Borrelia burgdorferi VlsE antigen for the serological diagnosis of Lyme borreliosis.

In this study, raising and development of antibody response to Borrelia burgdorferi infection in 66 Italian patients suffering from culture-confirmed Lyme borreliosis erythema migrans (EM) was investigated. Sixty-two of 66 cultures obtained from biopsies were identified as B. afzelii by PCR. A total of 175 serially collected serum samples were tested by using two different sets of commercial assays: Enzygnost Lyme link VlsE/IgG and Enzygnost Borreliosis IgM (DADE Behring, Marburg, Germany) and LIAISON Borrelia IgG and IgM (Diasorin, Saluggia, Italy). Considering only samples obtained at first presentation when EM was clinically evident, 49/66 patients (72.4%) were IgG or IgM positive by Enzygnost, whereas 33/66 (50.0%) patients were IgG or IgM positive by LIAISON. Taking into account the follow-up period, eight patients sero-converted for IgG or IgM by Enzygnost and four by LIAISON. Similar and very good specificity values were obtained by all methods. Testing sera obtained from blood donors (n = 300) and from patients suffering from some of the most common biological conditions possibly resulting in false-positive reactivity in Lyme disease serology (n = 100) showed that Enzygnost Lyme link VlsE/IgG was the more specific (98.3%), followed by LIAISON Borrelia IgG (96.5%), and considering IgM tests, Enzygnost Borreliosis IgM showed to be 95.3%% specific, whereas the LIAISON Borrelia IgM was 92.8% specific. Recombinant VlsE antigens obtained from all three B.burgdorferi genospecies pathogenic to humans (included in Enzygnost Lyme link VlsE/IgG) greatly improved serodiagnosis of Lyme disease.

A comparison of the efficacy and tolerability of meloxicam and diclofenac in the treatment of patients with osteoarthritis of the lumbar spine.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of meloxicam compared with diclofenac in patients with osteoarthritis of the lumbar spine. SUBJECTS: 229 patients with radiologically confirmed osteoarthritis of the lumbar spine. TREATMENT AND METHODS: Once-daily meloxicam 7.5 mg tablet or diclofenac 100 mg slow release tablet. Efficacy and tolerability parameters were assessed at baseline and after 3, 7 and 14 days of treatment. RESULTS: The two drugs had equal short-term efficacy, with pain on motion of lumbar spine significantly (p<0.05) decreased at Day 3. Secondary efficacy variables were also significantly improved at Days 3, 7 and 14. There were no statistically significant differences between the two drugs, although the global tolerability of meloxicam was significantly better than for diclofenac, as assessed by the investigators (p = 0.0072) and the patients (p = 0.049). CONCLUSIONS: Meloxicam and diclofenac were equivalent in relieving the acute pain associated with osteoarthritis of the lumbar spine. However, meloxicam was much better tolerated.

An appraisal of magnetic resonance imaging of the wrist in rheumatoid arthritis.

OBJECTIVES: To evaluate the role of magnetic resonance imaging (MRI) in the diagnosis, staging, and follow-up of the rheumatoid wrist. METHODS: A Medline search was performed to identify all publications from the years 1985 to 1999 concerning MRI of the wrist in patients with rheumatoid arthritis (RA). Additional papers were retrieved by scanning the references to the Medline-listed articles. Details of the MRI technique, as well as clinical data, were analyzed and compared. RESULTS: A total of 55 papers were identified. There were considerable variations in imaging sequence, section type, and slice thickness. Erosions and synovitis were the conditions that mostly profited from the adoption of MRI. Although the visualization of erosions was better detailed with MRI than with conventional radiography, erosions were only rarely related to clinical and laboratory parameters. Another advantage was that synovitis imaging, which can be enhanced by contrast agents, was amenable to quantitation. The extent of the synovial surface and the rate of contrast enhancement in a series of consecutive, rapidly acquired images were the most common measures. CONCLUSIONS: MRI of the rheumatoid wrist is a useful technique to ascertain the criteria for diagnosis and progression of RA, and to monitor the effects of treatment. Implementation of a standardized protocol could further increase its value.

Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis.

OBJECTIVE: To correlate microvascular abnormalities, evaluated by nailfold videocapillaroscopy (NVC), with the duration of both Raynaud's phenomenon (RP) and systemic sclerosis (SSc) from the date of diagnosis, in a large number of patients with SSc. METHODS: Ninety-seven consecutive patients were recruited and distributed into 3 groups on the basis of the morphological NVC patterns observed: "early" (E), "active" (A), and "late" (L). In each group the age of patients, age at onset, and the duration of RP as well as of overt SSc were investigated and correlated with the different NVC pattern variables. RESULTS: The early appearance of giant capillaries and hemorrhages (E pattern) is of great relevance for the early diagnosis of SSc. Therefore, these alterations are more evident in the active phase of the disease (A pattern). Conversely, the NVC observation of loss of capillaries and vascular architectural disorganization and the presence of ramified/bushy capillaries (L pattern) represents the clearest aspect of advanced SSc microvascular damage. These morphological alterations were found to correlate significantly with the duration of both RP and SSc, as well as with age of patients (p = 0.0001). No significant differences were observed when the variables were analyzed in the patients classified as having limited cutaneous SSc or diffuse cutaneous SSc. CONCLUSION: Classification of defined major nailfold patterns may be useful in assessing the appearance and progression of sclerodermic microangiopathy. As well, nailfold changes might represent a morphological reproduction of the evolution of SSc.

Anticardiolipin antibodies, free protein S levels and thrombosis: a survey in a selected population of rheumatoid arthritis patients.

OBJECTIVE: To investigate plasma levels of natural anticoagulant proteins such as protein S, protein C and antithrombin III in a selected population of patients with rheumatoid arthritis (RA) with and without anticardiolipin antibody (aCL) positivity, and to evaluate the possible relationships with an increased risk of thrombotic events in RA. METHODS: A total of 184 female RA patients attending our Extra-Articular Involvement RA Clinic were evaluated for aCL levels, total and free protein S, protein C and antithrombin III concentrations, and for the occurrence of thrombotic events. Patients were grouped as aCL positive (n = 35) and aCL negative (n = 149). RESULTS: Higher rates of venous and/or arterial thromboses were diagnosed in patients with RA compared to controls (P = 0.01). In particular, lower free protein S levels were found in aCL-positive patients with RA compared to both aCL-negative patients and controls (P = 0.001). Functional assays for protein C, antithrombin III as well as total protein S levels were found to be in the normal range in all patients and controls. CONCLUSION: The association observed between aCL positivity and decreased levels of free protein S in RA patients may represent one of the risk factors for thrombotic events.

Melatonin influences interleukin-12 and nitric oxide production by primary cultures of rheumatoid synovial macrophages and THP-1 cells.

Because some of the clinical symptoms related to rheumatoid arthritis (RA) synovitis, such as joint morning stiffness and gelling, might be related to the effects exerted by the diurnal rhythmicity of the neurohormone melatonin (MLT) on synovial immune cell activation, we decided to evaluate the influence of MLT on the production of IL-12 and nitric oxide (NO) on primary cultures of RA synovial macrophages. Synovial macrophages were also prestimulated with lipopolysaccaride (LPS). Results were compared with those obtained on cultured human myeloid monocytic cells (THP-1). A significant increase in IL-12 (p = 0.01) was found in media of MLT-stimulated synovial macrophages versus RMPI-treated synovial macrophage controls. Interestingly, a significant decrease of IL-12 (p < 0.0001) was observed in media of synovial macrophages previously activated with LPS and then treated with MLT, when compared to synovial macrophages treated with LPS alone. A significant increase in NO levels (p = 0.01) was found in MLT-stimulated synovial macrophages versus RMPI-treated synovial macrophage controls. Interestingly, a nonsignificant increase of NO levels was observed in media of synovial macrophages previously activated with LPS and then treated with MLT, when compared to cynovial macrophages treated with LPS alone. Finally, a significant increase in IL-12 (p = 0.03) and NO (p = 0.002) concentrations was observed in media of MLT-stimulated THP-1 cells versus RMPI-treated controls. Our results therefore show that MLT induces IL-12 secretion and NO production by unstimulated cultured RA synovial macrophages and human monocytic myeloid THP-1 cells. The unexpected and opposite effects on IL-12 and NO production in RA synovial macrophages treated with LPS may be related to dose-dependent mechanisms exerted by MLT or to altered cell priming in RA macrophages; these are matters of our further research. This study strongly supports the role of MLT in immune response modulation and in particular suggests a close relationship between diurnal rhythmicity of neuroendocrine pathways, cytokine and reactive oxygen intermediate production by monocyte/macrophages, and synovial arthritis symptomatology, at least in RA.

Androgenizing effects of cyclosporin A in rheumatoid arthritis.

In order to determine the influence of CsA on whole peripheral androgen metabolism, we evaluated 14 patients with RA over a period of 12 months. Patients were treated with low-dose CsA (2.5-3.5 mg/kg/day). Other drugs influencing androgen metabolism were excluded. Plasma levels of Test and of 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (Adiol-G), an important peripheral Test metabolite, were analyzed. Each patient was monthly examined for the first three months, and thereafter every three months. At each visit, the number of swollen and tender joints, as well as the visual analogic scale of pain, were evaluated. The laboratory parameters of RA activity (ESR, CRP, Hb) were also monitored, along with some safety serological indexes. Statistical analysis was performed by using nonparametrical tests. After 12 months of treatment, an evident increase in mean plasma Adiol-G concentration was observed in patients of both sexes (women's basal levels +/- SE = 2.89 +/- 0.58 ng/mL vs. 12 months = 5.71 +/- 1.33 ng/mL; men's basal levels = 4.87 +/- 0.91 vs. 9.20 +/- 0.68, respectively) (p < 0.001). The increase was already statistically significant after 4-5 weeks of treatment in male patients (p < 0.01) and after 12-14 weeks in female patients (p < 0.05). All the patients experienced the side effect of a low-degree hypertrichosis after a mean period of 4-8 weeks. Concerning clinical parameters, a significant improvement (p < 0.05) of the number of swollen and tender joints was observed after 12 months, as well as a reduction of CRP levels. No statistically significant correlation between hormonal levels and clinical or laboratory indexes of disease activity was observed. In conclusion, the appearance of a dose-related hypertrichosis and the increase in plasma androgen metabolites (Adiol-G) in CsA-treated patients should be regarded as possible markers of the influence of CsA on peripheral androgen metabolism, at the level of target cells and tissues.

Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids.

OBJECTIVE: To assess hypothalamic-pituitary-adrenocortical axis function in patients with rheumatoid arthritis (RA) not previously treated with glucocorticoids in relation to their inflammatory condition and in comparison to healthy controls. METHODS: We evaluated, in 10 premenopausal patients with RA and 7 age matched controls, plasma dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and cortisol concentrations, together with inflammatory cytokine levels [interleukin 6 (IL-6) and IL-12], both in basal conditions and after stimulation with ovine corticotropin releasing hormone (oCRH) and with low dose intravenous (5 microg) adrenocorticotropic hormone (ACTH). RESULTS: DHEA and DHEAS basal concentrations were found to be significantly lower (p<0.05) in premenopausal patients with RA than in controls. As expected, significantly higher basal levels of IL-6 and IL-12 (p<0.05) were found in patients with RA. After the low dose ACTH testing, the DHEA area under the curve value was found to be significantly lower (p<0.01) in patients than controls. Similar results, but without statistical significance, were observed after oCRH stimulation. DHEA levels at basal time showed a significant negative correlation with the erythrocyte sedimentation rate and platelet count, as well as with the Steinbrocker class of the disease (p<0.05). Normal plasma cortisol levels during oCRH and ACTH testing were found in patients with RA in spite of their inflammatory condition. After ACTH testing, IL-6 levels decreased significantly (p<0.05), whereas IL-12 levels were unchanged. No significant changes in IL-6 and IL-12 levels were found after oCRH testing. CONCLUSION: The abnormal androgen concentrations observed during testing in patients with RA might support the implication of adrenal androgens in the immune/inflammatory cytokine mediated mechanisms involved in the pathophysiology and clinical aspects of RA.

Prevalence of rheumatoid arthritis in Italy: the Chiavari Study.

OBJECTIVE: To ascertain the prevalence of rheumatoid arthritis (RA) in an Italian general population. METHODS: The study was performed in the years 1991-92 in Chiavari, a small town located on the Ligurian coast, and involved 4456 subjects aged 16 years or more from four general practices. The subjects received a postal questionnaire developed to detect patients with current or past inflammatory joint diseases. The age and sex distribution of the sample were similar to those of the Italian population from the 1992 census. Patients reporting a history of joint swelling in at least a pair of symmetrical joints were reviewed by a rheumatologist. The clinical records of non-responders and responders who failed to attend the clinic were also reviewed. RESULTS: 3294 of 4456 (73.9%) subjects answered to the questionnaire. The mean (SD) age of the 3294 responders was 48.3 (19.3) years; 53.7% of them were female. Swelling in at least two symmetrical joints was reported by 230 subjects (7%). Among them, 11 patients fulfilling the 1987 ARA criteria for RA were identified. The prevalence of RA was 0.33% (95% CI 0.13, 0.53) in the general population, 0.13% (95% CI 0, 0.31) in men, and 0.51% (95% CI 0.18, 0.84) in women. CONCLUSIONS: These data are consistent with the results of three earlier studies published in the fifties in the Italian literature and confirm that the prevalence of RA is low in Italy and has remained unchanged in the last 40 years.

Effect of cyclosporin on apoptosis in human cultured monocytic THP-1 cells and synovial macrophages.

OBJECTIVE: Cyclosporin A (CyA) is an immunosuppressant drug used for the treatment of rheumatoid arthritis (RA), that might affect programmed cell death (apoptosis) of the cells involved in the synovial inflammatory reaction. The effects of CyA on apoptosis were evaluated on cultured human monocytic myeloid cells (THP-1 cell line) and on RA synovial macrophages. METHODS: In order to induce THP-1 cell differentiation into adherent cells, an amount of these was treated with human recombinant IFN-gamma before incubation with CyA. Primary cultures of synovial macrophages were obtained from RA patients and treated in vitro with CyA. RESULTS: CyA, at the pharmacological range (100-300 ng/ml) employed in the treatment of RA, seems to induce, after 48-96 hrs, programmed cell death in differentiating THP-1 cells, whereas cultured synovial macrophages (fully differentiated monocytic cells) do not show any apoptosis at the same time. CONCLUSION: Short-term CyA treatment may induce increased apoptosis in immature and differentiating cultured monocytes. Cultured synovial macrophages (resident monocytic-derived and differentiated cells) seem to be resistant to the treatment as far as apoptosis is concerned.

Impaired quantitative cerebral blood flow in scleroderma patients.

Systemic Sclerosis (SSc) is a multisystem disease characterised by proliferation of vascular tissue, obliterative microvascular lesions and diffuse organ fibrosis. Despite widespread vascular disease, Central Nervous System complaints are only infrequently reported and it is uncertain whether they merely derive from systemic complications or whether they may be also caused by a primary vascular process within the brain. Regional cerebral blood flow (rCBF) was quantitatively measured by the 133Xenon clearance technique in twenty-seven consecutive SSc patients without relevant systemic complications and with different severity of vascular involvement, as staged by nailfold capillary videomicroscopy (NCV). Absolute, percent, and asymmetry rCBF values were compared (z-statistics) with age- and sex-matched healthy controls. Cerebral MRI and Mini-Mental State Examination (MMSE) were also performed. Doppler sonography of neck vessels and Transcranial Doppler sonography (TCD) were performed in patients presenting rCBF reduction. Cerebral hypoperfusion was found in the 52% of patients, i.e.: in 33% of patients with the 'early' NCV pattern, in 56% of patients with the 'active' pattern, and in 67% of patients with the 'late' NCV pattern. Thirty percent were the MRIs showing focal and/or diffuse signal abnormalities in the white matter of both hemispheres with the highest rate (44%) in the 'late' NCV pattern. MMSE disclosed mild dementia in one patient in the 'late' NCV group and some mistakes in 6 more patients, in the 'active' or 'late' NCV groups, whereas TCD failed to find significant stenosis of Willis' arteries. Cerebral hypoperfusion is shown for the first time in a substantial part of SSc patients without either neurological symptoms or relevant systemic complications. It is suggested that the rCBF reduction might be related to the systemic scleroderma microangiopathy although, probably due to the paucity of connective tissue in cerebral vessels, the vast majority of patients remains in a subclinical phase.

Effects of cyclosporin on joint damage in rheumatoid arthritis. The Italian Rheumatologists Study Group on Rheumatoid Arthritis.

According to the most recent literature, few antirheumatic drugs can claim disease-controlling properties over the anatomical joint damage in rheumatoid arthritis (RA). A small number of studies have favored one or another of the available agents, in particular parenteral gold salts, sulphasalazine and methotrexate, but the evidence regarding their efficacy is not convincing when analysed using methodological criteria known to be important in evaluating radiologic evidence of joint damage. The radiologic results in long-standing RA patients have shown that CsA may be of benefit in reducing disease progression. Data from the second year of a clinical trial designed to compare the disease-controlling, anti-rheumatic properties of CsA with those of conventional disease-modifying anti-rheumatic drugs (DMARDs) in early RA support the hypothesis that CsA may be useful in delaying the appearance of new joint erosion.