Frane Grubišić

Peripheral Blood Expression Profiles of Bone Morphogenetic Proteins, Tumor Necrosis Factor-superfamily Molecules, and Transcription Factor Runx2 Could Be Used as Markers of the Form of Arthritis, Disease Activity, and Therapeutic Responsiveness

Objective. To assess whether different forms of arthritis and disease activity could be distinguished by peripheral blood expression profiles of bone-regulatory factors including tumor necrosis factor (TNF)-superfamily [TNF-related apoptosis-inducing ligand (TRAIL), the Fas ligand (FasL), and the ligand for herpesvirus entry mediator (LIGHT)] and bone morphogenetic protein (BMP)-family members (BMP-2, BMP-4, BMP-6) as well as osteoblast differentiation gene Runx2. Methods. Blood cells from healthy controls (n = 25) and patients at different disease stages with rheumatoid arthritis (RA; n = 49), osteoarthritis (OA; n = 17), or spondyloarthritis, including ankylosing spondylitis (AS; n = 27) or psoriatic arthritis (PsA; n = 23), were processed for quantitative polymerase chain reaction. Gene expression was assessed in comparison with control samples, correlated with clinical data of different forms of arthritis, and analyzed for discriminative efficacy between groups by receiver-operation characteristic (ROC) curves. Results were confirmed on diagnostic RA (n = 5) and AS (n = 8) samples. Results. BMP-4, BMP-6, and Runx2 expressions were significantly decreased in patients with RA and OA versus controls. Patients with RA also had decreased FasL and LIGHT expression, while patients with AS had increased Runx2 expression. Negative correlation with disease activity was found for BMP-4, FasL, and Runx2 in RA and for Runx2 in PsA, while positive correlation was found for BMP-4 in PsA. Gene expression was higher in the therapy-resistant form of AS (for BMP-4, LIGHT, and Runx2) and in methotrexate-treated patients in RA (for BMP-2 and LIGHT). ROC curve analysis confirmed discrimination between groups, particularly decreased LIGHT and Runx2 for RA and increased Runx2 for AS. Conclusion. Our study identified BMP and Runx2 as possible biomarkers of bone metabolism in several forms of arthritis, while lower FasL and LIGHT were associated with RA. Correlation between gene expression and disease activity may be clinically useful in assessing therapeutic effectiveness and disease monitoring.

Vitamin D Serum Level, Disease Activity and Functional Ability in Different Rheumatic Patients

Background:The aim of the study was to determine the serum vitamin D levels in patients with psoriatic arthritis (PsA) and compare it with patients with rheumatoid arthritis (RA) and with osteoarthritis (OA), as well as to explore the relationship of the vitamin D level with indices of disease activity and functional ability in a real-life setting in a South-European country. Methods:In a cross-sectional study, 120 adult patients with established diagnosis of PsA, RA and OA were consecutively enrolled. Serum 25-hydroxyvitamin D and intact parathyroid hormone were determined. Parameters of disease activity and functional ability were obtained using standard instruments. Results:Serum vitamin D insufficiency (⩽75 nmol/L) was found in 74% of patients with PsA, 94% patients with RA and 97% of patients with OA, whereas vitamin D deficiency (⩽25 nmol/L) was found in 13% of patients with PsA, 39% of patients with RA and in 38% of patients with OA. Compared with RA, patients with PsA had significantly higher serum vitamin D (P = 0.002), and when controlling for age and gender, their serum vitamin D level was significantly associated with disease activity and functional activity. Conclusions:In the group of rheumatic patients, a high prevalence of serum vitamin D insufficiency/deficiency was found regardless of the type of arthritis. Patients with PsA might have higher levels of vitamin D than patients with RA, and this was associated with disease activity and functional ability. The results of this study indicate that prophylactic supplementation with vitamin D might be recommended for all rheumatic patients.

Association of systemic and intra-articular osteoclastogenic potential, pro-inflammatory mediators and disease activity with the form of inflammatory arthritis.

PurposeWe aimed to assess osteoclastogenic potential of peripheral blood mononuclear cells (PBMC) and synovial fluid-derived mononuclear cells (SFMC) in different forms of arthritis and to correlate it with inflammatory mediators within intra-articular and circulatory compartments.MethodsPaired PBMC and SFMC samples of patients with rheumatoid arthritis (RA; n = 10) and psoriatic arthritis (PsA; n = 10), and PBMC of healthy controls were cultured to assess osteoclastogenic potential by the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) and expression of OC-related genes (receptor activator of nuclear factor-κΒ (RANK), cFMS, and TRAP). Osteoclastogenesis was correlated with the arthritis-related inflammatory indicators in serum and synovial fluid (SF).ResultsNumber of OCs differentiated from PBMC was significantly higher in RA and PsA compared with control, with RA having more OCs compared with PsA. There was no difference in SFMC OC number between arthritic patients, but RANK expression in OCs differentiated from SFMC was higher in PsA compared with RA. SF of PsA patients more potently induced OC differentiation from control CD3-CD19-CD56-CD11b+CD115+ PBMC compared with RA, paralleled with higher RANK-ligand expression in PsA SFMC. Positive correlations of OC number with erythrocyte sedimentation rate, serum level of CCL2, and PBMC gene expression of interleukin-18 and Fas-ligand were observed.ConclusionOsteoclastogenic potential is systemically enhanced in patients with RA, paralleled by disordered systemic and local expression of proinflammatory mediators, whereas PsA involves specific deregulation in RANKL/RANK axis. Our study reveals arthritis-specific mediators associated with the form of arthritis, indicating clinical relevance for diagnosis and treatment.

Which clinical variables have the most significant correlation with quality of life evaluated by SF-36 survey in Croatian cohort of patient with ankylosing spondylitis and psoriatic arthritis?

The aim of our study was to assess clinical variables with the best correlation to quality of life (QOL) assessed by medical outcome survey Short-Form 36 (SF-36) in patients with spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We analyzed the cohort of 54 patients (22 patients with PsA and 32 patients with AS), who filled the Croatian version of SF-36. For each type of arthritis, patients were clinically evaluated using the extensive list of clinical variables categorized into subjective and objective group. For AS patients, subjective and objective variables (spinal mobility measurements, clinical assessment of spinal pain, patient assessments of disease activity and pain) correlated mainly with the physical functioning concept of SF-36. Patients assessments of fatigue correlated with the energy/fatigue subscale, whereas patient assessment of enthesial pain correlated with the pain subscale. Correlations between clinical variables and SF-36 concepts of PsA patients showed more diverse distribution than for AS. Objective variables (spinal mobility measurements, a 76-joint score, clinical assessment of spinal pain) correlated with concepts concerning physical health and pain. Several subjective patient assessments correlated with energy/fatigue, emotional well-being, pain and general health subscales. Both patient and physician assessment of PsA activity correlated with the role limitations due to emotional problems. Bath ankylosing spondylitis functional index (BASFI) had the strongest correlation with the physical functioning concept of SF-36 in both diseases. Our findings provide important information to help selecting the variables with strongest impact on QOL, for better planning the management strategies and achieving better rehabilitation results.

Cochrane Physical and Rehabilitation Medicine: A New Field to Bridge Between Best Evidence and the Specific Needs of Our Field

We wish to announce to the readers of your journal, as well as all those of the other journals relevant to Physical and Rehabilitation Medicine (PRM), the launch of Cochrane PRM, that will have its Official Exploratory Meeting in Brescia (Italy), 19-20 September 2016. The results will drive to complete the business plan under development and submit it for approval to Cochrane by October 2016. Cochrane does not need any presentation to your readers, due to the recognized role as leader of Evidence Based Medicine in all fields of Medicine. Cochrane exists to improve healthcare decisions and during the past 20 years, has helped to transform the health sector. In fact, Cochrane gathers and summarizes the best evidence from research to help people make informed choices about treatment. Cochrane is organized in groups that include:

Cochrane Rehabilitation: Organization and Functioning

INTRODUCTION Cochrane (www.cochrane.org) is an organization whose vision is a world of improved health where decisions about health and health care are informed by high-quality, relevant, and up-to-date synthesized research evidence. For this reason, it produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Cochrane is organized in different groups with different aims: review groups manage systematic reviews production, method groups develop the best methodology to produce evidence, centers and fields provide knowledge translation with a national/regional or topic-related focus, respectively. The knowledge translation strategy is a critical piece of work that contributes to dissemination, use, and impact of Cochrane evidence in decision-making, and is now at the center of the new developments of Cochrane. Rehabilitation is a cross-sectional topic that includes different health conditions of interest to many Cochrane Review Groups. Consequently, rehabilitation is considered by Cochrane as a “field,” a term used for groups that focus on health issues and/or interventions of importance to specific populations. The role of Cochrane Fields is to contribute to knowledge translation, as specified in Cochrane Strategy 2020, the official document that explains the future plans of Cochrane in terms of structure and function. Thus, Cochrane has created a new Cochrane Rehabilitation Field to strengthen this culture of knowledge translation.

Echoes of the Sarajevo Declaration on integrity and visibility of scholarly publications

To the Editor: We read with great interest the Sarajevo Declaration on Integrity and Visibility of Scholarly Publications published as the editorial in the Croatian Medical Journal (1). We appreciate the efforts made by the authors, Journal Editors Group comprised of the selected lecturers at the First Mediterranean Seminar on Science Writing, Editing & Publishing (SWEP 2016). We agree with the statements of the Declaration, which highlights the main problems with editing scholarly journals in non-mainstream science countries and provides incentive for improving their standards, integrity, and visibility. The point we wish to bring forth is that the Declaration omitted to refer to journals published in languages other than English. We understand that these journals are less visible and out of focus of general scientific community, but given the main scope of the Declaration, we feel that it would have been valuable mentioning that the Declaration applies not only to journals published in English but also to journals published in other languages. The reason is that the problem of poor management, lack of understanding of how indexing services operate, and corruptive and predatory practice are even more manifest in these journals, which are vastly not covered by any kind of surveillance, such as Jeffrey Beall’s List of Predatory Publishers (2). Therefore, our efforts should be directed at all scientific journals, including those published in national languages. We believe that this should also be clearly stated in the Declaration. We thank the authors for the Declaration and feel that, with our suggestion taken into account, we can enforce the ultimate goal of the Declaration, which is to improve scientific and publishing practice.

AB0026 Chemokine signals are critical for homing and enhanced differentiation of circulating osteoclast progenitor cells

Background Peripheral blood (PB) monocyte pool contains cells capable of differentiating into osteoclasts (OCs). These osteoclast progenitors (OCPs) contribute to osteoresorption in inflammatory arthritides under influence of the cytokine milieu and chemokine mediated trafficking. Objectives Our study aimed to define chemokine receptor profile of peripheral OCPs in rheumatoid arthritis (RA), with comparison to psoriatic arthritis (PSA), as well as their susceptibility to chemotactic signals. Methods 129 RA, 53 PSA and 110 control patients were enrolled after Ethical approval. PB samples and synovial fluid (SF) samples, with clinical data of disease activity, inflammation and autoantibody levels were collected. Patients starting anti-TNF therapy were followed up 6 months. TNF-α and CTX serum levels were measured by ELISA. Frequency of OCP-rich subpopulation (CD3-CD19-CD56-CD11b+CD14+), expression of OC differentiation (CD115, RANK) and chemokine (CCR1, CCR2, CCR4, CXCR4) receptors was assessed by flow cytometry. OCPs were sorted using FACS, cultured with M-CSF and RANKL, stained for TRAP enzyme and mature OCs counted. Levels of CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10 were measured using cytometric bead array, and of CXCL12 by ELISA. Osteoclastogenic effects of CCL2, CCL5 and CXCL10 were analyzed in cell culture, and chemotactic effects on OCPs were studied by cell migration assay using Transwell, with count of number of migrated cells and subsequently differentiated mature osteoclasts. Results OCP population was moderately enlarged in PB, further expanded in SF and correlated with TNF-α and rheumatoid factor (RF) levels in patients with RA. However, sorted OCPs generated similar number of mature OCs as control. RANK+ subpopulation was enlarged in SF vs PB and correlated with number of tender joints. In PSA, the OCP population was not enlarged, but had a higher RANK expression. OCPs in RA and PSA had higher expression of CCR1, CCR2, CCR4, CXCR4, and all except CCR4 showed positive PB-to-SF gradient. RA had higher levels of CCL2, CCL3, CCL4, CCL5, CXCL9 and CXCL10, with a positive PB-to-SF gradient for all except CCL5 and CXCL9. OCP frequency correlated with levels of CCL2 and CCL5. Subset expressing CXCR4 was associated with TNF-α, CTX and RF levels and was lower in patients treated with DMARD, who at the same time had lower osteoresorption (CTX). Subset expressing CCR4 showed significant negative trend during anti-TNF treatment. CCL2, CCL5 and CXCL10 showed significant osteoclastogenic effect. CCL5 showed greatest chemotactic effect, attracting the highest number of cells in the migration assay. At the same time, attracted cells possessed greater osteoclastogenic potential. Conclusions Our study provides evidence of the specific importance of certain chemokine signals for stimulation of OCP mobilization, subsequent tissue homing, and maturation, explaining local as well as generalized bone loss seen in RA. Novel insights in regards to migratory behavior and functional properties of PB OCPs in response to chemotactic signals could open way to new therapeutic targets in RA. Acknowledgements This work was supported by a grant from the Croatian Science Foundation (project number 5699). Disclosure of Interest None declared

Pedobarographic Profile of Gait in Patients with Ankylosing Spondylitis

nkylosing spondylitis (AS) is chronic inflammatory rheumatic disease which predominantly affects sacroiliac joints and spine and, during course of time, may also alter posture, movement patterns and regulation and quality of life. Clinical diagnostic tools for assessment of AS internalizations complement different qualitative and quantitative methods. Externalisations of axial skeleton alterations, followed by hip, knee, ankle and foot joints posture and movement adjustments, are quantified by conservative biomechanical approach. Items representing functional status and disease activity in AS patients correlated to pedobarographic status were anchored to previous research, i.e. Doward et al., 2003 ; Grazio et al., 2009 ; Aydina et al., 2015 ; Giacomozzi, 2010 ; Gruic et al., 2015 ; Gruic et al., 2016. Contrary to previous findings, multiple correlation between clinical scores and dynamic pedobarographic measurements was established.

Cochrane Physical and Rehabilitation Medicine: A New Field to Bridge Between Best Evidence and the Specific Needs of Our Field of Competence.

We wish to announce to the readers of PTJ , as well as all those of the other journals relevant to physical and rehabilitation medicine (PRM), the launch of Cochrane PRM, which will have its Official Exploratory Meeting in Brescia, Italy, September 19–20, 2016. The purpose of this meeting will be to complete the business plan currently under development and submit it for approval to Cochrane by October 2016. Cochrane is recognized as a leader of evidence-based medicine in all fields of medicine. Cochrane exists to improve health care decisions, and during the past 20 years, has helped to transform the health sector. In fact, Cochrane gathers and summarizes the best evidence from research to help people make informed choices about treatment. Cochrane is organized in groups, which include: