Is the fluorescence optical imaging (FOI) able to discriminate between rheumatoid arthritis patients with and without need of rituximab retherapy? A cohort study

ObjectiveTo evaluate the ability of fluorescence optical imaging (FOI) Xiralite in the discrimination between rheumatoid arthritis (RA) patients with and without need of rituximab (RTX) retherapy—in comparison to clinical, laboratory and musculoskeletal ultrasound parameters.Patients and methodsPatients with established RA were prospectively followed over 1 year by Disease Activity Score 28, patient’s global disease activity (visual analogue scale 0–100 mm), C reactive protein and erythrocyte sedimentation rate, ultrasound seven joint (US7) score and FOI in phases 1–3 and automatically generated PrimaVista mode (PVM) at baseline (before RTX) and after 3, 6 and 12 months. The need for RTX retherapy was decided by the treating rheumatologist—blinded to imaging data.Results31 patients (female 77.4%, mean age 60.1±11.4, mean disease duration 14.9±7.1 years) were included. Fourteen (45.2%) patients received RTX retherapy within 12 months. In the group with RTX retherapy, FOI in PVM mode was the only parameter that presented significant increase over time (β: 0.40, 95% CI: 0.08 to 0.71, p=0.013)—compared with the group without retherapy. In the prediction model via ROC analysis, FOI in PVM reached the highest values of all imaging, clinical and laboratory parameters which was associated with retherapy over 1 year with an area under the curve (AUC) of 0.78 (OR: 0.84, 95% CI: 0.72 to 0.98, p=0.031). US7 GS synovitis score revealed similar association with an AUC of 0.73 (p=0.049).ConclusionUS7 GS synovitis score and FOI in PVM are able to discriminate between patients with and without need for RTX retherapy better than clinical and laboratory parameters.

AB0045 THE RELATIONSHIP BETWEEN CD14 AND VIMENTIN-POSITIVE SYNOVIAL DENDRITIC-SHAPED CELLS AND SYNOVITIS IN RHEUMATOID ARTHRITIS

Background:Inflammation in rheumatoid arthritis (RA) is caused by multiple cell types, including infiltrating inflammatory cells, such as lymphocytes, neutrophils, macrophages, and spindle-shaped fibroblasts. Especially, we are focusing on fibroblast-like synoviocytes (FLSs). In our previous study, we have reported that FLSs were positive for multiple markers including CD14, CD68 and HLA-DR, and were dendritic-shaped cells constituting nursing phenomenon between lymph or plasma cells. In addition, in our recent study, we found that CD14+FLSs were positive for vimentin (VIM), which is a marker for mesenchymal cells. There are still many issues to be discussed regarding CD14+VIM+ cells.Objectives:To investigate the relationship between CD14+VIM+ cells and the degree of synovitis in rheumatoid arthritis.Methods:Synovial tissues collected from RA patients who underwent joint surgeries were prepared for this study. First, the proportions of CD14+ cells in RA synovial tissue and control were analyzed using flow cytometry and the concentrations of inflammatory cytokines released by CD14+ cells in RA synovial tissue and control were examined by ELISA. Next, the proportions of CD14+VIM+ cells in RA synovial tissue and control were examined immunohistologically and then we analyzed the results using image analysis software. Also, we statistically analyzed the relationship between the proportion of CD14+VIM+ cells, the degree of synovitis, and clinical data.Results:Results of flow cytometry showed that CD14+ cells were frequently observed in RA synovial tissue than control. Cultured CD14+ cells released more inflammatory cytokines than cultured CD14- cells. Also, results of immunohistological staining showed that many CD14+VIM+ cells were observed in RA synovial tissue than in control. The proportion of CD14+VIM+ cells was correlated with Krenn synovitis score. High proportion cases significantly showed high level of CRP and MMP-3.Conclusion:CD14+VIM+ cells might be involved in the mechanism of chronic immunological inflammation in RA and the proportion of these cells might influence the clinical data.References:[1]Ochi T, Yoshikawa H, Toyosaki-Maeda T, Lipsky PE. Mesenchymal stromal cells. Nurse-like cells reside in thesynovial tissue and bone marrow in rheumatoid arthritis. Arthritis Research&Therapy 2007; 9(1): 201.[2]Ochi T, Sawai T, Murakami K, Kamataki A, Uzuki M, Tomita T, et al. Nurse-like cells in rheumatoid arthritis: Formation of survival niches cooperating between the cell types. Mod Rheum 2018; 29: 1-5.[3]Krenn V, Morawietz L, Burmester GR, Kinne RW, Muller-Ladner U, Muller B, Haupl T. Synovitis score: discrimination between chronic low-grade and high-grade synovitis. Histopathology 2006; 49: 358-64.Disclosure of Interests:None declared

POS0490 SERUM MATRIX METALOPROTINASE 3 AS A MARKER TO DISCRIMINATE SUBCLINICAL DISEASE ACTIVITY FROM ULTRASOUND DEFINED REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Rheumatoid arthritis (RA) is a systemic disease which results in chronic inflammation that primarily involves synovial joints resulting in progressive joint destruction [1]. Detection of subclinical disease activity is important as radiographic progression was observed during remission course in some cases [2]. Ultrasound can detect subclinical activity and synovial inflammation, which predict relapse and radiographic progression [3].Matrix Metaloprotinase 3 (MMP-3) is an enzyme, which is involved in joint destruction in RA patients. MMP-3 was found to correlate with disease activity, joint erosions, radiographic progression, drug responsiveness and disease outcome in patients with active RA [4]. However no data about its role in detection of subclinical activity in patients with clinical remission.Objectives:To assess the role of MMP-3 as a marker to discriminate subclinical activity from ultrasound remission in rheumatoid arthritis patients with remission.Methods:This study was conducted on 45 RA patients fulfilling remission or low disease activity criteria according to DAS 28 AND 45 healthy controls. Ultrasound evaluation was done for all patients using modified German US7 score. According to US7 score patients were classified into two groups: group with sonographic remission in which GS is 0±1 and the other group with subclinical disease activity with higher GS. Both groups underwent clinical and laboratory evaluation including MMP-3.Results:Sonographic remission was achieved in 44% of patients (20 patients). There was no statistically significant difference as regard age, gender, smoking, disease duration, morning stiffness duration, CDAI, treatment and laboratory data apart from hemoglobin level between patients with subclinical disease activity and patients with remission. However, there is statistically significant difference between the two groups as regard joint deformity, extra articular manifestations, DAS 28, SDAI and hemoglobin level.There was statistically significant difference in serum MMP-3 between RA patients and healthy control group. Serum MMP-3 was higher in RA patients with subclinical activity than patients with sonographic remission but the difference was not statistically significant (figure 1). Serum MMP-3 was positively correlated with ESR and synovitis score.Figure 1.Conclusion:Serum MMP-3 has correlation with US synovitis score. However, serum MMP-3 was not able to differentiate patients with sonographic remission from patients with subclinical disease activity. Ultrasound is still the gold standard for detection of subclinical disease activity.References:[1]Ergin, S. (2000). “Romatoid Artrit ve Sjögren Sendromu.” Fiziksel Tip ve Rehabilitasyon, Güneş Kitapevi: 1549-1576.[2]Ogishima, H., H. Tsuboi, N. Umeda, M. Horikoshi, Y. Kondo, M. Sugihara, T. Suzuki, I. Matsumoto and T. Sumida (2014). “Analysis of subclinical synovitis detected by ultrasonography and low-field magnetic resonance imaging in patients with rheumatoid arthritis.” Modern rheumatology24(1): 60-68.[3]Filippucci, E., E. Cipolletta, R. M. Mirza, M. Carotti, A. Giovagnoni, F. Salaffi, M. Tardella, A. Di Matteo and M. Di Carlo (2019). “Ultrasound imaging in rheumatoid arthritis.” La radiologia medica124(11): 1087-1100.[4]Lerner, A., S. Neidhöfer, S. Reuter and T. Matthias (2018). “MMP3 is a reliable marker for disease activity, radiological monitoring, disease outcome predictability, and therapeutic response in rheumatoid arthritis.” Best Practice & Research Clinical Rheumatology32(4): 550-562.Disclosure of Interests:None declared

The histopathological synovitis score is influenced by biopsy location in patients with knee osteoarthritis

Introduction Osteoarthritis (OA) and rheumatoid arthritis (RA) represent the most common forms of arthritis, which are mainly caused by mechanical and inflammatory components, respectively. Determination of synovial inflammation in synovial biopsies via the histopathological Krenn score may be crucial for correct diagnosis and treatment. Specifically, it remains unclear whether synovitis scores differ among multiple biopsy locations within a single joint. Materials and methods Eighty synovial samples were taken from four standardized regions of the knee in 20 patients (ten primary OA, ten secondary OA) undergoing total knee arthroplasty (TKA) or total synovectomy. The Krenn synovitis score (grade 0–9) was determined in a blinded manner by two expert pathologists in all biopsies. Next to the inter-rater reliability, we evaluated the agreement of the determined scores among the four biopsy locations within each knee. Results The inter-rater reliability between the two pathologists was very high (Cohen’s kappa = 0.712; r = 0.946; ICC = 0.972). The mean synovitis score was significantly higher in knees with secondary than in primary OA (p = 0.026). Importantly, we found clear differences between the scores of the four different biopsy locations within the individual knee joints, with an average deviation of 10.6%. These deviations were comparable in knees with primary and secondary OA (p = 0.64). Conclusions While we confirmed the synovitis score as a reliable and reproducible parameter to assess the histopathological synovitis grade in the knee, the considerable variability within the joint indicates that multiple synovial biopsies from different regions should be obtained to enable reliable results of the synovitis score.

Subclinical synovitis in arthralgia: how often does it result in clinical arthritis? Reflecting on starting points for disease-modifying anti-rheumatic drug treatment

Objectives According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. ‘false positives’). Methods Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. Results Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. Conclusion Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44–89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.

Yttrium-90 radiosynoviorthesis hosszú távú (10 éves) eredményei inflammált térdarthrosisban

Absztrakt: Bevezetés: A radiosynoviorthesist (RSO) fájdalmas, terápiarezisztens, krónikus synovitis kezelésére alkalmazzuk az 1950-es évek óta, de a hosszú távú hatások felmérésére eddig nem készültek prospektív ellenőrzött vizsgálatok. Célkitűzés: Ennek a prospektív, obszervációs vizsgálatnak az volt a célkitűzése, hogy felmérje az izotópos synovectomia hatékonyságát inflammált térdosteoarthritisben (OA) 10 éves nyomon követésben. Módszer: Alapos előkészítés után a radionuklid-kezelést 90-Yttrium-citráttal végeztük Kellgren–Lawrence I–II. (n = 69) és III. stádiumú (n = 72) osteoarthritises betegekben, intraarticularis injekció formájában. Eredmények: A korai radiológiai stádiumban levő osteoarthritises betegekben „kiváló/jó” eredményeket értünk el már 1 év után az esetek 82,5%-ában, és 73,7%-ot a 8 éves kontrollvizsgálatokon. A felmérés az ízületi fájdalomra, a mobilitásra és a mozgásfunkciók megtartására vonatkozott. 10 évvel a beadás után az eredményesség 50%-ra csökkent, feltehetően a korral járó degeneratív folyamatok progressziója miatt. A III. stádiumú betegekben (akiknél az osteoarthritis előrehaladottabb volt) kezdetben 45,9%-os eredményt értünk el, és ez 41,2%-ra esett vissza a 8 éves utánkövetés során. Ebben a csoportban a betegek száma csökkent a 8–10. évre, azaz a 8. évben 51 beteg maradt, majd a 9. évben 30 beteg, a 10. évben pedig 9 beteg. Az utolsó évben az alacsony betegszám miatt a klinikai válaszok nem voltak biztonságosan megítélhetők. Következtetés: Az osteoarthritises ízületekben alkalmazott RSO hosszú távú eredménye a legtöbb betegben „kiváló” vagy „jó” volt. A radiokolloid hatása hosszú távon fennmarad, a 8–10. éves gyengébb eredmények az életkor előrehaladásával jelentkező degeneratív folyamatoknak és az alacsony betegszámnak tudható be. Ismert, hogy a hatékonyság függ a kezdeti diagnózistól (OA, RA, SpA, PsA, AHA, ReA stb.), a radiológiai stádiumtól (Kellgren–Lawrence I–IV.), illetve a synovitis score-tól. Eredményeink a nemzetközi tapasztalatokhoz hasonlóan arra utaltak, hogy a radiációs synovectomia alkalmazása elsősorban az alacsonyabb radiológiai stádiumban levő betegeknek javallott. Orv Hetil. 2020; 161(43): 1831–1839.

AB0054 SYNOVIAL CD163+ MACROPHAGES ARE ASSOCIATED WITH RADIOGRAPHIC JOINT DESTRUCTION IN RHEUMATOID ARTHRITIS

Background:CD163, a hemoglobin scavenger receptor, has been identified as a marker of M2 macrophages, it can promote the release of IL-10 and carbon oxide. Researches on inflammatory diseases and tumors have suggested that CD163 plays anti-inflammatory effect and promotes tumor growth and metastasis. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by chronic synovitis with inflammatory cells infiltration including considerable macrophages. However, little is known about the role of CD163+ macrophages in RA synovium.Objectives:To investigate the expression and clinical significance of synovial CD163+ macrophages in RA.Methods:Seventy-five RA patients were recruited and clinical data including disease activity, HAQ and Sharp/van der Heijde-modified Sharp score of bilateral hands and wrists were collected. Synovial tissues were obtained by needle biopsies or arthroscopy of knee joints. Eighteen osteoarthritis (OA) and seventeen orthopedic arthropathies (orth.A) patients were included as controls. All synovium were stained with H&E and immunohistochemically for CD163, CD3, CD20, CD38, CD68, and CD15. Histologic changes of synovitis in H&E stained sections were graded with Krenn’s synovitis score.Results:Positive CD163 expression were found in both lining synoviocytes and sublining inflammatory cells. Both densities of lining and sublining CD163+ macrophages in RA synovium were significantly higher than that in OA or Orth.A synovium (140.47±66.93 vs. 17.85±7.70 vs. 19.76±5.26 and 417.92±249.62 vs. 27.58±14.19 vs. 29.87±9.33, allP<0.001, Figure 1).According to Krenn’s synovitis score, there were 68% RA patients showing high synovitis (score>4). Both lining and sublining synovial CD163+ macrophages were significantly higher than those showing low synovitis (lining: 158.40±62.91 vs. 122.06±66.74, sublining: 462.96±62.91 vs. 371.65±271.54, bothP<0.05). Meanwhile, the densities of lining and sublining CD163+ macrophages were both positively correlated with Krenn’s synovitis score (r=0.238 and 0.343, bothP<0.05).For clinical relationship in RA, the density of sublining CD163+ macrophages was positively correlated with total Sharp score (mTSS) (r=0.399,P<0.001), joint space narrowing subscore (r=0.248,P=0.032) and joint erosion subscore (r=0.457,P<0.001). While the density of lining CD163+ macrophages was positively correlated with mTSS (r=0.319,P=0.005) and joint erosion subscore (r=0.358,P=0.002). Meanwhile, the densities of sublining and lining CD68+ macrophages were also positively correlated with mTSS (r=0.253 and 0.242, bothP<0.05), of which the correlation was weaker than that of CD163+ macrophages (Figure 2). There were no significant correlation between the density of CD163+ macrophages and disease activity or HAQ (allP>0.05).Conclusion:Synovial CD163+ macrophages are associated with radiographic joint destruction, which imply that CD163+ macrophages may play role in the pathogenisis of joint destruction in RA.Figure 1.Representative immunohistochemical findings of synovial CD163 expression. (A) Synovial CD163 expression in an Orth.A patient, an OA patient and a RA patient. (B) Densities of lining and sublining CD163+ macrophages in Orth.A, OA and RA patients.Figure 2.Spearman’s rank correlation analysis for synovial macrophages and mTSS in RA. (A) Correlation between sublining CD163+ macrophages and mTSS, joint space narrowing subscore, joint erosion subscore. (B) Correlation between lining CD163+ macrophages and mTSS, joint space narrowing subscore, joint erosion subscore.Funding: :This work was supported by National Natural Science Foundation of China (no. 81801606 and 81971527), Guangdong Natural Science Foundation (no. 2017A030313576, 2018A030313541 and 2019A1515011928).Figures:Disclosure of Interests:None declared

SAT0570 CLINICAL SIGNIFICANCE OF FINGER EXTENSOR PARATENONITIS DETECTED BY MUSCULOSKELETAL ULTRASOUND

Background:The extensor tendons over fingers are devoid of a tendon sheath, so that the term paratenonitis is used to describe extra-articular hyperemia or anechoic fluid collections along the extensor tendons of the fingers. Although the grading of paratenonitis is found in one sonographic scoring system of RA known as German US7, the clinical significance of paratenonitis is not fully understood.Objectives:To determine the clinical significance of finger extensor paratenonitis detected by ultrasound (US), especially in the patients with RA.Methods:We reviewed 1200 reports of the US examination underwent in our division since April 2015. The items necessary for scoring US5 scores (the ‘hand-limited version’ of the German US7) have been routinely recorded. The cases with finger extensor paratenonitis over the dorsal metacarpophalangeal joint (MCPJ) were determined. The severity of articular synovitis in the perilesional MCPJ were subjectively graded for grey-scale (GS) and power Doppler (PD) on a four-step scale (0-3) and scored using EULAR-OMERACT combined scoring system. In RA patients, US5 scores were determined for the involved hands.Results:Paratenonitis was found in 44 fingers in the 38 hands of the 36 patients with rheumatic diseases/disorders including 25 patients with RA (11 early RA and 14 established RA). Non-RA diseases/disorders included 4 cases of undifferentiated arthritis, 2 cases of PsA, 1 case each of SLE, Sjogren syndrome, reactive arthritis and other disorders.The 44 fingers were classified according to the absence or presence of articular synovitis in the perilesional MCPJ into “isolated paratenonitis” or “paratenonitis accompanied by synovitis”. The distribution of paratenonitis over the 1st-5thfingers of the dominant or non-dominant hands is shown in Figure 1. Paratenonitis was relatively frequently found in the 3rdand 2ndfingers of the dominant hands. Interestingly, articular synovitis in the perilesional MCPJ were found significantly more frequent in the cases of MCP2 in the dominant hands (73%) than in the cases of MCP3 in the dominant hands (25%) (p=0.039).Among the 27 hands with paratenonitis of 25 RA patients, US5 scores were compared based on the absence or presence of moderate to severe articular synovitis in the perilesional MCPJ (the combined score >1) (Figure 2). GS synovitis score, PD synovitis score and PD tenosynovitis score were significantly higher in those with moderate to severe perilesional MCP synovitis than in those without it (p=0.007, 0.0092 and 0.0458, respectively).Conclusion:Finger extensor paratenonitis over the dorsal MCPJ tends to occur in the 3rdand 2ndfingers of the dominant hand. In RA patients, paratenonitis accompanied by active perilesional MCPJ synovitis are presumably due to active disease, while isolated paratenonitis can also be caused possibly by degenerative changes due to overuse or deformity. Isolated paratenonitis may be more frequently found in the 3rdfinger than in the 2ndfinger of the dominant hand.References:NoneDisclosure of Interests:Takeshi Suzuki Speakers bureau: Abbvie, Asahi-kasei, Astellas, Bristol-Myers Squibb, Chugai, Eli Lilly, Mitsubishi-Tanabe, Novartis, UCB, Harumi Shirai: None declared

OP0242 META-ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA OF THE SYNOVIUM TO DEFINE SYNOVIAL FIBROBLAST PHENOTYPES ACROSS JOINT LOCATION AND DISEASE

Background:Up to now, three groups used single cell RNA sequencing (scRNA-seq) to analyse the synovium in arthritis using different methods and material to measure RNA expression on a single cell level: Ref. 1 used unsorted dissociated synovial cells and a droplet based method; Refs 2 and 3 performed scRNA-seq on sorted cell populations.Objectives:The aim of this study was to perform a meta-analysis of scRNA-seq data of the synovium in arthritis: 1) to define synovial fibroblast (SF) phenotypes, 2) to confirm differences across SF clusters between rheumatoid arthritis (RA) and osteoarthritis (OA) and 3) to analyse joint specific differences between SF phenotypes.Methods:In addition to the available count matrices [1-3], we used unsorted dissociated synovial cells from three patients with undifferentiated arthritis (UA) with a droplet-based method (10x Genomics). We followed a standard protocol [4] to integrate the datasets into a shared space, even in the presence of extensive technical and/or biological differences (“batch-corrected”). SF were selected as previously described (PDPN+,ISLR+,COL1A2+,PTPRC-) [1-3]. We used a minimum log2 FC of 0.25 for average expression of genes in a cluster relative to the average expression in all other clusters combined to define marker genes. R with Seurat, Monocle and clusterProfiler packages were used for scRNA-seq analysis, pseudotime trajectory analysis and pathway enrichement analysis, respectively. Quantitative PCR (qPCR) (n=6-14 per location and disease), immunohistochemistry (IHC) and Krenn synovitis score (n=5-15 per location and disease) were performed according to standard protocols.Results:Data from 29 RA, 3 UA and 6 OA patients were analysed. From a total of 29’448 cells, we identified 14’787 (50%) with a fibroblast phenotype. Of those, we determined 5 subpopulations (Fig. 1): 1)THY1-CD55hifibroblasts with high expression ofMMP1andMMP3(SF1), 2)THY1loCD34+fibroblasts expressing high levels ofPI16(SF2) 3)THY1hifibroblasts expressing high levels of periostin (POSTN) and collagens (e.g.COL1A1, COL3A1) (SF3), 4)THY1hifibroblasts expressingCXCL12(SF4) and 5)THY1lofibroblasts expressingCXCL12,NR4A1andCCL2(SF5). Fig. 2 shows pathway enrichment map of all marker genes; it organizes enriched terms into a network with edges connecting overlapping gene sets. Pseudotime trajectory axis derived from Monocle indicated that SF4 represent a state between SF3 and SF5. Pseudotemporal expression dynamics ofTHY1marked the progression of these three subtypes (Graph 1). SF1 and SF2 were proportionally underrepresented and SF3-5 overrepresented in RA (chi-squared = 37.18, p = 1.65e-07). The expression of POSTN, a signature gene of SF3, was not different between RA and OA tissues, but significantly correlated with the synovitis score (Spearman ρ = 0.55, p=0.02), in particular with pathological changes in the sublining. POSTN expression was higher in hand than in knee synovial tissues (mean ± SD IHC score: hand 8 ±2, knee 5 ±2) and in cultured SF (qPCR: 10-fold difference). Accordingly, SF3 was enriched in hand versus knee synovial tissues in the scRNA-seq dataset (chi-squared = 944.87, p < 2.2e-16).Fig. 1Fig. 2Graph 1Conclusion:In our meta-analysis, we found comparable subtypes of fibroblasts as in the individual analyses [1-3], showing the robustness of cell phenotype identification using scRNA-seq. The different SF phenotypes appear to be plastic cell states rather than fixed cell subtypes, whose development is controlled by an interrelation between pathological changes in the synovium and joint location.References:[1]Stephenson et al. Nat. Commun. 2018[2]Mizoguchi et al. Nat. Commun. 2018[3]Zhang et al. Nat Immunol. 2019[4]Stuart, Butler, et al. Cell 2019Disclosure of Interests:Raphael Micheroli: None declared, Mojca Frank-Bertoncelj: None declared, Sam G. Edalat: None declared, Kerstin Klein: None declared, Tadeja Kuret: None declared, Kristina Buerki: None declared, Adrian Ciurea Consultant of: Consulting and/or speaking fees from AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck Sharp & Dohme, Novartis and Pfizer., Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche, Caroline Ospelt Consultant of: Consultancy fees from Gilead Sciences.