Increased production of endothelin-1 in patients with inflammatory arthritides

Objective. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide, but its precise mechanism of action in vivo has remained unknown. Methods. We measured ET-1 activity by radioimmunoassay, in both plasma and synovial fluid from patients with inflammatory arthritides. Results. ET-1–like immunoreactivity was found in synovial fluid, at levels severalfold higher than those in plasma. Reverse-phase high-performance liquid chromatography showed an elution profile corresponding to actual ET-1. A single class of high-affinity binding sites for ET-1 in cultured synovial cells was also detected. Furthermore, ET-1 induced mild DNA synthesis in synovial cells. Conclusion. Taken together, these results indicate that ET-1 might contribute to the synovial proliferation seen in inflammatory arthritides, in an autocrine/paracrine manner.     

Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. I. Relativity to inflammatory activity

Lipoprotein metabolism was investigated in 69 patients with untreated active rheumatoid arthritis (n = 48) and in seronegative spondylarthropathies (n = 21). The patients had high inflammatory activity as measured by erythrocyte sedimentation rate and C-reactive protein (CRP). Serum cholesterol and cholesterol levels in the very-low-density lipoprotein (VLDL), low-density lipoprotein, and high-density lipoprotein fractions were reduced by 20% to 30% compared with healthy controls; and triglyceride levels in VLDL and high-density lipoprotein were reduced by 10% to 30%. There were significant correlations between the inflammatory activity and certain lipoprotein lipids, ie, between CRP and VLDL triglycerides, VLDL cholesterol, and serum triglycerides. The fractional elimination rate (K2) measured by an intravenous fat tolerance test was 30% higher in the patients than in the controls despite reduced tissue lipoprotein lipase activities. There was correlation between CRP and the K2 value. These findings suggest that it is the degree of inflammatory activity that governs the altered lipoprotein metabolism in untreated active chronic inflammatory arthritides. The relationships between CRP and VLDL and between CRP and K2 suggest that the VLDL particles may be altered by inflammatory process, and that the increased elimination may take place through the "scavenger pathway."     

The prevalence of Mycoplasma fermentans in patients with inflammatory arthritides.

OBJECTIVES: To search for evidence that Mycoplasma fermentans is involved in the pathogenesis of some forms of human arthritis by testing for the presence of mycoplasmal DNA in joint material. METHODS: M. fermentans DNA was detected by the identification of a 104-base pair amplification product of the polymerase chain reaction (PCR). RESULTS: M. fermentans DNA was detected in synovial fluid samples from six (17%) of 35 patients with rheumatoid arthritis (RA) and 18 (21%) of 85 patients with seronegative arthritis. These detection rates were significantly greater than in samples from patients with osteoarthritis or crystal synovitis, none of 26 of these being positive. CONCLUSIONS: M. fermentans could be involved in the pathogenesis of some forms of inflammatory arthritis and this possibility is worthy of further study.     

Ultrasonography in the diagnosis and management of patients with inflammatory arthritides

In primary care and internal medicine settings clinicians are often reluctant to take advantage of the resources that ultrasonography (US) offers as a diagnostic tool in the initial management of patients with inflammatory arthritis, despite the recognised importance of an accurate and timely diagnosis of rheumatoid arthritis (RA) and of early referral to ensure optimal patient management. Both grey-scale (GS) and power Doppler (PD) imaging have been extensively used in early detection of synovitis and bone erosions in patients with inflammatory arthritides. We reviewed the main data on the clinical use of US in the initial management of patients with inflammatory arthritis, focusing on RA diagnosis in patients with undifferentiated arthritis, prediction of disease severity, differential diagnoses and assessment of synovitis in children with juvenile idiopathic arthritis (JIA). The role of US in assessing treatment response and monitoring disease activity in clinical remission was also briefly evaluated. The reliability of US as a diagnostic tool in rheumatological diseases has greatly advanced in the last years and the use of this imaging technique, in association with conventional assessments such as physical examination and serological tests, should be considered more often also in primary care settings.     

Increased production of endothelin-1 in patients with inflammatory arthritides.

OBJECTIVE. Endothelin-1 (ET-1) is a potent vasoconstrictive peptide, but its precise mechanism of action in vivo has remained unknown. METHODS. We measured ET-1 activity by radioimmunoassay, in both plasma and synovial fluid from patients with inflammatory arthritides. RESULTS. ET-1-like immunoreactivity was found in synovial fluid, at levels severalfold higher than those in plasma. Reverse-phase high-performance liquid chromatography showed an elution profile corresponding to actual ET-1. A single class of high-affinity binding sites for ET-1 in cultured synovial cells was also detected. Furthermore, ET-1 induced mild DNA synthesis in synovial cells. CONCLUSION. Taken together, these results indicate that ET-1 might contribute to the synovial proliferation seen in inflammatory arthritides, in an autocrine/paracrine manner.     

Mycoplasma fermentans in rheumatoid arthritis and other inflammatory arthritides

OBJECTIVE: To evaluate the association between infection with Mycoplasma fermentans (Mf) and rheumatoid arthritis (RA) and other inflammatory arthritides. METHODS: Screening of synovial fluid samples (SF) for Mf was done by culture and by polymerase chain reaction (PCR) in 38 and 34 RA patients, respectively, 8 undifferentiated arthritis (UDA), 9 reactive arthritis (ReA), and in 40 other arthritides. The prevalence of antibodies to Mf in these SF was determined by both ELISA and immunoblotting (IB). Antibodies were measured also in sera of 88 RA patients, 28 ReA, 14 UDA, 71 other arthritides, and in 102 healthy blood donors. RESULTS: All SF were culture-negative for Mf, while 7 SF were positive by PCR (6/34 RA and 1/8 UDA). SF from patients with other arthritides and ReA were PCR-negative. The prevalence of anti-Mf antibodies in SF of RA patients was significantly higher than in SF of other arthritides (p = 0.01). In 47% (17/38) of all RA (including the 6 PCR-positive patients), the level of antibodies to Mf in their SF was higher than that in sera, compared to 7.5% (3/40) in other arthritides (p = 0.0002). There was no significant difference in the prevalence of serum antibodies to Mf between patients with RA, other arthritides, and healthy controls. By IB with Mf sonicate, binding to Mf peptides P107, P48, and P29 was detected in SF of 7/11 RA patients but not in 11 patients with traumatic arthritis. Specific binding to Mf membrane lipoproteins was also more prevalent in SF of RA patients than in other arthritides (p = 0.038). CONCLUSION: The finding that both Mf DNA and specific antibodies to Mf were present in the SF of RA patients suggests that in some RA patients Mf may play a role in initiating or perpetuating synovitis.     

Intra-articular therapy of chronic arthritides]

The intraarticular therapy with the aim of the direct influence on the pathologically changed synovial membrane increasingly gains significance. On the basis of own results as well as literary data the present possibilities of the local treatment of chronic arthritides are described. After discussion of the advantages and disadvantages of the individual usable preparations a scheme of therapy elaborated for the use of local therapeutics in chronic synovialitis is described. Exact indications for the use of the intraarticular as well as operative methods for therapy of chronic synovialitis must still be established.     

Fertility outcomes in women with hypopituitarism

BACKGROUND: Women with hypopituitarism are known to have a poor outcome once pregnancy has been achieved by ovulation induction. There are no data, however, recording the efficacy of ovulation induction and pregnancy rates in this group of subfertile women. METHODS: The outcome of fertility treatments in all 19 women with hypopituitarism attending the fertility clinics of University College London Hospitals over the past 20 years was audited. RESULTS: Ovulation was achieved in almost all women (95%) but occurred in only 60% of treatment cycles. Pregnancy was achieved in 47% of women or 11% of cycles resulting in a live birth rate of 6.7% per cycle. Seven of the 18 pregnancies (39%) miscarried. Only 42% of women treated achieved a live birth. CONCLUSION: Ovulation induction in women with hypopituitarism yields relatively low pregnancy rates in comparison to other causes of anovulation and a high miscarriage rate. Pituitary hormone deficiency beyond gonadotrophins has a major adverse effect on achieving pregnancy.     

Prevention of disuse muscle atrophy in chronic arthritides

This article briefly reviews the causes and physiologic considerations of skeletal muscle disuse atrophy. This is a common problem associated with chronic arthritides. Methods of preventing or modifying this disability are presented.     

Polymorphonuclear granulocytes in rheumatic tissue destruction VIII. Considerations on the inflammatory cartilage destruction in chronic arthritides in comparison with liver injuries by PMN's

Inflammatory cartilage destruction in chronic arthritides is usually regarded as the process owing to chondrocytic chondrolysis or ingrowth of pannus tissue. Besides these two mechanisms a third one-cartilage degradation directly mediated by polymorphonuclear granulocytes (PMN's) of the synovial fluid-seems to be underestimated. There is growing evidence that PMN's are involved in several non-bacterial organ destructions (e.g., alcoholic hepatitis); thus, two case reports are presented demonstrating cartilage destruction by PMN's via the synovial fluid. It is shown by light and electron microscopy that in florid rheumatoid arthritis, PMN's from the inflamed synovial fluid can gain access to the cartilaginous surface. The adherence of PMN's to the superficial matrix, eventually mediated by immunocomplexes, may activate these cells with the subsequent secretion of destructive enzymes as well as reactive oxygen species. Cartilage degradation may be the consequence. From the morphological findings it is deduced that this mechanism may have important implications for inflammatory cartilage loss.     

Hypoxanthine, xanthine, and urate in synovial fluid from patients with inflammatory arthritides.

As nucleotide catabolism increases during tissue injury the appearance of purine metabolites in inflamed synovial fluid might be of value in understanding the joint damage in inflammatory arthritides. In this study, therefore, synovial and plasma concentrations of hypoxanthine, xanthine, and urate in 16 patients with rheumatoid arthritis (three with psoriatic arthropathy) were analysed. It was found that their plasma concentrations of hypoxanthine were greater than those of a reference group of healthy subjects. The synovial fluid concentrations of hypoxanthine, xanthine, and urate were higher than corresponding concentrations in plasma. Positive correlations were found between the respective plasma and synovial fluid values of xanthine and urate. These findings indicate a local enhanced purine metabolism in inflamed joint tissue and diffusion of oxypurines from joint cavity to plasma. No relation was found between measured metabolites and disease duration, radiological joint findings, or synovial fluid cells. Except for a weak correlation between plasma urate and serum haptoglobin, measured purine metabolites were not related to laboratory measures of systemic inflammation.     

Expression of decay-accelerating factor on synovial lining cells in inflammatory and degenerative arthritides

Summary The decay-accelerating factor (DAF) is a complement regulatory cell surface protein that protects cells from complement-mediated lysis. We analysed synovial tissue biopsies from patients with chronic arthritides for the presence of DAF using immunohistochemistry. DAF was expressed in the synovial lining cell layer both in rheumatoid arthritis (RA) and in osteoarthritis (OA). DAF was also on vascular endothelial cells of synovial tissue. A significant correlation was found between the expression of DAF and of HLA-DR in the lining layer, suggesting that DAF may be induced during a local inflammatory response. In addition, C5b-9 terminal complement complexes were found in several DAF-positive cases, suggesting that complement activation might, in itself, induce DAF expression. We propose that the occurrence of DAF may represent a physiological mechanism for local complement regulation in synovial tissue.     

Serum lipoprotein in active rheumatoid arthritis and other chronic inflammatory arthritides. II. Effects of anti-inflammatory and disease-modifying drug treatment

Serum lipids and lipoprotein patterns were prospectively analyzed in 33 previously untreated patients with active chronic inflammatory arthritides during different anti-inflammatory and disease-modifying drug regimens. Before treatment the lipoprotein pattern was characterized by low cholesterol concentrations in all lipoprotein fractions and low triglyceride concentrations in the very-low-density lipoprotein fraction as well as in the high-density lipoprotein fraction. During treatment with prednisolone combined with azathioprine or cyclophosphamide (n = 10), a reduction of the disease activity was achieved and the lipoprotein pattern was normalized; similar results were noted in a small group of patients (n = 4) treated with prednisolone alone while nonsteroidal anti-inflammatory drug therapy (n = 9) neither significantly affected the lipoprotein pattern nor the inflammatory activity measured by the acute-phase reactants. The long-term treatment with penicillamine (n = 4) and chloroquine (n = 6) induced both a clinical remission of the disease and a reduction of the inflammatory activity. The lipoprotein concentrations started to reverse to the normal values during penicillamine treatment. In contrast, in the chloroquine-treated group the alterations in lipoprotein lipid concentrations were further pronounced, ie, the cholesterol and triglyceride concentrations in serum and the very-low-density lipoprotein fraction decreased.     

Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides

Interleukin-6 (IL-6), also called 26-kd protein, hybridoma plasmacytoma growth factor, beta 2-interferon, or B cell stimulatory factor 2, is a recently described human cytokine with multiple growth and differentiation activities. Using a very sensitive bioassay based on the growth factor activity of this protein for B cell hybridomas, we found that IL-6 activity was significantly elevated in synovial fluid from patients with rheumatoid arthritis (RA) or other inflammatory arthritides, as compared with that in a group of patients with osteoarthritis. Moreover, IL-6 was detected in about one-third of the serum samples from patients with RA. In the latter group, we found a significant correlation between serum IL-6 activity and serum levels of C-reactive protein, alpha 1-acid glycoprotein, alpha 1-antitrypsin, fibrinogen, and haptoglobin, which indicates that IL-6 is related to disease activity in patients with RA.