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Global prevalence of psoriasis is ranging from 0.91 % to 8.5 % [1]. Exact numbers are missing for Slovakia. 1-5% range is the most probable while 2 % is also mentioned as an average prevalence for the European population. There is approximately 110 thousand patients suffering from psoriasis when extrapolating from total population of 5.5 million [2]. Extracutaneous manifestation is observed in 11–30 % of patients after years of solely skin symptoms presentation [3, 4, 5, 6]. Objective: To estimate prevalence of psoriatic arthritis among psoriatic patients population visiting dermatology out-patient irrelevant of the disease duration and the treatment regimen. To compare the sensitivity of both tests (ToPAS and PASE) used, evaluate possible PsA risk factors. Methods: This was a prospective, non-interventional, epidemiological, observational study conducted using a survey administered to psoriatic patients by their dermatologists. 10–20 consequent outpatients with psoriasis in each center in 43 regional dermatology officies were screened for the presence of extra-cutaneous symptoms (i.e. joint pain, enthesitis, dactylitis, nail involvement) using questionnaire, developed specificaly for this study, and by the PASE and ToPAS questionnaires. Patients without personal history of PsA and „positivity“ of PASE and/or ToPAS were sent to the center for confirmation / exclusion of the diagnosis by applying CASPAR criteria. Outcomes were statistically processed. Results: 177 (21.8 %) of total of 831 psoriatic patients had PsA. 9 of 177 (5.35 %) has been newly diagnosed. There was almost equal number of men (50.5 %) and women (49.5 %). Plaque psoriasis has been most frequent type – 76.9 %. 43.2 % of PsA patients reported the onset of the disease after 40 years of life. Time interval between onset of psoriasis and PsA has been less than 10 years in 20.2 %, 10–20 years in 20.8 % and more than 20 years in 16.1 %. Most frequent co-morbidity in the study population was hypertension 23.2 %, asthma 3 % and diabetes 2.4 %. Average value of BSA and PASI was higher in PsA vs. non-PsA group: 24 vs. 20 and 10 vs 9, respectively. The sensitivity (72.6 % vs 58.9 %, P=0.01) and specificity (81.3 % vs 80.5 %) of ToPAS was higher compared to PASE. Conclusion: 21.8 % PsA prevalence in psoriatic population in Slovakia is within the range observed in other studies. ToPAS test showed comparable results in terms of specificity, but significantly better results in terms of sensitivity and its early application should be of major importance because of the diagnostic process acceleration. The effect of an early diagnosis on the total patient outcome should be an objective of further research. This project was supported from educational grant of Pfizer Inc.

The aim of our study was to investigate adrenocortical function in the context of disease activity and inflammatory status in premenopausal RA females. Adrenal glucocorticoid and androgen responses to the 1 µg ACTH 1-24 test were investigated in 23 premenopausal RA and in 15 age- and BMI-matched healthy females. Twelve RA patients were on low-dose prednisone (3.2 had lower (p3.2 had lower (p

Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria

Strontium accumulation and distribution are determined in bones of rats after strontium ranelate administration by using time-of-flight SIMS technique. Strontium ranelate is a newly developed drug effective in osteoporosis treatment by reducing bone resorption and promoting bone formation. The motivation is to study the strontium accumulation and distribution in bones and possible accumulations of strontium in soft tissues such as brain, liver and heart, are tested. The investigated rats are divided in the control group, one without strontium ranelate administration, and the other group of rats after five weeks of administration, with daily dose of 400 mg/kg. When the strontium ranelate-treated bone samples are compared with the control, strontium is spectrally resolved and clearly identified within two-dimensional distribution. Similar contours of calcium and strontium in two-dimensional images support the hypothesis that strontium is capable of replacing calcium atoms as a part of the strontium ranelate mechanism in the osteoporosis treatment. Molecular ions, characteristic for biological samples as phospholipids, cholesterol and fatty acids are also identified. Strontium presence in heart, brain and liver tissues is not observed. Chemical characterization of biological samples in intact form without any chemical labeling by using SIMS could be, in this way, helpful in medical diagnostics.

An episode of gastroenteritis triggered severe necrosis of all extremities in a previously asymptomatic male. Hepatic and renal involvement were also manifest, while the hematological picture was one of thrombotic microangiopathic hemolytic anemia. Antiphospholipid antibodies were negative. He responded well to a combination of plasma exchange, anticoagulation (heparin), parenteral steroids, and antibiotics, as well as vasodilators (prostacycline) and hyperbaric oxygen, but died because of a cerebral hemorrhage. The differential diagnosis included thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, or seronegative catastrophic antiphospholipid (Asherson's) syndrome. The dangers of administering such a combination of therapies with anticoagulation, as well as vasodilatation (prostacycline) and hyperbaric oxygen, are highlighted by the case report and emphasized.

Objective: To compare the performance of the several different diagnostic criteria sets currently in use for polymyalgia rheumatica (PMR). Methods: 213 patients attending eight rheumatological centres in eight different European countries were studied. All had recently been referred and were considered by the senior investigator at each centre, selected because of their experience in treatment of PMR, to have this condition. By use of a standard international proforma, the requisite diagnostic points in each criteria set were sought. Sensitivity for each criterion from each set was then calculated, as well as the sensitivity of each criteria set as a whole. Results: Of four criteria sets compared, the Bird (1979) criteria performed best with a sensitivity of 99.5%, and the Hunder (1982) criteria second best, with sensitivity of 93.3%. These both performed significantly better than the two other criteria sets, though each of these was admittedly developed for rather specialised reasons. Conclusions: Although this study compares homogeneity, we suggest the Bird 1979 or Hunder 1982 criteria should be used whenever possible. Studies that have used alternative criteria may have less sensitivity in diagnosis.

A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p < 0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.

Objective: To develop response criteria for polymyalgia rheumatica (PMR) for monitoring treatment and comparing alternative treatments regimens. Methods: 76 patients, mean (SD) age 68.7 (7.7) years, were enrolled. Corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) were the only drugs allowed during the observation period. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), α2 globulin, serum iron, pain, physician's global assessment (PGA), morning stiffness (MST), muscle tenderness (MT), myalgia, and the elevation of upper limbs (EUL) were determined regularly. The daily corticosteroid and NSAID doses as the corticosteroid response time were recorded. To ensure evaluation of an adequate number of patients (n = 57) week 24 was chosen for final analysis. Results: ESR, CRP, α2 globulin, pain, PGA, MST, myalgia, MT, and EUL showed significant improvement (p

AIM To elucidate the role of core and skin thermoreceptors in the release of growth hormone (GH) and prolactin (PRL), a sequence of two experiments using whole-body (head-out) and partial (one forearm) hot water immersions was performed. METHODS Experiment 1: Nine healthy men were exposed to head-out and partial water immersions (25 min, 38-39 degrees C). RESULTS Head-out immersion increased the core temperature (38.0 +/- 0.1 vs. 36.7 +/- 0.1 degrees C, P < 0.001) and plasma concentration of the hormones (GH, 16.1 +/- 4.5 vs. 1.2 +/- 0.4 ng mL(-1), P < 0.01; PRL, 9.1 +/- 1.0 vs. 6.4 +/- 0.4 ng mL(-1), P < 0.05). During the partial immersion the core temperature was slightly elevated (36.8 +/- 0.1 vs. 36.6 +/- 0.1, P < 0.001), the concentration of GH increased (4.8 +/- 1.7 vs. 0.6 +/- 0.3, P < 0.05), while plasma PRL decreased (7.6 +/- 0.8, 6.0 +/- 0.6, 5.2 +/- 0.6, P < 0.01). Experiment 2: Seven volunteers immersed one forearm once in 39 degrees C and once in 38 degrees C water. The measurements were performed in 5-min intervals. The GH concentration increased gradually from the beginning of the immersions (min 10; 39 degrees C: 1.9 +/- 1.0 vs. 0.6 +/- 0.3 ng mL(-1), P < 0.01; 38 degrees C: 0.19 +/- 0.03 vs. 0.14 +/- 0.03, P < 0.05) and peaked after their completion (39 degrees C: +10 min, 3.7 +/- 2.0, P < 0.001; 38 degrees C: +15 min, 0.86 +/- 0.61, P < 0.01). The core temperature was unchanged until min 15 of the 39 degrees C bath. Thereafter, it increased about 0.15 degrees C above the baseline (P < 0.01). Immersion in 38 degrees C water did not induce core temperature changes. CONCLUSIONS Peripheral thermoreceptors are involved in GH release when the body is exposed to elevated environmental temperature while a substantial elevation of core temperature is a precondition of PRL release.

Chorea is a rare complication of systemic lupus erythematosus (SLE) and is strongly related to the presence of antiphospholipid antibodies. Various infections may also be triggering factors in the development of choreiform movements. Additionally, Salmonella infection is the most common opportunistic bacterial infection in SLE patients. We report a case of a 33-year-old woman with SLE who developed lupus erythematosus-associated chorea with multiple involuntary movements and cognitive disturbances. Because the methylprednisolone therapy administered appeared to lead to Salmonella enteritidis infection, intravenous immunoglobulin (IVIg) in a total dose 100 g was administered after which a remarkable improvement of the abnormal movements and cognitive function was noted. Within 7 days, the patient had returned to normal. We therefore conclude that IVIg therapy may be an effective therapeutic approach for the treatment of the acute cerebral complications of SLE, especially in cases in whom other therapeutic strategies are ineffective or harmful.

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.

Low serum vitamin D concentrations have been reported in several autoimmune disorders.To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE).378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE.A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson's correlation coefficient r=-0.12, p=0.018).In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.

So far, high prevalence of metabolic symptoms accompanying diffuse idiopathic skeletal hyperostosis (DISH) appears not definitely elucidated because of their possible origin from other disorders such as diabetes and/or body mass differences. From such reasons this study was aimed to compare non-diabetic DISH patients to a group of age and BMI matched controls in order to distinguish the influence of DISH proper on metabolic parameters free of additional metabolic effects caused by diabetes and/or body weight differences.Both groups of patients were subjected to oral glucose tolerance test (OGTT) and fasting serum levels of glucose, insulin, C-peptide, growth hormone, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) were assayed. Fasting serum total cholesterol, HDL cholesterol, triglycerides, non-esterified fatty acids (NEFA) and uric acid were determined as well. The indices of insulin sensitivity and insulin secretion were calculated.With the exception of decreased NEFA serum level and decreased insulinogenic index and insulin/C-peptide ratio in DISH patients any other significant differences in serum parameters and indices of insulin sensitivity were not found.The data obtained suggest impaired beta-cell pancreatic stimulation and increased insulin hepatic extraction in DISH. It is assumed that the above mentioned conditions, if persisting for a long time, might lead to decreased ability of insulin to maintain normal serum glucose level and consequently to insulin resistance which is highly prevalent in symptomatic DISH patients.

Clinical and experimental data indicate the involvement of adrenal steroids in the complex of rheumatoid arthritis (RA) pathogenesis. A subtle adrenocortical hypocompetence has been suggested in a subset of glucocorticoid-naïve premenopausal females with RA.The interrelations among adrenal steroids: cortisol (CORT), 17alpha-hydroxyprogesterone (17-OHP), androstenedione (ASD), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) were evaluated in 15 glucocorticoid-naïve premenopausal females with RA and in 14 age- and body mass index- matched healthy females at basal and during insulin-induced hypoglycemia states. Spearman's correlations were used to analyze baseline plasma concentrations as well as areas under response curves of these steroids levels as assayed during the basal and/or insulin-induced hypoglycemia status.Six among 15 RA patients, but none of 14 controls had combined "lower" quartile range of basal cortisol (431 nmol/l) and lower DHEAS (2.79 micromol/l) levels, i.e., concentrations within the lowest quartiles of the control group (p = 0.017). In all subjects combined, basal correlations were significantly positive between ASD and other steroids (CORT, 17OHP, DHEA, DHEAS). When patient and control groups were analyzed separately, the positive basal correlation between ASD and CORT was significant only in RA patients (p = 0.030). In contrast, a positive basal correlation between ASD and DHEA was significant only in controls (p = 0.004). When comparing the areas under response curves (AUCs), the correlation of ASD and CORT was significantly negative in RA (p = 0.009), but positive in controls (RA vs control difference in Spearman's correlations, p = 0.002). The correlation between AUCs of ASD and DHEA was strongly positive in controls (p = 0.006), but not in RA (RA vs. control difference p = 0.044).The results suggest relative hypocompetence of adrenocortical function in premenopausal RA females. Different patterns of correlations of the adrenal steroids during basal vs. stimulatory testing suggested certain alterations in adrenal synthetic pathways or deficiencies in the dynamics of steroidogenesis in RA.

Because of well known association between the exposure to persistent organochlorinated pollutants (POPs) and impaired immune system, it was attempted to check possible coincidence of nuclear and thyroperoxidase antibodies with the levels of major POPs.Antinuclear antibodies. (ANA) were estimated by indirect immunofluorescence test using Hep2- cells and thyroperoxidase antibodies (TPOab) by electrochemiluminiscent immunoassay in the cohort of 253 adults (82 males and 171 females) aged 21-75 years, among them 144 (46 males and 98 females) from the area polluted (POLL) by polychlorinated biphenyls (PCB) and 109 (36 males and 73 females) from the area of background pollutrion (BCGR). In the same cohort fifteen congeners of PCB and also total DDE (2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene) and hexachlorobenzene (HCB) were estimated by high resolution gas chromatography/mass spectrometry.Prevalence of ANA only was significantly higher in POLL than in BCGR in males (p0.001) and females (p0.001) and the same was true for the prevalence of TPOab in males (p0.05) and females (p0.01) from POLL. In addition, also the prevalence of coincident ANA+TPOab in males (p0.001) and females (p0.05) was significantly higher in POLL. In a total of 253 pooled males and females from both areas and stratified in terms of PCB level quintiles. The prevalence of ANA in the 4th and 5th quintile of each among three pollutants (PCB, DDE and HCB) was significantly higher (p0.01 or0.001) and showed the parallel increase with the level of all pollutants.Significantly increased prevalence of ANA either only or in coincidence with TPOab was found related to increasing level of PCB, DDE and HCB.

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.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.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.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.

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.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.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.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.

Background Psoriasis is one of the most common extra-articular manifestations in patients with ankylosing spondylitis (AS). TNF inhibitors (TNFi) are highly effective for signs and symptoms of AS and psoriasis. However, there is some evidence about exacerbation or new onset of cutaneous psoriasis during anti TNF therapy. Objectives To examine the incidence rate of worsening or new onset of psoriasis in AS patients during anti-TNF therapy Methods AS patients with TNFi were retrospectively analysed in database of patients with biological therapy in Slovakia. This analysis covered AS patients with infliximab, etanercept, adalimumab and golimumab since March 3rd 2003, when the first patient initiated TNFi until December 31st 2013. Duration of anti-TNF treatment was calculated on patient-years (PYs). Disease activity was evaluated by BASDAI, ESR, CRP and global patient assessment of disease activity. History of psoriasis in each patient was explored and worsening of psoriasis or the first episode cases during anti-TNF therapy were analysed. Incidence rate was calculated on 100 PYs, and differences among TNFi were assessed. Results 385 patients with AS on TNFi were analyzed, of them 327 men (85%) and 58 women (15%). Mean age of patients at the time of initiation of TNF blockers was 39.0 (±10.7) years, median was 37 years (IQR 31-47). Total time on anti-TNF therapy was calculated on 1129 patient-years. 81 patients were exposed to infliximab for a total of 274 PYs, 102 patients were exposed to etanercept for 394 PYs, 155 patients were treated with adalimumab 390 PYs, and 47 patients were under the treatment with golimumab 72 PYs. Cutaneous psoriasis was present in 20 patients (5.2%) in history before starting TNFi – 8 patients on infliximab (9.9%), 8 patients on adalimumab (5.2%), 2 patients on etanercept (2.0%) and 2 patients on golimumab (2.0%). During anti-TNF therapy, exacerbation of cutaneous psoriasis was found only in 2 patients, but first episode cases were described in 6 ones. In every case, dermatologist verified the diagnosis of cutaneous psoriasis, and 50% of all cases had palmo-plantar pustular form of psoriasis, reflecting possible paradoxical reaction of the TNFi. Incidence of paradoxical psoriatic reaction was calculated on 0.71/100 PYs. Relatively more paradoxical psoriatic reactions during anti-TNF therapy were observed in patients with infliximab (1.09/100 PYs) and golimumab (1.41/100 PYs) than in patients with adalimumab and etanercept (both 0.51/100 PYs). Conclusions Incidence of paradoxical psoriatic effects of anti-TNF therapy in AS patients is very low. Our findings demonstrate that palmo-plantar pustular psoriasis is the most common form of paradoxical skin lesions. They were less frequent in patients treated with etanercept than in patients treated with monoclonal antibodies infliximab and golimumab. Disclosure of Interest None declared

Background TNF-inhibitors (TNFi) have brought new perspectives for AS patients to control disease activity and improve quality of life. However, some concerns still exist about their safety, especially in long term use. Objectives To evaluate persistence of AS patients on anti-TNF therapy, to identify the most common reasons of TNFi discontinuation, and to find out any difference in survival curves among these drugs Methods AS patients with TNFi in Slovakia were retrospectively analysed since March 3rd 2003 until December 31st 2013. Duration of anti-TNF therapy was calculated on patient-years (PYs). Disease activity was evaluated by BASDAI, ESR, CRP and global patient assessment of disease activity. Adherence to therapy was evaluated using Kaplan-Meier analysis and results were expressed as cumulative survival. Logrank analysis was used to compare survival curves among TNFi. Hazard ratio (HR) for drug discontinuation was calculated for each individual TNFi. Cox proportional-hazard regression analysis was used for evaluation of risk factors of treatment discontinuation. Adverse events leading to drug discontinuation were closely monitored. Statistical analyses were performed using MedCalc Software, version 12.5, Ostend, Belgium. Results 385 patients with AS on TNFi were analyzed, of them 327 men (85%) and 58 women (15%). Mean age of patients at the time of initiation of TNFi was 39.0 (±10.7) years. Total time on anti-TNF therapy was calculated on 1129 patient-years. 81 patients were exposed to infliximab for 274 PYs, 102 patients to etanercept for 394 PYs, 155 patients to adalimumab for 390 PYs, and 47 patients to golimumab for 72 PYs. Baseline disease activity was high with mean BASDAI 6.1 (±1.3), ESR 53.7 (±27.6) mm/h, CRP 37.3 (±28.5) mg/L, and significantly dropped during the treatment. 98.1% patients remained on therapy with TNFi in 3rd month, 87.1% in 1st year, 74.5% in 2nd year, 59.9% in 3rd year, and 47.8% in 4th year. Patients with infliximab remained on anti-TNF therapy significantly shorter (median 50.0 months), than patients with etanercept or adalimumab (both equally 78.0 months, p=0.0257). HR for discontinuation of infliximab was 1.65-times higher than for etanercept, and 1.8 times higher than for adalimumab. From baseline parameters only ESR (p=0.0004, 95% CI 1.0049-1.0172) and CRP (p=0.0005, 95% CI 1.0041-1.0146) influenced drug survival in AS patients, other parameters like age, gender, disease duration, HLA-B27+, BASDAI and BASFI had no influence. The most common reason of drug discontinuation was lost of efficacy (43.2%), following adverse events (24.8%), extra-articular manifestations (16%), incompliance (5.6%), death (4.8%), remission (1.6%) and other reasons (4%). Patients with infliximab had to stop their treatment mostly due to adverse events (38.7%), with etanercept due to worsening of extra-articular manifestations (34.2%) and with adalimumab due to loss of efficacy (61.1%). Conclusions Patients with etanercept, following with adalimumab tend to remain longer on their therapy, compared to infliximab. The most common reason of drug discontinuation was loss of efficacy following adverse events. Type of drug discontinuations might reflect the character of TNFi used. Disclosure of Interest None declared

Polymyalgia rheumatica (PMR) and giant cell or temporal arteritis (TA) are related chronic inflammatory conditions which typically affect the aged subjects. Typical features of PMR include general symptoms of inflammation as well as severe muscle pain in shoulder and pelvic girdle. The manifestation of TA depends on localization of affected artery, usually branch vessels of the aortic arch. Etiology of PMR and TA remains unclear. The association with HLA system and characteristics of the inflammatory response are discussed in this paper. Age related changes in neuroendocrine system could also represent a pathogenic factor in genetically disposed individuals. Complex bi-directional neuroendocrine-immune relations are further modified by ongoing chronic inflammation. Good clinical response to glucocorticoids in PMR patients supports the assumption that the actual levels of cortisol are lower than would be expected during ongoing inflammation. Moreover, decreased levels of adrenal androgens have been observed in PMR and thus possible adrenal androgens supplementation during glucocorticoid treatment sketches new prospects for the treatment of PMR and TA.

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.

Death through apoptosis is the main process by which aged cells that have lost their function are eliminated. Apoptotic cells are usually detected microscopically by changes in their morphology. However, determination of early apoptotic events is important for in vitro (and ex vivo) studies. The main objective of the present study is to find the most sensitive method for apoptosis detection in human peripheral blood mononuclear cells (PBMCs) by comparing six different methods following five different means of immunological stimulation at 3 and 5 days. Each of six apoptosis quantification methods, except the trypan blue exclusion test, is a combination of two stains, one for the specific detection of apoptotic cells and the other for the unspecific detection of dead cells. Values for apoptosis and mortality were compared with a reference method. The choice of apoptosis detection method is more important following 3 days of stimulation than after 5 days of stimulation (P = 2 × 10(−6) versus P = 1 × 10(−2)). In contrast, we find mortality measurements following the different means of stimulation highly significant at both 3 and 5 days (F (2.28) = 7.9, P = 1.4 × 10(−6) at 3 days and F (2.28) = 8.5, P = 4.5 × 10(−7 )at 5 days). Variation as a result of the combination of specific PBMC stimulation and the method used to detect apoptosis is reduced considerably with time (F (1.58) + 3.7, P + 3 × 10(−7) at 3 days to F = (1.58) = 0.97, P = 0.5 at 5 days). Based on Tukey's test, YO‐PRO‐1 is the most sensitive stain for apoptosis and, when combined with 7‐AAD, provides an accurate measure of apoptosis and mortality. In conclusion, we propose YO‐PRO‐1/7‐AAD as a new combination and low‐cost alternative for the sensitive detection of early apoptosis.

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.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).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 (p0.05), 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 (p0.001, r = 0.741) and TSH (p0.05, 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.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.

Livedo reticularis (LR) is a skin vasculopathy that has been frequently described in patients with anti-phospholipid syndrome (APS) and reported to be present in association with valvular heart pathology and strokes (i.e. Sneddon's syndrome).In a cohort of APS patients we investigated the possible association of LR with various clinical aspects of APS such as pregnancy morbidity, central nervous system (CNS) and cardiac manifestations.Livedo reticularis was found in 50/308 (16%) of APS patients, and there was a significant association with cerebrovascular accidents (CVA), migraines and epilepsy (p = 0.01, 0.002, and 0.02 respectively). A similar association was also detected between LR, and the presence of cardiac valve thickening and vegetations (p = 0.001). No association with venous thrombosis, recurrent fetal loss, IUGR or toxemia was found.Livedo reticularis is a frequent cutaneous manifestation in patients with APS. Its high association with cardiac and CNS thrombosis may suggest that LR-APS patients compose a subset at higher risk for thrombosis, and thus may require a closer follow-up and a more aggressive anticoagulation.

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).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.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.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.

A randomised, double-blind study was performed to assess the efficacy and tolerability of lumiracoxib in patients with rheumatoid arthritis (RA). Patients received lumiracoxib 200mg once daily (o.d.) (n= 280), lumiracoxib 400mg o.d. (n= 281), naproxen 500 mg twice daily (n= 279) or placebo (n= 284) for 26 weeks. The primary efficacy variable was response to treatment according to ACR20 criteria (adjusted for prohibited concomitant or excessive rescue medication use and discontinuations due to unsatisfactory therapeutic response) at week 13. Safety and tolerability was also assessed. Significantly more patients receiving lumiracoxib than placebo were responders according to ACR20 criteria at week 13 (41.1 and 42.7% for lumiracoxib 200 and 400 mg o.d., respectively; 32.4% for placebo; both p0.05). The proportion responding to naproxen (39.1%) was not significantly different from placebo. Prespecified gastrointestinal adverse events were more frequent with naproxen than with either lumiracoxib dose or placebo. Lumiracoxib is therefore an effective and well-tolerated therapy for RA.

We studied the effect of prolactin (PRL) inhibition by bromocriptine (BRC) in the first phase of adjuvant induced arthritis (AA), up to day 11 (BRC1-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 BRC1-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−1, p2/NO−3 rose in rats with AA to 28.7±2.5 μmolL−1 against. 13.9±1.9 μmolL−1 in controls (p−1, p

To elucidate the role of core and skin thermoreceptors in the release of growth hormone (GH) and prolactin (PRL), a sequence of two experiments using whole-body (head-out) and partial (one forearm) hot water immersions was performed.Experiment 1: Nine healthy men were exposed to head-out and partial water immersions (25 min, 38-39 degrees C).Head-out immersion increased the core temperature (38.0 +/- 0.1 vs. 36.7 +/- 0.1 degrees C, P0.001) and plasma concentration of the hormones (GH, 16.1 +/- 4.5 vs. 1.2 +/- 0.4 ng mL(-1), P0.01; PRL, 9.1 +/- 1.0 vs. 6.4 +/- 0.4 ng mL(-1), P0.05). During the partial immersion the core temperature was slightly elevated (36.8 +/- 0.1 vs. 36.6 +/- 0.1, P0.001), the concentration of GH increased (4.8 +/- 1.7 vs. 0.6 +/- 0.3, P0.05), while plasma PRL decreased (7.6 +/- 0.8, 6.0 +/- 0.6, 5.2 +/- 0.6, P0.01). Experiment 2: Seven volunteers immersed one forearm once in 39 degrees C and once in 38 degrees C water. The measurements were performed in 5-min intervals. The GH concentration increased gradually from the beginning of the immersions (min 10; 39 degrees C: 1.9 +/- 1.0 vs. 0.6 +/- 0.3 ng mL(-1), P0.01; 38 degrees C: 0.19 +/- 0.03 vs. 0.14 +/- 0.03, P0.05) and peaked after their completion (39 degrees C: +10 min, 3.7 +/- 2.0, P0.001; 38 degrees C: +15 min, 0.86 +/- 0.61, P0.01). The core temperature was unchanged until min 15 of the 39 degrees C bath. Thereafter, it increased about 0.15 degrees C above the baseline (P0.01). Immersion in 38 degrees C water did not induce core temperature changes.Peripheral thermoreceptors are involved in GH release when the body is exposed to elevated environmental temperature while a substantial elevation of core temperature is a precondition of PRL release.

Elevated plasma prolactin and mild hypocortisolemia have been observed in patients with rheumatic disorders. This study was designed to assess the potential inhibitory effect of hyperprolactinemia on hypothalamic-pituitary-adrenocortical function. Hypoglycemia was induced by intravenous insulin injection (0.1 IU/kg) in 10 female volunteers of fertile age during their follicular phase twice: 60 min after either domperidone (10 mg orally) or placebo administration. Blood samples were collected from an indwelling catheter inserted into the cubital vein at -60, 0, 30, 45, 60 and 90 min. The concentrations of prolactin, adrenocorticotropic hormone (ACTH), cortisol, epinephrine, norepinephrine and glucose were measured in plasma. Domperidone administration significantly increased plasma prolactin concentrations (71 +/- 11 ng/ml vs. 14 +/- 6 ng/ml; p0.001), while basal plasma concentrations of ACTH, cortisol, norepinephrine and epinephrine were unaffected. Insulin-induced hypoglycemia resulted in a significant rise in the mean plasma ACTH levels from 10 +/- 1 pg/ml (domperidone) and 11 +/- 1 pg/ml (controls) to 148 +/- 19 pg/ml (domperidone) and 139 +/- 12 pg/ml (controls) at 45 min (p0.001), in plasma cortisol from 407 +/- 62 nmol/l (domperidone) and 391 +/- 42 nmol/l (controls) to 925 +/- 60 nmol/l (domperidone) and 810 +/- 52 nmol/l (controls) at 60 min (p0.001), and in plasma epinephrine from 40 +/- 26 pg/ml (domperidone) and 16 +/- 3 pg/ml (controls) to 274 +/- 55 pg/ml (domperidone) and 352 +/- 61 pg/ml (controls) at 30 min; (p0.001). The significant increase in ACTH, cortisol and epinephrine responses to hypoglycemia was similar in both groups. We observed mild norepinephrine response to hypoglycemia but this was irrespective of the medication. In conclusion, pharmacologically-induced hyperprolactinemia did not induce significant changes of hypothalamic-pituitary-adrenocortical function and did not influence sympathoadrenal activity in healthy young women.

Background: Canakinumab, a fully human anti-IL-1β antibody has been shown to control inflammation in gouty arthritis. This study evaluated changes in health-related quality of life (HRQoL) in patients treated with canakinumab or triamcinolone acetonide (TA). Methods: An 8-wk, dose-ranging, active controlled, single-blind study in patients (≥18 to ≤80 years) with acute gouty arthritis flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to canakinumab 10, 25, 50, 90, 150 mg sc or TA 40 mg im. HRQoL was assessed using patient reported outcomes evaluating PCS and MCS, and subscale scores of SF-36® [acute version 2]) and functional disability (HAQ-DI©). Results: In canakinumab 150 mg group, the most severe impairment at baseline was reported for physical functioning and bodily pain; levels of 41.5 and 36.0, respectively, which improved in 7 days to 80.0 and 72.2 (mean increases of 39.0 and 35.6) and at 8 wks improved to 86.1 and 86.6 (mean increases of 44.6 and 50.6); these were higher than levels seen in the general US population. TA group, showed less improvement in 7 days (mean increases of 23.3 and 21.3 for physical function and bodily pain). Functional disability scores, measured by the HAQ-DI© decreased in both treatment groups (Table 1). Conclusions: Gouty arthritis patients treated with canakinumab showed a rapid improvement in physical and mental well-being based on SF-36® scores. In contrast to the TA group, patients treated with canakinumab showed improvement in 7 days in physical function and bodily pain approaching levels of the general population. Disclosure statement: U.A., A.F., V.M., D.R., P.S. and K.S. are employees and shareholders of Novartis Pharma AG. A.P. has received research support from Novartis Pharma AG. N.S. has received research support and consultancy fees from Novartis Pharmaceuticals Corporation, has served on advisory boards for Novartis, Takeda, Savient, URL Pharma and EnzymeRx, and is/has been a member of a speakers' bureau for Takeda. A.S. has received consultation fees from Novartis Pharma AG, Abbott, Bristol-Myers Squibb, Essex, Pfizer, MSD, Roche, UCB and Wyeth. All other authors have declared no conflicts of interest

Objectives To analyze the Slovakian experiences in a national multicenter open label non-interventional phase IV study which evaluated tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) and an inadequate response to conventional disease-modifying antirheumatic drugs (DMARDs) or tumor necrosis factor inhibitors (TNFs). Methods A prospective open label, single arm study with descriptive statistics used to analyze primary endpoint DAS28 and secondary endpoints: physical disability (HAQ) and safety. Adult patients with moderate to severe active RA who are on infusions therapy of TCZ (8mg/kg) every 4 weeks, after inadequate clinical response to a stable dose of DMARDs. Study has been approved by local ethical committees and all patients provided informed consent before enrollment. TCZ can be given with methotrexate (MTX), or as monotherapy in case of intolerance to MTX or when treatment with MTX was inappropriate. Results In 62 RA patients reached one year retention rate 89%. 7 patients were prematurely withdrawn: one of them because of ineffectiveness, 4 adverse events and 2 other reason (withdrawal of inform consent or loss of control). After one year 63% of enrolled patients were in remission (DAS28 Conclusions TCZ in Slovakian RA patients in open label study demonstrated high degree of one year retention rate (89%) with remission in 63% and low activity of disease in other 19% patient, without new safety signals. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1516

Background Several studies have demonstrated low 25(OH)D3 serum levels, which could influence pathogenesis and clinical outcomes of immune-mediated diseases such as rheumatoid arthritis (RA) (1,2). Objectives In order to investigate the necessity to implement specific vitamin D patient related outcomes we performed a pilot European multicentre study, involving individuals from different countries/latitudes, to explore 25(OH)D3 serum levels and their possible correlation with disease activity and related outcomes in RA patients during winter season. Methods We enrolled 270 RA patients (not treated with vitamin D supplementation) and 180 healthy subjects as controls (CNT), from Rheumatology centers in 10 European countries. RA patients mean disease duration was 10±9 years and mean age 56±10 years. Patients informed consent was obtained before collecting blood samples. Complete medical history, health assessment questionnaire (HAQ), rheumatoid arthritis impact disease score (RAID), disease activity scale (DAS28) were recorded. 25(OH)D3 serum levels were evaluated centrally using chemiluminescence immunoassay with an automatic analyser (LIAISON, DiaSorin), and classified as normal (>30 ng/ml), insufficient (between 20 and 30 ng/ml) or deficient (

Background Beta-glucans are naturally occurring polysaccharides, which are integral constituents of the cell wall of bacteria, plants and yeasts. They modify biological response, have anticarcinogenic activity and enhance non-specifically the host immune system by activating the complement system, enhancing the function of macrophages, leukocytes and natural killer cells. Their antioxidant, analgesic and anti-inflammatory effects are suggested as well. Objectives The aim of this study was to evaluate the effect of prophylactic and therapeutic dose of β-(1,3/1,6)-D-glucan isolated from mushroom Pleurotus ostreatus (β-glucan-PO) on the methotrexate (MTX) treatment of adjuvant arthritis (AA) in rats. Methods Rats with AA were treated with methotrexate (1 mg/kg/week), β-glucan-PO in a prophylactic dose (1 mg/kg every second day) or their combination for a period of 28 days from adjuvant application. In a second test, MTX (1 mg/kg/week) and β-glucan-PO in a therapeutic dose (15 mg/kg every day) were applied from day 13 to day 35 after immunization. Body mass, hind paw swelling, arthrogram scores, and the level of serum albumin were measured as markers of inflammation and arthritis. Results Preventive treatment with a low dose of MTX significantly inhibited the markers of both inflammation and arthritis. MTX and its combination with β-glucan-PO significantly (p Conclusions Prophylactic and therapeutic administration of β-glucan-PO alone significantly reduced both the hind paw swelling and arthrogram scores. In addition, β-glucan-PO increased the efficacy of basal treatment with MTX in rats with adjuvant arthritis. In patients with rheumatoid arthritis this immunomodulator may prevent the secondary infections and restore impaired immunological homeostasis. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1811

Background TNF-α inhibitors are highly effective for signs and symptoms of ankylosing spondylitis (AS) including acute anterior uveitis (AAU). However, there are some concerns that etanercept does not seem to prevent a relapse and may even trigger an attack of uveitis. Objectives To examine the incidence rate of AAU flares in AS patients during anti-TNF therapy in Slovakia, and to assess whether there is any difference between TNF-α inhibitors. Methods AS patients on anti-TNF therapy were retrospectively analyzed in database of AS patients with biological therapy in Slovakia. This analysis covered AS patients on infliximab, etanercept, adalimumab and golimumab since March 3rd 2003, when the first patient was initiated on TNF-α blocker until December 31st 2013. Duration of anti-TNF treatment was calculated on patient-years (PYs). The number of attacks of AAU before start and during anti-TNF therapy was assessed by patient history and ophthalmology reports. Incidence of AAU flares was calculated on 100 PYs, and differences between monoclonal antibodies and etanercept were assessed. Results All together 372 patients with AS with TNF-α inhibitors were analyzed, of them 318 men (85%) and 54 women (15%). The mean age of patients at the time of initiation of TNF-α blockers was 38.9 years (19-72). Total time on biologic treatment was calculated on 1147 patient-years. 78 patients were exposed to infliximab for a total of 279 PYs, 98 patients were exposed to etanercept for 402 PYs, 151 patients were treated with adalimumab 396 PYs, and 45 patients were under the treatment with golimumab 70 PYs. In general, acute uveitis was present at 26.37% of patients in history before starting biologics. There was no significant difference of uveitis history rates between TNF-α blockers. 268 patients (72%) did not have any attacks of uveitis before and during anti-TNF treatment, 78 patients (21%) had uveitis before, but not after treatment, 19 patients (5%) had uveitis before and also after treatment and 7 patients (2%) developed uveitis for the first time after treatment. In generally, uveitis was present less frequently during anti-TNF therapy than in patients9 history before the treatment, what may reflect positive effect of TNF-α inhibitors on suppression of AAU. However, patients exposed to etanercept had more frequent attacks of uveitis during the treatment, and also there were more patients on etanercept with the first onset of AAU after the treatment compared to monoclonal antibodies. Incidence of AAU flares after infliximab was calculated on 1.07 per 100 PYs, after adalimumab on 1.51 per 100 PYs, and after golimumab on 2.86 per 100 PYs. Patients treated with etanercept had more frequent flares of AAU (6.96 per 100 PYs). Conclusions Prevalence of AAU in patients with AS before anti-TNF therapy in Slovak database of patients with biologics was 26.37%, what is expected and comparable result with other epidemiological studies. TNF-α inhibitors reduced reoccurrence of AAU. The frequency of AAU flares during anti-TNF therapy was generally low, and it was less frequent at patients treated with monoclonal antibodies than at patients treated with etanercept. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5470

Alzheimer's disease (AD) is a degenerative disease of the brain, which causes dementia. The disease is characterised by three main pathogenic factors: senile plaques, neurofibrillary tangles and inflammation. the participation of the local inflammatory reaction is confirmed especially by the results of studies dealing with activated microglia, reactive astrocytes, complement system, cytokines, reactive mediators of oxygen and nitrogen (free radicals), all of which participate significantly in inflammatory processes. These inflammatory markers are locally produced by brain cells, and occur in close proximity of beta-amyloid and tau protein deposits. Moreover, some epidemiologic and pilot clinical studies have proven that long-term administration of anti-inflammatory drugs have a protective effect on the onset of AD. Out of them, non-steroidal anti-inflammatory drugs (NSAIDs) are most extensively investigated medicaments. Despite some contradictory findings, the prevalent majority of these studies prove that long-term application of anti-inflammatory treatment can delay the onset, or at least slow down the progression of AD, namely in people between 65 and 75 years of age. The most appropriate prophylactic effect seems to be achieved by specific inhibitors of cyclooxygenase-2 (COX-2), namely celecoxib and rofecoxib. These preparations protect the gastrointestinal tract better than classical NSAIDs which inhibit both isoenzymes--COX-1 and COX-2. COX-2 is expressed in higher concentrations in the degenerating cells of the brain and this excessive expression can be decreased by selective inhibitors. The latter decrease also the excessive activation of some transcription factors (PPARgama and the nuclear factor kapa-B), which are responsible for the initiation of transcription of a number of pro-inflammatory genes. The selective inhibitors COX-2 can thereby have an anti-inflammatory effect operating on several levels. (Tab. 1, Fig. 1, Ref. 75.)

The aim of our work was to investigate the presence of hyaluronan (HA) in the rat air pouch and its behaviour in response to inflammatory stimuli.HA levels (by a microplate assay) and the leucocyte count were determined in the fluid obtained from air pouches in which acute or subacute inflammation had been induced by the injection of monosodium urate crystals (MSU) or high density polyethylene (HDPE) debris respectively and in relative controls.In control pouches of both groups, remarkable levels of HA were found; these levels were higher in the very first hours (2475 and 1850 micrograms/l at 6 hrs) and then gradually decreased. In pouches injected with MSU, HA moderately increased (p0.001) after 6 hrs, reached a peak after 12 hrs (p0.001) and began to taper at 24 hrs (p0.001). The leucocyte count was also increased at 6 hrs (p0.001), became higher at 12 hrs (p0.001) and tapered at 24 hrs (p0.001). In the HDPE pouches, HA levels were significantly reduced with respect to controls after 6 hours (p0.001), increasing later (p0.001) to reach a peak at 24 hrs (p0.001), and returning to the original levels, or even below, in the following 72 hours.These data confirm that the pouch lining produces fair amounts of HA and provide evidence that, in this system, HA levels seem to be influenced by the degree of inflammation even if with variable behaviour in relation to the different characteristics and phases of phlogosis. The present data suggest that the air pouch is a useful experimental model for studies on HA metabolism in either acute or chronic inflammation.

The aim was to search for periodical fluctuations in daily occurrence of gout attacks during the synodic lunar cycle. 126 gout attacks were recorded between 1972 and 1994 at known calendar dates. The synodic plexogram, displaying the number of attacks for each day of the cycle, was processed by cosinor regression. A pronounced cycling was found, with highest peaks under the new and full moon (syzygigies). Thus, the maximal occurrence of attacks coincides with the peaking lunisolar tidal effect. Similar relation of attacks to synodic moon was seen in bronchial asthma of children, and a reciprocal one in paroxysmal tachyarrhythmia. Differing pathogenetic backgrounds of these diseases substantiate the observed differences in their putative reactions on the changing cosmogeophysical environment.

The term "oral tolerance" means antigen specific suppression of immune response after oral application of antigen. Primary mechanisms by which oral tolerance is mediated include: deletion, anergy and active cellular suppression. The determining factor in this process is the dose of applied antigen. High doses of antigen develop deletion and anergy of cells while low doses of antigen result in bystander suppression. Recently bystander suppression has attracted attention in the treatment of autoimmune diseases. This process is connected with induction of regulatory T cells of Th2/Th3 phenotypes in gut with characteristic profile of anti-inflammatory cytokines as IL-4, IL-10 and TGF-beta. By means of circulation the lymphocytes enter the affected place and when meeting again with the antigen, they produce the same profile of cytokines which they originally made in the gut. These cytokines then suppress local autoimmune and inflammatory reaction independently of the antigen type. After successful trials of treatment with low doses of orally applied collagen type II in animal models of experimental arthritis, this treatment was also studied in clinical trials in humans with rheumatoid arthritis. Although the results obtained to this date are very promising they can not be considered final. Several questions still need to be solved: identification of responders, determination of character and amount of collagen applied as well as the route of application. Another promising therapeutic approach could be the simultaneous application of collagen and the compounds enhancing the cell response of Th2 or Th3 lymphocytes such as TGF-beta, IL-2, antibodies to IL-12 which can augment the oral tolerance. In clinical praxis the treatment of osteoarthrosis with collagen type I has also been successfully applied. Induction of oral tolerance is new approach in the treatment of rheumatoid arthritis and as each new therapy, it requires refinement. In the future it is expected that an improved study design and a better understanding of the underlying mechanisms of oral tolerance will lead to an increased efficacy of the therapy in humans similar to the effectiveness previously demonstrated in animal models.

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.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.The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p0.05). 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).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).

ACE takes part in the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin-II and inactivating bradykinin. ACE gene insertion/deletion polymorphism is associated with the level of circulating enzymes--subjects with the DD genotype have higher levels of circulating ACE than subjects with the II genotype and show an increased tendency towards impaired vascular function and structure. Patients with systemic lupus erythematosus (SLE) suffer from differentially expressed vascular pathology. We attempted to determine whether the type of ACE polymorphism could contribute to this pathology.101 SLE patients fulfilling the ACR criteria were investigated. The I/D polymorphism was ascertained by PCR, followed by electrophoresis of the amplified fragments and UV visualization.The frequency of the D allele was higher in the SLE group (0.623) than in the controls (0.520) (chi 2 test, p0.025). The distribution of the ACE genotype in SLE group was different from that in the control group (p0.05). An association between the DD genotype and visceral damage (p0.006) was observed.Our results suggest that in the multifactorially determined vascular pathology of SLE, changes associated with I/D polymorphism could influence vessel wall inflammation (monocyte adhesion and activation with cytokine release, T-lymphocyte metabolism), a tendency towards vascular impairment (neointimal proliferation, vasospasm, platelet activation, myocyte proliferation) and lead to the subsequent ischemia. The ACE gene could serve as the visceral damage indicator in SLE.

To study the correlation between serum adenosine deaminase (ADA) activity and clinical activity in patients with systemic lupus erythematosus (SLE). The patterns of two ADA isoenzymes, ADA1 and ADA2, were also analysed in healthy controls and patients to determine the source of increased ADA activity in patients.Total serum ADA activity (tADA) was measured spectrophotometrically. The isoenzyme pattern of ADA was analysed by the HPLC method using a specific inhibitor of ADA1, erytro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Disease activity was assessed using the European Consensus Lupus Activity Measurement index (ECLAM).Serum tADA activity was significantly increased in patients compared to healthy controls (mean +/- SD; 476.9 +/- 145.3 vs 254.0 +/- 98.9 ncat/L, p0.001). The isoenzyme analyses showed that the increased total ADA activity in the patients was mainly due to increased ADA2 activity (371.3 +/- 154.8 vs 214.2 +/- 47.9 ncat/L in healthy controls, p0.001). The mean values for ADA1 activity in the patients (64.6 +/- 37.9 ncat/L) and healthy controls (69.2 +/- 26.9 ncat/L) were similar. A strong correlation was found between serum ADA activity and disease activity as measured by ECLAM (Spearman's rank correlation coefficient 0.74, p0.0001, linear regression coefficient 0.68, p0.01).Serum ADA activity is closely associated with SLE activity and appears to be useful as a new disease activity parameter of SLE.

Background In the investigator-initiated prospective trial CYLOFA-LUNE [1] we tested the hypothesis that immunosuppressive regimen based on Cyclosporine A (CYA) may have similar efficacy but greater safety than that based on cyclophosphamide (CPH). Lupus patients with biopsy-proven proliferative glomerulonephritis were randomly assigned to a treatment protocol based on either CyA or CPH. Objectives The main purpose of the current analysis was to ascertain the long-term renal outcome of patients randomised in the CYCLOFA-LUNE trial. Methods Data for kidney function, and adverse events (death, cardiovascular event, tumor, premature menopause) were collected by a cross-sectional suvey for 38 of 40 patients initially randomised 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. Conclusions The data confirm that both regimens based either on CPH or CyA achieved good and similar clinical results in the very long term References Zavada J, Pesickova S, Rysava R, et al. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study. Lupus. 2010 Oct;19(11):1281-9 Acknowledgements Supported by the project (Ministry of Health, Czech Republic) MZO 00023728. Disclosure of Interest None Declared