. METHODS: A total of 499 female RA patients were recruited to this cross-sectional study assessing REE scores on disease activity indices (the routine assessment of patient index data 3 [RAPID3], the disease activity score 28, and the clinical/simplified disease activity index [CDAI/SDAI]) and the levels of RA-associated autoantibodies (rheumatoid factor and anticyclic citrullinated peptide [anti-CCP] antibodies). Age-matched healthy female controls (n = 131) were also enrolled. RESULTS: REE did not differ between RA patients (all patients, and those in remission or not) and controls, or between RA patients in remission or not (p > 0.05 for all comparisons). Increased REE in total RA patients was associated with younger age and a higher body mass index (BMI) (p < 0.001 and p < 0.001, respectively), but not with disease activity index scores on any of RAPID3, CDAI, or SDAI. BMI was the only clinical parameter exhibiting a significant relationship with REE quartiles (Q1 to Q4; p < 0.001); none of disease duration, functional status, or anti-CCP antibody titer in RA patients was significantly related to REE, based on analysis of covariance. CONCLUSIONS: We found no association between REE and disease activity in RA patients, implying that energy metabolism in RA patients might be independent of RA-associated systemic inflammation.
Adult ; Age Factors ; Aged ; Arthritis, Rheumatoid/blood/diagnosis/*metabolism/physiopathology ; Biological Markers/blood ; Body Mass Index ; Case-Control Studies ; Cross-Sectional Studies ; *Energy Metabolism ; Female ; Humans ; Inflammation Mediators/blood ; Middle Aged ; Peptides, Cyclic/immunology ; Predictive Value of Tests ; *Rest ; Rheumatoid Factor/blood ; Severity of Illness Index