Effects of tofacitinib therapy on arginine and methionine metabolites in association with vascular pathophysiology in rheumatoid arthritis: A metabolomic approach.

Introduction: Rheumatoid arthritis (RA) has been associated with changes in lipid, arginine and NO metabolism with increased cardiovascular (CV) risk. The aim of this study is to evaluate the effect of tofacitinib, a Janus kinase (JAK) inhibitor, on arginine and methionine metabolism in correlation with inflammation, functional and pathological vascular changes during one-year treatment of patients with RA. Materials and methods: Thirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) levels. We assessed brachial artery flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) by ultrasound at baseline and after 6 and 12 months. We also determined plasma L-arginine, L-citrulline, L-ornithine, inducible nitric oxide synthase (iNOS), asymmetric (ADMA) and symmetric dimethylarginine (SDMA), L-N-monomethyl-arginine (L-NMMA), cysteine, homocysteine, and methionine levels at these time points. Results: Twenty-six patients (13 on each arm) completed the study. CRP, ESR and DAS28 decreased significantly during one-year treatment with tofacitinib. Arginine and ADMA showed a negative univariate correlation with CRP but not with FMD, PWV or IMT. Tofacitinib at 10 mg bid significantly increased L-arginine, L-ornithine, iNOS and methionine levels after 12 months. ADMA and SDMA levels did not change in our study. Methionine showed negative correlation with FMD at baseline and positive correlation with PWV after 12 months. No change was observed in FMD and PWV but a significant increase was measured in IMT at 6 and 12 months. Multivariate analysis indicated variable correlations of L-arginine, L-citrulline, ADMA, L-NMMA, homocysteine and methionine with DAS28, CRP, ESR and RF but not with anti-CCP after one-year treatment. With respect to vascular pathophysiology, only PWV and methionine correlated with each other. Conclusion: One-year tofacitinib treatment suppressed systemic inflammation and improved functional status in RA. FMD, PWV have not been affected by one-year tofacitinib treatment., while IMT increased further despite treatment. Increased arginine and methionine might contribute to the anti-inflammatory effects of tofacitinib. Increased arginine availability with no changing ADMA may protect FMD and PWV from deterioration. The increase of IMT in the anti-inflammatory environment cannot be explained by arginine or methionine metabolism in this study.

Effects of Classical Breathing Exercises on Posture, Spinal and Chest Mobility among Female University Students Compared to Currently Popular Training Programs.

Worldwide, university students' physical health and posture are declining due to a sedentary lifestyle. The aim of our study was to evaluate the effectiveness of physiotherapeutic breathing exercises on posture and spinal mobility among healthy female university students compared to other training methods. Sixty-one female students of the University of Debrecen were assigned to breathing exercise (BE; n = 15), yoga (Y; n = 16), Pilates (P; n = 15) programmes and interval-training (IT; n = 15). Each training session lasted one hour, performed twice a week for 7 weeks. Students were assessed using standardized clinical tests. All programmes resulted in significant improvement in chest expansion. Results of Schober's test showed substantial improvement using BE (p < 0.05), Y, P (p ≤ 0.01) programmes. Significant changes in occiput-to-wall distance (Y, P p ≤ 0.01) (BE p ≤ 0.001) were observed in three groups except the IT group. Fingertip-to-floor test (Y, P p < 0.05) results showed significant changes in two groups. The most outstanding effects on lateral flexion were achieved using BE (right, left p ≤ 0.001) programme. A comparison with results achieved using yoga and Pilates revealed that the physiotherapeutic breathing exercise programme is an equally effective method to significantly improve spinal mobility and correct postural problems in healthy young women.

Alterations of Selected Hemorheological and Metabolic Parameters Induced by Physical Activity in Untrained Men and Sportsmen.

Optimal tissue oxygen supply is essential for proper athletic performance and endurance. It also depends on perfusion, so on hemorheological properties and microcirculation. Regular exercise is beneficial to the rheological status, depending on its type, intensity, and duration. We aimed to investigate macro and microrheological changes due to short, high-intensity exercise in professional athletes (soccer and ice hockey players) and untrained individuals. The exercise was performed on a treadmill ergometer during a spiroergometry examination. Blood samples were taken before and after exercise to analyze lactate concentration, hematological parameters, blood and plasma viscosity, and red blood cell (RBC) deformability and aggregation. Leukocyte, RBC and platelet counts, and blood viscosity increased with exercise, by the largest magnitude in the untrained group. RBC deformability slightly impaired after exercise, but showed better values in ice hockey versus soccer players. RBC aggregation increased with exercise, dominantly in ice hockey players. Lactate increased mostly in soccer players, and the respiratory exchange rate was the lowest in ice hockey players. Overall, short, high-intensity exercise altered macro and microrheological parameters, mostly in the untrained group. Significant differences were found between the two sports. The data can be useful in training status monitoring, selection, and in revealing the causes of physical loading symptoms.

Changes of Metabolic Biomarker Levels upon One-Year Anti-TNF-α Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis: Associations with Vascular Pathophysiology.

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 < 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 < 0.05). On the other hand, these metabolic parameters were significantly associated with disease duration, CV history, CRP, obesity, PWV, and IMT (p < 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.

Associations of vascular and bone status in arthritis patients.

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 < 0.05). Moreover, total and trabecular BMD determined by QCT inversely correlated with IMT (p < 0.05). On the other hand, among vascular parameters, platelet-derived growth factor BB and IMT correlated with DXA femoral and QCT total BMD, respectively (p < 0.05). In the RM-ANOVA analysis, anti-TNF treatment together with baseline osteocalcin, procollagen 1 N-terminal propeptide (P1NP) or vitamin D3 levels determined one-year changes in IMT (p < 0.05). In the MANOVA analysis, baseline disease activity indices (DAS28, BASDAI), the one-year changes in these indices, as well as CRP exerted effects on multiple correlations between bone and vascular markers (p < 0.05). As the pattern of interactions between bone and vascular biomarkers differed between baseline and after 12 months, anti-TNF therapy influenced these associations. We found a great number of correlations in our RA and AS patients undergoing anti-TNF therapy. Some of the bone markers have been associated with vascular pathophysiology, while some vascular markers correlated with bone status. In arthritis, systemic inflammation and disease activity may drive both vascular and bone disease.

Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients.

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<0.017 after Bonferroni's correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. 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.

Relationship between arterial stiffness and regular physical activity / Az artériás érfali merevség és a rendszeres testmozgás kapcsolata.

Összefoglaló. A cardiovascularis megbetegedések kialakulását és progresszióját jelentosen befolyásolja az életmód, ezen belül a fizikai aktivitás. A rendszeres testmozgás csökkenti a szív- és érrendszeri kórképek kockázatát, többek között a magas vérnyomásra, a zsíranyagcsere-eltérésekre és az elhízásra gyakorolt kedvezo hatásán keresztül, továbbá független tényezo a cardiovascularis halálozás szempontjából is. Az artériás érfali merevség az elasztikus artériák falát alkotó extracelluláris mátrix degeneratív eltéréseinek következtében alakul ki a különbözo kockázati tényezok hatására. Korábban, különbözo populációkon már igazolták az érfali merevség prediktív értékét a cardiovascularis események kialakulásának tekintetében. A pulzushullám-terjedési sebesség mérése a leggyakrabban alkalmazott módszer az érfali merevség meghatározására. A pulzushullám-terjedési sebesség mérésének hasznát a cardiovascularis kimenetel és élettartam becslésében számos populációs szintu követéses vizsgálat igazolja. Jelen munkánkban áttekintjük a rendszeres fizikai aktivitás, az érfali merevség, az érelmeszesedés és a cardiovascularis események közötti összefüggéseket. Összefoglaljuk az edzésnek és az érfali merevség paramétereinek kapcsolatát egészséges populáción vizsgáló legfontosabb tanulmányok eredményeit. Megállapítjuk, hogy az érfali merevség figyelemre méltó, érdekes biomarker a cardiovascularis kockázat becslése során a rendszeresen sportoló személyek esetén is. Mindezek alapján, tekintve annak prognosztikai hasznát, felmerül a pulzushullám-terjedési sebesség mérésének beillesztése a klinikai döntéshozatali folyamatba mind amator, mind professzionális sportolók esetében. Orv Hetil. 2021; 162(16): 615-622. Summary. The development and progression of cardiovascular disorders is importantly dependent on lifestyle factors, including physical activity. Regular physical activity decreases cardiovascular morbidity by ameliorating risk factors such as hypertension, dyslipidemia and obesity, moreover, also independently affects cardiovascular mortality. Arterial stiffness results from a degenerative process affecting mainly the extracellular matrix of elastic arteries under the effect of risk factors. Previously, the independent predictive value of arterial stiffness for cardiovascular events has been demonstrated in various populations. Pulse wave velocity is the most commonly used method for the assessment of arterial stiffness. The value of measuring pulse wave velocity to predict cardiovascular health outcomes and longevity has been established in several population-based longitudinal studies. In this review, we summarize the main associations between regular physical exercise, arterial stiffness, atherosclerotic burden and incident cardiovascular events. We cite findings from the major studies focusing on the effect of training on arterial stiffness parameters in healthy subjects. We conclude that arterial stiffness is emerging as an interesting biomarker for cardiovascular risk stratification in subjects doing regular physical activity. Therefore, the incorporation of pulse wave velocity measurement into clinical decision-making could be indicated in the case of both amateur and professional athletes, given the prognostic information it provides. Orv Hetil. 2021; 162(16): 615-622.

Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-α Therapy.

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)/ß2 glycoprotein I (ß2-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/ß2-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/ß2-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/ß2-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/ß2-GPI, suPAR, and BNP.

Angiotensin Converting Enzyme Activity in Anti-TNF-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients.

INTRODUCTION: Angiotensin-converting enzyme (ACE) and ACE2 have been implicated in the regulation of vascular physiology. Elevated synovial and decreased or normal ACE or ACE2 levels have been found in rheumatoid arthritis (RA). Very little is known about the effects of tumor necrosis factor α (TNF-α) inhibition on ACE or ACE2 homeostasis. In this study, we assessed the effects of one-year anti-TNF therapy on ACE and ACE2 production in RA and ankylosing spondylitis (AS) in association with other biomarkers. PATIENTS AND METHODS: Forty patients including 24 RA patients treated with either etanercept (ETN) or certolizumab pegol (CZP) and 16 AS patients treated with ETN were included in a 12-month follow-up study. Serum ACE levels were determined by commercial ELISA, while serum ACE2 activity was assessed using a specific quenched fluorescent substrate. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. In addition, CRP, rheumatoid factor (RF) and ACPA were also measured. All assessments were performed at baseline and 6 and 12 months after treatment initiation. RESULTS: Anti-TNF therapy increased ACE levels in the full cohort, as well as in the RA and AS subsets. ACE2 activity increased in the full cohort, while the ACE/ACE2 ratio increased in the full cohort and in the RA subset (p < 0.05). Uni- and multivariable regression analyses determined associations between ACE or ACE/ACE2 ratios at different time points and disease duration, CRP, RF, FMD and IMT (p < 0.05). ACE2 activity correlated with CRP. The changes of ACE or ACE2 over 12 months were determined by treatment together with either RF or FMD (p < 0.05). CONCLUSIONS: Anti-TNF treatment may increase ACE and ACE2 in the sera of RA and AS patients. ACE and ACE2 may be associated with disease duration, markers of inflammation and vascular pathophysiology. The effects of TNF inhibition on ACE and ACE2 may reflect, in part, the effects of these biologics on the cardiovascular system.

Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVES: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging (dual-energy X-ray absorptiometry, DXA) and laboratory biomarkers in order to determine bone health and to study the effects of anti-tumor necrosis factor (TNF) biologics in RA and AS. PATIENTS AND METHODS: Thirty-six RA and 17 AS patients undergoing 1-year etanercept (ETN) or certolizumab-pegol (CZP) therapy were studied. Bone density was assessed by DXA at baseline and after 12 months. Serum C-reactive protein (CRP), calcium, phosphate, parathyroid hormone (PTH), vitamin D3, osteocalcin, procollagen type I N-propeptide (P1NP), C-terminal telopeptide (ßCTX), osteoprotegerin, sclerostin (SOST), Dickkopf-1 (DKK-1), soluble receptor activator nuclear kappa B ligand (sRANKL), and cathepsin K (cathK) levels were determined at baseline and after 6 and 12 months. RESULTS: TNF-α inhibition was clinically effective. Anti-TNF-α halted further bone loss over 1 year. In general, anti-TNF therapy significantly increased P1NP, SOST levels, and the P1NP/ßCTX ratios, while decreased DKK-1 and CathK production at different time points in most patient subsets. In the full cohort and in RA, baseline and/or 12-month bone mineral density (BMD) at multiple sites exerted inverse relationships with CRP and ßCTX, and positive correlation with SOST. In AS, L2-4 BMD after 1-year biologic therapy inversely correlated with baseline ßCTX, while femoral neck BMD rather showed inverse correlations with CRP. CONCLUSIONS: Anti-TNF therapy slowed down generalized bone loss, in association with clinical improvements, in both diseases. TNF blockade may enhance bone formation and suppress joint destruction. Anti-TNF therapy may act inversely on DKK-1 and SOST. Independent predictors of BMD were SOST and ßCTX in RA, whilst CRP in AS.Key Points• One-year anti-TNF therapy halted generalized bone loss in association with clinical improvement in arthritides.• Anti-TNF therapy may inversely act on DKK-1 and SOST.• Independent predictors of BMD were SOST and ßCTX in RA, while CRP in AS.

The effects of breathing exercises in comparison with other exercise programs on cardiorespiratory fitness among healthy female college students.

BACKGROUND: We wished to determine the effects of breathing exercises (BE) on endurance performance compared to those of different fitness training programmes. METHODS: Endurance was measured by the Cooper 12-minute Run Test and voluntary breath-holding time test before and after the training period. Altogether 69 healthy female college students were assigned into four groups. The first group (N.=15) participated in a breathing-exercise programme (BE). The 3 intensity training groups included constant-training (CT; N.=22), interval-training (IT; N.=17), and Fartlek-training groups (FT; (N.=15). All programmes were conducted for one hour twice a week for 7 weeks. RESULTS: The results of the Cooper test improved significantly in all four groups (P<0.01). The voluntary breath-holding time test showed significant increase in all groups but the CT group. In the BE group the rate of improvement was 9.23% (P=0.014). In the FT group the intensity was 75-85% of maximal heart rate (HRmax), the rate of improvement was 15.2% (P=0.011). In the IT group, the percentage of increase was 9.94% (P=0.039). Finally, the CT resulted in an improvement 8.45% (P=0.063). CONCLUSIONS: Results derived from the present study suggest that BE may be an effective alternative to improve endurance performance in healthy female college students.

Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis.

Accelerated atherosclerosis, increased cardiovascular morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Vascular function, clinical and laboratory markers and the effects of anti-TNF therapy were assessed in arthritides. Fifty-three 53 patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. 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. A significant improvement of brachial artery FMD was observed after 6 months (p = 0.004). A tendency of FMD improvement was also observed after 12 months (p = 0.065). ccIMT did not change throughout the year. PWV significantly improved after 12 months (p = 0.034). Higher baseline ccIMT (p = 0.009) and PWV (p = 0.038) were associated with clinical non-response (cNR) versus response (cR) to biologics. Multiple analysis confirmed the association of baseline ccIMT with age (p = 0.003) and cNR (p = 0.009), as well as that of baseline PWV with age at diagnosis (p = 0.022) and current chest pain (p = 0.004). Treatment itself determined the 12-month changes in FMD (p = 0.020) and PWV (p = 0.007). In a mixed cohort of RA and AS patients, TNF inhibition improved or stabilized vascular pathophysiology. Inflammation may be associated with FMD, while, among others, cNR may influence vascular function.

Correction to: Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

In the Original Publication, the e-mail address of the author Milan Petronijevic is incorrect. The correct e-mail address is milanpetronijevic@yahoo.com.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

Gene expression analysis of vascular pathophysiology related to anti-TNF treatment in rheumatoid arthritis.

OBJECTIVES: Impaired vascular pathophysiology and increased cardiovascular (CV) mortality are associated with rheumatoid arthritis (RA). To date, no genomic analysis of RA- and RA treatment-related vascular pathophysiology has been published. In this pilot study, we performed gene expression profiling in association with vascular pathophysiology in RA patients. METHODS: Sixteen and 19 biologic-naïve RA patients were included in study 1 and study 2, respectively. In study 1, genetic signatures determined by microarray were related to flow-mediated vasodilation (FMD), pulse-wave velocity (PWV), and common carotid intima-media thickness (IMT) of patients. In study 2, clinical response (cR) vs non-response (cNR) to 1-year etanercept (ETN) or certolizumab pegol (CZP) treatment, as well as "vascular" response (vR) vs non-response (vNR) to biologics, were also associated with genomic profiles. Multiple testing could not be performed due to the relatively small number of patients; therefore, our pilot study may lack power. RESULTS: In study 1, multiple genes were up- or downregulated in patients with abnormal vs normal FMD, IMT, and PWV. In study 2, there were 13 cR and 6 cNR anti-tumor necrosis factor (TNF)-treated patients. In addition, 10, 9, and 8 patients were FMD-20%, IMT-20%, and PWV-20% responders. Again, vascular responder status was associated with changes of the expression of various genes. The highest number of genes showing significant enrichment were involved in positive regulation of immune effector process, regulation of glucose transport, and Golgi vesicle budding. CONCLUSION: Differential expression of multiple genetic profiles may be associated with vascular pathophysiology associated with RA. Moreover, distinct genetic signatures may also be associated with clinical and vascular responses to 1-year anti-TNF treatment.

Peripheral Lymphocyte Multidrug Resistance Activity as a Predictive Tool of Biological Therapeutic Response in Rheumatoid Arthritis.

OBJECTIVE: Multidrug resistance (MDR) transporters may be used as biomarkers to monitor disease progression in RA and as a predictive tool to establish responsiveness to biological therapy. In this multicenter clinical trial, we aimed to assess the predictive value of activity measurement of transporters MDR1, MD resistance protein (MRP)1, and breast cancer resistance protein (BCRP) for biological therapeutic response in RA before the initiation of biological therapy as well as 4 to 6 and 12 weeks after. METHODS: Peripheral blood samples were collected from 27 responders and 12 nonresponders to biological disease-modifying antirheumatic drugs (bDMARD) at the indicated timepoints as well as from 35 healthy controls. MDR activity factor (MAF) of MDR1, MRP1, and BCRP was measured in CD3+ and CD19+ cells using the Solvo MDQ Kit and cell surface staining by flow cytometry following peripheral blood mononuclear cells isolation. RESULTS: At the start of therapy, MAFC (composite MAF of MRP1 and MDR1) and MAFMDR values, and at 4 to 6 weeks of treatment, MAFC, MAFMRP, and MAFMDR values of CD3 cells were higher in nonresponders compared to responders. Receiver-operation characteristic curve analysis revealed that RA patients with MAFC values above 21.3 in CD3 cells at the start of bDMARD therapy are likely to be nonresponders. At 4 to 6 weeks of treatment, these also predict unfavorable response: MAFC values above 20.3, MAFMRP values above 6.0, and MAFMDR values above 13.9 in CD3 cells. CONCLUSION: Our results indicate that the determination of MAFC values in CD3 cells of patients with RA may be of predictive value prior to the initiation of biological therapy, to establish whether the patient will demonstrate sufficient therapeutic response.

Autoimmune and angiogenic biomarkers in autoimmune atherosclerosis.

Several inflammatory, proteolytic, angiogenic and bone-associated factors play a role in the development of autoimmune, accelerated atherosclerosis in rheumatic diseases. Some of these may serve as biomarkers of vascular pathology and may be useful in the follow-up of vascular damage and outcome. Multi-biomarker profiles rather than a single markers would likely be optimal in this respect.

Impact of adalimumab on clinical outcomes, healthcare resource utilization, and sick leave in patients with ankylosing spondylitis: an observational study from five Central and Eastern European countries.

BACKGROUND: Patients with ankylosing spondylitis (AS) are substantial users of healthcare resources due to chronic and potentially disabling disease. This study assessed the impact of adalimumab on clinical outcomes, healthcare resource utilization, and sick leave in patients with AS in five Central and Eastern Europe (CEE) countries. METHODS: This was an observational study in the routine clinical setting. Patients diagnosed with AS and starting treatment with originator adalimumab were followed for 12 months by assessing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] and Ankylosing Spondylitis Disease Activity Score [ASDAS]) and physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]). Data on healthcare resource utilization and sick leave were collected prospectively and compared with historical data before adalimumab initiation, as well as between treatment responders and non-responders defined by BASDAI-50. RESULTS: The total effectiveness population comprised 450 patients with on average long-standing AS, high disease activity, and functional impairment. At 12 months of adalimumab therapy, mean ASDAS and BASFI scores were in the range of low disease activity and normal physical function, respectively. The mean number of hospital admissions, hospital inpatient days, and healthcare provider visits were decreased by 67.9, 83.0, and 46.3%, respectively. The number and length of sick leaves were decreased by 65.6 and 81.4%, respectively. Reductions were higher in treatment responders than non-responders. CONCLUSION: Originator adalimumab in routine clinical practice in five CEE countries produced clinically meaningful improvements in disease activity and physical function, and it was associated with reductions in healthcare resource utilization and sick leave.

Effects of targeted therapies on the bone in arthritides.

Inflammatory arthritides, such as rheumatoid arthritis (RA) and spondyloarthritides (SpA) have been associated with both localized bone resorption and/or formation, and generalized osteoporosis. Systemic inflammation may be the major driver for bone loss in arthritis. In RA and peripheral SpA the RANK-RANKL-OPG network is involved in bone resorption, while in axial SpA the Wnt-ß-catenin axis and its inhibitors (DKK-1, sclerostin) are the most relevant. Targeted therapies including biologics and small molecule tyrosine kinase inhibitors may interfere with inflammatory bone metabolism. Most of these compounds are able to slow down radiographic progression and osteoporosis in arthritides. In very early cases of non-radiological SpA, there may be a window of opportunity allowing to prevent syndesmophyte formation. The inability of targeted therapies to increase the production of DKK-1 and sclerostin may explain the lack of efficacy of TNF inhibitors to halt syndesmophyte formation in SpA. Further clinical trials are needed to better understand the bone effects of targeted therapies.