Rheumatoid Effusion Research Articles

Drug discovery in rheumatoid arthritis with joint effusion identified by text mining and biomedical databases.

Rheumatoid arthritis is a long-term systemic disease that primarily affects multiple synovial joints throughout the body. Some patients with severe joint effusion even require repeated arthrocentesis or arthroscopic debridement to relieve symptoms, which causes them much suffering mentally and physically. This text-mining study was designed to find potential drugs that target key genes in this disease. Firstly, we performed text mining by two keywords ("rheumatoid synovitis" and "joint effusion") to get a common set of genes. Secondly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis performed on these genes, and protein-protein interaction (PPI) network was constructed. Subsequently, the significant genes clustered in the PPI network were chose to execute gene-drug interaction analysis for potential drug discovery. Through text mining, 68 overlapping genes were identified as an initial set of key genes. Construction of the initial gene set's PPI network showed that 25 genes clustered in a significant gene module. Ultimately, 8 out of 25 genes could be targetable by a total of 19 drugs. The final 8 genes (PTGS2, TNF, VEGFA, IL1B, CCL2, VWF, IL6, and ESR1) and 19 drugs may provide significant therapeutic value for rheumatoid arthritis patients with joint effusion.

12. Dramatic improvement of chronic pleural effusion with abatacept treatment in longstanding rheumatoid arthritis, after chest sepsis during treatment with anti-TNF-α

Introduction Rheumatoid arthritis (RA) is a systemic inflammatory disorder, with various pulmonary manifestations, including parenchymal disease (interstitial lung disease), inflammation of the pleura (thickening and effusions), and inflammation of the airways and pulmonary vasculature (vasculitis and pulmonary hypertension). These changes may reflect chronic immune activation, increased susceptibility to infection, or direct toxicity from disease modifying or biological therapy. This case report describes a 69-year-old male with longstanding seropositive rheumatoid arthritis who developed severe pneumonia during adalimumab treatment, with subsequent persistent right basal pleural effusion. Treatment with abatacept has resulted in remission with significant decrease in size of the pleural effusion.

A Case of Massive Recurrent Rheumatoid Effusion

Rheumatoid arthritis (RA) is a well-known auto-immune disease affecting the joints, its signature signs being bone erosions and joint deformity. Other than arthritis, RA can also affect other organs in the body, such as eyes, heart, lungs, etc. In our case we are going to discuss an elderly lady with RA, presenting with large pleural effusion as presenting complaint.

Adverse changes in tendon–muscle physiology and physical function caused by an isolated acute rheumatoid knee effusion: A case study

Introduction Patients with rheumatoid arthritis (RA) have reduced muscle mass, probably due to the catabolic effects of systemic inflammation and disuse (1). This loss leads to reduced strength and physical function (1,2). In addition, the presence of effusion in the knee joint results in reflex inhibition of the quadriceps as demonstrated by reduced electromyogram (EMG) activity and diminished strength (3,4). The wider characteristics of the tendon–muscle complex have not been investigated in acute RA or in joint effusions of other etiologies. In exercise science, electrophysiologic methods are used to investigate tendon– muscle properties in healthy populations. These include assessments of muscle-specific force (force/cross-sectional area), architecture (fiber fascicle length and pennation angle), voluntary activation capacity, contractile properties, and tendon stiffness. Application of these techniques in aging and disuse has demonstrated adverse changes in tendon and muscle properties that result in impaired function but respond well to exercise training (5,6). We have previously applied these methods in patients with well-controlled RA and found that tendon stiffness was reduced (Matschke V et al: unpublished observations), while muscle quality (specific force, voluntary activation capacity, contractile properties) was unaffected (7,8). To our knowledge, these electrophysiologic methods have not been applied in acute RA, probably due to difficulties arising from confounding factors such as pain, fatigue, and the acute effects of inflammation in other joints.

Overnight variations in IL-6 in synovial fluid and plasma in patients with active rheumatoid arthritis

Aim: To investigate for the first time overnight variations in absolute values and patterns of synovial fluid IL-6, and other proinflammatory cytokines including IL-1β and TNF, and to relate them to blood concentrations of cytokines and cortisol in rheumatoid arthritis. Patients & methods: Six people with active rheumatoid arthritis and large knee effusions who had received no recent glucocorticoids were admitted overnight. Blood and synovial fluid samples were obtained at 13 time points between 21:00 and 10:00. Results: The geometric mean synovial fluid IL-6 concentration increased significantly from 1483 pg/ml at 21:00 to 5084 pg/ml at 08:00 (repeated measures ANOVA p < 0.001). The geometric mean plasma IL-6 and cortisol concentrations increased significantly overnight. In a random coefficient model including data from all participants, the estimated mean synovial fluid IL-6 value began to rise approximately 6 h before the estimated mean plasma IL-6, which in turn began to rise approximately 3 h before ...

FLUID CYTOLOGY UPDATE: THE MANY FACES OF MESOTHELIAL CELLS AND MALIGNANT CELLS IN FLUID CYTOLOGY, DIAGNOSTIC PITFALLS AND ANCILLARY STUDIES

Fluid cytology has a clinical significance in the management of patients with malignancy. Effusions are often the first clinical symptom of malignant tumors or of their metastatic manifestation. In known malignancies effusins are an omnious sign. In one third of malignant effusions, cytology gives the first indication of malignancy. Therefore, cytological diagnoses of effusions are of great clinical importance. Microscopic evaluation of body fluid cytology is not always straightforward. The two lectures and the afternoon workshop session review the literature, describe the cytomorphological criteria in the diagnosis of reactive/proliferative mesothelial cells, inflammatory/ infectious conditions and neoplastic lesions in body fluid with emphasis on the many faces and similarities of reactive mesothelial cells and malignant cells. The lectures will review several interesting cases in fluid cytology with emphasis on problematic areas in body cavity luid cytology. The cytological criteria of benign conditions and malignant neoplasms in fluid cytology preparations are different from those in fine needle aspiration specimens procured from the same lesions. For example, monolayered sheets as commonly seen in fine needle aspiration smears from adenocarcinomas are not present in effusion preparation. Small cell undifferentiated carcinomas in effusion may show proliferative spheres of tumour cells that wrap around one another with an onionskin appearance. Lymphomas in effusion may show marked apoptosis or vacuolization. One of the great challenges in the cytological diagnosis of effusions is the distinction between reactive mesothelial cells/histiocytes and malignant cells. Furthermore, numerous diagnostic pitfalls of fluid cytology may be encountered such as mesothelial cell hyperplasia, collagen balls, endometriosis, endosalpingiosis; psammoma bodies, pseudoeosinophilia, fluid eosinophilia, rheumatoid arthritis effusion, lupus pleuritis, effusins with small cells, malignant effusion with single cell population; mucinous and serous tumours in female patients, cancer treatment effects, liver cirrhosis effusion, renal failure effusions, and pancreatitis effusins. Preparation of cell blocks and ancillary studies are of value in the work‐up and management of patients who present with cytologic mimickers of malignancy on fluid cytology. The first lecture will start with an instructor‐audience interactive discussion on the cytomorphological criteria in the diagnosis of reactive/proliferative mesothelial cells, inflammatory/ infectious conditions and neoplastic lesions in body fluid. The second lecture will address the diagnostic pitfalls of papillary structures, vacuolation of mesothelial cells, psammoma bodies, collagen balls, endometriosis, endosalpingiosis, and the borderline tumours reporting. The second lecture will also address the role of ancillary studies such as special stains, immunocytochemical staining, flow cytometric studies and EM in body fluid cytological examination.

Commentary on the British Thoracic Society guidelines for the investigation of unilateral pleural effusion in adults

The publication of guidelines for the investigation of unilateral pleural effusion in adults by the British Thoracic Society has focused attention on this subject which, although comprising only a small proportion of laboratory workload, is a fairly common clinical problem. We critically reviewed the guidance applicable to clinical biochemistry laboratories and found a number of deficiencies. In particular, the need for anaerobic sample collection for pH measurement and preservation of samples for glucose assay is not mentioned and health and safety issues related to the handling of potentially infected fluids are also not considered. There are discrepancies between recommendations in the text and in the accompanying diagnostic algorithm, which require clarification. Measurement of total protein is an essential first step in the analysis of pleural fluid and will usually distinguish transudates from exudates. Measurement of lactate dehydrogenase activity is only required when total protein results are equivocal. There are practical difficulties with measurement of fluid pH as recommended in the guidelines and there is little evidence that such measurements are valuable. Similarly, there is little evidence to support the recommendation for measurement of complement in suspected rheumatoid effusions, and the recommendation for amylase isoenzyme studies if acute pancreatitis is a possibility is not practical. The different nature of pleural fluid demands a good understanding of the handling of these samples, the limitations of the analytical methods and the subsequent result interpretation by laboratory staff. We propose a modified diagnostic algorithm reflecting our criticisms of the original. Dialogue between the laboratory and local clinicians, possibly with the production of local guidelines, informed by these recommendations, should help optimize diagnostic management of patients with pleural effusion.

Rheumatoid Pleural Effusion in the Absence of Arthritic Disease

Rheumatoid pleural effusion is an unusual complication of rheumatoid disease that typically presents subsequent to other more common manifestations of rheumatoid illness. The case of a 72-year-old woman with a rheumatoid pleural effusion is discussed. The patient presented with dyspnea, but without any history of rheumatoid arthritis. The patient was treated by thoracentesis, followed by video-thoracoscopy and pulmonary decortication. Postoperatively, the patient's effusion partially reaccumulated. Steroid therapy resulted in prompt and permanent resolution of the effusion. The patient remains asymptomatic 1 year after her presentation. The biochemical, serologic, and cytologic characteristics of rheumatoid effusions are reviewed.

Neurone-specific enolase levels in pleural effusions in patients with rheumatoid arthritis.

High pleural fluid levels of neurone-specific enolase (NSE) have been reported, not only in patients with small cell lung cancer but also in those with chronic inflammatory diseases. NSE concentrations were determined in pleural fluid and serum from 342 patients with pleural effusions including 17 with rheumatoid arthritis. The median NSE concentration in pleural fluid was higher in rheumatoid effusions than in any other condition studied. The median pleural fluid:serum NSE ratio was highest in patients with rheumatoid arthritis (11.6) and about unity in all other diseases including small cell lung cancer (0.9). In patients with rheumatoid arthritis pleural fluid concentrations of NSE correlated inversely with pleural fluid glucose concentrations and the pH of the pleural fluid. A high pleural fluid:serum NSE ratio was found consistently in pleural effusions from patients with rheumatoid disease.

Human T-cell responses to Mycoplasma arthritidis-derived superantigen.

When injected into mice, Mycoplasma arthritidis causes a chronic arthritis that resembles rheumatoid arthritis, histologically. The organism produces a superantigen termed Mycoplasma arthritidis mitogen or MAM, that in humans preferentially expands T cells whose antigen receptors express V beta 17. T cells with this phenotype appear to be increased in rheumatoid synovial effusions. We describe a novel approach to isolating and characterizing human MAM-reactive T-cell lines and determining their T-cell receptor (TCR) V beta usage. Lines were prepared from T cells that clustered with dendritic cells during a 2-day exposure to MAM. Cluster and noncluster fractions of T cells were then expanded by using feeder cells and a polyclonal mitogen. Most of the MAM reactivity was found in dendritic T-cell clusters, as were most of the T cells expressing TCR V beta 17. After expansion, 76% of the cluster-derived T-cell lines were MAM reactive, while no reactivity was seen in cell lines derived from the noncluster fraction. Of the MAM-reactive lines, 49% expressed V beta 17 on some or all of the cells. Cell lines from both cluster and noncluster fractions were analyzed for TCR V beta mRNA expression by PCR amplification. Other V beta genes (5.1, 7, 8, 12, and 20) were found to be expressed by lines that were MAM reactive, although these were not a major component of the cluster-derived T cells. Some non-cluster-derived lines expressed V beta s 17, 12, and 7, but these proved to be nonreactive to MAM. Therefore, dendritic cells can be used to immunoselect and characterize T cells that express superantigen-reactive TCRs.

Interleukin-8 (IL-8) in synovial fluid of rheumatoid and nonrheumatoid joint effusions

IL-8 was measured in knee joint synovial fluid of 60 patients with rheumatoid arthritis, 8 with gout, 6 with osteoarthritis and 4 with meniscus lesions. IL-8 could be demonstrated in most SF samples. The highest levels were observed in rheumatoid joint effusions, yet mean levels were not significantly different between the different subgroups (mean +/- SE; RA 1537 +/- 3049 pg/ml, gout 570 +/- 952 pg/ml, OA/ML 178 +/- 188 pg/ml). In RA patients, IL-8 levels could not be related to various serological, clinical or radiological parameters. However, a correlation was observed between SF levels of IL-8 with those of lactate, LDH, beta 2-microglobulin and glucose. These observations suggest that next to the laboratory parameters IL-8 will be a parameter of the activity of the local inflammatory process. The results also demonstrate that IL-8 is not a disease-specific marker of joint inflammation.

Interleukin-6 can prime THP-1 macrophages for enhanced production of tumor necrosis factor-α in response to LPS

Although interferon-γ has been shown to effectively prime macrophages for enhanced production of tumor necrosis factor-α (TNFα), it is reasonable to assume that other cytokines present in the extracellular environment may likewise facilitate cytokine biosynthesis. For example, interleukin-6 (IL-6) is synthesized by synovial lining macrophages and fibroblasts, and has been detected (along with TNFα) in rheumatoid synovial effusions. Therefore, the purpose of the present study was to determine whether IL-6 influences the production of IL-1β and/or TNFα by THP-1 macrophages. Although IL-6 treatment alone resulted in only a slight increase in TNFα levels, administration of IL-6 followed by Sal. minnesota LPS resulted in a synergistic potentiation of TNFα production by THP-1 macrophages. The priming effect of IL-6 could be reversed by boiling, or by the addition of a neutralizing polyclonal antibody against IL-6. Notably, IL-6 only weakly enhanced interleukin-1β production. In summary, the ability of IL-6 to potentiate TNFα production by THP-1 macrophages may provide insight into the regulation of the cytokine network in inflammatory diseases, such as rheumatoid arthritis.

Inflammation of the visceral pleura, a nonspecific asbestos‐related pleural reaction: Chest radiograph and computed tomograph correlation

Nonspecific pleuritis, i.e., inflammation of the visceral pleura, is recognized by the presence of pleural strands on the routine posteroanterior chest radiograph. The computed tomograph counterparts of these strands are seen as interlobular septal intrusions and lenticular or wedge-shaped subpleural opacities. The pleural reaction is nonspecific and may be found with asbestos exposure, traumatic hemorrhagic effusions, pulmonary embolism, viral pleurisy, malignant pleural effusions, and lupus or rheumatoid effusions. The asbestos-related pleural changes may be found alone or in association with parietal pleural plaque formation or with asbestotic lung fibrosis.

Partial purification and characterisation of a synovial fluid inhibitor of osteoblasts.

A polypeptide inhibitor of osteoblast proliferation is described which occurs in synovial effusions of patients with rheumatoid arthritis. Partial purification of the inhibitor showed a molecular weight of approximately 81,000 by gel electrophoresis. This polypeptide seems to be unique as no inhibitor of osteoblasts of similar molecular weight has been previously described in rheumatoid synovial effusions.

IL-6/IFN-beta 2 in synovial effusions of patients with rheumatoid arthritis and other arthritides. Identification of several isoforms and studies of cellular sources.

We have looked for IL-6, a cytokine that has immunomodulating and inflammation-associated activities, in joint exudates (fluid and mononuclear cells) from patients with rheumatoid arthritis and other arthritides using both biologic and biochemical assays. IL-6 was assessed by its ability to stimulate alpha 1-antichymotrypsin secretion from the human hepatoma cell line Hep3B clone 2, an activity which is blocked by an antiserum to Escherichia coli derived IL-6, and by the growth of the IL-6-dependent murine hybridoma 7TD1 cell line. IL-6 isoforms in synovial fluid were characterized by immunoaffinity chromatography followed by Western blotting. The presence of IL-1 in synovial fluids and its production by synovial fluid mononuclear cells was monitored by Western blotting and indirect immunofluorescence with polyclonal anti-IL-1 beta antisera. In an analysis of 30 effusions from 27 rheumatoid patients with acutely inflamed joints, abundant quantities of IL-6 (greater than 2 ng/ml) were detected in 23 by the alpha 1-antichymotrypsin bioassay. Several rheumatoid synovial fluids also had elevated IL-6 levels in the 7TD1 bioassay. Seven of nine nonrheumatoid effusions also contained high levels of IL-6 (greater than 2 ng/ml). No IL-1 (less than 0.25 ng/ml) could be detected by Western blotting in 10 rheumatoid effusions even though eight of these contained high levels of IL-6. The IL-6 activity could be neutralized with a rabbit antiserum to rIL-6. Multiple IL-6 isoforms (25, 30, 45 kDa) were present in two rheumatoid and one traumatic effusion studied. Fresh mononuclear cells isolated from various synovial effusions did not appear to make IL-6 constitutively, as no IL-6 could be detected in the media of cells cultured for 12 to 18 h after isolation. Similarly, there was no constitutive production of IL-1 by these cells. However, synovial fluid mononuclear cells could be induced to secrete both IL-6 and IL-1 after stimulation with LPS. The LPS-responsive cells were monocytes and not lymphocytes or dendritic cells. These findings suggest that IL-6 is involved in inflammatory joint disease. However, the primary cells synthesizing it may be located in the synovial lining instead of the joint exudate.

Interleukin-1 production by mononuclear cells from rheumatoid synovial effusions

The polypeptide interleukin-1 (IL-1) is a cytokine that may mediate inflammation and connective tissue damage in rheumatoid arthritis (RA). We examined cytokine production by normal blood and by rheumatoid synovial mononuclear cells with sensitive (picomolar) assays. The assays were immunolabeling and immunoblotting with rabbit anti-IL-1β sera, and proliferation of the murine D10 cell line to IL-1. Little or no cytokine was detected in rheumatoid joint fluid or in exudate mononuclear cells from patients with acute rheumatoid flares. The mononuclear cells could be induced to make IL-1 upon stimulation with lipopolysaccharide (LPS). The responsive cells were monocytes, since all could be double-labeled with anti-IL-1 and the monocyte-specific CD14 antibody. More than 80% of the synovial fluid monocytes made IL-1β after 24 hr in 2 ng/ml LPS. Other agents failed to induce IL-1 from enriched populations of monocytes including interferon gamma (IFN-γ), poly (I/C), phorbol myristate acetate (PMA), concanavalin A (Con A), phytohemagglutinin (PHA), and anti-CD3 antibodies. Relatively high levels of dendritic cells (DC) were present in RA effusions, but these did not produce IL-1 in response to any of the above stimuli. Blood dendritic cells also did not make IL-1, whereas blood monocytes responded comparably to synovial exudate cells. The data indicate that rheumatoid exudate monocytes make very little IL-1 during acute flares of arthritis and that this cytokine is primarily a macrophage rather than a dendritic cell product.

Cholesterol crystals in shoulder synovial fluid.

Samples of 1945 synovial fluids have been examined from patients with a wide variety of joint disorders. Typical cholesterol crystals were seen in only 14 of these samples, all from the shoulders of six patients with severe rheumatoid arthritis and persistent shoulder effusions.

Low synovial clearance of iodide provides evidence of hypoperfusion in chronic rheumatoid synovitis.

Iodide clearance was measured in the chronic knee effusions of 11 patients with rheumatoid arthritis and 9 patients with osteoarthritis. The mean (+/- SE) iodide clearance of 1.92 +/- 0.30 ml/minute in rheumatoid arthritis effusions did not differ significantly from the 2.19 +/- 0.52 ml/minute found in osteoarthritis effusions. Clearance values in rheumatoid arthritis patients ranged widely (0.79-3.22 ml/minute). Iodide clearance in these patients correlated directly with synovial fluid (SF) pH (r = 0.731, P = 0.005), SF glucose:serum glucose ratio (r = 0.746, P = 0.004), and SF temperature (r = 0.878, P = 0.001), and directly with SF lactate (r = -0.782, P = 0.002) and percentage of SF neutrophils (r = -0.581, P = 0.03). These relationships support the hypothesis that rheumatoid synovitis is often marked by tissue hypoperfusion, and that the "sickest" rheumatoid joints (as defined by physiologic indices) are the most ischemic.

Intraarticular volume and clearance in human synovial effusions.

Intraarticular volumes were measured by radiolabeled albumin (RISA) distribution in chronic knee effusions from 11 rheumatoid arthritis patients and 9 osteoarthritis patients. Volumes of synovial fluid obtained at joint aspiration were substantially less than those found by RISA dilution. Up to 24 hours was needed for full distribution of RISA throughout the intraarticular compartment. Measured 123I and RISA radioactivity over the knee described monoexponential rate constants, lambda (minute-1). The clearance of 123I and RISA from synovial effusions was derived by the formulation volume (ml) X lambda (minute-1) = clearance (ml/minute). RISA clearance in rheumatoid effusions was significantly greater than that found in osteoarthritis effusions. Intraarticular volume and isotope clearance were easily quantified and provide measures for further evaluating the microvascular physiology of synovial effusions.

Diagnostic value of total and differential leukocyte counts in pleural effusions.

Total and differential leukocyte counts in pleural fluid were determined prospectively in 140 consecutive patients undergoing diagnostic thoracentesis. The total number of leukocytes was higher in exudates than in transudates. Lymphocytes predominated overwhelmingly (more than 80% of all leukocytes) in 29 of the 31 effusions with verified or probable tuberculous etiology and in 18 of the 24 with malignant etiology, as well as in 20 exudative pleural effusions of other causes. The significant differences in the percentage of lymphocyte distinguished tuberculous effusions from parapneumonic (p less than 0.001), nonspecific (p less than 0.001) and rheumatoid effusions (p less than 0.005), as well as from effusions caused by undefined connective tissue disease (p less than 0.001). Eosinophilia (more than 10%) of the pleural fluid was not present in any patient with proven tuberculosis and in only one patient with malignant effusion (malignant mesothelioma) but did occur in 12 of the 26 patients with nonspecific effusion. These results show that a great lymphocytic predominance is characteristic particularly of tuberculous but also of malignant pleural effusions, although this predominance cannot be regarded as disease-specific. Eosinophilia of the pleural fluid--usually a nonspecific sign--indicates nontuberculous, nonmalignant etiology.