Expression of c-myc protein in skin and synovium in psoriasis and psoriatic arthritis.

Monoclonal antibody against c-myc protein was used in the avidin-biotin-peroxidase complex procedure to examine frozen sections of psoriatic and normal skin and psoriatic synovium for the presence of c-myc protein. A significantly greater percentage (88%) of epithelial cells from psoriatic skin lesions stained for c-myc than uninvolved skin (62%) from both psoriatics and normals (p less than 0.001). The intensity of the stain appeared weaker in normal skin specimens. Greater than 95% of psoriatic hyperplastic synovial lining cells stained strongly for c-myc. In all cases, the c-myc staining was confined to the nuclei with no evidence of cytoplasmic staining.     

Dramatic regulation of heparanase activity and angiogenesis gene expression in synovium from patients with rheumatoid arthritis

OBJECTIVE: Although heparanase is recognized as a proangiogenic factor, the involvement of heparanase in rheumatoid arthritis (RA) is unclear. In this study, we assessed heparanase activity in synovial fluid (SF) and synovial tissue (ST) from patients with RA or osteoarthritis (OA), and analyzed the expression of angiogenic pathway-focused genes in ST from RA and OA patients. METHODS: SF and ST were obtained from the knees of patients with either RA or OA and from asymptomatic donors with no documented history of degenerative or inflammatory joint diseases. Heparanase activity was determined by an enzymatic assay using a radiolabeled substrate, and the presence of heparanase in ST was demonstrated by Western blotting. The expression of angiogenesis genes, including heparanase, in ST was analyzed by real-time quantitative polymerase chain reaction. RESULTS: Heparanase activity was dramatically higher (>100-fold) in SF and ST from RA patients than in SF and ST from OA patients and asymptomatic donors. Active heparanase enzyme was detected and heparanase messenger RNA was up-regulated in ST from RA patients. We also found that angiogenesis gene expression was significantly regulated in RA synovium, and was correlated with heparanase activity. CONCLUSION: These findings are novel and contribute to our understanding of joint destruction in RA, suggesting that heparanase may be a reliable prognostic factor for RA progression and an attractive target for the treatment of RA.     

ACTH expression in synovium of patients with rheumatoid arthritis and Lewis rats with adjuvant arthritis

 Adrenocorticotropic hormone (ACTH) and another pro-opiomelanocortin-derived neuropeptide, β-endorphin (β-End), are stimulated by corticotropin-releasing hormone (CRH) at the anterior pituitary. CRH and β-End have predominantly proinflammatory effects in peripheral inflammatory sites. We have supposed that inflammatory stimuli develop ACTH as well as β-End. In this study, we investigated the expression of ACTH in inflamed synovial tissue from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and at inflammatory joints with adjuvant-induced arthritis (AA) in female Lewis (LEW/N) rats. The expression of ACTH immunostaining was significantly greater in synovium of RA patients than in that of OA patients (P < 0.0001), and correlated with the extent of inflammatory mononuclear cell infiltration. Extensive and intense intracellular ACTH immunostaining, which correlated with the advance in arthritis score, was observed in the synovial lining layer, inflammatory mononuclear cells, and fibroblast-like cells of synovium and chondrocytes in LEW/N rats with AA. In addition, we performed double immunostaining of the same sections from arthritic joints in rats with anti-ACTH and anti-CRH antibodies. ACTH and CRH colocalized in inflammatory mononuclear cells and fibroblast-like cells. ACTH may play a role in the pathogenesis of RA as well as CRH. Received: July 4, 2001 / Accepted: January 23, 2002 Correspondence to: H. Sano     

Urocortin expression in synovium of patients with rheumatoid arthritis and osteoarthritis: relation to inflammatory activity

Peripherally produced CRH acts as a local auto/paracrine proinflammatory agent. Urocortin is a new member of the CRH family that acts through the family of CRH receptors. In this study, we demonstrated that the expression of urocortin mRNA in synovia of patients with rheumatoid arthritis was greater than that of patients with osteoarthritis. Also, we detected urocortin and CRH receptor immunoreactivity in the synovial lining cell layer, subsynovial stromal cells, blood vessel endothelial cells, and mononuclear inflammatory cells from the joints of rheumatoid arthritis and osteoarthritis patients. The expression of immunoreactive urocortin was significantly greater in rheumatoid arthritis than osteoarthritis (P < 0.0001) and correlated with the extent of inflammatory infiltrate. CRH receptor immunoreactivity was strong in mononuclear inflammatory cells of rheumatoid arthritis synovia. Urocortin stimulated IL-1beta and IL-6 secretion by human peripheral blood mononuclear cells in vitro. These findings suggest that, like CRH, urocortin is present in peripheral inflammatory sites, such as rheumatoid synovium, and acts as an immune-inflammatory mediator.     

Asymptomatic erosive peripheral psoriatic arthritis: a frequent finding in Italian patients

SIR, Painless spondylitis [1], sacroiliac joint involvement[2] and enthesitis [3] have been well described in patientssuffering from psoriatic arthritis (PsA). Two years ago we firstdescribed the occurrence of two cases of asymptomatic erosivepsoriatic polyarthritis [4]. That report demonstrated that inthe peripheral joints the inflammatory process of PsA can alsoinduce bone damage without occurrence of pain, swelling andother clinical signs of arthritis. Furthermore, we showed thatsilent PsA can occur in a destructive manner     

Disease activity and biologic use in patients with psoriatic arthritis or rheumatoid arthritis

Clinical Rheumatology - To compare disease burden and biologic use among psoriatic arthritis (PsA) or rheumatoid arthritis (RA) patients recruited to the Corrona registry. Retrospective study of...     

Inflammatory infiltrate and interleukin-8 expression in the synovium of psoriatic arthritis – an immunohistochemical and mRNA analysis

Psoriatic arthritis is an inflammatory arthropathy that ultimately can lead to joint destruction. In this study, we investigated the immunophenotype of the inflammatory cells and the expression of interleukin-8 (IL-8), which is the hallmark chemoattractant cytokine of psoriasis in synovial membranes from patients exhibiting active psoriatic synovitis (n=9). The tissue samples were examined by immunohistochemistry, Western blot analysis and in situ hybridisation. The inflammatory infiltrate consisted predominantly of CD3⁺ T lymphocytes, with a higher proportion of CD4⁺ than CD8⁺ T lymphocytes in six cases. CD3⁺ T lymphocytes were focally distributed near small blood vessels and the enlarged synovial intima. CD1⁺ interdigitating reticulum cells were not detected. CD22⁺ B lymphocytes and plasma cells were found in small aggregates without KiM4⁺ follicular dendritic cells. KiM8⁺ macrophages were located in the synovial intima and were distributed in a diffuse pattern near the synovial lining cells. CD15⁺ neutrophil granulocytes were detected in four cases. They were preferentially located in the vicinity of blood vessels and the synovial intima. IL-8 was found at a high level in the synovial lining cells and to a lesser extent in cells located in the perivascular areas. Immunofluorescence double staining showed IL-8 to be expressed in KiM8⁺ multinucleated giant cells, KiM8⁺ macrophages and CD3⁺ T lymphocytes. IL-8 receptor A was demonstrated in the synovial lining and in macrophages and lymphocytes. IL-8 was detected by immunoblot analysis of the synovial tissue at 8.4 kD. Employing in situ hybridisation, IL-8 mRNA was strongly and preferentially expressed in the synovial intima, as well as in macrophages and lymphocytes. The immunophenotype of the psoriatic arthritis inflammatory cells shows great similarity to the inflammatory infiltrate found in the synovial tissue of patients with rheumatoid arthritis. The preferential expression of IL-8 and IL-8 mRNA in the enlarged synovial intima and in lymphocytes and macrophages suggests that IL-8 exerts its action through activated mononuclear cells and T lymphocytes. It seems to play a role in regulating leucocyte traffic into the enlarged synovial intima and may contribute to the aggressive synovitis of patients with psoriatic arthritis. Received: 14 August 1997 / Accepted: 25 August 1997     

A polyarticular onset predicts erosive and deforming disease in psoriatic arthritis

OBJECTIVES: To analyse the factors predicting erosive-deforming arthropathy in patients with psoriatic arthritis (PsA). METHODS: A prospective cohort study was undertaken with 71 patients diagnosed as having PsA (44 men and 27 women, mean age 47 (SD 12) years). At the recruitment period patients had disease without evidence of radiological damage. Patients were studied and followed up according to a standard protocol from January 1991 to June 2001. Erosive and deforming disease was defined by the presence of erosions, joint space narrowing, subluxation, and/or ankylosis of peripheral joints. Univariate and multivariate analyses were performed to evaluate factors predicting erosive and deforming disease. RESULTS: At the end of the study 32 of 71 (45%) patients had developed erosive and deforming disease. Among them, 18 of 32 (56%) had a polyarticular onset, two of 32 (6%) showed a distal interphalangeal joint disease onset, six of 32 (19%) presented with oligoarthritis, and six of 32 (19%) presented with axial disease as the form of disease onset (p=0.001). Mean time to detect erosions or joint space narrowing was 20 (SD 4) months. Men showed fewer erosions than women (p=0.05). Patients who carried the HLA-B27 antigen showed less erosive disease than patients who lacked it (p=0.05). Patients with erosive and deforming disease had poorer functional performance than those without it as measured with the Health Assessment Questionnaire (HAQ) and the American College of Rheumatology (ACR) criteria (p<0.05 with both measurements). In multivariate analysis, only a polyarticular onset remained as an indicator of erosive and deforming disease (odds ratio (OR) 37, 95% confidence interval (95% CI) 3.6 to 88, p=0.025). CONCLUSIONS: A polyarticular onset (five or more swollen joints) of PsA was the unique independent risk factor which predicted the appearance of erosive and deforming disease over time. These data may be useful for clinicians treating patients with PsA, as it may guide treatment towards a more aggressive and earlier intervention.     

Localized monocyte chemotactic protein-1 production correlates with T cell infiltration of synovium in patients with psoriatic arthritis

OBJECTIVE: To examine normal and psoriatic skin and synovial tissue from patients with psoriatic arthritis (PsA) for evidence of monocyte chemotactic protein-1 (MCP-1) mediated T cell chemotaxis. METHODS: Peripheral blood (PB), synovial fluid (SF), normal and psoriatic skin, and synovial biopsies were obtained from patients with PsA (n = 19) and compared to samples from normal (n = 5) and disease (n = 5) controls (NC, DC). Immune cell populations in PB and SF samples were assessed by immunofluorescent labeling and flow cytometry, levels of soluble MCP-1 were determined by quantitative ELISA, and immunohistochemistry was used to detect T cell subsets and macrophages and MCP-1 protein in frozen skin and synovial tissue sections. RESULTS: CD8+ but not CD4+ T cells were elevated in SF compared to PB, and the majority of these cells expressed CD45RO. Plasma MCP-1 levels in PsA were elevated relative to NC. MCP-1 levels were significantly higher than paired plasma samples in patients with recent onset (< 6 mo) synovitis (n = 10). A positive correlation was observed between synovial T cell numbers and MCP-1 levels in SF. MCP-1 protein was present in all tissues examined, but most intense expression was observed in synovium. CONCLUSION: Elevated concentrations of MCP-1 concomitant with memory T cell infiltration in PsA SF suggests that MCP-1 mediated chemotaxis is involved in the recruitment of T lymphocytes into the synovial compartment of patients with PsA.     

Rhythm profile in patients with psoriatic arthritis

OBJECTIVE: To analyze the rhythmic profile in patients with psoriatic arthritis (PA). DESIGN: In order to evaluate the rhythmic profile of patients with PA, we have carried out ambulatory 24 hour ECG recordings in 22 patients presented consecutively to the Holter ECG laboratory. SETTING: Patients followed in a specialised rheumatology consultation, in Santa Maria Hospital. PATIENTS: We have studied 22 patients (pts), 10 male and 12 female, aged 49.8 +/- 8.4 years, presenting PA diagnosed in average 12.9 years before. A group of 36 individuals, 25 male and 11 female, aged 37 +/- 8 years and without disease, were used as control. RESULTS: All patients were in sinus rhythm with a mean heart rate of 71 +/- 6 (min - 51.5 +/- 7.0 and max - 130.3 +/- 15.0). In 8 (36.6%) there were sinus bradycardia less than 50/min and sinus tachycardia (greater than 120/min) in 15 patients (68.1%). Two patients (9%) presented supraventricular tachycardia and one had AV block. There were premature atrial systoles in 14 pts (63.6%), and ventricular arrhythmias in 9 (40.9%). In control group, there were sinus bradycardia in 16.6%, sinus tachycardia in 33.3%, premature atrial systoles in 33.3% and ventricular arrhythmias in 25% of them; in 11% there were conduction disturbances. CONCLUSIONS: a) Premature atrial systoles were the rhythm disturbance more prevalent. b) Patients with PA presented a significant higher incidence of sinus bradycardia and sinus tachycardia. c) Cardiac conduction disturbances were not frequent. d) Our results may suggest the presence of a subtle autonomic dysfunction in patients with psoriatic arthritis.     

Gastrointestinal comorbidities in patients with psoriatic arthritis

Comorbidities associated with psoriatic arthritis (PsA) include cardiovascular diseases, diabetes mellitus, and obesity. This study evaluated the association between PsA and common gastrointestinal (GI) diseases. A retrospective study was performed in Israel’s largest health care provider database between 2002 and 2013. 3161 PsA patients were matched for age and sex with 31610 randomly selected patients. We searched these patients’ records for the presence of peptic ulcer disease (PUD), reflux esophagitis, Crohn’s disease, ulcerative colitis, irritable bowel syndrome (IBS) and celiac disease. T-test was used to compare continuous variables and a Chi-square test was used for categorical variables. Multivariate logistic regression models were used to assess the association between PsA and GI comorbidities. PsA was associated with Crohn’s disease (OR 2.4, 95 %CI: 1.75–3.32, p < 0.0001), ulcerative colitis (OR 2.1, 95 %CI: 1.33–3.26, p = 0.001), reflux esophagitis (OR 1.6, 95 %CI: 1.44–1.78, p < 0.0001), PUD (OR 1.5, 95 %CI: 1.31–1.63, p < 0.0001) and IBS (OR 1.4, 95 %CI: 1.01–1.86, p = 0.045). After controlling for known risk factors, the association remained significant between PsA and Crohn’s disease (OR 2.2, 95 %CI: 1.59–3.03, p < 0.0001), ulcerative colitis (OR 1.9, 95 %CI: 1.21–3.00, p = 0.005), reflux esophagitis (OR 1.5, 95 %CI: 1.31–1.63, p < 0.0001), and PUD (OR 1.3, 95 %CI: 1.12–1.47, p < 0.0001). No significant association was found between PsA and celiac disease. In the current study PsA was associated with gastrointestinal morbidities including Crohn’s disease, ulcerative colitis, PUD and IBS. Physicians treating patients with PsA should be aware of these associations.     

Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment

BACKGROUND: The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets. OBJECTIVE: To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs. METHODS: Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast-like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase-1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis. RESULTS: The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast-like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFalpha), interleukin (IL) 1beta, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis. CONCLUSION: These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFalpha blockade, there may be a rationale for treatments directed at IL1beta, IL6 and IL18.     

Neuropeptides in synovium of patients with rheumatoid arthritis and osteoarthritis

The presence of neural elements in synovial tissue proper has earlier been suggested on the basis of nonspecific silver impregnation techniques and is now confirmed in a study based on specific demonstration of cytoskeletal neurofilaments and various neuropeptides. With both the neurofilament and neuropeptide antisera, nerves were seen predominantly in a perivascular location, there being fewer nerves freely in the stromal tissue. In the synovium of patients with rheumatoid arthritis (RA), free stromal nerves stained with neurofilament antiserum often lacked neuropeptide immunoreactivity, while this was not the case in normal synovium or synovial samples from patients with osteoarthritis (OA). Furthermore, the intensity of staining of neurotransmitter peptides was weaker in RA than in OA or normal synovial tissue. It is suggested that neurogenic inflammation may play a role in RA and that neuropeptide nerves possibly release their mediators in RA.     

Characterisation of uveitis in patients with psoriatic arthritis

OBJECTIVE: The purpose of this study is to describe the clinical characteristics of uveitis related to psoriatic arthritis (PsA), and also to compare the uveitis in PsA to the uveitis in spondyloarthropathy (SA). METHODS: Sixteen patients with uveitis and PsA were evaluated in a tertiary care uveitis clinic. These patients were compared retrospectively to a series of 89 patients with uveitis and SA. RESULTS: Eight (50%) of the 16 patients with uveitis had strictly peripheral arthritis, while two (12.5%) had axial only, and six (37.5%) had axial and peripheral arthritis. Patients with uveitis and axial disease were more likely to be male (100% v 38%) and HLA-B27 positive (6 of 6 typed positive v 0 of 3 typed positive) when compared with those with uveitis and peripheral arthritis only. Compared with patients with SA, those with PsA were more likely to have insidious onset (19% v 3%), simultaneously bilateral (37.5% v 7%), chronic duration (31% v 6%), or posterior (44% v 17%) uveitis. Complications of uveitis were similar in the SA and PsA groups. CONCLUSION: Uveitis in patients with PsA was more likely to be insidious in onset, continuous, posterior, and active bilaterally compared with uveitis in patients with SA. Patients with uveitis and axial involvement were more likely to be male and HLA-B27 positive compared with patients with uveitis and peripheral arthritis alone. Patients with seronegative arthritis and uveitis that begins insidiously, lasts longer than six months, is bilateral, or is posterior, should be carefully questioned about the presence of either psoriasis or inflammatory bowel disease.     

Sonographic study of calcaneal entheses in erosive osteoarthritis, nodal osteoarthritis, rheumatoid arthritis and psoriatic arthritis

OBJECTIVE: To establish by ultrasonography (US) the frequency of calcaneal entheses involvement in erosive osteoarthritis (EOA), nodal osteoarthritis (NOA), RA and PsA, and to compare these results in order to aid clinicians in the differential diagnosis among these diseases. A comparison between US results and radiography was also made. METHODS: The heels of 56 consecutive outpatients with EOA, 209 with NOA, 158 with RA and 125 with PsA were studied by US and radiography. A control group of 50 subjects was examined by US. RESULTS: US showed no significant difference in inferior calcaneal enthesophytosis among the four diseases. The frequency of posterioinferior enthesophytosis was lower in RA (34%) in comparison with the other diseases (57% in EOA, 47% in NOA, 49% in PsA). Achilles enthesitis was found in 8% of PsA and in 2% of RA. Retrocalcaneal bursitis was found in 18% of RA and in 6% of PsA. Posterior erosions were present in 12% of RA and 5% of PsA. Inferior erosions were present in 6% of RA and in 1% of PsA. Plantar fasciitis was found in 26% of RA, in 37% of PsA, and in 15% of NOA and 12% of EOA. Subcalcaneal panniculitis was observed in 10% of RA and in 1% of PsA. In the control group, only posterioinferior and inferior enthesophytosis (22% and 18% respectively) were found. Kappa statistics show excellent agreement between US and radiography in detecting posterioinferior (kappa = 0.89) and inferior enthesophytosis (kappa = 0.83), and entheseal erosions (kappa = 0.86). CONCLUSIONS: The calcaneal lesions that could be found in EOA are similar to those observed in NOA. The frequency of calcaneal enthesophytosis is similar in EOA, NOA, and PsA, but inflammatory lesions of calcaneal entheses and of the adjacent bursae are more frequent in RA and in PsA. In terms of heel involvement, EOA seems to be similar to NOA. US shows an excellent concordance with radiography in detecting entheseal cortical bone abnormalities.