Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project.

OBJECTIVE: The aim of this work was to assess baseline serum levels of established biomarkers related to inflammation and oxidative stress in samples from alkaptonuric subjects enrolled in SONIA1 (n = 40) and SONIA2 (n = 138) clinical trials (DevelopAKUre project). METHODS: Baseline serum levels of Serum Amyloid A (SAA), IL-6, IL-1ß, TNFα, CRP, cathepsin D (CATD), IL-1ra, and MMP-3 were determined through commercial ELISA assays. Chitotriosidase activity was assessed through a fluorimetric method. Advanced Oxidation Protein Products (AOPP) were determined by spectrophotometry. Thiols, S-thiolated proteins and Protein Thiolation Index (PTI) were determined by spectrophotometry and HPLC. Patients' quality of life was assessed through validated questionnaires. RESULTS: We found that SAA serum levels were significantly increased compared to reference threshold in 57.5% and 86% of SONIA1 and SONIA2 samples, respectively. Similarly, chitotriosidase activity was above the reference threshold in half of SONIA2 samples, whereas CRP levels were increased only in a minority of samples. CATD, IL-1ß, IL-6, TNFα, MMP-3, AOPP, thiols, S-thiolated protein and PTI showed no statistically significant differences from control population. We provided evidence that alkaptonuric patients presenting with significantly higher SAA, chitotriosidase activity and PTI reported more often a decreased quality of life. This suggests that worsening of symptoms in alkaptonuria (AKU) is paralleled by increased inflammation and oxidative stress, which might play a role in disease progression. CONCLUSIONS: Monitoring of SAA may be suggested in AKU to evaluate inflammation. Though further evidence is needed, SAA, chitotriosidase activity and PTI might be proposed as disease activity markers in AKU.

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0-10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Chronic inflammation and low-dose glucocorticoid effects on glucose metabolism in premenopausal females with rheumatoid arthritis free of conventional metabolic risk factors.

Chronic systemic inflammation is associated with increased cardiovascular mortality in patients with rheumatoid arthritis (RA). The aim of our study was to investigate association of glucose metabolism and inflammatory markers in a group of patients with rheumatoid arthritis free of other metabolic risk factors. Twenty-two premenopausal RA females (11 patients on low-dose GC (<8.5 mg/day of prednisone or equivalent), 11 patients without glucocorticoid therapy) and 15 age- and BMI-matched healthy females underwent the oral glucose tolerance test. The insulin sensitivity indices according Matsuda (ISI(MAT)) and Cederholm (ISI(CED)) as well as HOMA2 %S were calculated. Cytokines, lipid profile, non-esterified fatty acids (NEFA) and plasminogen activator inhibitor-1 (PAI-1) were measured in baseline blood samples. Despite elevated interleukin IL-6 and TNF alpha, glucose, insulin and C-peptide responses to oral glucose load as well as ISI(MAT), ISI(CED), PAI-1 and NEFA were comparable in both RA groups and healthy controls. HOMA2 %S correlated with disease activity. In conclusions, low-dose glucocorticoid treatment does not lead to glucose metabolism impairment in RA patients without other metabolic risk factors. Increased cardiovascular mortality and morbidity is probably due to a direct effect of systemic inflammation on myocardium and/or blood vessels.

[Prevalence of rheumatic manifestations and non-organ specific autoimmunity in patients with autoimmune thyreopathy]. / Výskyt reumatických manifestácií a orgánovo nespecifickej autoimunity a chorých s autoimunitnou tyreopatiou.

INTRODUCTION: A variety of rheumatic manifestations (RM) has been described in association with autoimmune thyroiditis (AIT). In the past, most of these manifestations were attributed to the underlying thyroid dysfunction, in particular hypothyroidism. AIT is often associated with non-organ specific autoimmunity. Increased prevalence of non-organ specific autoantibodies in patients with AIT without any evidence of rhemautic manifestations is clinically unclear. Aim of this study was to find out the frequency of apperance of non-organ specific antibodies in serum in patients with AIT and prevalence of RM (arthralgia/arthitis). PATIENTS AND METHODS: The group consisted of 80 patients with diagnosis AIT. The diagnosis of AIT was made according to established criteria. This diagnosis was primarily based on laboratory markers including thyroid hormone levels (TSH, fT4, fT3), the detection of antithyroid antibodies (anti-TPO, anti-TG, anti-RTSH antibodies) and on ultrasound examination (imaging signs of thyroid autoimmunity) of thyroidal gland. None of the above patients had a history of systemic autoimmune disorders. In the group of patients with AIT we evaluated the prevalence of non-organ specific antibodies (ANA/Hep 2, ENA scr., SSA, SSB, nRNP, dsDNA, DNP, RF, ACLA scr., ANCA/MPO, ANCA/PR3) and presence of RM (arthritis/arthralgia). The control group consisted of 34 patients with no overt history of AIT or systemic autoimmune disorders. RESULTS: In the group of patients with AIT ANA positivity was found in 36/80 (45%) patients compared with 5/34 (14.7%) in healthy controls (p < 0.05). The prevalence of ANA autoantibodies was significantly higher in patients with AIT than in healthy controls. Other levels of non-organ specific antibodies (ENA scr., SSA, SSB, nRNP, dsDNA, DNP, RF, ACLA scr., ANCA/MPO, ANCA/PR3) were not significantly different among patients with AIT and healthy controls. 40/80 (50%) of patients with AIT had artralgia compared with 7/34 (20.6%) in healthy controls (p < 0.05) and 19/80 (23.75%) of patients with AIT had arthritis compared with 1/34 (2.9%) in healthy controls (p < 0.05). The prevalence of RM (arthralgia and arthritis) in group of patients with AIT was significantly higher than in healthy controls. CONCLUSION: The prevalence ofANA autoantibodies and RM (arthralgia/arthritis - both) was significantly higher in patients with AIT than in healthy controls.

[Systemic lupus erythematosus--a contemporary view of its genetic determination, immunopathogenesis and therapy]. / Systémový lupus erythematosus--súcasný pohl'ad na genetickú determináciu, imunopatogenézu a liecbu.

Systemic lupus erythematosus (SLE) is an organ non-specific autoimmune disorder, with multiple immunopathogenic mechanisms being implicated in its development. The most conspicuous feature of the disease is an exaggerated synthesis of various types of autoantibodies, followed by the formation of immune complexes that deposit in tissues and elicit an inflammatory response. Apart from antibodies, dendritic cells, T cells and cytokines are substantially involved in the pathogenesis of SLE and class I interferons seem to play a crucial role. SLE is a genetically determined disease. HLA system and complement system genes, apoptosis regulating genes and IgG Fc-gamma receptor genes are among the multiple genes implicated in SLE. The role of hormones, both estrogen and progesterone, in SLE activity has been reported. Some monoclonal antibodies have recently proved effective in the treatment of SLE.

The effectiveness for prevention of tuberculosis in patients with inflammatory rheumatic diseases treated with TNF inhibitors.

BACKGROUND: New biologic therapies blocking TNF undoubtly constitute a considerable advancement in the management mentioned diseases, but are also associated with higher risk of activation of tuberculosis. METHODS: An assessment of tuberculosis activation rate in the group of patients with rheumatoid arthritis, juvenile idiopatic arthritis, ankylosing spondylitis and psoriatic arthritis threated by anti-TNF inhibitors since January 1st 2001 to June 30th 2007 in Slovakia and went in for special anti-tuberculosis screening before start of therapy. RESULTS: A total 537 rheumatic patients received the anti-TNF therapy. There were 346 rheumatoid arthritis patients, 68 juvenile idiopatic arthritis patients, 71 patients suffered from ankylosing spondylitis and 52 from psoriatic arthritis. Duration of anti-TNF therapy was 843 of patient-years. Infliximab took 203 patients with duration of therapy 348 patient-years, etanercept 201 patients with duration of therapy 331 patient-years and adalimumab 133 patients with duration of therapy 164 patient-years. The activation of tuberculosis reached the incidence 0.37% (2 cases for 537 patients) representing 0.237 cases for 100 patient-years. Both patients had extrapulmonary forms of tuberculosis which was in one patient disseminated, but they fully recovered after the anti-TNF drugs were stopped and chemotherapy was completed. CONCLUSION: Our results demonstrate a low incidence of tuberculosis activation during anti-TNF treatment in patients with inflammatory rheumatic diseases in the Slovak Republic and confirm the high effectiveness ours specified complex screening measures (Tab. 3, Ref. 13). Full Text (Free, PDF) www.bmj.sk.

Hormone response to stress in rat strains of different susceptibility to immunologic challenge.

OBJECTIVE: The aim of this study was to compare the changes in plasma levels of hormones involved in modulation of the immune system function after exposure to stress in two rat strains with different susceptibility to immunoantigens. METHODS: Adult rat males of Lewis (LEW) and Fischer 344 (FIS) strains were exposed to restrain stress for 2 hours and blood samples were collected during stress exposure. Other groups of animals were exposed to restrain stress for 2 hours and sacrificed 3 hours later for blood and organ collection. Corticosterone, testosterone, dehydroepiandrosterone, 17beta-estradiol and progesterone were estimated by radioimmunoassay, epinephrine and norepinephrine levels were determined by radioenzymatic method. RESULTS: The levels of plasma corticosterone and catecholamines were significantly higher during stress exposure in FIS as compared to LEW rats. Greater decrease of testosterone levels and higher levels of estradiol were noted after exposure to stress in LEW rats. Higher values of progesterone plasma levels were noted in FIS rats after stress. CONCLUSIONS: These results demonstrated the differences in the response of catecholamines, adrenal and gonadal steroids after exposure to stress in LEW and FIS rats with lower levels of hormones with anti-inflammatory action in LEW rats.

[Levels of hormones in plasma and in synovial fluid of knee joint of patients with rheumatoid arthritis]. / Hladiny hormónov v plazme a v synovialnej tekutine kolenného klbu pri reumatoidnej artritíde.

BACKGROUND: Dysfunction of endocrine system is very likely one of the important risk factors involved in the pathogenesis of rheumatoid arthritis. The aim of the present study was to investigate the levels of selected hormones in plasma and in synovial fluid of knee joint of patients with rheumatoid arthritis or with osteoarthritis, which could affect the inflammatory processes. METHODS AND RESULTS: Thirty nine patients with rheumatoid arthritis (22 females and 17 males) and 12 patients with osteoarthritis (6 females and 6 males) were investigated. Concentrations of the following hormones were determined in plasma and synovial fluids: cortisol, 17-beta-estradiol, progesterone, dehydroepiandrosterone, aldosterone, testosterone, prolactin, insulin and C-peptide by using radioimmunoassay kits. Increased levels of 17-beta-estradiol and insulin were found in patients with rheumatoid arthritis as compared to those with osteoarthritis. The plasma concentrations of other hormones under study were not significantly different in these groups of patients. Higher levels of 17-beta estradiol, progesterone and aldosterone were noted in inflammatory knee exudate of patients with rheumatoid arthritis. The levels of other hormones in exudates of patients with rheumatoid arthritis and those with osteoarthritis were not significantly different. The ratio of 17-beta estradiol / cortisol, 17-beta estradiol / testosterone and 17-beta estradiol / dehydroepiandrosterone showed increased proportions of estrogens over androgens or glucocorticoids in exudate from patients with rheumatoid arthritis. CONCLUSIONS: These results demonstrated that steroid and peptide hormones are transferred to synovial fluid of knee. The presence of insulin, C-peptide and aldosterone was described for the first time in synovial fluid. In patients with rheumatoid arthritis a predomination of the levels of proinflammatory estrogens over androgens was found in knee exudate. Also the levels of aldosterone and progesterone were elevated in inflammation knee exudate. This suggests that these hormones present in synovial fluid may affect the local rheumatoid inflammatory processes.

[Ankylosing spondylitis--the current situation and new therapeutic options]. / Ankylozujúca spondylitída--súcasný stay a nové moznosti liecby.

Ankylosing spondylitis (AS) is a chronic, immunologically mediated rheumatic disease whose progression largely depends on the extent of inflammatory activity. In contrast to rheumatoid arthritis (RA), therapeutic control of AS is very limited. Therapy of ankylosing spondylitis should not only control inflammatory processes, but also prevent structural damages and maintain the functions. Until recently, physiotherapy and non-steroidal antiphlogistics (NSA) therapy was a gold standard of AS treatment. NSA therapy alleviates inflammatory pain of spine in 60 to 80% of patients. According to the most recent findings, long-term administration of NSA can affect also X-ray progression. DMARD therapy, which is efficient in RA, has insignificant effect on axial form of AS. Sulfasalazine proved to be efficacious against peripheral form of AS; administration of MTX and leflunomide is not supported by controlled studies. Peripheral arthritis and enthesitis is usually treated by short-term application of corticoids. The fact remains that an important role in AS immunopathogenesis is played by TNF alpha whose increased levels were found in patients with AS in serum, synovial fluid and SI joints. Anti-TNF therapy with infliximab and etanercept proved to be highly efficacious in patients with AS resistant to conventional therapy. Infliximab and etanercept reduced the disease activity (50% improvement in more than half of patients), improved the function and slowed down the structural damage. MRI studies of anti-TNF therapy proved reduction of inflammatory activity in SI joints and spine. Other studies verified the efficacy of adalimumab in AS therapy and showed that adalimumab is a promising drug. Also, several randomized clinical studies proved efficacy of thalidomide whose administration, however, is limited by its severe adverse effects. Until now, the results of studies focused on pamidronate therapy appear to be rather controversial. Better understanding of AS pathogenesis led to implementation of new therapeutic procedures that significantly improve activity and functional condition of patients.

Attenuated insulin response and normal insulin sensitivity in lean patients with ankylosing spondylitis.

Chronic low-grade inflammation is associated with insulin resistance. The aim of this study was to determine insulin response to intravenous glucose load and insulin sensitivity in patients with ankylosing spondylitis (AS). Fourteen nonobese male patients with AS and 14 matched healthy controls underwent frequent-sampling intravenous glucose tolerance test (FSIVGTT). Insulin secretion and insulin sensitivity were calculated using the computer-minimal and homeostasis-model assessment 2 (HOMA2) models. Fasting glucose, insulin, cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride levels, HOMA2, glucose effectiveness, insulin sensitivity and insulin response to FSIVGTT did not differ between patients and controls. Tumor necrosis factor-alpha and interleukin (IL)-6 concentrations tended to be higher in AS patients than in controls. Second-phase beta-cell responsiveness was 37% lower (p = 0.05) in AS patients than in controls. A negative correlation was found between the percentage of beta-cell secretion and IL-6 in all subjects (r = -0.54, p = 0.006). We found normal insulin sensitivity but attenuated glucose utilization in the second phase of FSIVGTT in AS patients. Our results indicate that elevated IL-6 levels may play a pathophysiological role in attenuating beta-cell responsiveness, which may explain the association between elevated IL-6 levels and increased risk for type 2 diabetes.

Peptide hormones and histamine in plasma and synovial fluid of patients with rheumatoid arthritis and osteoarthrosis.

OBJECTIVES: Hormones other than adrenal and gonadal steroids may play also a significant role in the pathogenesis of rheumatoid arthritis. The aim of this study was to investigate the levels of selected peptide hormones and histamine in synovial fluid of knee joints and in plasma of patients with rheumatoid arthritis and with osteoarthrosis. METHODS: The concentrations of insulin, C-peptide, prolactin, growth hormone, free triiodothyronine (FT3), thyrotropin (TSH), and histamine were determined in synovial fluid and plasma of 27 patients with rheumatoid arthritis (RA) and in 12 patients with osteoarthrosis (OA). RESULTS: The presence of peptide hormones in synovial fluid was demonstrated. The levels of TSH and growth hormone were lower in synovial fluid than in plasma in both groups, while those of prolactin were comparable in synovial fluid and in plasma. The levels of C-peptide (p < 0.05), insulin and FT3 were higher in synovial fluid than in plasma of OA patients, but lower in synovial fluid of RA patients as compared to their levels in plasma. Significant positive correlations between the levels in plasma and synovial fluid were observed in prolactin (p < 0.001, r = 0.741) and TSH (p < 0.05, r = 0.88) only. After age adjustment, no significant differences in synovial fluid and in plasma levels of all hormones were found between OA and RA patients. The levels of histamine in plasma were similar in RA and OA patients, in synovial fluid of both groups histamine was found in almost undetectable amounts. CONCLUSIONS: The selected peptide hormones, e.g. insulin, C-peptide, prolactin, growth hormone, FT3 and TSH, are present in synovial fluid of RA and OA patients, some of them in the concentrations comparable to these in plasma. The role of the locally present hormones in pathogenesis of RA has to be investigated in further studies and analyses.

Hormone concentrations in synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: Alterations in local concentrations of hormones, affecting directly synovial cells, could be involved in the modulation of the rheumatic inflammatory processes. The aim of present study was to investigate the levels of selected hormones (steroids, peptide and thyroid hormones) in synovial fluid of knee joint of patients with rheumatoid arthritis (RA) and control individuals with non-rheumatic exudate (with osteoarthrosis, OA). METHODS: Thirty-eight patients, 22 female and 16 males, with rheumatoid arthritis (RA) and 12 subjects with osteoarthrosis (OA, control group, 6 females and 6 males) participated in the study. Concentrations of cortisol (CS), 17-beta-estradiol (ES), dehydroepiandrosterone (DHEA), progesterone (PRG), aldosterone ALD), prolactin (PRL), insulin (INS), and C-peptide were determined by radioimmunoassay in synovial fluid. Insulin binding to isolated cell membrane of cells from synovial sediment was estimated by using radioiodine labeled insulin. In a group of patients (10 with RA and 4 with OS), the levels of free threeiodothyronine (FT3), TSH and growth hormone (GH) were also determined in synovial fluid. RESULTS: Increased levels of ES in synovial fluid of RA patients were observed, and higher differences were noted in men. TE concentrations were moderately elevated in synovial fluid of RA patients, however the ratio of ES/TE was significantly higher in male RA compared to OA patients. Higher levels of PRG, ALD and growth hormone were noted in synovial fluid of RA patients. Besides the steroid hormones the presence of insulin and C-peptide was noted in synovial fluid and the correlation between the levels of these two peptides was highly significant. The concentrations of INS and C-peptide in synovial fluid of patients from RA and OA group were not significantly different, however, highly significant increase of insulin binding to isolated membrane of synovial cells was found. Concentrations of cortisol, dehydroepiandosterone, prolactin, TSH and FT3 in synovial fluid were not significantly different in RA and OA groups. CONCLUSIONS: Besides the steroids also insulin, c-peptide, GH and FT3 were found in synovial fluid. The elevated ALD and GH levels in synovial fluid of RA patients and the presence of INS in synovial fluid with increase of INS binding to plasma membranes of cells from synovial fluid of RA patients suggest that besides the gonadal steroids also these hormones may affect the local inflammatory processes.

Low levels of dehydroepiandrosterone sulphate in plasma, and reduced sympathoadrenal response to hypoglycaemia in premenopausal women with rheumatoid arthritis.

OBJECTIVES: To evaluate the function of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system in premenopausal women with rheumatoid arthritis (RA). METHODS: Insulin-induced hypoglycaemia (0.1 IU/kg) was produced in 15 glucocorticoid-naive patients with long term RA with low disease activity and in 14 healthy women matched for age and body mass index. Concentrations of glucose, adrenocorticotropic hormone (ACTH), cortisol, Delta4-androstenedione (ASD), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), 17alpha-hydroxyprogesterone (17OHP), epinephrine (EPI), norepinephrine (NE), interleukin 6 (IL6), and tumour necrosis factor alpha (TNFalpha) were analysed in plasma. RESULTS: Patients had comparable responses of glucose, cortisol, ACTH, ASD, and 17OHP to hypoglycaemia, without any signs of hypothalamic insufficiency. Patients had lower basal DHEAS than controls (3.03 (0.37) micromol/l v 5.1 (0.9) micromol/l, respectively; p<0.05); borderline lower basal DHEA levels (p = 0.067); while the response of DHEA to hypoglycaemia was comparable to that of controls. Patients with RA had lower EPI (p = 0.005) and NE (p<0.001) responses to hypoglycaemia. TNFalpha and IL6 were higher (p<0.05) in patients with RA (TNFalpha 8 (2.8) pg/ml in RA v 1.1 (0.5) pg/ml in controls and IL6 15.1 (6.7) pg/ml v 1.4 (0.7) pg/ml). CONCLUSIONS: Lower basal DHEAS levels, without concomitant differences or changes in DHEA, ASD, 17OHP, and cortisol responses to hypoglycaemia in patients with RA, indicate an isolated decrease in adrenal androgen production. Significantly lower responses of EPI and NE to hypoglycaemia may suggest sympathoadrenal hyporeactivity in patients with RA.

The effects of hyaluronan on bone resorption and bone mineral density in a rat model of estrogen deficiency-induced osteopenia.

Hyaluronan, or hyaluronic acid (HA), is an essential component of extracellular matrices. HA of appropriate molecular weight and concentration can induce osteoblast differentiation and bone formation in vitro. The aim of our study was to evaluate the effects of HA of different molecular weights on ovariectomy (OVX)-induced bone loss in rats. Adult female Sprague Dawley rats were subjected to bilateral OVX or sham surgical procedure (sham). OVX rats were treated with: HA of molecular weight of 0.75 MDa at a dose of 1 mg/kg/day and with HA of molecular weight of 1.62 MDa at a dose of both 0.5 mg/kg/day and 1 mg/kg/day. HA was applied orally once a day during the 8-week period after ovariectomy. Body weight, urinary pyridinoline (Pyr), deoxypyridinoline (DPyr) corrected for urinary creatinine, serum nitrite/nitrate concentrations and whole body and femoral bone mineral density (BMD) were measured. HA treatment had no effect on the body weight gain in OVX rats. Excretion of urinary Pyr and Dpyr significantly increased in OVX rats compared to sham controls. The higher molecular weight HA (1.62 MDa) significantly reduced urinary Pyr and DPyr concentrations measured on day 28 after ovariectomy (p < 0.001). Serum concentrations of nitric oxide metabolites, nitrite/nitrate significantly decreased in OVX rats in comparison with sham controls (p < 0.001). HA of both 0.75 MDa and 1.62 MDa molecular weights significantly enhanced serum nitrite/nitrate concentrations in OVX rats. There was a clear reduction of whole body and femoral BMD in untreated OVX rats. The higher molecular weight HA decreased both whole body and femoral BMD loss. Our results show that orally applied HA of high molecular weight (1.62 MDa) inhibits bone resorption and provides a protective effect on bone density in ovariectomized rats.

Hypothalamic-pituitary-adrenal axis function in ankylosing spondylitis.

OBJECTIVE: To assess basal function and responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in patients with ankylosing spondylitis during dynamic testing. METHODS: Insulin induced hypoglycaemia (IIH) (Actrapid HM 0.1 IU/kg, as intravenous bolus) was induced in 17 patients and 11 healthy controls matched for age, sex, and body mass index. Concentrations of glucose, adrenocorticotrophic hormone (ACTH), cortisol, insulin, dehydroepiandrosterone sulphate (DHEAS), 17alpha-hydroxyprogesterone, interleukin 6 (IL-6), and tumour necrosis factor alpha (TNFalpha) were determined in plasma. RESULTS: Comparable basal cortisol levels were found in the two groups, with a trend to be lower in ankylosing spondylitis. In the ankylosing spondylitis group, there were higher concentrations of IL-6 (mean (SEM): 16.6 (2.8) pg/ml v 1.41 (0.66) pg/ml in controls; p<0.001) and TNFalpha (8.5 (1.74) pg/ml v 4.08 (0.42) pg/ml in controls; p<0.01). Glucose, insulin, ACTH, DHEAS, and 17alpha-hydroxyprogesterone did not differ significantly from control. The IIH test was carried out successfully in 11 of the 17 patients with ankylosing spondylitis, and the ACTH and cortisol responses were comparable with control. General linear modelling showed a different course of glycaemia (p = 0.041) in the ankylosing spondylitis patients who met the criteria for a successful IIH test compared with the controls. CONCLUSIONS: The results suggest there is no difference in basal HPA axis activity and completely preserved responsiveness of the HPA axis in patients with ankylosing spondylitis. The interpretation of the different course of glycaemia during IIH in ankylosing spondylitis requires further investigation.

[Prediction of changes in bone density during alendronate treatment in postmenopausal women]. / Predikcia zmien kostnej denzity pri liecbe alendronátom u postmenopauzálnych zien.

Alendronate is an aminobisphosphonate, a selective inhibitor of osteoclast-mediated bone resorption. Due to its influence a decline of markers of bone turnover occurs. The latter react much sooner than it is possible to detect significant changes of bone density. In the submitted trial the authors investigated changes of selected markers: total alkaline phosphatase (ALP), osteocalcin (OC), N-terminal telopeptide fragment of collagen type I (NTx) after 3 months' treatment with alendronate, the influence on bone density after one year's treatment in 50 postmenopausal women with densitometrically verified osteoporosis. After one-year treatment in the whole group a significant increase of bone density occurred in the area L2-L4 by 4.52% (SD = 3.9), neck of the femur by 2.24% (SD = 3.6), trochanter by 2.81% (SD = 3.0) and total by 1.89% (SD = 2.7). Total ALP and OC in serum, similarly as NTx in urine declined significantly already after 3 months treatment and the decline persisted also after one year of treatment. With the change of bone density after one year correlated significantly only NTx. A decline of NTx after 3 months by more than 30% as compared with the baseline value was recorded in 81% patients and this change predicted a significant rise of the bone density in the area of the neck of the femur, on average by 30. Urinary NTx is a promising predictor of the effect of alendronate treatment. Its drop by more than 30% after 3 months justifies the assumption that bone density increased after one year's treatment.

Non-inflammatory enthesopathies of the spine: a diagnostic approach.

Ankylosing vertebral hyperostosis, or hyperostotic disease, is an ossification of the entheses, the regions of insertion of tendons, ligaments or joint capsules into the bone. These ossifications create intervertebral bridges (ossifications of the common anterior, lateral and posterior intervertebral ligaments as well as of the ligamentum flavum), which are responsible for the potential signs of the disease: back and neck pain and stiffness, spinal cord compression at the cervical level and lumbar canal stenosis at the lumbar level. The bony epiphyses are the sites of bony appositions, or enthesophytes, which may compromise joint mobility and increase the risk of secondary osteoarthritis, causing hip and knee disorders in particular. These degenerative joint diseases may eventually necessitate total replacement. In this case, the risk of re-ossification around the prosthesis must be averted by the immediate postoperative prescription of anti-inflammatory medication for 1-2 weeks.

Intravenous immunoglobulin treatment of lupus nephritis.

OBJECTIVE: To evaluate the clinical response of treatment-resistant membranous and membranoproliferative lupus nephritis to intravenous immunoglobulin (IVIg). METHODS: Seven lupus nephritis patients who failed to respond to at least prednisone and cyclophosphamide were studied. A kidney biopsy showing either membranous or membranoproliferative glomerulonephritis was available in six patients. They were treated with six courses (patients 1 and 2) or 1 or 2 courses (patients 3 through 7) of high-dose IVIg. For patients 3 through 7, the plasma levels of albumin, total cholesterol, urea, creatinine, dsDNA antibody titers, and daily proteinuria were measured just before the IVIg therapy, immediately on completion, and 6 months later. RESULTS: All seven patients had a beneficial response to IVIg. In patient 1, decrease in proteinuria was evident 2 weeks after IVIg was started, nephrotic syndrome gradually disappeared, and she had no proteinuria in 3 years' follow-up. Decline in proteinuria was evident in patient 2 after the 4th IVIg course, but proteinuria reached the pretreatment level 4 months after the therapy ended. In patients 3 through 7, the mean daily proteinuria before IVIg (5.3 +/- 2.1 g) decreased after 1 or 2 IVIg courses (3.3 +/- 1.4 g), and further decreased when measured 6 months later (2.1 +/- 1.3 g). Similarly, the plasma cholesterol level decreased while the plasma albumin level increased after IVIg. CONCLUSIONS: IVIg might be effective in treatment-resistant membranous or membranoproliferative lupus nephritis. Future studies should concentrate on determining the preferred treatment protocol of IVIg for the various classes of lupus nephritis.

Suppression of adjuvant arthritis in rats with chronic bromocriptine treatment does not prevent associated oxidative stress.

We studied the effect of prolactin (PRL) inhibition by bromocriptine (BRC) in the first phase of adjuvant induced arthritis (AA), up to day 11(BRCl-AA), and in the whole time course of AA, up to day 23 (BRC-AA), on the development of the disease in male Lewis rats. On day 24, arthritic rats showed inhibition of PRL secretion, but not PRL mRNA expression in adenopituitaries. BRC treatment suppressed PRL serum levels and PRL mRNA expression in adenopituitaries. In BRC/-AA group PRL levels and PRLmRNA were at the level of rats with AA. Serum corticosterone (CORT) was stimulated by AA from 16.9+/-5.8 to 59.1+/-8.7 ngml(-1), p<0.05, to the same level in BRC-control (BRC-C) and BRC-AA group and further potentiated in BRCI-AA group (148.2+/-33.1 ngml(-1), p<0.05 vs. group with AA). Hind paw swelling was reduced but not completely inhibited in BRC1-AA group and totally prevented in BRC-AA rats as was the core temperature (36.5+/-0.1 degrees C vs. 37.4+/-.0.1 degrees C in AA rats on day 23, p<0.01). Serum concentration of NO-ZNO-3 rose in rats with AA to 28.7+/-2.5 &mgr;mo1L-1 against. 13.9+/-1.9 &mgr;molL(-1) in controls (p<0.01), remained elevated in BRC-AA group and was potentiated in BRC1-AA group (48.2+/-3.5 &mgr;mol(-1), p<0.01 vs. AA or BRC1-AA group) Thiobarbituric acid reactive substances (TBARS) and antioxidant capacity in the spleen were enhanced in rats with AA and to the same extent in BRC-AA or BRC1-AA groups. These results show a discrepancy between the suppression of clinical symptoms and persisting oxidative stress in AA rats after the BRC induced PRL inhibition. The potentiation of nintric oxide (NO-) production after the sudden cessation of PRL inhibition during the disease may promote further joint damage.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) dimorphism in patients with systemic lupus erythematosus.

OBJECTIVE: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance. METHODS: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls. RESULTS: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042). CONCLUSION: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).