BIOMARKERS IN RHEUMATOLOGY, WHAT DO WE REALLY KNOW?

The diagnosis of rheumatic diseases is made mostly on the basis of clinical signs and symptoms. However, we rheumatologists very oft en rely on serological and proteomic biomarkers that help to our pure clinical judgement, which is a central element of medical profession. Identifying biomarkers that can contribute the diagnosis, efficacy measurement, prognosis and treatment selection will be described in this paper. Personalized treatment strategy in the daily clinic using genomic, transcriptomic and proteomic screening is the era of the future medicine. However, heterogeneous manifestations of rheumatic diseases make interpreting of some conflicting results on biomarkers difficult. Therefore, multibiomarker approach may prove useful. In this paper, several well-established and novel biomarkers that have already been incorporated to the routine clinical setting or that are just studied for diagnostic and prognostic purposes will be discussed. References: 1. Jog NR, James JA. Biomarkers in connective tissue diseases. J Allergy Clin Immunol. 2017 Dec;140(6):1473–1483 2. Miossec P, Verweij CL, Klareskog L, et al; Group for Respect of Ethics and Excellence in Science (GREES). Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies. Ann Rheum Dis. 2011 Oct;70(10):1713–8. 3. Smolen JS, Aletaha D. Forget personalised medicine and focus on abating disease activity. Ann Rheum Dis. 2013 Jan;72(1):3–6

Laboratory biomarkers or imaging in the diagnostics of rheumatoid arthritis?

none3openŠenolt, Ladislav; Grassi, Walter; Szodoray, PeterŠenolt, Ladislav; Grassi, Walter; Szodoray, Pete

The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear cells via the TLR4 signalling pathway in rheumatoid arthritis

Objectives. S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells. Methods. Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12. The production of IL-1β, IL-6 and TNF-α was measured by ELISA. Receptor for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4) signalling were examined. For signalling pathway blocking studies, inhibitors of myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-κB) and the mitogen activated protein (MAP) kinases p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) were used. MAP kinase activation was evaluated by western blotting. Results. Stimulation of PBMCs with S100A4 significantly up-regulated IL-1β, IL-6 and TNF-α production compared with unstimulated cells (P < 0.001). Importantly, the production of these cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12; however, it was less pronounced compared with S100A9. Furthermore, enhanced production of proinflammatory cytokines in S100A4-stimulated PMBCs was at least partly mediated via TLR4, but not RAGEs, and by activation of the transcription factor NF-κB and the MAP kinases p38 and ERK1/2. Conclusion. This is the first study to demonstrate that S100A4 can induce an inflammatory response mediated by TLR4 and by the activation of NF-κB and the kinases p38 and ERK1/2 in mononuclear cells from patients with RA. Therefore S100A4 may be a potential therapeutic target for immune-mediated disease

The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies

Objectives. The S100A4 protein is known as a metastasis promoting factor; however, its involvement in non-malignant diseases such as RA and psoriasis has been recently described. The aim of this study was to investigate the expression and possible role of S100A4 in idiopathic inflammatory myopathies. Methods. S100A4 protein expression was detected by immunohistochemistry in muscle tissue from control individuals (n = 11) and patients with PM and DM (n = 8/6). IF staining was used to co-localize S100A4 with selected cells. Cytokine expression and protein synthesis in S100A4-treated cells were analysed by RT-PCR and ELISA. Results. S100A4 protein was significantly up-regulated in muscle tissue of patients with inflammatory myopathies compared with control individuals and was associated particularly with the presence of mononuclear infiltrates. Only few regenerating muscle fibres in PM/DM expressed S100A4. Then we analysed the effect of S100A4 on human myocytes and peripheral blood mononuclear cells (PBMCs). Although S100A4 did not affect myocytes, stimulation of PBMCs with S100A4 significantly induced the expression and synthesis of TNF-α, IL-1β and IL-6, but not of IFN-α. We showed that S100A4 is not directly involved in perforin/granzyme B-induced apoptosis and that it does not modulate the expression of Bax and Bcl2 mRNA in myocytes and PBMCs. Conclusion. Increased expression of S100A4 in inflamed muscle tissue highlights its potential role in the pathogenesis of inflammatory myopathies. S100A4 may act as a cytokine-like factor indirectly promoting muscle fibre damage by stimulating mononuclear cells to increase the synthesis of pro-inflammatory cytokine

Response to Secukinumab on Synovitis using Power Doppler Ultrasound in Psoriatic Arthritis: 12-week Results from a Phase III Study, ULTIMATE

Objectives: To investigate the dynamics of response of synovitis to interleukin (IL)-17A inhibition with secukinumab in patients with active psoriatic arthritis (PsA) using Power Doppler ultrasound. Methods: The randomised, placebo-controlled, Phase III ULTIMATE study enrolled PsA patients with active ultrasound synovitis, and clinical synovitis and enthesitis having an inadequate response to conventional disease-modifying anti-rheumatic drugs (DMARDs) and naïve to biologic DMARDs. Patients were randomly assigned to receive either weekly subcutaneous secukinumab (300 or 150 mg according to the severity of psoriasis) or placebo followed by 4-weekly dosing thereafter. The primary outcome was the mean change in the ultrasound Global European League Against Rheumatism and Outcome Measures in Rheumatoid Arthritis Clinical Trials Synovitis Score (GLOESS) from baseline to week 12. Key secondary endpoints included American College of Rheumatology 20 and 50 responses. Results: Of the 166 patients enrolled, 97% completed 12 weeks of treatment (secukinumab, 99%; placebo, 95%). The primary end point was met, and the adjusted mean change in GLOESS was higher with secukinumab than placebo (-9 [0.9] vs -6 [0.9], difference [95% CI]: -3 [-6; -1]; one-sided p = 0.004) at week 12. The difference in GLOESS between secukinumab and placebo was significant as early as one week after initiation of treatment. All key secondary endpoints were met. No new or unexpected safety findings were reported. Conclusion: This unique ultrasound study shows that apart from improving the signs and symptoms of PsA, IL-17A inhibition with secukinumab leads to a rapid and significant reduction of synovitis in PsA patients. Keywords: Clinical outcome; GLOESS; Joints; OMERACT; Power Doppler ultrasound; PsA; Responsiveness; Secukinumab; Synovitis; biological DMARDs

Educational needs and preferences of young European clinicians and physician researchers working in the field of rheumatology

Funding Information: CB: Grant BE 5191/1-1 of the Deutsche Forschungsgemeinschaft.Objectives: To understand the educational needs and preferences of young clinicians and physician researchers in the field of rheumatology in Europe. Methods: An international online survey was performed as a joint venture of ESCET and EMEUNET. The survey assessed the acceptance of and the access to the current European League Against Rheumatism (EULAR) educational portfolio, as well as the unmet educational needs and learning preferences among individuals below the age of 40 years working in rheumatology in Europe. Results: Among 568 European clinicians and physician researchers, 65% indicated that the existing EULAR educational portfolio adequately covers their educational needs. Within the EULAR portfolio, the online course on rheumatic diseases and the postgraduate course were the most appreciated. Participants were very much in favour of new educational courses on imaging techniques, and 63% of participants indicated a particular interest in musculoskeletal ultrasound. A strong interest in refresher (60%) and general review (55%) courses was observed. Lack of funding was considered the major obstacle to participating in existing EULAR programmes. Finally, participants showed diverse preferences regarding learning modalities with common interests in live courses and conferences. Conclusions: EULAR's training opportunities are well appreciated among young clinicians and physician researchers in rheumatology. The results from this survey will help to develop EULAR's future educational portfolio.publishersversionPeer reviewe

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Tato disertační práce pojednává o využití vybraných biomarkeru při hodnocení OA a RA. Dále řeší vzájemné vztahy těchto markerů, což přispívá к bližšímu pochopení patogeneze obou chorob. Z vybraných markerů jsme hodnotili ukazatele oxidačního stresu a zánětlivé aktivity (pentosidin, CRP), parametry degradace kloubní chrupavky (COMP), metabolického obratu kosti (OPG, RANKL, deoxypyridinolin, pyridinolin). markery imunity (anti-CCP) a protein asociovaný s metastázami S100A4. U pacientů s OA kolennich kloubů jsme prokázali zvýšené hladiny pentosidinu a jejich pozitivní vztah к ukazateli destrukce kloubní chrupavky COMP v synoviálni tekutině. Navíc jsme zjistili prediktivní význam pentosidinu při hodnocení progrese OA kolennich kloubů u časné formy OA, kdy jedinci s časným začátkem choroby a s vyššími koncentracemi pentosidinu vykazovali rychlejší rentgenovou progresi postiženého kloubu. Naše výsledky tak poukazují na asociaci oxidačního zatížení organismu a degradaci kloubní chrupavky, a staví pentosidin mezi několik nových potenciálních biologických markerů OA. Vyšší rozptyl sérových hodnot pentosidinu u pacientů s OA a u kontrolní skupiny však představuje limitující faktor pro diagnostické využití pentosidinu. V porovnání s pacienty s RA jsme u pacientů s OA kolennich kloubů pozorovali vyšší koncentraci COMP...Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the most common forms of musculosceletal disorders that affect diarthrodial joints, lead to joint damage and disability. Extra-articular manifestations accompanied the joint disease only in RA. Diagnosis of both conditions most commonly bears on the conventional radiography. Mostly in OA, radiographic changes often occur late in the disease and are largely irreversible. Molecular markers could reflect joint damage, inflammation, or immune response. Current investigation revealed potential uses of molecular markers, ranging from understanding pathogenesis of the diseases to predicting and monitoring the outcome of the treatment. The aim of the thesis was to analyze several biochemical markers in serum, synovial fluid and synovial tissue samples from patients with RA and OA. and to evaluate their diagnostic and predictive values as well as their contribution to the pathogenesis of the diseases. We found increased serum pentosidine concentrations in OA patients that were ol a predictive value of the joint space narrowing in OA of the knee joint and correlation between pentosidine and cartilage oligomeric matrix protein (COMP) in synovial fluid that make pentosidine one of the new potential biomarkers of the OA. Scrum level of COMP was similar among...Department of Rheumatology First Faculty of Medicine and Rheumatology InstituteRevmatologická klinika 1. LF UK v Praze a Revmatologický ústavFirst Faculty of Medicine1. lékařská fakult

název v anglickém jazyce není uveden

Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the most common forms of musculosceletal disorders that affect diarthrodial joints, lead to joint damage and disability. Extra-articular manifestations accompanied the joint disease only in RA. Diagnosis of both conditions most commonly bears on the conventional radiography. Mostly in OA, radiographic changes often occur late in the disease and are largely irreversible. Molecular markers could reflect joint damage, inflammation, or immune response. Current investigation revealed potential uses of molecular markers, ranging from understanding pathogenesis of the diseases to predicting and monitoring the outcome of the treatment. The aim of the thesis was to analyze several biochemical markers in serum, synovial fluid and synovial tissue samples from patients with RA and OA. and to evaluate their diagnostic and predictive values as well as their contribution to the pathogenesis of the diseases. We found increased serum pentosidine concentrations in OA patients that were ol a predictive value of the joint space narrowing in OA of the knee joint and correlation between pentosidine and cartilage oligomeric matrix protein (COMP) in synovial fluid that make pentosidine one of the new potential biomarkers of the OA. Scrum level of COMP was similar among..