Objective: To investigate the efficiency and safety of the fixed combination of perindopril/amlodipin in a treatment if grade I and grade II arterial hypertension and arterial stiffness values after only two weeks of treatment. Design and method: The open clinical prospective controlled study was designed. The study was designed for two weeks and two group were formed. The first group was comprised of arterial hypertension grade I patients and group 2 of arterial hypertension grade 2. The cardiovascular risk profile was notified for all patients. The peripheral and central blood pressure, pulse wave velocity, stroke volume, augmentation index, pulse pressure, heart rate, the reflection index were analyzed before and two weeks after treatment. For the grade I arterial hypertension the fixed combination of perindopril/amlodipin was used in a dose of 5 mg/5 mg, and for grade 2 arterial hypertension dosage was 10 mg/10 mg. Therapy was given as a single tablet advised to be taken in the evening. The average grade I hypertension values were 158/92mmHg, and for grade II the average value was 162/102mmHg. The average vascular age for grade I arterial hypertension was 4,5 years, and for grade II arterial hypertension the average vascular age was 8,5years. Results: Results obtained from this short study showed significant lowering of blood pressure and the improvement of arterial stiffness values and in the vascular age was detected as well in both group. The average values of arterial hypertension felt within normal range after treatment in a both groups after two weeks of therapy. Patient compliance and satisfaction was notified. There were no side effects. Conclusions: The fixed combination of perindopril/amlodipin in a dose of 5 mg/5 mg for grade I arterial hypertension and 10 mg/10 mg for grade II arterial hypertension was proven to be effective in all patients. No adverse events were observed. The compliance of patients was excellent and evening dose is more preferable than morning regime. The arterial stiffness values are not constant and permanent. They are rather flexible and arterial hypertension values major dependent. The lower arterial hypertension, the lower arterial stiffness and vasc ular age.

Background: Rheumatoid arthritis (RA) is a debilitating chronic disease with an unmet need for additional therapeutic approaches. Activating neuro-immune reflex pathways by stimulation of the vagus nerve (VNS) could represent a novel means of treating RA [1] and other immune-mediated inflammatory diseases. Last year we reported a 12-week proof-of-concept study using a VNS device, approved for drug-resistant epilepsy, showing reduction in the DAS28-CRP clinical disease activity score, with concomitant reductions in TNF and IL-6 levels [2]. Objectives: To understand the long term safety and efficacy of this novel treatment approach, we followed the patients in a 24 months long-term extension study and report on the safety and clinical efficacy data. Methods: VNS devices were implanted into 17 RA patients, mostly with insufficient response to multiple conventional and biologic disease-modifying antirheumatic drugs (DMARDs), on stable background of methotrexate (≤25 mg weekly) therapy. The devices electrically stimulated the vagus nerve, 1–4 min/day, over a 12 week open label period. On completion, subjects were offered to enroll into a follow-up study, where the study physicians were given flexibility to alter VNS dosing parameters and/or to add a biologic DMARD to the treatment regimen. DAS28-CRP and Health Assessment Questionnaire-Disability Index (HAQ-DI) were collected over 2 years. Results: All subjects electively continued on VNS treatment through 24 months of the long term follow-up study. Biologic DMARDs were started in 1 and restarted in 8 of 17 subjects; of these, 4 were non-responders to VNS, and 5 had stable improvement but had not yet achieved disease remission on VNS alone (table 1). At the start of the follow-up study, the mean DAS28–28 and HAQ-DI were significantly reduced compared to the pre-implant baseline (mean difference±SE in DAS28-CRP=-1.60±0.37, p<0.0001; mean difference±SE in HAQ-DI = -0.44±0.21, p<0.037), and the depth of effect was retained through 24 months. At 24 months, there was no significant difference in DAS28-CRP between the subjects using VNS monotherapy or those using a combination of VNS and biologic DMARDs (VNS monotherapy= 3.76±1.77 vs. VNS and biologic DMARD= 3.21±1.44, p<0.54). No difference in the adverse events profile between the two groups was seen.Table 1 Two Year Efficacy of VNS Treatment. Mean DAS28-CRP at primary study baseline (month -3-5) and at visits over 2 years of long term follow up (months 0-24). Conclusions: The data presented here demonstrate that VNS in subjects with RA is associated with a substantial reduction in disease activity that is sustained for 24 months without untoward safety signals. In addition, the data suggest that biological DMARDs can be initiated safely in combination with VNS treatment, though this requires further study in larger cohorts. These results support further development of VNS devices as an alternative therapeutic approach for RA treatment, which potentially can safely be combined with biologic DMARDs. References [1]Van Maanen M, et al. The cholinergic anti-inflammatory pathway: towards innovative treatment of rheumatoid arthritis. Nat Rev Rheumatol2009;5:229–32. [2]Koopman FA, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci USA2016;113(29):8284–9. Disclosure of Interest: F. Koopman: None declared, A. Musters: None declared, M. Backer: None declared, D. Gerlag Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, which has an interest in SetPoint, S. Miljko: None declared, S. Grazio: None declared, S. Sokolovic: None declared, Y. Levine Shareholder of: SetPoint Medical, Employee of: SetPoint Medical, D. Chernoff Shareholder of: SetPoint Medical, Adamas Pharmaceuticals, OLLY Nutrition, NAIA Pharma, Aquinox Pharma, Consultant for: Adamas Pharmaceuticals, OLLY Nutrition, NAIA Pharma, Aquinox Pharma, Crescendo BioScience, Employee of: SetPoint Medical, N. de Vries Grant/research support from: Abbvie, Janssen Biologics BV, Ergomed Clinical Research, GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Roche, Consultant for: MSD, Pfizer, P.-P. Tak Shareholder of: GlaxoSmithKline, Employee of: GlaxoSmithKline, which has an interest in SetPoint

SB5 is a biosimilar agent for adalimumab (ADA). The aim of this study was to evaluate the efficacy, pharmacokinetics (PK), safety, and immunogenicity of SB5 in comparison with reference ADA in patients with rheumatoid arthritis (RA).

Introduction Leptin is a cytokine-like hormone which has a complex role in inflammation. However, the importance of leptin in the pathogenesis of rheumatoid arthritis (RA) is far from being fully elucidated. The aim of the study was to determine serum leptin levels in RA patients and to evaluate whether there is an association between disease activity, anthropometric indices and leptin levels. Material and methods This hypothesis-generating study included 55 RA patients and 25 matched healthy subjects. The serum leptin concentration was determined by enzyme-linked immunosorbent assay (ELISA). Results Median serum leptin level in RA patients of 27.4 ng/ml (14.5–54.9 ng/ml) was statistically significantly higher (p = 0.03) compared with the median leptin value of 16.3 ng/ml (9.6–38.8 ng/ml) determined in healthy controls. The serum leptin level in the high disease activity group was significantly higher (p < 0.0005) than that in the low disease activity group and in healthy controls. A significant difference (p = 0.001) in serum leptin level was also found when the high disease activity group was compared with the moderate disease activity group. In the RA group a statistically significant positive correlation (rho = 0.390; p = 0.003) was observed between serum leptin level and disease activity score (DAS28). Conclusions The present results show that serum leptin levels are increased and significantly associated with disease activity in patients with RA and may have a valuable role in the inflammatory reactions and pathogenesis of RA.

In this case, we present a patient with unilateral salivary gland enlargement and periorbital edema with erythematous rash. We discuss the differential diagnosis and the relevant therapy. Mediterr J Rheumatol 2017;28(1):57-8 https://doi.org/10.31138/mjr.28.1.57 Article Submitted 21/09/2016; Revised form 28/11/2016; Accepted 13/12/2016 Corresponding author: Alexandros A. Drosos, MD, FACR, PhD Professor of Medicine/Rheumatology Rheumatology Clinic, Department of Internal Medicine Medical School of the University of Ioannina Ioannina 45110, Greece Tel.: +302651007503 Fax: +302651007054 E-mail: adrosos@cc.uoi.gr Dermatomyositis sine myositis – Case presentation Evripidis Kaltsonoudis, Eleftherios Pelechas , Alexandros A. Drosos Rheumatology Clinic, Department of Internal Medicine, Medical School University of Ioannina, Ioannina, Greece MEDITERRANEAN JOURNAL OF RHEUMATOLOGY 28 1 2017 58 2. Although Sjögren’s syndrome could manifest with parotid gland enlargement (unilateral or bilateral) as the first manifestation,3 in this case, the patient did not have xerostomia, xerophthalmia and also had a negative Schirmer’s test and a negative salivary gland biopsy. Finally, the laboratory workup did not show any specific autoantibodies. 3. In order to diagnose SLE, 4 out of 11 criteria should be met.4 In our case, the patient had (subjective) photosensitivity, and a (weakly) positive ANA titer only two of those criteria. Patients with Dermatomyositis are at times difficult to distinguish from patients with subacute cutaneous lupus erythematosus.5 4. Dermatomyositis sine myositis or amyopathic Dermatomyositis is a rare but distinct subtype of Dermatomyositis.6 It is diagnosed in patients with typical cutaneous manifestations (consisting of heliotrope rash, facial erythema and edema, Gottron’s papules and periungual telangiectasia) in whom there is no evidence of muscle weakness and who repeatedly have normal serum muscle enzyme levels. There is a female to male preponderance (3:1) and the onset of the disease usually occurs in early adulthood. Dermatomyositis sine myositis should be aggressively treated even in the absence of muscle involvement since intense and prolonged skin inflammation can result in cutaneous ulceration and calcinosis. Treatment is based on systemic immunosuppressive therapy (high dose corticosteroids, methotrexate, azathioprine, mycophenolate) or immunomodulatory therapy (high dose intravenous immunoglobulins). In the presented case, the patient was treated with high dose of methylprednisolone (32mg) once a day along with calcium and vitamin D supplements. A month later, the patient showed significant improvement of the rash (Figure 1 right). In addition, she did not develop muscle weakness or muscle enzyme abnormalities. In conclusion, DsM, even a rare condition, should be a differential to be borne in mind for clinicians because it needs an aggressive treatment in order to prevent chronic skin changes and systemic complications such as pulmonary involvement. Finally, a close observation of the patient is mandatory, as DsM has been associated with different types of malignancies. CONFLICT OF INTEREST The authors declare no conflict of interest.

The First Mediterranean Seminar on Science Writing, Editing & Publishing (SWEP 2016) was held in Sarajevo, Bosnia & Herzegovina from 2nd to 3rd December 2016. It was organized by Academy of Medical Sciences of Bosnia and Herzegovina, running concurrent sessions as part of its Annual Meeting titled “ “Days of AMNuBiH - Theory and Practice in Science Communication and Scientometrics”. Hotel Bosnia in the city centre was the chosen venue. On the first day, nineteen presentations on various issues of science writing and publication ethics were delivered by speakers from Croatia, Serbia, Macedonia, Albania, Bosnia & Herzegovina and the UK (Asim Kurjak, Milivoj Boranić, Doncho Donev, Osman Sinanović, Miro Jakovljević, Enver Zerem, Dejan Milošević, Silva Dobrić, Srećko Gajović, Izet Mašić, Armen Yuri Gasparyan, Šekib Sokolović, Nermin Salkić, Selma Uzunović, Admir Kurtčehajić, Edin Begić and Floreta Kurti). Each presentation had a take-home message for novice and seasoned authors, encountering numerous problems in non-Anglophone research environment. Lecturers, who were internationally recognized editors of regional journals, generously shared their experience of adhering to the best ethical guidance. Elegant presentations by Srećko Gajović (Editor-in-Chief of the Croatian Medical Journal) and Armen Yuri Gasparyan (past Chief Editor of the European Science Editing) showcased their accomplishments that strengthened ties between authors from all over the world. Gasparyan reflected on educational resources of editorial associations, such as the International Committee of Medical Journal Editors (ICMJE) and the Committee on Publication Ethics (COPE), and called not just to declare the adherence to, but also to enforce their ethical guidance in daily practice. Editors of Medical Archives, Croatian Medica Journal, Vojnosanitetski Pregled, Psychiatria Danubina, Acta Informatica Medica, Materia Socio-Medica, The Donald School Journal of Ultrasound in Obstretics and Gynecology, Acta Medica Saliniana and Medicinski Glasnik presented their editorial strategies aimed at attracting best authors and resolving problems with authorship, conflicts of interest, and plagiarism. Topical education on science writing and editing was considered as an inseparable part of continuing professional development in biomedicine. Armen Yuri Gasparyan (UK) was offered an opportunity to interact with more than 70 participants, attending the SWEP 2016 on the second day. The lecturer talked about author contributions, disclosures of conflicts of interests, plagiarism of ideas and words, research performance and impact indicators, and targeting ethical journals. Topics were presented in a way to help non-Anglophone authors, reviewers and editors avoid common ethical problems. Dr Gasparyan stressed the importance of regularly arranging such meetings across Balkan and Mediterranean countries to eradicate plagiarism and other forms research misconduct. The organizers of the SWEP 2016 awarded selected keynote speakers with certificates of lifetime achievement in journal editing, and decided to run the Seminar annually with support of Balkan and Mediterranean editors and publishers. The SWEP 2016 marked a turning point in the process of regional developments since all attending editors opted for nurturing enthusiasm of the organizers and launching the Mediterranean Association of Science Editors and Publishers (MASEP). The Seminar was a great success with its impressive scientific and social activities. It attracted more than 100 students, researchers, editors, and publishers from Bosnia & Herzegovina and neighbouring countries. Proceedings, in the form of short reports, were published in Acta Informatica Medica and archived in PubMed Central. New friendships were forged between regional experts in editing and young specialists during those unforgettable two days of intensive discussions and informal interactions (a-y).

Изет Машич1, 2,*, Един Бегич3, 4, Дончо M. Донев5, Сречко Гайович6, Армен Ю. Гаспарян7, Миро Яковлевич8, Деян Б. Милошевич9, 10, Осман Синанович2, 11, Шекиб Соколович12, Сельма Узунович13, Энвер Зерем14, 15 1Медицинский факультет, Университет Сараево, Сараево, Босния и Герцеговина 2Академия медицинских наук Боснии и Герцеговины, Сараево, Босния и Герцеговина; https://orcid.org/0000-00029080-5456 3Медицинский факультет, Школа науки и технологий Сараево, Сараево, Босния и Герцеговина 4Центр охраны здоровья, Маглай, Босния и Герцеговина; http://orcid. org/0000-0001-6842-262X 5Институт социальной медицины, медицинский факультет, Университет им. св. Кирилла и Мефодия в Скопье, Скопье, Республика Македония; https://orcid.org/0000-0002-5237-443X 6Хорватский институт исследований мозга, Школа медицины при Загребском университете, Загреб, Хорватия; http://orcid.org/0000-0001-86685239 7 Отделение ревматологии и отдел исследований и развития, Дадли группа Благотворительного фонда Системы общественного здравоохранения (Образовательный фонд Университета Бирмингема, Великобритания), Расселовский Ходл Госпиталь, Дадли, Уэст-Мидлендс, Великобритания; https://orcid.org/0000-0001-8749-6018 a.gasparyan@gmail.com 8Отделение психиатрии, Центральная университетская клиника Загреба, Загреб, Хорватия 9Факультет естественных наук, Университет Сараево, Сараево, Босния и Герцеговина 10Aкадемия наук и художеств Боснии и Герцеговины, Сараево, Босния и Герцеговина; http://orcid.org/0000-00015060-3318 11Отделение неврологии, Университетский клиническй центр Тузлы, медицинский факультет, Университет Тузлы, Тузла, Босния и Герцеговина; http://orcid.org/0000-0001-8957-7284 12Институт болезней сердца, Университетский клинический центр Сараево, Сараево, Босния и Герцеговина; http://orcid.org/0000-00016321-4186 13Отделение лабораторной диагностики, Институт общественного здоровья и продовольственной безопасности, Зеница, Босния и Герцеговина; http:// www.orcid.org/0000-00031852-1572 14Отделение медицинских наук, Академия наук и художеств, Сараево, Босния и Герцеговина 15Отделение гастроэнтерологии и гепатологии, Университетский клинический центр Тузлы, Тузла, Босния и Герцеговина; http://orcid. org/0000-0001-6906-3630

Objective: The goal of this paper was to present the effects of the vagus nerve stimulation (VNS) on a blood pressure (BP) and heart rate (HR) in arterial hypertension patient. Design and Method: The pilot study (SPM-005) was designed to evaluate the eficiancy and safety profile of the neurostimulation of the cholinergic anti-inflammatory pathways using the active implantable device for the vagus nerve stimulation in rheumatoid arthritis patient. We investigated the VNS on the BP and HR in 68 years old female patient with a long-standing arterial hypertension and the lisinopril and hydrochlorothiazide in a therapy. Her BMI was 25.4 This device that is surgically implantated under the skin provides the electrical impulses to the vagus nerve of the left side of the body. Results: The basic value of arterial hypertension under medication was within normal range. BP was 120/80 mmHg before implantation and HR was 72/min. Following immediate VNS, the BP raised to 140/90 mmHg and HR was 70/min. The 4 hours after VNS, BP was 130/70 mmHg and HR was 86/min. After 24 hours, BP was 160/100 mmHg and HR 80/min. On a day 7, BP was 130/80 mmHg and HR 74/min. Day 21, BP was 135/84 mmHg, and HR 83/min. Day 28, BP was 135/85 mmHg, and HR was 87/min. After 3 months, BP was 160/100 mmHg and HR 82/min. The Amlodipine 5 mg and Doxazosin 2 mg was added to ACE inhibitor and diuretics. After 6 months, BP was still high with a values of 170/95 mmHg and HR of 70/min. Doxazosin dosage was increased to 4 mm daily. One year after, BP was 130/80 mmHg and HR 72/min. Conclusions: There was a slight increase in a blood pressure following the first VNS, but not in a heart rate. No significant correlation betwen BP and HR was observed.

Significance Rheumatoid arthritis (RA) is a chronic, prevalent, and disabling autoimmune disease that occurs when inflammation damages joints. Recent advances in neuroscience and immunology have mapped neural circuits that regulate the onset and resolution of inflammation. In one circuit, termed “the inflammatory reflex,” action potentials transmitted in the vagus nerve inhibit the production of tumor necrosis factor (TNF), an inflammatory molecule that is a major therapeutic target in RA. Although studied in animal models of arthritis and other inflammatory diseases, whether electrical stimulation of the vagus nerve can inhibit TNF production in humans has remained unknown. The positive mechanistic results reported here extend the preclinical data to the clinic and reveal that vagus nerve stimulation inhibits TNF and attenuates disease severity in RA patients. Rheumatoid arthritis (RA) is a heterogeneous, prevalent, chronic autoimmune disease characterized by painful swollen joints and significant disabilities. Symptomatic relief can be achieved in up to 50% of patients using biological agents that inhibit tumor necrosis factor (TNF) or other mechanisms of action, but there are no universally effective therapies. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in animal models. One well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals that inhibit cytokine production and attenuate experimental arthritis severity in mice and rats. It previously was unknown whether directly stimulating the inflammatory reflex in humans inhibits TNF production. Here we show that an implantable vagus nerve-stimulating device in epilepsy patients inhibits peripheral blood production of TNF, IL-1β, and IL-6. Vagus nerve stimulation (up to four times daily) in RA patients significantly inhibited TNF production for up to 84 d. Moreover, RA disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation targeting the inflammatory reflex modulates TNF production and reduces inflammation in humans. These findings suggest that it is possible to use mechanism-based neuromodulating devices in the experimental therapy of RA and possibly other autoimmune and autoinflammatory diseases.

Introduction: The commonest mitral regurgitation etiologies are degenerative (60%), rheumatic post-inflammatory, 12%) and functional (25%). Due to the large number of patients with acute MI, the incidence of ischaemic MR is also high. Ischaemic mitral regurgitation is a complex multifactorial disease that involves left ventricular geometry, the mitral annulus, and the valvular/subvalvular apparatus. Ischaemic mitral regurgitation is an important consequence of LV remodeling after myocardial infarction. Research Objectives: The objective of this study is to determine the role of echocardiography in detecting and assessment of mitral regurgitation mechanism, severity, impact on treatment strategy and long term outcome in patients with myocardial infarction during the follow up period of 5 years. Also one of objectives to determine if the absence or presence of ischaemic MR is associated with increased morbidity and mortality in patients with myocardial infarction. Patients and methods: The study covered 138 adult patients. All patients were subjected to echocardiography evaluation after acute myocardial infarction during the period of follow up for 5 years. The patients were examined on an ultrasound machine Philips iE 33 xMatrix, Philips HD 11 XE, and GE Vivid 7 equipped with all cardiologic probes for adults and multi-plan TEE probes. We evaluated mechanisms and severity of mitral regurgitation which includes the regurgitant volume (RV), effective regurgitant orifice area (EROA), the regurgitant fraction (RF), Jet/LA area, also we measured the of vena contracta width (VC width cm) for assessment of IMR severity, papillary muscles anatomy and displacement, LV systolic function ± dilation, LV regional wall motion abnormality WMA, LV WMI, Left ventricle LV remodeling, impact on treatment strategy and long term mortality. Results: We analyzed and follow up 138 patients with previous (>16 days) Q-wave myocardial infarction by ECG who underwent TTE and TEE echocardiography for detection and assessment of ischaemic mitral regurgitation (IMR) with baseline age (62 ± 9), ejection fraction (EF 41±12%), the regurgitant volume (RV) were 42±21 mL/beat, and effective regurgitant orifice area (EROA) 20±16 mm2, the regurgitant fraction (RF) were 48±10%, Jet/LA area 47±12%. Also we measured the of vena contracta width (VC width cm) 0,4±0,6 for assessment of IMR severity. During 5 years follow up, total mortality for patients with moderate/severe IMR–grade II-IV (54.2±1.8%) were higher than for those with mild IMR–grade I (30.4±2.9%) (P<0.05), the total mortality for patients with EROA ≥20 mm2(54±1.9%) were higher than for those with EROA <20 mm2(27.2±2.7%) (P<0.05), and the total mortality for patients with RVol ≥30 mL (56.8±1.7%) were higher than for those with RVol<30ml (29.4±2.9%) (P<0.05). After assessment of IMR and during follow up period 64 patients (46%) underwent CABG alone or combined CABG with mitral valve repair or replacement. In this study, the procedure of concomitant down-sized ring annuloplasty at the time if CABG surgery has a failure rate around 24% in terms of high late recurrence rate of IMR during the follow period especially after 18–42 months. Conclusion: The presence of ischaemic MR is associated with increased morbidity and mortality. Chronic IMR, an independent predictor of mortality with a reported survival of 40–60% at 5 years. Ischaemic mitral regurgitation has important prognosis implications in patients with coronary heart disease. Recognizing the mechanism of valve incompetence is an essential point for the surgical planning and for a good result of the mitral repair. It is important that echocardiographers understand the complex nature of the condition. Despite remarkable progress in reparative surgery, further investigation is still necessary to find the best approach to treat ischaemic mitral regurgitation.