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Objective.Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with cardiovascular disease. The treatment of arthritis by tumor necrosis factor-α (TNF-α) inhibitors may decrease the serum concentrations of vascular biomarkers. We determined circulating levels of oxidized low-density lipoprotein (oxLDL)/β2 glycoprotein I (β2-GPI) complexes, antibodies to 60 kDa heat shock protein (anti-Hsp60), soluble urokinase plasminogen activator receptor (suPAR), and B-type natriuretic peptide (BNP) fragment in sera of RA and AS patients undergoing anti-TNF treatment.Methods.Fifty-three patients with RA/AS were treated with etanercept or certolizumab pegol for 1 year. Circulating oxLDL/β2-GPI complex (AtherOx), anti-Hsp60 IgG, and BNP8-29 fragment levels were assessed by ELISA. suPAR levels were determined by suPARnostic Quick Triage test. Flow-mediated vasodilation (FMD), carotid intima-media thickness (CIMT), and arterial pulse wave velocity (PWV) were determined by ultrasound.Results.One-year anti-TNF treatment significantly decreased oxLDL/β2-GPI levels, as well as suPAR levels in patients with critically high suPAR levels at baseline. In RA, BNP levels were higher in seropositive vs seronegative patients. Serum levels of these vascular biomarkers variably correlated with lipids, anticitrullinated protein antibodies, rheumatoid factor, and C-reactive protein. CIMT positively correlated with BNP, and PWV with suPAR and anti-Hsp60, whereas FMD inversely associated with anti-Hsp60. In repeated measures ANOVA analysis, disease activity supported the effects of anti-TNF treatment on 12-month changes in oxLDL/β2-GPI. CIMT supported the effects of therapy on changes in anti-Hsp60 and suPAR.Conclusion.These biomarkers may be involved in the pathogenesis of atherosclerosis underlying RA/AS. TNF inhibition variably affects the serum levels of oxLDL/β2-GPI, suPAR, and BNP.

Epidemics and pandemics have happened throughout the history of mankind. Before the end of the 20th century, scientific progress successfully eradicated several of the pathogens. While no one has to be afraid of smallpox anymore, there are some new pathogens that have never caused human disease before. Coronaviruses are a family of enveloped RNA viruses. In the 21st century, three of them have caused serious pandemics, including severe acute respiratory syndrome in 2002 and Middle East Respiratory Syndrome in 2012. In 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease-19 (COVID-19) pandemic, which has destroyed hundreds of thousands of lives and continues to rage.

The distinction between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related and community-acquired pneumonias poses significant difficulties, as both frequently involve the elderly. This study aimed to predict the risk of SARS-CoV-2-related pneumonia based on clinical characteristics at hospital presentation. Case-control study of all patients admitted for pneumonia at Semmelweis University Emergency Department. Cases (n = 30) were patients diagnosed with SARS-CoV-2-related pneumonia (based on polymerase chain reaction test) between 26 March 2020 and 30 April 2020; controls (n = 82) were historical pneumonia cases between 1 January 2019 and 30 April 2019. Logistic models were built with SARS-CoV-2 infection as outcome using clinical characteristics at presentation. Patients with SARS-CoV-2-related pneumonia were younger (mean difference, 95% CI: 9.3, 3.2–15.5 years) and had a higher lymphocyte count, lower C-reactive protein, presented more frequently with bilateral infiltrate, less frequently with abdominal pain, diarrhoea, and nausea in age- and sex-adjusted models. A logistic model using age, sex, abdominal pain, C-reactive protein, and the presence of bilateral infiltrate as predictors had an excellent discrimination (AUC 0.88, 95% CI: 0.81–0.96) and calibration (p = 0.27–Hosmer-Lemeshow test). The clinical use of our screening prediction model could improve the discrimination of SARS-CoV-2 related from other community-acquired pneumonias and thus help patient triage based on commonly used diagnostic approaches. However, external validation in independent datasets is required before its clinical use.

Background: Cardiovascular (CV) morbidity, mortality, and metabolic syndrome are associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Here, lipids and other metabolic markers in relation to vascular function and clinical markers were evaluated in RA and AS patients undergoing one-year anti-TNF therapy. Patients and methods: Fifty-three patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Various lipids, paraoxonase (PON) and arylesterase (ARE) activities, myeloperoxidase (MPO) and adipokine levels were determined overtime. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. Results: Anti-TNF therapy decreased ARE activity, MPO, adiponectin, and chemerin levels after 12 months (p &lt, 0.05). Lipids, PON activity, and leptin remained unchanged. Regression analyses suggested variable associations of IMT, PWV, and FMD with ARE, MPO, leptin, and lipids (p &lt, 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p &lt, 0.05). One-year anti-TNF treatment together with baseline leptin (p = 0.039) or CRP (p = 0.016) levels determined 12 months of lipid changes overtime. TNF inhibition together with baseline disease activity determined ARE activity changes (p = 0.046). Anti-TNF therapy and baseline chemerin levels determined IMT changes overtime (p = 0.003). Conclusions: Assessment of various metabolic parameters together with disease activity, CRP, and ultrasound-based techniques may exert additional value in determining CV burden and in monitoring the effects of biologics on preclinical vascular pathophysiology.

Abstract: Venous thromboembolism (including deep vein thrombosis and pulmonary embolism) is a group of diseases with high morbidity. Mortality caused by venous thromboembolism is also highly significant. It is one of the most frequent preventable causes of death in hospital treated patients. It is not easy to assess the real prevalence of the disease because of the frequent symptomless manifestations (as autopsies become less and less frequent, the number of post-mortem diagnoses also decreases) and also because the disease often generates after hospital discharge. There are a number of factors contributing to the development of venous thromboembolism in hospital treated patients. The significance of risk factors differs in the case of patients treated in surgical and medical departments. In this review, the thromboprophylaxis of mainly medical inpatients are discussed. Though there are guidelines about indications and methods of venous thromboprophylaxis, yet it is an unsolved problem to enforce them worldwide and also in Hungary. Despite the effective prophylactic methods, results cannot be considered satisfactory. The number of days spent in hospital and also the number of re-admisson are elevated because of venous thromboembolism. Beside this, the complications also lead to the worsening of the quality of life of these patients, moreover, to disability or death. The financial burden of the health system is also significant. Improvement of the efficacy of the prevention of venous thromboembolism is a highly important issue of health policy. Orv Hetil. 2019; 160(17): 654–661.

Cardiovascular (CV) disease and osteoporosis (OP) have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Bone and vascular biomarkers and parameters along with the effect of 1-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS. Thirty-six patients treated with etanercept or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were previously assessed by ELISA. Bone density was measured by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) were assessed by ultrasound. Multiple correlation analyses indicated associations between bone and vascular markers. Osteoprotegerin, sclerostin and cathepsin K were significantly associated with FMD, IMT and PWV, respectively (p

Background. People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort. Methods. All diabetes cases ( n = 1,347 ) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type. Results. Altogether, n = 131 / 1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12 / 64 ± 10 years, diabetes duration was 13 ± 10 / 7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5 / 8 ± 5 -year follow-up, n = 28 / 494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76). Conclusions. Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus.

Abstract Introduction Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. Methods Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. Results We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p Conclusions BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Objective. Monophasic glucose response (MGR) during an oral glucose tolerance test (OGTT) and gestational diabetes mellitus (GDM) are predictors of type 2 diabetes mellitus (T2DM). We investigated the association between current MGR and (1) glucose tolerance during a pregnancy 3 years before and (2) current glucose tolerance status. We also sought (3) other determinants of MGR. Research Design and Methods. We conducted a nested case-control study of GDM (n=47 early GDM, diagnosed between 16 and 20 weeks of gestation; n=40 late GDM, diagnosed between 24 and 28 weeks of gestation) and matched healthy controls (n=37, normal glucose tolerance during pregnancy) all free from diabetes at follow-up 3.4±0.6 years after delivery. Glucose tolerance was determined by 2-hour 75 g OGTT. Monophasic and biphasic groups were defined based on serum glucose measurements during OGTT. Results. The biphasic group was younger, had lower triglyceride levels and area under the OGTT glucose curve, and was less frequently diagnosed with early GDM (25 vs. 45%, all p<0.05). Women with a biphasic response also tended to have lower systolic blood pressure (p<0.1). No differences were found in fasting and 2-hour glucose and insulin levels, or BMI. According to multiple logistic regression, MGR was associated with prior early GDM (OR 2.14, 95% CI 0.92-4.99) and elevated triglyceride levels (OR 2.28, 95% CI 1.03-5.03/log (mmol/l)). Conclusions. We found that more severe, early-onset GDM was an independent predictor of monophasic glucose response suggesting that monophasic response may represent an intermediate state between GDM and manifest type 2 diabetes.

Weight-bearing (WB) on the lower extremities is an important outcome parameter in the rehabilitation of poststroke hemiparesis. However, the patients often regain this ability by compensatory movement patterns.Our goal was to characterize with a simple method the trunk alignment of healthy subjects and stroke patients (n = 17 for both groups) during standing and following lateral weight shift (WS). To describe trunk alignment, five markers were placed on the subjects' back, and the angles of the trunk at both sides were defined by the lines drawn from the posterior angle of the acromion and the iliac crest on the same body side to the seventh thoracic spinal process. Weight distributions on the lower extremities during standing and lateral WS were determined with a force platform.The patients had significantly limited WB capacity on their paretic limb, which was accompanied with significant asymmetry in the trunk alignment during standing and following WS to the paretic side.Our results show that this patient population tends to use abnormal compensatory movement patterns to optimize weight shifting, and changes of trunk alignment play a key role in this. This should be taken into consideration during rehabilitation.

Objective We wished to determine bone alterations in systemic sclerosis (SSc) patients by conventional densitometry (DXA), peripheral quantitative computed tomography (pQCT), and bone biomarkers. Methods We included 44 SSc patients and 33 age-matched healthy controls. Lumbar spine and femoral neck bone mineral density (BMD) was assessed by DXA. Volumetric BMD was measured by pQCT at the radius. FRAX, 25-hydroxyvitamin-D3 (25-OH-D3), parathyroid hormone, osteocalcin, C-terminal collagen telopeptide, and procollagen type I amino-terminal propeptide were also assessed. Results SSc patients had lower L2–4 BMD (0.880 ± 0.108 vs. 0.996 ± 0.181 g/cm2; p = 0.019) and femoral neck (FN) BMD (0.786 ± 0.134 vs. 0.910 ± 0.090 g/cm2; p = 0.007) by DXA. In SSc vs. controls, pQCT indicated lower mean cortical (328.03 ± 103.32 vs. 487.06 ± 42.45 mg/cm3; p 3; p = 0.037). Vitamin D3 deficiency was more common in SSc vs. controls (60.0% vs. 39.3%; p = 0.003). L2–4 (p = 0.002) and FN BMD (p = 0.015) positively correlated with BMI. pQCT assessments confirmed an inverse correlation between pulmonary manifestation and total (p = 0.024), trabecular (p = 0.035), and cortical density (p = 0.015). Anti-Scl70 positivity inversely correlated with pQCT total density (p = 0.015) and the presence of digital ulcers with cortical density (p = 0.001). We also found that vertebral and FN BMD as determined by DXA significantly correlated with pQCT total, trabecular, and cortical density (p Conclusion The results of our study suggest that bone loss in SSc patients may be associated with lower BMI, anti-Scl70 positivity, and the presence of pulmonary manifestations and digital ulcers. Both DXA and pQCT are appropriate tools to evaluate the bone alterations in SSc patients.

Objectives There is a direct correlation between 25-hydroxyvitamin D (25[OH]D) levels and insulin sensitivity. Furthermore, women with gestational diabetes (GDM) may have lower levels of 25(OH)D compared to controls. The present study intended to investigate 25(OH)D levels and their association with insulin sensitivity and insulin secretion in women with prior GDM and in controls 3.2 years after delivery. Methods A total of 87 patients with prior GDM and 45 randomly selected controls (age range, 22 to 44 years) with normal glucose tolerance during pregnancy nested within a cohort of all deliveries at Saint Margit Hospital, Budapest, between January 1 2005, and December 31 2006, were examined. Their 25(OH) D levels were measured by radioimmunoassay. Insulin sensitivity and fasting insulin secretion were estimated using the homeostasis model asssessment (HOMA) calculator and early insulin secretion by the insulinogenic index based on a 75 g oral glucose tolerance test. Results There was no significant difference in 25(OH)D levels between cases and controls (27.2±13.1 [±SD] vs. 26.9±9.8 ng/L). There was a positive association between HOMA insulin sensitivity and 25(OH)D levels (beta = 0.017; 95% CI 0.001 to 0.034/1 ng/mL) that was robust to adjustment for age and body mass index. There was a nonsignificant association between HOMA insulin secretion and 25(OH)D (p=0.099), while no association was found with the insulinogenic index. Conclusions Prior GDM status was not associated with 25(OH)D levels; however, 25(OH) D levels were associated with HOMA insulin sensitivity. It is hypothesized that the association between HOMA insulin secretion and 25(OH)D levels is related to the autoregulation of fasting glucose levels because no association between 25(OH)D and insulinogenic index was found.

Career situation of first and presenting author Instructor. Introduction Osteoporosis has been associated with systemic sclerosis (SSc). Objectives We wished to determine bone alterations in SSc patients by conventional densitometry (DXA), peripheral quantitative computed tomography (pQCT) and bone biomarkers. Methods We included 44 SSc patients and 33 age-matched healthy controls. Lumbar spine and femoral neck bone mineral density (BMD) was assessed by DXA. Volumetric BMD was measured by pQCT at the radius. FRAX, 25-hydroxyvitamin-D3 (25-OH-D3), parathyroid hormone, osteocalcin, C-terminal collagen telopeptide and procollagen type I amino-terminal propeptide were also assessed. Results SSc patients had lower L2–4 BMD (0.880±0.108 vs. 0.996±0.181 g/cm2; p=0.019) and femoral neck (FN) BMD (0.786±0.134 vs. 0.910±0.090 g/cm2; p=0.007) by DXA. In SSc vs controls, pQCT indicated lower mean cortical (328.03±103.32 vs 487.06±42.45 mg/cm3; p Conclusions The results of our study suggest that bone loss in SSc patients may be associated with lower BMI, anti Scl70 positivity, and the presence of pulmonary manifestations and digital ulcers. Both DXA and pQCT are appropriate tools to evaluate the bone alterations in SSc patients. Acknowledgements This research was supported by Hungarian National Scientific Research Fund (OTKA) grant No. K 105073 (H.P.B. and Z.S.); by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program ’(Z.S.); by the European Union grants GINOP-2.3.2-15-2016-00015 and GINOP-2.3.2-15-2016-00050 (Z.S.). Disclosure of Interest None declared.

Career situation of first and presenting author Student for a master or a PhD. Introduction During the treatment of rheumatoid arthritis (RA) we intend to achieve remission or low disease activity. In this regard, the most effective way is targeted therapy. Oral JAK inhibitor, tofacitinib appeared as a new therapeutic option, beside biological therapies, which has already proven its safety and effectivity in RA. Objectives The aim of this study was to assess the clinical and immunological effects of one-year tofacitinib therapy in patients with RA. Methods Altogether 30 RA patients with active disease were recruited and treated with tofacitinib in this 12 months follow-up study. Mean duration of rheumatoid arthritis were 7.7±5.0 years. Half of the patients haven’t received biological treatment prior tofacitinib therapy, other half of the patients switched to tofacitinib therapy after completing washout. 15 patients received 2 × 5 mg and 15 patients received 2 × 10 mg tofacitinib daily for 12 months. Assessments were performed at baseline, month 6 and 12. Levels of CRP and IgM rheumatoid factor (RF) antibodies were measured by quantitaive nephelometry and levels of anti-CCP assesed by ELISA. Lymphocyte subsets (CD3+, CD4+, CD8+ T cells, CD19+ B cells and CD56+/CD3- NK cells) were assesed by cytofluorimetry. In addition, disease activity (DAS28), age and disease duration were also measured. Results Tofacitinib therapy was clinically effective, significant improvements in physical function were observed in 26 patients. 4 patients (two from both arms) quit the study due ineffectivity. There were significant decrease in levels of DAS28 (p Conclusions One year tofacitinib therapy effectively reduced disease activity and systemic inflammation. The therapy also improved functional capacity. JAK inhibition signficantly decreased the number and ratio of CD3+ and CD4+ T cells and increased number and ratio of CD19+ B cells in 12 months. Tofacitinib is a safe and effective treatment for rheumatoid arthritis. It makes an effect, partly, via modifing lymphocyte subsets. Acknowledgements This research was supported by an investigator-initiated research grant from Pfizer. Disclosure of Interest None declared.

Background:Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with osteoporosis. There have been very few data on the use of peripheral quantitative computed tomography (QCT) in anti-TNF-treated patients.Objectives:We wished to assess volumetric bone mineral density (BMD) by forearm QCT in conjunction with dual-energy X-ray absorptiometry (DXA) and bone biomarkers in RA and AS.Methods:Forty RA and AS patients treated with etanercept (ETN) or certolizumab pegol (CZP) were included in a 12-month follow-up study. Peripheral QCT and DXA BMD were determined. Bone biomarkers, such as PTH, osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin, DKK-1 and cathepsin K (CATHK) were assessed by ELISA.Results:There was no further bone loss during anti-TNF treatment. Volumetric and areal BMD showed significant correlations with each other (pConclusion:QCT confirmed that biologics may attenuate bone loss. Disease activity, CATHK, RANKL and VITD may predict the effects of anti-TNF treatment on volumetric BMD changes. There may be differences between RA and AS in this respect.Acknowledgements:This research was supported by Hungarian National Scientific Research Fund (OTKA) grant No. K 105073 (H.P.B. and Z.S.); by the European Union and the State of Hungary and co-financed by the European Social Fund in the framework of TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program ’(Z.S.); by the European Union grant GINOP-2.3.2-15-2016-00050 (Z.S.); and by the Pfizer Investigator Initiated Research Grants no. WS1695414 and WS1695450 (Z.S.).Disclosure of Interests:Balázs Juhász: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Anita Pusztai: None declared, Agnes Szentpetery: None declared, Zsófia Pethö: None declared, Nóra Bodnár: None declared, Attila Hamar: None declared, Levente Bodoki: None declared, Harjit Pal Bhattoa: None declared, Éva Szekanecz: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Szilvia Szamosi Speakers bureau: Roche, Csaba Horváth: None declared, Sándor Szántó Speakers bureau: Abbvie, MSD, Novartis, Consultant of: Abbvie, Novartis, Gabriella Szücs Speakers bureau: Roche, Boehringer, Actelion, Sager, Consultant of: Actelion, Boehringer, Hennie Raterman: None declared, WIllem Lems Speakers bureau: Pfizer, Amgen, Lilly, UCB, Galapagos, Consultant of: Pfizer, Amgen, Lilly, UCB, Galapagos, Oliver FitzGerald Speakers bureau: AbbVie, Janssen, Pfizer, Consultant of: BMS, Celgene, Eli Lilly, Janssen, Pfizer, Grant/research support from: AbbVie, BMS, Eli Lilly, Novartis, Pfizer, Zoltán Szekanecz Speakers bureau: Pfizer, Roche, Abbvie, Novartis, Lilly, Sanofi, Consultant of: Pfizer, Abbvie, Novartis, Grant/research support from: Pfizer, UCB.

Background:Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the ageing population, even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis (RA) and spondyloarthropathies. Both RA and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss, accelerated atherosclerosis, increased CV morbidity and mortality.Objectives:Bone and vascular biomarkers and parameters along with the effect of one-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS.Methods:Fifty-three patients including 36 RA patients treated with etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were assessed by ELISA. Bone density was assessed by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and pulse-wave velocity (PWV) were assessed by ultrasound. The effects of vascular markers on bone and bone effects on vasculature undergone statistical analysis.Results:Serum levels of vascular endothelial growth factor (VEGF), PDGF-BB, angiopoietin 2 (Ang2) and cathepsin K (CathK) decreased, procollagen type 1 N-propeptide (P1NP) and sclerostin (SOST) levels increased, soluble receptor activator nuclear kappa B ligand (sRANKL) and osteoprotegerin (OPG) levels showed no differences. When bone and vascular markers were correlated with each other, at baseline, OPG correlated with Ang2 and adiponectin. SOST correlated positively with ccIMT. DXA L2-4 BMD, DXA L1 BMD and DXA femoral neck (FN) BMD correlated with FMD and CRP. QCT trabecular BMD correlated with ccIMT and PON1. According to the univariate analysis, FMD correlated with OPG, ccIMT correlated with SOST and QCT trabecular BMD. Ang1, Ang2 and PDGF-BB showed correlation with Dickkopf-1 (DKK1). Ang2 also correlated with OPG. As suggested by the multivariate analysis, OPG determined FMD; DKK1 was an independent predictor of Ang1, Ang2 and PDGF-BB. OPG was a predictor of Ang2.Conclusion:In our study of anti-TNF treated RA and AS patients, vascular and bone parameters showed numerous correlations. The therapy was clinically effective, it halted further bone loss over 1 year and reduced the production of angiogenic markers.Acknowledgments:This research was supported by an investigator-initiated research grant from Pfizer.Disclosure of Interests:Monika Czókolyová: None declared, Katalin Gulyás: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Zsófia Pethö: None declared, Szilvia Szamosi: None declared, Attila Hamar: None declared, Anita Pusztai: None declared, Emese Balogh: None declared, Nóra Bodnár: None declared, Levente Bodoki: None declared, Agnes Szentpetery: None declared, Harjit Pal Bhattoa: None declared, György Kerekes: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Sándor Szántó: None declared, Gabriella Szücs: None declared, Hennie Raterman Grant/research support from: UCB, Consultant of: Abbvie, Amgen, Bristol-Myers Sqibb, Cellgene and Sanofi Genzyme, WIllem Lems Grant/research support from: Pfizer, Consultant of: Lilly, Pfizer, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen

Background:Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with inflammatory atherosclerosis, increased cardiovascular (CV) morbidity and mortality. Numerous proteins may serve as biomarkers of inflammatory atherosclerosis. The treatment of arthritis by tumour necrosis factor α (TNF-α) inhibitors may decrease the serum concentrations of these biomarkers.Objectives:In this study we wished to determine circulating levels of oxidized LDL (oxLDL) - β2 glycoprotein I (β2GPI) complexes (AtherOx), anti-hsp60 antibodies, soluble urokinase plasminogen activator receptor (sUPAR) and N-terminal B-type natriuretic peptide (NT-proBNP) in sera of RA and AS patients. We also wished to assess the effects of anti-TNF treatment on these biomarkers.Methods:Altogether 53 arthritis patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 17 AS patients treated with ETN were included in a 12-month follow-up study.Circulating oxLDL/β2gpI complexes, anti-human Hsp60 immunoglobulin G (IgG) levels and BNP8-29fragment levels were assessed by ELISA. suPAR levels were assessed by suPARnostic®Quick Triage test. All laboratory assessments were performed at baseline, as well as 6 and 12 months after treatment initiation. Results were associated with DAS28, BASDAI, CRP.Results:In the mixed cohort of 53 arthritis patients, the circulating levels of oxLDL/β2gpI significantly decreased after 12 months of anti-TNF therapy (0.20±0.11 U/ml) compared to baseline (0.24±0.10 U/ml; p=0.014). There was a tendency of non-significant decrease after 6 months (0.23±0.14 U/ml) versus baseline. Anti-Hsp60 antibody levels did not change after 6 months (158.6±138.6 AU/ml) and 12 months (167.3±143.3 AU/ml) compared to baseline (170.3±140.4 AU/ml). Among the patients, 21.2% had low, 36.4% “observe”, 9.1% high and 33.3% critical suPAR levels. suPAR levels showed a tendency of non-significant decrease after 6 months (11.3±17.7 ng/ml) and 12 months (10.3±15.3 ng/ml) versus baseline (11.5±16.4 ng/ml). However, when the four serum level categories described above were considered, suPAR concentrations exerted significant decrease in RA patients with critical suPAR levels (>9ng/ml) (p=0.04). Similarly, BNP fragment levels showed only a tendency of decrease after 6 months (518.2±422.4 pmol/l) and 12 months (484.1±418.2 pmol/l) versus baseline (530.8±441.8 pmol/l). However, serum BNP levels at baseline and after 12 months were significantly increased in CCP positive compared to CCP negative RA patients (baseline: 670.6±323.0 versus 138.0±436.4 pmol/l; p=0.030 and 12 months: 652.9±283.2 versus 456.5±423.1 pmol/l; p=0.021), as well as in RF positive compared to RF negative RA patients (baseline: 680.6±381.6 versus 292.9±198.3 pmol/l; p=0.007 and 12 months: 668.9±346.5 versus 312.2±207.0 pmol/l; p=0.001).Conclusion:One-year anti-TNF therapy significantly decreased circulating oxLDL/β2gpI complex levels. This therapy also decreased suPAR levels in patients with critically high suPAR. BNP fragment levels were associated with seropositivity in RA. These vascular biomarkers may reflect the effects of TNF inhibition on endothelial activation.Acknowledgments:This study was sponsored by an investigator-initiated grant from Pfizer.Disclosure of Interests:Anita Pusztai: None declared, Attila Hamar: None declared, Ágnes Horváth: None declared, Edit Végh: None declared, Nóra Bodnár: None declared, György Kerekes: None declared, Monika Czókolyová: None declared, Szilvia Szamosi: None declared, Levente Bodoki: None declared, Katalin Hodosi: None declared, Andrea Domjan: None declared, Gábor Nagy: None declared, Ibolya Szöllösi: None declared, Luis Lopez Employee of: Retired employee of Corgenix Inc., Eiji Matsuura: None declared, Zoltán Prohászka: None declared, Sándor Szántó: None declared, Zoltán Nagy: None declared, Yehuda Shoenfeld: None declared, Zoltán Szekanecz Grant/research support from: Pfizer, UCB, Consultant of: Sanofi, MSD, Abbvie, Pfizer, Roche, Novertis, Lilly, Gedeon Richter, Amgen, Gabriella Szücs: None declared

Background Rheumatoid arthritis (RA) has been associated with cardiovascular disease and metabolic syndrome. Numerous pro-inflammatory cytokines (e.g. TNF-α, IL-1, IL-6) are released, which cytokines cause increased reactive oxygen species (ROS) production and thereby contribute to the increased lipid peroxidation and reduction of many antioxidants. These processes not only lead to the deterioration of joints and other tissues but may also contribute to comorbidities, such as atherosclerosis. Objectives The aim of this study was to assess the effects of anti-TNF therapy on different metabolic markers, such as PON1 (paraoxonase 1), arylesterase, chemerin and adiponectin. We also investigated whether these biomarkers correlated with various demographic, clinical and laboratory markers. Methods We treated 37 RA patients with either etanercept (ETN) or certolizumab pegol (CZP) in a 12 month follow-up study. Assessments were performed at baseline, and 3, 6 and 12 months after treatment initiation. Serum chemerin and adiponectin concentrations were measured by commercially available ELISA kits (R and D System, MN and USA). PON1 and arylesterase activities were measured by spectrophotometry. In addition, age, disease duration, disease activity (DAS28), CRP, anti-CCP, IgM rheumatoid factor and plasma lipid levels were also assessed. Arterial flow-mediated vasodilation (FMD), carotid intima-media thickness (cIMT) and arterial pulse-wave velocity (PWV) were assessed by ultrasound. Results Anti-TNF treatment resulted in a significant decrease in the levels of chemerin (p Conclusions Metabolic factors, such as certain adipokines, PON1 and arylesterase may play a role in oxidative stress and atherosclerosis associated with RA. Anti-TNF treatment may affect adipokine levels. Disclosure of Interest None declared

Introduction Stroke has been associated with rheumatoid arthritis (RA). Vascular physiology should be assessed in the preclinical vascular state. Assessment of intracranial vessels includes transcranial doppler (TCD). TCD performance requires intact temporal acoustic windows (TAW). Failure of TAW (TAWF) is present in 8%–20% of people. This may be due to pathological bone metabolism. Objectives We assessed RA patients and healthy controls by transcranial Doppler (TCD), carotid ultrasonography and brain MRI. We wished to determine preclinical pathophysiological changes in the cerebral vasculature. Methods TAWF, temporal bone thickness and texture were determined by ultrasound and CT. BMD and T-scores of multiple bones were determined by DEXA. Several bone biomarkers were assessed by ELISA. Altogether 63 female RA patients and 60 age-matched controls underwent TCD assessment of the medium cerebral (MCA), basilar and vertebral arteries. Pulsatility(PI), resistance(RI) indices and circulatory reserve capacity (CRC) were determined. The presence of carotid plaques and intima-media thickness (cIMT) were also determined. Intracerebral vascular lesions were investigated by brain MRI. RA subsets include MTX- and biologic-treated patients. Results In RA, the right and left TAW were undetectable in 35% and 53% of patients, respectively. In controls, TAWF was only present in 20% of subjects. Temporal bone was thicker, and texture was more heterogeneous in RA patients was controls (p Conclusions TAWF, thicker and heterogeneous temporal bones were associated with RA. These features have been associated with bone loss and OPG production. Bone loss seen in RA may result in OPG release and stimulation of bone formation around TAW. This may be the first study to show increased distal MCA and basilar artery occlusion in RA as determined by TCD. RA patients also exert CRC defect. We also confirmed increased carotid plaque formation, increased cIMT. Biologics may beneficially influence some parameters in the intracranial vessels. Disclosure of interest None declared

Introduction Prevoius studies have shown an increased risk of cardiovascular disease in rheumatoid arthritis (RA), due to RA-associated inflammation. Different vascular biomarkers, such as anti-hsp65 antibodies, asymmetric dimethylarginine (ADMA) and B-type natriuretic peptide (BNP) have been associated with atherosclerosis and RA. Anti-hsp65 antibodies were found in RA patients and these antibodies linked also to inflammation and atherosclerosis. ADMA is an endogenous competitive inhibitor of NOS and consequential can lead to increased nitrosative and oxidative stress. ADMA has been implicated with atherosclerosis, and also with rheumatoid arthritis. BNP also associated to cardiovascular diseases. Objectives The aim of this study was to assess the effects of anti-TNF therapy on different vascular biomarkers, such as anti-hsp65, ADMA and BNP in patients with RA and their correlation with different laboratory and clinical markers. Methods Altogether 36 RA patients were recruited and treated with either etanercept (ETN) or certolizumab pegol (CZP) in this 12 months follow-up study. Assessments were performed at baseline, at month 6 and 12. Amounts of IgG antibodies reacting with recombinant M. bovis hsp65 (Lionex, Braunschweig, Germany) were measured by ELISA. ADMA was assesed by HPLC with fluorescent detection. BNP fragments were assessed by commercially avaiable ELISA kit (Biomedica, Vienna). In addition, disease activity (DAS28), age, disease duration, CRP, IgM rheumatoid factor (RF), anti-CCP (aCCP) and plasma lipid levels were also measured. Arterial flow-mediated vasodilation (FMD), carotid intima-media thickness (cIMT) and arterial pulse-wave velocity (PWV) were assessed by ultrasound. Results There were no significant changes in the levels of anti-hsp60, ADMA and BNP due to anti-TNF therapy. However, baseline level of BNP is correlated with the levels of RF (R=0.479, p=0.004) and aCCP (R=0.591, p Conclusions BNP levels were significantly higher in RF +compared to RF- patients, which imply that BNP may associate with RF positivity. Specific biomarkers, such as ADMA, anti-hsp60 and BNP may play important role cardiovascular disease in RA. Acknowledgements The work is supported by the GINOP-2.3.2-15-2016-00015/I-KOM TEAMING project. Disclosure of interest None declared

Insulin therapy is the most effective treatment of diabetes. It is proven to prevent microvascular disease and likely to decrease the risk of cardiovascular complications. However, these benefits are associated with a 2-3 times increased risk of hypoglycaemia and a faster weight gain compared to other antidiabetic medications. In addition, one study found elevated all-cause mortality among patients on intensive therapy (requiring more frequent insulinisation). Insulin has growth factor properties that may translate to increased mitogenicity. These factors could prevent the medical team or the patient from initiation or intensification of insulin therapy. The authors describe evidence on long-term remission related to transient intensified insulin therapy at diabetes diagnosis. The currently recommended method of insulin initiation is once daily basal insulin treatment that offers different schedules for intensification. The authors review the pharmacokinetics of analogue insulins that translate to similar efficacy to human insulins with a 20-30% lower risk of hypoglycaemia. Orv. Hetil., 2015, 156(36), 1443–1450.

Despite several therapeutic possibilities the morbidity and mortality of thromboembolic disorders remain high. Improving drug compliance – i. e. keeping up the doctor’s prescriptions – may be an effective tool to reach better results. To improve patients’ compliance, the risk factors of non-compliance should be recognized. Among these patients’ fear of adverse effects of drugs, their lack of knowledge about their illness and medication, forgetfulness, and other social, economic factors may be the most important. Furthermore, adherence may be worsened when the patient feels that the decision has been made over his/her head. Sustained medical adherence is important because anticoagulation may be a life-long treatment. The new oral anticoagulants make the matter of compliance to be current. These new type of drugs do not need regular laboratory monitoring and, therefore, compliance cannot be strictly followed. There are several studies concerning drug compliance to anticoagulant medications. Improvement of adherence is based on regular patient education after reviewing the factors of non-compliance, which needs teamwork with important roles of doctors, pharmacists, dietetics and nurses. Careful and accurate work of the participants of primary care might be complemented by the activity of anticoagulant clinics. Orv. Hetil., 2015, 156(32), 1281–1287.

Background Prognosis of rheumatoid arthritis (RA) should be assessed early during the disease course. Rapid radiological progression (RRP) has been defined as a ≥% unit increase in van der Heijde-Sharp score within a year. The matrix risk model has been developed by Vastesaeger et al in 2009. This tool calculates RRP based on non-radiographic indicators such as baseline CRP, RF and swollen joint count. Objectives We wished to test the matrix prediction model int he very first Hungarian cohort study. Methods In this non-interventional, cross-sectional retrospective study carried out in 11 Hungarian arthritis centres, we assessed high risk (≥40%) of RRP in biologic-naive RA patients with active disease. In order to obtain a representative sample, patients were selected from each centre by a random technique. RRP was calculated according to the matrix model described by Vastesaeger et al. As a secondary endpoint, we compared methotrexate (MTX) responders vs non-responders with respect to RRP. Results We screened data of 1843 RA patients. Finally, data obtained from 1356 patients could be used for RRP prediction and MTX responsiveness. The mean age of patients was 55.5 years, 84.7% were women. The mean disease duration was 8.4 years. At the time of the assessment, mean CRP was 17.7 mg/l, RF was 139,3 IU/ml, mean DAS28 was 5.00 and mean swollen joint count was 6.56. High risk ((≥40%) of RRP could be determined in 18.2% of patients. Among continuous variables other than those used for calculation of RRP risk, RA patients with the risk of RRP≥40% (n=247) had significantly lower age than those with RRP Conclusions In the first bioloigc-naive Hungarian RA cohort assessed for RRP, RRP occurs in almost one-fifth of the patients. These patients differ from others in various clinical and serological parameters. RRP has also been associated with non-response to MTX. References Vastesaeger N, Xu S, Aletaha D, St Clair EW, Smolen JS. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology (Oxford). 2009 Sep;48(9):1114–21. Disclosure of Interest None declared

Introduction. Obstructive sleep apnea syndrome (OSAS) has been recently shown to be associated with an increased risk of traffic accidents. Expensive and not widely available polysomnography (PSG) is the gold standard for diagnosing OSAS. The questionnaire developed by the Obstructive Sleep Apnoea Working Group in 2013 in Brussells (termed the Brussels Questionnaire) was created as a screening strategy for those who apply for a driver’s license. Aim. The aim of this study was to evaluate the sensitivity and specificity of the Brussels Questionnaire for detecting OSAS. Material and Methods. 285 patients who reported to the Sleep Disorders Centre of the Neurology Department of the Hungarian Defence Forces Military Hospital for the portable monitoring (PM) completed the Brussels Questionnaire. A score of 10 or higher out of 24 indicated a high risk of OSAS. The results of the questionnaire were then compared with the results of the PM as well as of the polysomnography (PSG) when available. Results. After the comparison of the results obtained with PM and the Brussels Questionnaire, the sensitivity and specificity of the questionnaire were calculated and amounted 0.64 and 0.49, respectively. After the comparison of the results obtained with PSG and the Brussels Questionnaire, the sensitivity and specificity of the questionnaire were calculated and amounted 0.83 and 0.55, respectively. The score of 10 points was found to be the optimal cut-off value. Conclusions. The Bruxelles Questionnaire is a simple screening tool for OSAS in candidates for driver’s license, with a sensitivity of 0.64 and a specificity of 0.49. Its specificity and sensitivity are similar to those of other frequently used questionnaires.

Introduction. Typical symptoms of Parkinson’s disease (PD) are motor symptoms. However, the non-motor symptoms, which may occur in any phase of the disease, are now in the center of the clinical attention. These symptoms include neuropsychiatric dysfunctions, dysautonomy, sleep disorders, and sensory symptoms, such as pain. Sleep disorders are common in PD patients. Aim. The aim of our study was to estimate the prevalence and characteristics of obstructive sleep apnea syndrome (OSAS) in patients with PD. We also wanted to analyze the sleep architecture in Parkinson’s disease using polysomnography. Material and methods. 50 patients who had visited the Neurology Department of Hungarian Defence Forces Military Hospital between February 2014 and April 2016 were recruited for the study. Every patient with idiopathic Parkinson’s disease stage 1 to 3 was included, regardless of their sleeping complaints. Every patient underwent nocturnal, in-laboratory polysomnography, the results of which were subsequently assessed by a somnologist. Sleep stages were distinguished and the Apnea-Hypopnea Index (AHI) was calculated according to the recommendations of the Task Force of the American Academy of Sleep Medicine. Results. The total in-laboratory sleep time ranged from 189 minutes to 501 minutes, with the mean value of 298 minutes. Total sleep time was reduced (< 5 hours) in 28 patients (56%). Sleep latency was prolonged (< 0.5 hours) in 33 patients (> 66%). In older patients (≥ 75 years old), the sleep latency was longer. The normal sleep efficiency of > 85% was seen in only 8 patients. The sleep efficiency ranged from 56% to 89%, with a mean value of 74.1%. 9 patients in our study group had 3 rapid eye movement (REM) sleep episodes, 37 patients had 2 REM episodes and 4 patients had only 1 REM episode. There was a negative correlation between the score on Epworth Sleepiness Scale (ESS) and the number of REM episodes. REM sleep onset latency was prolonged (> 2 hours) in 82% (n = 42) of our patients. Periodic limb movements in sleep (PLMS) were seen in 18 patients. There was a negative correlation between age and PLMS index. All the patients in our study who had been diagnosed with restless leg syndrome (RLS) had PLMS . Sleep latency was prolonged in 7 out of 17 patients suffering from RLS. 64% (n = 32) of our patients were diagnosed with OSAS. The prevalence of severe, moderate and mild OSAS was 22%, 32% and 10%, respectively. Patients with moderate and severe OSAS (AHI > 15 hours) had higher age than patients without OSAS (p < 0.005). The mean ESS score was higher in OSAS patients (p = 0.05). Snoring was present in 78% of the OSAS patients. Apnea witnessed by a partner was the most specific symptom, present in 92% of OSAS patients. We did not find significant differences between the groups with and without OSAS in regard of UPDRS (unified PD rating scale) and Hoehn & Yahr’s modified evaluation scale and Schwab & England’s functional evaluation scale. Conclusions. OSAS is a common sleep disorder in PD patients. It has a higher prevalence in older PD patients and it is associated with greater daytime sleepiness. Snoring is the most sensitive symptom, and apneas witnessed by a partner are the most specific symptom of OSAS in PD patients.

Introduction Genetic and autoimmune risk factors contribute to the development of thrombotic thrombocytopenic purpura (TTP) but triggers are needed to bring about acute disease. The aim of the study was to investigate the association of neutrophil activation with acute TTP, to assess whether neutrophil activation changes during plasma exchange therapy and to show if complement- and neutrophil activation are parallel, characteristic processes in acute TTP. Materials and Methods Altogether 49 EDTA-plasma samples of 21 TTP patients with acute disease and 17 in remission were investigated along with 20 healthy controls. A stable complex of PMNE-proteinase-inhibitor was measured by ELISA (Calbiochem, Merck-Millipore, Darmstadt, Germany). Results Acute disease was associated with significantly increased PMNE levels, the group medians were similarly low in TTP patients in remission and in healthy controls. Increased PMNE levels were characteristic for hematologically active and ADAMTS13 deficient form of TTP. PMNE concentration inversely correlated to disease activity markers platelet count (r = − 0.349, p = 0.032) and hemoglobin levels (p = − 0.382 p = 0.018). Achievement of remission was associated with significant reduction of plasma PMNE levels (p = 0.031, Wilcoxon test). There was positive correlation between PMNE levels and complement activation markers C3a and Bb. Conclusions We report increased PMNE levels in acute TTP and showed its association to activity markers of acute TTP and complement activation. Effective treatment of an acute TTP episode resulted in marked decrease in PMNE levels. Our data support and extend previous observations that neutrophil extracellular traps may be released in acute TTP and potentially contribute to the pathophysiology of this disease.

Fallbericht Es wird uber einen bilateralen, simultanen, retinalen Zentralvenenverschluss (ZVV) bei Protein-S-Mangel berichtet. Der 27-jahrige mannliche Patient stellte sich mit einer plotzlichen bilateralen Sehverschlechterung in unserer Klinik vor. In der allgemeinen Anamnese des Patienten wurde vom Tod des Vaters durch eine pulmonale Embolie im Alter 33 Jahren berichtet. Im Zuge eines Thrombophiliescreenings wurde beim Patienten ein Protein-S-Mangel festgestellt.

To estimate and compare the prevalence of self-reported diabetes based on nationally representative surveys of the Hungarian adult population in 2002 (published data - Hungarostudy) and a survey in 2012.A cross-sectional computer-assisted telephone interview survey on a stratified representative sample of community-dwelling adults (n=1000) in 2012. To describe self-reported diabetes prevalence and its temporal changes generalized linear models were used and results were compared to figures from Hungarostudy.Age standardized prevalence of self-reported type 2 diabetes was 11.7% (95%CI 10.0-13.8%) without gender or rural-urban differences in 2012. People with self-reported diabetes were older than controls (mean [SE]: 63.9 [0.9] vs. 45.9 [0.3] years, p0.0001). The prevalence of diabetes sharply increased after 40 years of age and peaked at age 70 (27.7% [2.5], pWe reported an alarming increase in the prevalence of self-reported type 2 diabetes in the last decade that mostly affects working age people. If this trend continues, a major public health crisis in Hungary can be envisaged.

Summary. Background: Ultra-large von Willebrand factor and deficiency of its cleaving protease are important factors in the events leading to thrombotic microangiopathy; however, the mechanisms involved are only partly understood. Whereas pathological activation of the alternative complement pathway is linked to atypical hemolytic uremic syndrome, the role of complement activation in thrombotic thrombocytopenic purpura (TTP) is unknown. The aim of this study was to investigate whether signs of complement activation are characteristic of TTP. Patients and methods: Twenty-three patients with TTP (18 women, median age 38 years) and 17 healthy controls (13 women, median age 38 years) were included. Complement parameters (C3, Factors H, I, B and total alternative pathway activity) together with complement activation fragments (C3a) or complexes (C1rs-INH, C3bBbP, sC5b9) were measured by ELISA or RID. ADAMTS13 activity and anti-ADAMTS13 inhibitory antibodies were measured by the VWF-FRET73 assay. Results: Increased levels of C3a, and SC5b9 were observed in TTP during acute episodes, as compared with healthy controls. Decreased complement C3 levels indicative of complement consumption occurred in 15% of acute TTP patients. Significant decrease of complement activation products C3a and SC5b9 was observed during plasma exchange (PEX). The sustained presence of anti-ADAMTS13 inhibitory antibodies in complete remission was associated with increased complement activation. Conclusion: These data document in an observational study the presence of complement activation in TTP. Further investigation is needed to determine its potential pathogenetic significance.

Multiple myeloma (MM) is a B-cell neoplasm characterized by infiltration of the bone marrow with malignant plasma cells, synthesizing and secreting monoclonal immunoglobulin fragments. The malignant transformation of this terminally differentiated plasma cell is the result of a multistep transformation process. In spite of recent advances in this field, the cause and the exact molecular genetic basis of MM remain obscure. In this review, an attempt has been made to summarize the genetic alterations having functional significance in the generation and progression of MM, and also the existing relationship between genetic abnormalities and chemosensitivity, as well as the typical genetic alterations in various MM subgroups. Factors known to have a role in the conversion of monoclonal gammopathy of unknown significance (MGUS) to MM are also reviewed.

Multiple myeloma (MM) is a currently incurable disease caused by the proliferation of malignant plasma cells. Although the pathogenesis of the disease still remains unclear, recent research in the biology of MM has produced new insights into the factors that control the growth and survival of myeloma cells. Among the growth factors, interleukin-6 (IL-6) has an essential role. Evidence suggests that IL-6 is not only a growth factor, but also a survival factor in MM, inhibiting apoptosis in myeloma cells. IL-6 interacts with several factors which are involved in the pathogenesis of MM, such as adhesion molecules, tumour suppressor genes and oncogenes. Considering the essential role of IL-6, it could serve as a target for new therapeutic interventions. Neutralizing the effect of IL-6 may result in a regression of tumour progression.

Human herpesvirus type 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV) is a new member of the γ-herpesvirus family. It is an unusual herpesvirus in that it carries a large number of genes that encode oncoproteins or cell signaling proteins. In addition to being the causative agent of both HIV-associated and non-HIV-associated Kaposi’s sarcoma this DNA tumor virus has been implicated in the pathogenesis of several diseases. These include multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM), multicentric Castleman’s disease (MCD), body cavity-based lymphoma (BCBL), and various other conditions such as sarcoidosis and pemphigus. While the causative role of the viral infection is fairly certain in the development of BCBL and multicentric Castleman’s disease, HHV-8 may act through a different mechanism to induce plasma cell malignancies. It has been suggested - though the finding is still controversial -that infection of bone marrow stromal dendritic cells by HHV-8 might be a key factor in the etiology and pathogenesis of monoclonal gammopathies. The aim of this review is to provide a short introduction into the tumorigenic potential of HHV-8 as well as to detail the available data and possible mechanisms on the involvement of this virus in different hematologic diseases.

Amyloidosis is still enigmatic. The etiology and mechanism of storage and organ impairment are still unknown. Not all amyloidogen molecules are definitely pathogenic; some precursors of tissue amyloid are structurally analogous to normal substances produced in the organism. This paper reviews the currently accepted categories, aspects of etiology and pathogenesis, and therapeutic trends of amyloidosis with a special emphasis on plasmapheresis.—

Background Multi-Drug Resistance (MDR) protein function is an independent prognostic marker in certain haematological malignancies. Immune activation is also linked to the expression of MDR proteins in autoimmune disorders. Furthermore, MDR protein function may predict patient response to traditional DMARD, as well as biological treatment helping the physician to tailor the therapy. Switching the patient to biologicals is often challenging due to unpredictable drug susceptibility and high cost, especially in patients with mildly elevated DAS28 scores. However, MDR protein activity values can objectively reflect the actual disease activity of RA patients. Objectives In this observational cohort trial, we wished to assess lymphocyte MDR protein activity in RA patients on biological therapy in comparison to healthy controls in order to predict response to treatment. Methods We measured the activity of three clinically relevant MDR proteins (MRP1/ABCC1, MDR/ABCB1, BCRP/ABCG2) expressed in MDR activity factor (MAF) values in CD3+, CD4+ and CD19+ cells of 23 responder and 8 primary non-responder RA patients before (at 0 week) as well as at 2, 6 and 12 weeks after patients were switched to biological therapy according to the EULAR guideline. For this purpose, a novel flow cytometry based, CE-IVD certified diagnostic kit was applied. DAS28 scores, CRP, IL-6, aCCP and RF values were also recorded on each occasion. 35 age-matched, healthy controls were included. Results There was an inverse correlation between MAF of BCRP/ABCG2 in CD3 and CD4 cells and DAS28 at 0 week in RA patients. Multiple correlations between MAF values and inflammatory parameters were also observed. While DAS28 and IL-6 values decreased as the treatment progressed, MAF of MRP1/ABCC1 on CD3 cells was increased at 12 weeks. A positive correlation was noted between MAF of BCRP/ABCG2 on CD3 cells at 0 week and IL-6 at 12 weeks (p=0.0274, r =0.4095) in RA patients. MAF of CD3 BCRP/ABCG2 and CD3 MRP1/ABCC1 were higher in non-responders compared to responders at 0 week. Conclusions Our results suggest that low BCRP/ABCG2 and MRP1/ABCC1 MAF activities on CD3 cells may predict the need to start biological therapy in RA patients whose symptoms do not improve on classical DMARD treatment. Further decrease of CD3 BCRP/ABCG2 and increase in CD3 MRP1/ABCC1 MAF upon follow-up may indicate a good therapeutic response to biological therapy. References Agarwal V, Mittal SK, Misra R: Expression of multidrug resistance-1 protein correlates with disease activity rather than the refractoriness to methotrexate therapy in rheumatoid arthritis. Clin Rheumatol 2009, 28(4):427–433. Jansen G, Scheper RJ, Dijkmans BA: Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview. Scand J Rheumatol 2003, 32(6):325–336. Disclosure of Interest None declared

Antiphospholipid syndrome is characterized by arterial and venous thromboembolic events and persistent laboratory evidence of antiphospholipid antibodies. Obstetric complications such as recurrent miscarriage, early delivery, oligohydramnios, prematurity, intrauterine growth restriction, fetal distress, fetal or neonatal thrombosis, pre-eclampsia/eclampsia, and HELLP syndrome are also hallmarks of antiphospholipid syndrome. This syndrome is one of the diseases associated with the most severe thrombotic risk. Changes in the hemostatic system during normal pregnancy also result in a hypercoagulable state resulting in elevated thrombotic risk. Thromboembolic events are responsible of the vast majority of maternal and fetal deaths. Administration of appropriate thromboprophylaxis helps prevent thromboembolic complications during pregnancy in women with antiphospholipid syndrome and also give birth to healthy children. It is important to centralize the medication and management of these patients. It helps in the thoughtful care of these pregnant women encountering serious problems. Orv. Hetil., 2012, 153, 1207–1218.

Myelodysplastic syndromes are a heterogeneous group of clonal bone marrow disorders, which are considered to be cancers and have a tendency to transform into acute myeloid leukemia. MDS are characterised by the underproduction of normal blood cells. Diseaseinduced cytopenias result infections and bleeding complications. The diverse pathobiology of the disease is manifested by a varied clinical course, with some patients having more indolent disease and longer life expectancy, and others presenting with aggressive variants that rapidly progress to AML. The frequency of the disease is the highest in the elderly. Number of diagnoses has increased in the past decade as a consequence of the increased recognition, and the aging of the population. Prognosis is influenced by the age and co-morbidities of the patient and also by the cytogenetic abnormalities. Risk stratification is based on the number of myeloblast in the bone marrow, the number of cytopenias and the cytogenetic abnormalities. The most widely used prognostic systems are the International Prognostic Scoring System (IPSS) and the WHO classification-based Prognostic Scoring System (WPSS). The latter system incorporates transfusion burden as well (Greenberg, 1998). From the standpoint of both disease biology and prognosis, it is important to distinguish primary MDS from therapy-related MDS; the latter is closely related to therapy-related AML and develops in the setting of prior exposure to chemotherapy (eg, alkylating agents, topoisomerase II inhibitors), radiotherapy, radiation accidents, benzene, or other toxins and is prognostically worse than primary MDS. Response to therapy is highly worse in this group of patients (Tefferi, 2010; Graubert, 2010). Treatment of MDS in the past was restricted to supplementation of the missing cell type thus relieving the patient’s symptoms. Advances over the last decade have given a multitude of treatment options. Therapeutic options now exist that not only reduce diseaserelated symptoms, improve quality of life, but alter the natural history of the disease as well.

Both chromophobe carcinoma and sarcomatoid carcinoma of the kidney are rare. The former is characterized by a relatively good prognosis, while the latter is a highly aggressive tumor. Coexistence of the two components in one renal tumor, which has been reported only rarely, is therefore paradoxical. Both sarcomatoid and chromophobe renal carcinoma were diagnosed in a 52-year-old woman following nephrectomy and resection of metastases in the right lobe of the liver. She died of the disease two months after the first operation; only the sarcomatoid component of her tumor was seen in the liver metastasis and the recurrent carcinoma. Differences in phenotype, immunophenotype and DNA-ploidy patterns of the two components are reported. The intensive p53 staining observed only in the sarcomatoid area supports the role of the TP53 gene in the transformation of chromophobe renal carcinoma to sarcomatoid carcinoma.

Purpose To report late ocular (primary endpoint) and other toxicity, disease control, and survival (secondary endpoints) after intensity-modulated radiotherapy (IMRT) for sinonasal tumors. Methods and Materials Between 1998 and 2009, 130 patients with nonmetastatic sinonasal tumors were treated with IMRT at Ghent University Hospital. Prescription doses were 70 Gy ( n = 117) and 60–66 Gy ( n = 13) at 2 Gy per fraction over 6–7 weeks. Most patients had adenocarcinoma ( n = 82) and squamous cell carcinoma ( n = 23). One hundred and one (101) patients were treated postoperatively. Of 17 patients with recurrent tumors, 9 were reirradiated. T-stages were T1–2 ( n = 39), T3 ( n = 21), T4a ( n = 38), and T4b ( n = 22). Esthesioneuroblastoma was staged as Kadish A, B, and C in 1, 3, and 6 cases, respectively. Results Median follow-up was 52, range 15–121 months. There was no radiation-induced blindness in 86 patients available for late toxicity assessment (≥6 month follow-up). We observed late Grade 3 tearing in 10 patients, which reduced to Grade 1–2 in 5 patients and Grade 3 visual impairment because of radiation-induced ipsilateral retinopathy and neovascular glaucoma in 1 patient. There was no severe dry eye syndrome. The worst grade of late ocular toxicity was Grade 3 ( n = 11), Grade 2 ( n = 31), Grade 1 ( n = 33), and Grade 0 ( n = 11). Brain necrosis and osteoradionecrosis occurred in 6 and 1 patients, respectively. Actuarial 5-year local control and overall survival were 59% and 52%, respectively. On multivariate analysis local control was negatively affected by cribriform plate and brain invasion ( p = 0.044 and 0.029, respectively) and absence of surgery ( p = 0.009); overall survival was negatively affected by cribriform plate and orbit invasion ( p = 0.04 and p = 0.001). Conclusions IMRT for sinonasal tumors allowed delivering high doses to targets at minimized ocular toxicity, while maintaining disease control and survival. Avoidance of severe dry eye syndrome and radiation-induced blindness suggests IMRT as a standard treatment for sinonasal tumors.

Introduction While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM®) to BCG in patients after transurethral resection (TURB) of BC. Materials and methods This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and ≥ 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed. Results Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001). Discussion This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted. Trial registration The trial has been registered in the ISRCTN registry http://isrctn.org under the registration number ISRCTN35881130.

There are conflicting results regarding the role of tau (MAPT) haplotypes in neurodegenerative disorders. Recent reports suggest that ethnicity factors and gene-gene interactions may influence the risk of developing Alzheimer's disease (AD). The present study investigates possible synergism between MAPT haplotype and ApoE state in Hungarian Caucasian AD cases (n=91) and control (n=83) population. The difference in MAPT H1 allele frequency did not reach significant level in AD (78%), and control individuals (73.5%), however ApoE4 carriers were significantly overrepresented in AD (34.1% vs. 20%) compared to the control population. Though a specific combination of ApoE4 and H1 alleles were found to be associated to AD (14.5% vs. 30.8%), synergistic genetic interaction could not be inferred. Our findings support the notion that while ApoE4 might be involved in AD pathology the MAPT H1 allele neither associates nor interacts through an epistasis with ApoE4 in the development of the disease.

Introduction Mapping cognitive functions in schizophrenia is important for approaching the etiological background of the disease. Objectives To examine the explicit and the implicit learning processes with experimental psychological methods in neurocognitive subgroups identified by us earlier (Szendi et al, 2010). Aims To find substantial cognitive differences between the neurocognitive subgroups Methods Patients with schizophrenia (n=19) and matched healthy control persons (n=11) participated in the study. The patients were recruited randomly from the patient pool which constitued the subject base for the original clustering process, we enrolled n=9 patients from the cluster S, and n=10 from the cluster Z. Besides the comprehensive neuropsychiatric assessment, the explicit learning performances were tested by a verbal learning task, while the implicit learning by the Alternating Serial Reaction Time Task. Results While the whole group of patients did not differ from the healthy persons regarding either the explicit or the implicit memory tasks, the performances of the two subgroups of patients showed a double dissociation in these tasks. Whereas patients belonging to cluster S could recall significantly less words in the explicit cued recall test after the word-list learning than patients in cluster Z (and the healthy persons), the performance of patients in cluster Z in the implicit sequence-specific learning fell behind the cluster S (and the healthy group). Conclusions The double dissociation of explicit and implicit memory's impairments suggests that the neurocognitive background of the two subgroups of schizophrenia (S vs Z) might substantially differ from each other. Financial support: KTIA_NAP_13-2-2014-0020

It has been suggested that human herpesvirus 8 (HHV-8), also known as KSHV (Kaposi's sarcoma-associated human herpesvirus), might possess a promoting effect in the development and progression of monoclonal gammopathies. In this study, the presence of Epstein-Barr virus (EBV), human cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and human herpesvirus 8 (HHV-8) were tested in patients with multiple myeloma (MM) using both serologic and nucleic acid amplification techniques. The transient reactivation or continuous presence of EBV, CMV, HHV-6 and HHV-8 could be detected in, respectively, 36, eight, 13 and 29 of 69 MM patients; nine, one, four and six of 16 monoclonal gammopathy of unknown significance patients; and seven, four, zero and five of 10 Waldenstrom's macroglobulinemia patients. The total number of MM patients was 95. HHV-8 PCR-positivity was significantly more frequent in the MM group than in the control group of patients with non-Hodgkin's lymphoma (NHL). However, serologic testing did not reveal significant differences between the two patient groups. The number of MM patients with concomitant herpesvirus infections as detected by PCR was as follows: 15 double, seven triple and two quadruple virus nucleic acid positive. In 13/95 MM patients, the simultaneous presence of acute EBV infection and HHV-8 PCR-positivity was detected compared with none of the control group (P=0.009). These results indicate that in addition to HHV-8, the transitional reactivation of EBV may also play a role in the pathogenesis of MM.

Background and Objective: The role of prolactin in immunoregulation and normal hemopoiesis is well known. However, prolactin also seems to be involved in the pathomechanism of malignancies and autoimmune diseases. Elevated serum prolactin levels were reported in patients with malignant lymphoma, colon and breast carcinoma, systemic lupus erythematosus and rheumatoid arthritis. Recently we demonstrated prolactin immunostaining in bone marrow cells of patients with multiple myeloma. Design and Methods: Serum prolactin levels of 56 patients with multiple myeloma, as well as serum β2-microglobulin, and interleukin-6 concentrations were determined in this study. Results: Patients with advanced disease showed a significant increase in serum prolactin concentration, while patients with a clinical stage of I and II, and also control patients had normal values. The concentration of serum β2-microglobulin and interleukin-6 changed in parallel with that of serum prolactin in patients with multiple myeloma. Determining serum prolactin levels several times during the disease process in a given patient clearly showed that the prolactin concentration was increasing during the disease progression. Interpretation and Conclusions: Our results indicate a role of prolactin in disease progression in multiple myeloma.

In certain types of solid tumours and lymphomas prolactin (PRL) potentiates tumour cell proliferation and exerts anti-apoptotic effect. Tumour cells themselves can produce PRL and express PRL-receptors. Hyperprolactinemia is associated with different tumours, also. Multiple myeloma (MM) is a haematological malignancy caused by the clonal expansion of terminally differentiated plasma cells in the bone marrow. Recently, we demonstrated PRL immunostaining in bone marrow cells of MM patients and an elevated level of serum PRL of MM patients with advanced disease. In the present study, we tested the effect of PRL on a U266 human myeloma cell line and demonstrated constitutive and melphalan-stimulated intracytoplasmic PRL in U266 cells. Exogeneous PRL inhibited the proliferation and immunoglobulin (Ig) production of U266 myeloma cells. Concerning etoposide-induced apoptosis, PRL had a double-faceted effect depending on the applied dose: high, pharmacological doses (corresponding to hyperprolactinemia), inhibited apoptosis, whereas near physiological doses exerted a pro-apoptotic effect. These data indicate a definite effect of PRL on a human myeloma cell line. We demonstrated a direct inhibition of PRL on tumour cell growth, while its reciprocal effect on apoptosis refers to an important regulatory role of PRL.

The role of prolactin (PRL) in the physiological regulation of the immune system and in hematopoiesis is well known. There is also evidence of the significance of PRL in several pathological conditions such as autoimmune diseases and some malignancies, e.g. colon and breast carcinomas and also B cell malignancies. Multiple myeloma is known as a B cell malignancy. It is the result of malignant transformation of a single clone of neoplastic plasma cells that synthesize abnormal amounts of monoclonal immunoglobulins or immunoglobulin fragments. In our present studies, the possible expression of PRL in bone marrow cells obtained from diagnosed multiple myeloma (17 cases) or nonmyeloma (5 cases) patients was examined by the method of immunocytochemistry. Samples obtained from those multiple myeloma patients (13 cases) who had not received chemotherapy for 6 months prior to these studies showed a positive immunocytochemical reaction for PRL. Bone marrow smears of patients diagnosed with multiple myeloma who had received chemotherapy within 6 months of the study and also the smears of patients without diagnosed multiple myeloma failed to show a positive immune reaction for PRL. In the case of a patient who was examined prior to and also after a period of 3 months of chemotherapy, the PRL-immunopositive bone marrow cells had disappeared due to the treatment. According to the light microscopic analysis of the cell morphology, PRL-immunopositive cells in the bone marrow were mainly, but not exclusively, plasma cells. There was no correlation between the positive PRL staining of cells and the type of monoclonal immunoglobulin or the ratio of plasma cells detected in the bone marrow. Taken together, our results indicate a possible role of PRL in multiple myeloma. Further experiments are necessary to identify the prognostic value of PRL in multiple myeloma.