Simvastatin inhibits cytokine production and nuclear factor-kB activation in interleukin 1beta-stimulated synoviocytes from rheumatoid arthritis patients.

OBJECTIVES: Recent studies demonstrated in vivo the effectiveness of statins in reducing the inflammatory response in rheumatic diseases, and still more recently, simvastatin has been reported to inhibit in vitro IL-6 and IL-8 production by unstimulated fibroblast-like-synoviocytes (FLS) from rheumatoid arthritis (RA) patients. However, no data are available on the effect of statins on the production of these cytokines induced by IL-1, which plays a crucial role in joint inflammation in the course of active RA in vivo. METHODS: In 12 RA patients, synovial tissue specimens were taken to obtain cultures of FLS. Cultures were incubated with IL-1 +/- simvastatin (5-50 micromol/l), and IL-6 and IL-8 production was evaluated (ELISA), also following the addition of mevalonate and its isoprenoid derivatives. Moreover, nuclear factor-kB (NF-kB) activation (immunocytochemistry and Western Blot analysis) were also evaluated. RESULTS: Culture incubation with IL-1 produced a dramatic increase (up to 40-fold) in cytokine production with respect to unstimulated cells. Simvastatin significantly inhibited (about 20%) IL-6 and IL-8 production from IL-1-stimulated FLS. This effect was completely reverted by the concomitant incubation with mevalonate or geranylgeraniol (but not farnesol or squalene). Moreover, simvastatin produced a clear-cut inhibition of IL-1-induced NF-kB activation. CONCLUSION: Simvastatin significantly inhibits the production of IL-6 and IL-8 also in IL-1-stimulated FLS, even though to a lesser extent than in unstimulated cells, via a HMG-CoA-reductase block with an interference in prenylation process and NF-kB activation. Our results further support the rationale for the use of statins in the treatment of rheumatoid synovitis.

Hyperhomocysteinemia: a cardiovascular risk factor in autoimmune diseases?

Epidemiological studies conducted over the past 25 years have provided ample support for the association of mild hyperhomocysteinemia (HHcy) with an elevated risk of atherothrombosis. Since autoimmune disorders (AD) are frequently associated with relevant and early signs of atherothrombotic damage not adequately explained by the traditional risk factors involved in the onset of cardiovascular disease (CVD), a large interest has been shown to the putative role of mild HHcy in this setting. On the basis of such considerations, we focused the attention on the relationship between homocysteine (Hcy) and CVD in patients affected with autoimmune diseases, reviewing the most recent literature data and also providing our original experience. Although the large amount of available studies clearly shows that HHcy represents a common finding in patients affected with several autoimmune diseases, the actual role of Hcy in the development of CVD in the course of AD is not clear yet, perhaps, with the only exception of the systemic lupus erythematosus. In the other conditions, the role of Hcy in the pathogenesis of vascular complications is still a matter of debate, as the result of conflicting reports and/or lack of an adequate body of investigation.

Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthritis patients.

OBJECTIVE: Hyperhomocysteinemia is commonly observed in Rheumatoid Arthritis (RA) patients, thus putatively accounting in part for the high rate of cardiovascular events in these subjects. Homocysteine (Hcy) is known to exert a pro-inflammatory effect putatively contributing to the progression of atherosclerotic lesions by cytokine production from several vascular cell-types. In order to evaluate the possibility that Hcy may play a direct pro-inflammatory activity also in the joints of RA patients, we investigated: (i) the joint concentration of Hcy, and (ii) the effect of Hcy on cytokine production by unstimulated and IL-1beta-stimulated human RA cultured synoviocytes. METHODS: In 5 RA and 5 controls subjects, Hcy was measured in the blood and knee synovial fluid, and specimens of synovial tissue were taken to obtain cell cultures. Cultures were incubated with Hcy (10-100 micromol/l) +/- IL-1beta, and IL-6 and IL-8 concentrations were evaluated in the supernatants (ELISA) together with the activation of nuclear factor-kB (NF-kB) (immunocytochemistry). RESULTS: Hcy was present in synovial fluids, with a mean concentration significantly higher in RA patients than in controls (9.0 +/- 1.1 vs 5.9 +/- 1.2 micromol/l). Hcy enhanced IL-6 and IL-8 production in RA synoviocytes only (up to 35%). Moreover, Hcy produced a clear-cut activation of NF-kB in rheumatoid cells only. CONCLUSION: Hcy enhances IL-1-dependent cytokine production by rheumatoid synoviocytes at a concentration measurable in RA joints in vivo. Thus, in RA patients, Hcy may not only represent an important risk factor for the progression of cardiovascular diseases, but it may also contribute to the joint damage.

Simvastatin reduces MMP-3 level in interleukin 1beta stimulated human chondrocyte culture.

OBJECTIVES: Matrix metalloproteinases (MMPs) produced by chondrocytes play a role in the development of cartilage degradation in joint diseases. Moreover, inhibition of MMP secretion by macrophages accumulating in arteriosclerotic plaques would account for the plaque stabilising activity of statins in cardiovascular patients. Recently, simvastatin has been shown to inhibit both developing and established collagen induced arthritis in a murine model. We thus decided to investigate the effect of simvastatin on the production of MMP-3 from cultured interleukin (IL)1 stimulated human chondrocytes. METHODS: Cells from human cartilage, obtained from eight subjects with osteoarthritis undergoing surgery for total hip prostheses, were cultured in the presence of different concentrations of simvastatin (5, 10, and 50 micromol/l) with and without IL1beta (5 ng/ml). MMP-3 level was measured in the culture medium after 48 h of incubation. RESULTS: IL1beta stimulation of chondrocytes increased MMP-3 concentration in the cultures (from 0.69 (0.09) to 1.94 (0.12) ng/microg protein). Incubation with simvastatin was associated with a dose dependent reduction in MMP-3 increase, both in the presence (-15%, -17%, and -26% with 5, 10, and 50 micromol/l, respectively) and in the absence (-32% with 50 micromol/l) of IL1beta. The inhibiting effect of simvastatin was completely reversed by the addition of mevalonate (100 micromol/l) or farnesol (10 micromol/l). CONCLUSIONS: Our data show that simvastatin, by blocking HMGCoA-reductase and interfering in the prenylation processes, is able to inhibit MMP-3 production from cultured human chondrocytes that have been either unstimulated or stimulated with IL1beta, thus suggesting a possible additional mechanism for statins in counteracting chronic joint disease related cartilage damage.

Ultrasound and clinical evaluation of quadricipital tendon enthesitis in patients with psoriatic arthritis and rheumatoid arthritis.

Enthesitis is an inflammatory lesion of the tendon, ligament and capsular insertions into the bone, and it is a fundamental element in the diagnosis of spondyloarthropathies. Sonography is the method of choice for studying periarticular soft tissues because it is capable of detecting both the early (oedema, thickening) and late alterations (erosions and enthesophytes); it is also an inexpensive, biologically harmless and easily repeatable technique. The aim of this study was to compare the prevalence of quadricipital enthesitis in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients, and to document any clinical and echostructural differences in this lesion between the two diseases. The results show that enthesitis is more frequent in PsA patients, more than half of whom are asymptomatic. Knee inflammation was found in the PsA patients with enthesitis regardless of the concomitant presence of joint effusion; none of the RA patients suffered from enthesitis alone. Quadricipital enthesitis is more frequent in male patients. There was no significant correlation between the presence of peripatellar psoriatic lesions and enthesitis. Sonographic examinations of patients with enthesitis revealed that those with RA had predominantly inflammatory lesions, whereas PsA patients also showed major new bone deposition.

Ultrasound and clinical evaluation of quadricipital tendon enthesitis in patients with psoriatic arthritis and rheumatoid arthritis.

Enthesitis is an inflammatory lesion of the tendon, ligament and capsular insertions into the bone, and it is a fundamental element in the diagnosis of spondyloarthropathies. Sonography is the method of choice for studying periarticular soft tissues because it is capable of detecting both the early (oedema, thickening) and the late alterations (erosions and enthesophytes); it is also an inexpensive, biologically harmless and easily repeatable technique. The aim of this study was to compare the prevalence of quadricipital enthesitis in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) patients, and to document any clinical and echostructural differences in this lesion between the two diseases. The results show that enthesitis is more frequent in PsA patients, more than half of whom are asymptomatic. Knee inflammation was found in the PsA patients with enthesitis regardless of the concomitant presence of joint effusion; none of the RA patients suffered from enthesitis alone. Quadricipital enthesitis is more frequent in male patients. There was no significant correlation between the presence of peripatellar psoriatic lesions and enthesitis. Sonographic examinations of patients with enthesitis revealed that those with RA had dominantly inflammatory lesions, whereas PsA patients also showed major new bone deposition.

Bone mineral density in patients with psoriatic arthritis.

OBJECTIVE: Little information is available concerning bone mass in patients with psoriatic arthritis (PsA): the existence of less severe periarticular osteoporosis is considered possible, but there are no data concerning the existence of systemic osteoporosis. We investigated bone mineral density (BMD) in patients with PsA. METHODS: We studied 186 patients with non-axial PsA and 100 healthy subjects, equally divided into 3 groups: women of child-bearing age, women in menopause, and men. No patient had previously received steroid treatment. In all patients, evaluation was made of disease duration, inflammation indices (erythrocyte sedimentation rate, C-reactive protein), functional indices (Steinbrocker scale), and the Health Assessment Questionnaire (HAQ). BMD was measured by fan-beam x-ray densitometry of the lumbar spine, femur, and total body (evaluating the whole skeleton, as well as the spine, trunk, and upper and lower limbs). Ultrasound densitometry of the heel was also performed. RESULTS: BMD was significantly lower in the arthritic than in the healthy subjects regardless of sex, menopausal status, or age, as expressed in g/cm2 (lumbar spine 1.112 vs 1.326; femoral neck 0.870 vs 1.006; total body 1.125 vs 1.203) or by T and Z scores (lumbar T = -1.36, Z = -0.98; femoral neck T = -1.12, Z = -0.83; total body T = -1.09, Z = -0.65). Ultrasound densitometry of the heel was similarly altered (stiffness 96 vs 77; T -1.78; Z -1.29). Among the PsA patients, demineralization in at least one skeletal region was observed in 67% of premenopausal women (marked in 11%), 100% of postmenopausal women (marked in 47%), and 80% of the men (marked in 29%). In premenopausal women, demineralization did not correlate with the disease variables; in postmenopausal women and the men, it correlated with a decline in the functional indices and the HAQ score. This was confirmed by analysis of the relative risk of osteoporosis expressed in odds ratios (HAQ: 1.6; age: 1.4; years since menopause: 1.7). CONCLUSION: Demineralization was observed in more than 2/3 of our PsA patients without axial involvement. This demineralization was not related to the indices of inflammation or disease duration, but there is a delayed correlation with HAQ score, as well as age and the number of years since menopause.

[Evaluation of the efficacy and tolerance of radioactive fangotherapy in gonarthrosis. Comparative study versus short wave therapy]. / Valutazione dell'efficacia e della tollerabilità della fangobalneoterapia radioattiva nella gonartrosi. Studio comparativo versus marconiterapia.

BACKGROUND: Spa therapy is frequently used in daily rheumatological practice, but its benefit remains to be evaluated. The purpose of this paper is to evaluate the effectiveness and tolerability of mud-packs and mineral baths with fluorurate radioactivity water from the thermal resort of Merano (Bolzano) versus short wave therapy in patients with osteoarthritis of the knees. METHODS: Forty-eight patients were treated for a period of two weeks with mineral water baths and mineral mud-packs and twenty-four patients were treated with short-wave therapy for the same period. Assessment criteria were spontaneous pain ratings on a visual analogue scale (VAS), functional impairment (Lequesne's index), quality of life index (AIMS1), analgesic and/or non-steroidal anti-inflammatory drugs consumption and patient and physician assessment of effectiveness and tolerability of treatments. These criteria were recorded at the beginning and at the end of the treatments and after 3 months. RESULTS: A significant improvement (p < 0.0001) in the Lequesne's index, in the VAS and a significant decrease in analgesic consumption was achieved in both groups up to 15 days. The improvement remains to the end of the follow-up period only in the group treated with spa therapy. CONCLUSIONS: This study suggests that spa therapy has a prolonged, beneficial, symptomatic effect in osteoarthritis of the knees.