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Multiple biochemical biomarkers have been previously investigated for the diagnosis, prognosis and response to treatment of articular cartilage damage, including osteoarthritis (OA). Synovial fluid (SF) biomarker measurement is a potential method to predict treatment response and effectiveness. However, the significance of different biomarkers and their correlation to clinical outcomes remains unclear. This systematic review evaluated current SF biomarkers used in investigation of cartilage degeneration or regeneration in the knee joint and correlated these biomarkers with clinical outcomes following cartilage repair or regeneration interventions.PubMed, Institute of Science Index, Scopus, Cochrane Central Register of Controlled Trials, and Embase databases were searched. Studies evaluating SF biomarkers and clinical outcomes following cartilage repair intervention were included. Two researchers independently performed data extraction and Quality Assessment of Diagnostic Accuracy Score 2 (QUADAS-2) analysis. Biomarker inclusion, change following intervention and correlation with clinical outcome was compared.9 studies were included. Study heterogeneity precluded meta-analysis. There was significant variation in sampling and analysis. 33 biomarkers were evaluated in addition to microRNA and catabolic/anabolic ratios. Five studies reported on correlation of biomarkers with six biomarkers significantly correlated with clinical outcomes following intervention. However, correlation was only demonstrated in isolated studies.This review demonstrates significant difficulties in drawing conclusions regarding the importance of SF biomarkers based on the available literature. Improved standardisation for collection and analysis of SF samples is required. Future publications should also focus on clinical outcome scores and seek to correlate biomarkers with progression to further understand the significance of identified markers in a clinical context.PROSPERO CRD42022304298. Study protocol available on PROSPERO website.

Background:Up to 30% of Psoriasis (PsO) patients are prone to develop Psoriatic Arthritis (PsA). Agreement on how to identify PsO patients at risk of developing PsA is still lacking (1).Objectives:To identify predictors of PsA development in PsO patients through a systematic literature review (SLR) and meta-analyses (MA).Methods:MEDLINE, EMBASE and COCHRANE databases were searched (up to February 22nd, 2020). The PICO framework (population = PsO patients; intervention = clinical, environmental, imaging and genetic features; comparator = not applicable; outcome = PsA development) was used to design searches and define the eligibility of studies for inclusion. The MA focuses on 3 major features as possible predictors: i) PsO skin and nail involvement; ii) musculoskeletal (MSK) complaints; iii) inflammation and structural damage detected by imaging (Table 1). The sample estimates of the relative risk were pooled only when the studies were homogeneous in terms of cohort of patients, follow-up, study design and metrics.Results:4698 articles were screened for eligibility, 110 underwent a full reading and 29 were finally included. Figure 1 shows the study flow-chart for article selection. Though pooling was judge not appropriate, 5/7 prospective studies significantly support a predictive value of PsA development in patients with severe PsO (n=174635). While the predictive value of nail involvement is not well defined (n=2202), the pooled estimate from two cohort studies (n=474) supports nail pitting as predictor of PsA (RR=2.14 [1.32; 3.46]). Moving to the MSK complaints, the risk of developing PsA is about two times greater in PsO with than without arthralgia (pooled RR: 2.15 [1.16, 3.99]) within 2 years. Lastly, PsO patients with inflammation or structural damage detected by imaging are nearly four times more likely to develop PsA within 1-2 years (pooled RR from 4 cohort studies (n=247): 3.72 [2.12; 6.51]) (Table 1). The incidence rate of PsA varies from 1.34 to 5.9/100 p-ys in PsO and from 10.9 to 12.5/100 p-ys in PsOAr.Table 1.Studies reporting the major features as possible predictors of PsA development.PsO skin – severityPsO nail involvementPsO nail lesionsVariablesRelative Risk [95%CI]Follow-upWilson, 2009PsO nail involvementHRadjusted: 2.24 [1.26; 3.98]13.1±8.8 ysFaustini, 2015PASI score + PsO nail involvement/σ= -0.18[-0.84; 0.48] RR: 0.95 [0.37; 2.47]1.2±0.2 ysEder, 2016PASI score PsO nail involvement Type of PsO nail lesionsHR (>20vsHRunadjusted: 1.36 [0.76; 2.45] HRunadjusted: 2.21 [1.24; 3.92]4.1±2.1 ysEder, 2017PASI score + Type of PsO nail lesionsHRunadjusted: 1.05 [1.01; 1.09] HRunadjusted: 1.98 [0.83; 4.74]3.8±2.1 ysLewinson, 2017PsO severity defined from medicationsHRadjusted (moderate/severe vs mild): 5.02 [4.18; 6.04]5.1 ysEgeberg, 2018PsO severity defined from medicationsRR (severe vs mild): 1.31 [1.18; 1.46]18 ysElnady, 2019PASI score + PsO nail Involvement/σ= 0.79[-0.37; 1.95] RR: 1.43 [0.38; 5.31]2 ysGreen, 2020PsO severity defined from medicationRR (severe vs mild): 2.79 [2.49; 3.13]5.8 ysMSK-complaintsVariablesIncident-PsA casesFollow-upFaustini, 2015ArthralgiaRR: 1.98 [0.75; 5.19]1.2±0.2 ysEder, 2017ArthralgiaHRadjusted: 2.59 [1.15; 5.88]3.8±2.1 ysZabotti, 2019ArthralgiaRR: 4.44 [0.54; 36.72]1.6±0.5 ysSimon D, 2020ArthralgiaRR: 2.04 [0.86; 4.86]2.4±1.5 ysSub-clinical inflammation or structural damage detected by imagingVariablesIncident-PsA casesFollow-upFaustini, 2015MRIRR: 2.10 [0.75; 5.90]1.2±0.2 ysElnady, 2019MSK-USRR: 5.38 [1.17; 24.63]2 ysZabotti, 2019MSK-USRR: 6.86 [0.83; 56.63]1.6±0.5 ysSimon D, 2020HR-pQCTRR: 4.32 [1.96; 9.55]2.3±1.4 ysConclusion:Arthralgia and inflammation and/or structural damage detected by imaging are predictive features, likely prodromal, of PsA development. PsO severity and nail pitting are clinical manifestations related to PsA development.Figure 1.References:[1]Zabotti A, et al. Curr Rheumatol Rep. 2020 May 16;22(6):24. doi: 10.1007/s11926-020-00891-x.Disclosure of Interests:Alen Zabotti Speakers bureau: UCB, Novartis, Janssen, Paid instructor for: Amgen, Consultant of: Janssen, Orazio De Lucia Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Garifallia Sakellariou Consultant of: AbbVie, Novartis, Alberto Batticciotto Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Gilberto Cincinelli: None declared, Ivan Giovannini: None declared, Luca Idolazzi Speakers bureau: Eli Lilly, UCB, Celgene, MSD, Abbvie, Novartis, Paid instructor for: UCB, Gabriella Maioli Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Ilaria Tinazzi Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Daniel Aletaha Speakers bureau: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Salvatore De Vita Consultant of: GSK, Roche, Grant/research support from: Not relevant for this type of study, Antonio Marchesoni Speakers bureau: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Josef S. Smolen Speakers bureau: Not relevant for this type of study, Consultant of: Not relevant for this type of study, Grant/research support from: Not relevant for this type of study, Annamaria Iagnocco Speakers bureau: not relevant for this type of study, Paid instructor for: not relevant for this type of study, Consultant of: not relevant for this type of study, Grant/research support from: not relevant for this type of study, Dennis McGonagle Speakers bureau: ABBVIE, CELGENE, PFIZER, MSD, NOVARTIS, JANSSEN, UCB, GILEAD, BMS, LILLY, Grant/research support from: ABBVIE, CELGENE, PFIZER, MSD, NOVARTIS, JANSSEN, UCB, GILEAD, BMS, LILLY, Roberto Caporali Speakers bureau: Abbvie, Amgen, BMS, Celltrion, Galapagos, Gilead, Lilly, Pfizer, Roche, UCB, Sanofi, Fresenius Kabi, Samsung bioepis, MSD, Consultant of: Galapagos, Gilead, Lilly, Janssen, MSD

Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biologic therapy is traditionally regarded as immunosuppressive and capable to increase the infectious risk, Dupilumab does not display these characteristics and may be even protective in certain cases. We investigated the link between Dupilumab therapy and SARS-CoV-2 infection.We carried out a comprehensive data mining and disproportionality analysis of the WHO global pharmacovigilance database. One asymptomatic COVID-19 case, 106 cases of symptomatic COVID-19, and 2 cases of severe COVID-19 pneumonia were found.Dupilumab treated patients were at higher risk of COVID-19 (with an IC0.25 of 3.05), even though infections were less severe (IC0.25 of -1.71). The risk of developing COVID-19 was significant both among males and females (with an IC0.25 of 0.24 and 0.58, respectively). The risk of developing COVID-19 was significant in the age-group of 45-64 years (with an IC0.25 of 0.17).Dupilumab use seems to reduce COVID-19 related severity. Further studies are needed to better understand the immunological mechanisms and clinical implications of these findings. Remarkably, the heterogenous nature of the reports and the database structure did not allow to establish a cause-effect link, but only an epidemiologically decreased risk in the patients subset treated with dupilumab.

Introduction Les formes sévères de COVID-19 comportent à une hyperinflammation systémique intense ; ce qui a justifié des essais thérapeutiques avec des immunomodulateurs régulièrement utilisés chez les patients atteints de maladies systémiques auto-immunes ou inflammatoires Depuis février 2021 où les premières recommandations EULAR sur l’utilisation de thérapeutiques immunomodulatrices dans le COVID-19 ont été publiées [1], de nouveaux essais thérapeutiques ont été réalisés ce qui rend nécessaire une mise à jour ces recommandations. Matériels et méthodes Selon les procédures standardisées de l’EULAR [2], les résultats d’une revue de la littérature systémique réalisée jusqu’au 15 décembre 2020 puis mise à jour jusqu’au 14 juillet 2021 incluant tous types d’études ont été présentés à un groupe de travail multidisciplinaire composé d’experts internationaux comprenant des rhumatologues, des immunologistes translationnels, des hématologues, des pédiatres, des patients et des professionnels de la santé. La mise à jour des recommandations a été discutée et votée par l’ensemble du panel d’experts sur la base des résultats présentés, principalement des essais randomisés contrôlés (ECT) sur différents traitements immunomodulateurs. Résultats La mise à jour comprend deux principes généraux et dix recommandations. Les recommandations concernent uniquement la prise en charge des patients présentant des formes de COVID-19 modérées à sévères ou critiques, faute de preuves suffisantes avec très peu d’ECT concernant les patients asymptomatiques et ceux avec des formes légères de la maladie. Les molécules suivantes ont montré une efficacité dans le traitement de formes modérées à sévères ou critiques du COVID-19. L’association de glucocorticoïdes et de tocilizumab est bénéfique dans les cas de COVID-19 nécessitant une oxygénothérapie et dans les cas critiques de COVID-19. L’utilisation d’inhibiteurs de Janus kinase (baricitinib et tofacitinib) et peut-être d’Ac anti-GM-CSF est prometteuse dans les mêmes populations. Les anticorps monoclonaux anti-SARS-CoV-2 et l’utilisation de plasma convalescent pourraient trouver une application dans les phases précoces de la maladie et dans certains sous-groupes de patients immunodéprimés. D’autres immunomodulateurs comme l’hydroxychloroquine, la colchicine ou l’anakinra n’ont pas démontré leur efficacité sur la mortalité et ou sur l’aggravation clinique (évolution vers une détresse respiratoire), quel que soit le stade de la maladie. Conclusion Un nombre grandissant d’ECT soutiennent l’efficacité de l’association de glucocorticoïdes et d’autres agents immunomodulateurs tels que le tocilizumab dans le traitement de formes modérée à sévère et critique du COVID-19. De plus, certaines études en cours pourraient confirmer l’efficacité potentielle d’autres approches thérapeutiques comme les inhibiteurs de JAK ou les Ac anti-GM-CSF. L’implication des rhumatologues, en tant qu’experts des maladies inflammatoires et auto-immunes systémiques et des traitements immunomodulateurs est nécessaire dans le design des nouveaux essais cliniques et dans l’élaboration de nouvelles recommandations pour la prise en charge du COVID-19.

Background:Ultrasound (US) is an imaging adjunct to clinical joint examination adding sensitivity and objectivity to the assessment of inflammation. Previous studies in PsA have shown disparity between ultrasound and clinical findings with significant subclinical joint inflammation. A clinical challenge in PsA is to interpret tender joints (TJ) that are not swollen (SJ). As US is not widely used, alignment of clinical with US assessment is needed to determine its future role.Objectives:To determine how joint clinical examination relates to US findings in very early DMARD naïve PsA.Methods:Newly diagnosed DMARD naïve PsA patients, fulfilling CASPAR criteria, were recruited into the Leeds Spondyloarthropathy Register for Research and Observation (SpARRO), a prospective observational cohort study. US examination of 48 joints per patient was conducted by trained ultra-sonographers, blinded to clinical details with semi-quantitative scoring (0-3) for gray scale (GS) and power Doppler (PD). TJ and SJ counts were independently recorded. Cross-sectional baseline analysis was performed. The prevalence-adjusted and bias-adjusted kappa (PABAK) was calculated to determine agreements between clinical and US parameters. Spearman’s rank correlation coefficient was calculated to identify permutations of TJ/SJ correlating with GS ≥2, PD≥1 or both.Results:A total 5927 joints were scanned in 155 PsA patients. The mean age was 44.4 years, (SD 12.8), median disease duration 5.1 weeks (0.4-13.1); median TJC=7 (3-14) and SJC=2 (1-7). Oligoarthritis was present in 63.9% (99/155). US GS≥2 was frequently detected in the feet at MTPs1-4 (37.4- 53.6 %) and wrists (26.5- 33.6%). PD was most prevalent at wrists (17.5%) and MTP1 (12.6%) but observed less in other joints. Erosions were less frequent, the commonest site being MTP5 (17/310, 5.4%).Overall, SJ demonstrated high agreement (pTable 1.Agreement between TJ or SJ with GS≥2 & PD ≥1 and correlations for tender with/ without swollen combinations for right sided hand/feet joints.TenderSwollenT+ S-T+ S+Joint (Right)A (%)PABAKA (%)PABAKrrWrist75.50.51*89.10.78*-0.090.35*MCP184.10.68*87.50.75*0.090.44*MCP277.70.55*83.10.66*0.080.35*MCP379.10.58*84.50.69*0.0050.50*MCP478.40.57*86.40.72*0.070.22†MCP587.80.76*95.60.91*-0.030.49*MTP169.80.40*83.90.68*-0.03-MTP279.10.58*90.50.81*0.060.11MTP377.00.54*88.50.77*0.050.22‡MTP477.70.55*87.20.74*-0.0020.23‡MTP579.90.60*89.90.80*0.150.09T+= tender, S+ =swollen, S- = not swollen, A=agreement (%), r =coefficient, † pConclusion:Swollen joints demonstrate higher agreement with US synovitis (PD≥1 alone or GS ≥2 & PD ≥1 combined) than tender joints in early PsA. In addition, joints that are tender but not swollen have poor correlation with US synovitis at the individual joint level indicating that swelling is a better clinical discriminator of active synovitis, and factors other than synovial inflammation may drive tenderness in very early, DMARD naïve PsA. These results suggest re-appraisal of clinical joint counts is needed to refine treatment decision making in early PsA.Disclosure of Interests:Sayam Dubash: None declared, Oras Alabas: None declared, Xabier Michelena: None declared, Leticia Garcia-Montoya: None declared, Gabriele De Marco: None declared, Mira Merashli: None declared, Richard Wakefield Speakers bureau: Novartis, Janssen, GE, Philip Helliwell: None declared, Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC, Ai Lyn Tan: None declared, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB

Background:Dactylitis is a hallmark feature of Psoriatic arthritis (PsA) and Spondyloarthritis (SpA) defined as a uniform swelling of a digit (“sausage digit”). Dactylitis is associated with radiographic damage in chronic PsA. However, there are a paucity of data on the significance of dactylitis and its potential impact in disease burden in early PsA.Objectives:To characterize a very early DMARD naïve PsA cohort based on clinical presence or absence of dactylitis at disease onset.Methods:PsA subjects fulfilling the CASPAR classification criteria, were recruited into a prospective observational cohort, the Leeds Spondyloarthropathy Register for Research and Observation (SpARRO) after providing informed written consent. Clinical data including tender (TJC) and swollen joint counts (SJC) were independently assessed. Dactylitis was recorded per digit (finger or toe) as tender (hot) or non-tender (cold). Differences in baseline characteristics were evaluated using percentages to describe categorical variables and means and standard deviations for continuous variables, p value of the mean/proportion difference was calculated. Ultrasound (US) examination was conducted by trained ultra-sonographers blinded to clinical details. Bone erosions were defined on US if intra-articular discontinuity was present in two perpendicular planes at any of 46 joints: wrists, MCP1-5, PIP2-5, DIP2-5, MTP1-5, knees, ankles, subtalar, talonavicular.Results:A total of 177 PsA patients were recruited. Dactylitis was seen in nearly half the cohort [n=83 (47%)]. Patients with dactylitis had significantly more early morning stiffness, higher TJC and SJC, compared with non-dactylitis (Table 1). A total of 211 digits with dactylitis were recorded in 83 patients. Dactylitis of multiple digits was seen in 47/83 (57%) patients whilst a single dactylitic digit occurred in 36/83 (43%). Foot involvement was more prevalent (141/211, 67%) than hands (70/211, 33%). “Hot” or tender dactylitis was more frequently detected (153/211, 72.5%) than “cold” or non-tender dactylitis (58/211, 27.5%). The most prevalent sites for hot dactylitis were toes 2-4thand fingers 2-3rd.Table 1.VariableNo Dactylitis (n=94)Dactylitis (n=83)P valueAge, mean (SD) years44.4 (12.8)43.7 (13.2)>0.05Male38 (40.4%)42 (50.6%)>0.05Disease duration, median (IQR) weeks4.7 (0.0-11.4)5.2 (1-22.4)>0.05Early Morning stiffness, mean (SD) mins82.8 (145.4)170.5 (230.2)0.0025*TJC (78), mean (SD)8.3 (10.9)13.7 (14.0)0.004*SJC (76), mean (SD)2.2 (3.2)8.4 (8.0)Psoriasis94/94 (100.0%)76/83 (91.6%)0.004*PASI, mean (SD)3.6 (4.0)3.0 (4.1)>0.05Nail Dystrophy51/94 (54.3%)41/83 (49.4%)>0.05mNAPSI, mean (SD)4.9 (7.1)7.5 (14.0)>0.05MASES, mean (SD)1.6 (2.9)1.5 (2.4)>0.05BMI, mean (SD)29.1 (6.4)28.6 (5.6)>0.05Smoker19.0 (20.2%)9.0 (10.8%)>0.05Elevated CRP (>10 mg/L)24 (25.5%)36 (43.4%)>0.05PsAQoL, mean (SD)6.2 (6.6)6.2 (6.1)>0.05HAQ, mean (SD)0.79 (0.71)0.84 (0.65)>0.05US Erosions (n=154)12/83 (14.4%)21/71 (29.5%)0.023*US defined erosions were significantly more prevalent in the dactylitis group: 34 erosions in 21/71 patients (29.5%) versus 16 erosions in 12/83 (14.4%) patients in non-dactylitis. Sites prone to erosive damage in both groups were the wrists, MCP1,2 and MTP4,5. The right MCP2 (n=6) and MTP5 (n=6) were most commonly eroded in the dactylitis group, but erosions corresponding at the dactylitic digit level were overall low.Conclusion:This study identifies a more severe phenotype in very early DMARD naïve PsA presenting with dactylitis with higher prevalence of ultrasound erosions. Longitudinal follow up will determine whether dactylitis represents a poor prognostic factor in very early PsA, which may be a useful discriminator for risk stratification in future PsA management recommendations.Disclosure of Interests:Sayam Dubash: None declared, Oras Alabas: None declared, Xabier Michelena: None declared, Gabriele De Marco: None declared, Leticia Garcia-Montoya: None declared, Richard Wakefield Speakers bureau: Novartis, Janssen, GE, Ai Lyn Tan: None declared, Philip Helliwell: None declared, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC, Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB

Background:Enthesitis is a key musculoskeletal manifestation of psoriatic arthritis (PsA). EULAR guidelines recommend biologics for patients with enthesitis and an inadequate response to or intolerance of nonsteroidal anti-inflammatory drugs, although no guidance on specific biologics is offered. In the EXCEED head-to-head, double-blind study (NCT02745080), secukinumab (SEC) and adalimumab (ADA) showed a similar efficacy in joints and in resolution of enthesitis at Week 52 for patients with PsA,1 although a detailed analysis of enthesitis was not conducted.Objectives:To explore detailed enthesitis treatment response, including temporal and additional enthesitis assessment data, in patients with PsA treated with SEC or ADA over 52 weeks.Methods:In this post hoc analysis, patient data from EXCEED were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Baseline characteristics of these groups were summarized. Median time to resolution of LEI/SPARCC enthesitis score in patients receiving SEC or ADA was assessed using Kaplan-Meier analysis. Efficacy was further assessed among the enthesitis subset by LEI and SPARCC change from baseline, resolution of enthesitis (LEI/SPARCC) at Weeks 24 and 52, and resolution of enthesitis at Week 52 by baseline enthesitis severity. Relapse of enthesitis after a first resolution was evaluated at Weeks 24 and 52. Missing data were imputed by nonresponder imputation.Results:Baseline demographics were well balanced in the LEI/SPARCC enthesitis subsets, although a higher proportion of all patients with enthesitis were women vs those with no enthesitis (LEI: 54.6% vs 40.5%; SPARCC: 53.2% vs 36.2%). Patients with baseline enthesitis had higher disease activity vs patients without enthesitis (LEI/SPARCC enthesitis vs no LEI/SPARCC enthesitis: tender joint count of 78 joints [22.8/22.1 vs 15.8/13.8], Health Assessment Questionnaire-Disability Index [1.3/1.3 vs 1.1/1.1], and mean Psoriasis Area and Severity Index [6.4/6.1 vs 5.1/5.3]). Median time to resolution of LEI and SPARCC enthesitis was similar between patients receiving either SEC or ADA (Table 1). Both treatment groups experienced a similar mean change from baseline in LEI and SPARCC enthesitis counts and a similar resolution of LEI and SPARCC at Weeks 24 and 52 (Table 1). Achievement of enthesitis resolution was similar between treatment groups irrespective of disease severity (Figure 1). The proportion of patients who experienced relapse after achieving resolution was low across both treatments (Table 1).Conclusion:In EXCEED, patients with baseline enthesitis presented with higher disease burden, consistent with the FUTURE trials.2 SEC and ADA showed similar kinetics of response and efficacy on enthesitis, irrespective of baseline enthesitis severity.References:[1]McInnes IB, et al. Lancet. 2020;395(10235):1496-1505.[2]Coates LC, et al. Arthritis Res Ther. 2019;21(1):266.Table 1.Clinical Improvements Among Patients With Baseline LEI or SPARCC Enthesitis Treated with Secukinumab or Adalimumab (nonresponder imputation)Secukinumab300 mgAdalimumab40 mgOutcomesaLEI(n=234)SPARCC(n=301)LEI(n=264)SPARCC(n=331)Baseline enthesitis count, mean (SD)2.6 (1.5)5.0 (3.8)2.8 (1.6)5.4 (4.0)Median time to enthesitis resolution, days (95% CI)85 (57–113)113 (85–169)85 (57–86)88 (85–114)Enthesitis count, mean improvement from baseline (SD) Week 24−1.6 (1.6)−3.3 (3.5)−1.6 (1.6)−3.1 (3.5) Week 52−1.8 (1.6)−3.6 (3.2)−2.1 (1.7)−3.9 (3.8)Resolution of enthesitis, n (%) Week 24116 (49.6)138 (45.8)115 (43.6)144 (43.5) Week 52142 (60.7)160 (53.2)146 (55.3)170 (51.4)Enthesitis relapse, n/M (%) Week 2437/210 (17.6)38/274 (13.9)49/232 (21.1)47/293 (16.0) Week 5240/208 (19.2)56/267 (21.0)32/208 (15.4)41/263 (15.6)LEI, Leeds Enthesitis Index; M, number of evaluable patients; SPARCC; Spondyloarthritis Research Consortium of Canada Enthesitis Index.a Based on respective enthesitis measures.Figure 1.Acknowledgements:This study was funded by Novartis Pharma AG. The authors thank Richard Karpowicz, PhD, of Health Interactions, Inc, for providing medical writing support/editorial support, which was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).Disclosure of Interests:Gurjit S. Kaeley Consultant of: Novartis Pharmaceuticals Corporation, Georg Schett Speakers bureau: AbbVie, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, and Pfizer, Consultant of: AbbVie, Bristol Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, and UCB, Grant/research support from: Bristol Myers Squibb, Celgene, GSK, Eli Lilly, and Novartis, Philip G Conaghan Consultant of: or Speakers bureau: AbbVie, AstraZeneca, Bristol Myers Squibb, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, Gilead, Novartis, and Pfizer, Grant/research support from: UK National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Dennis McGonagle Speakers bureau: Roche, Sobi, and Novartis, Grant/research support from: Novartis, Frank Behrens Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, Merck Sharp & Dohme, Celgene, Roche, and Chugai, Grant/research support from: Pfizer, Janssen, Chugai, Celgene, and Roche, and has received investigator fees from Eli Lilly, Philippe Goupille Grant/research support from: and/or Consultant of/Speakers bureau: AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celgene, Chugai, Janssen, Lilly, Medac, Merck Sharp & Dohme, Nordic Pharma, Novartis, Pfizer, Sanofi, and UCB, Corine Gaillez Employee of: Novartis Pharma AG, Bhumik Parikh Employee of: Novartis Pharmaceuticals Corporation, Xiangyi Meng Employee of: Novartis Pharmaceuticals Corporation, Catherine Bakewell Consultant of: and/or Speakers bureau: AbbVie, Novartis, Pfizer, Janssen, UCB, and Sanofi Genzyme/Regeneron

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Rheumatologists have the best experience of studying and treating these complicated hyperinflammatory processes.Objectives:To summarize the available information on pathophysiology of COVID-19.Methods:As part of a EULAR taskforce, two systematic literature reviews were performed one on pathophysiology and one on immunomodulatory therapies. Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection; I (intervention): any intervention/no intervention; C (comparator): any comparator; O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration. The results pertaining to pathophysiology of COVID-19 are presented here.Results:Of the 55496 records yielded, 85 articles were eligible for inclusion. Included studies were at variable risk of bias and exploring various aspects of disease pathogenesis from immune to non-immune cells (Table 1). Pro-inflammatory cytokines’ expression including IL-6, was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. Innate and adaptative immune cell compartments were differentially affected by SARS-CoV-2 infection: neutrophils displayed an immature differentiation state and also increased neutrophil extracellular traps (NETs) formation. Dendritic cell number was reduced and classical monocytes was increased although displaying a reduced expression of HLA-DR. The lymphoid compartment was also affected: lymphopenia was present with a reduced number of CD4+ and CD8+ T lymphocytes and more frequent PD1+CD8+ T cells corresponding to an exhausted phenotype. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalization, disease progression or severity, and mortality. Differences in SARS-CoV-2 manifestations in adults and children were highlighted.Conclusion:Overall, SARS-CoV-2 infection affects both innate and adaptative immune responses in a variable way, according to both disease severity and individual parameters. This SLR informs the EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.Table 1.Studies on SARS-CoV-2 infection pathogenesisResearch questionNCytokines profile7Immune profile18Algorithm17Children3Comorbidities1Endothelial dysfunction and platelets8Gut and microbiota3Genetics and variants8Histology7Antibodies profiles8Viral load and immune response4Interferon3Immunosenecsnce3Total90**Some manuscripts were including in several research questions. Total number of studies included n=85.Disclosure of Interests:Aurelie Najm Speakers bureau: BMS, Consultant of: BMS, Alessia Alunno: None declared, Xavier Mariette Speakers bureau: BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, Consultant of: BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, Benjamin Terrier Speakers bureau: Roche, Chugai, Vifor Pharma, GSK, AstraZeneca, Terumo BCT, LFB and Grifols, Consultant of: Roche, Chugai, Vifor Pharma, GSK, AstraZeneca, Terumo BCT, LFB and Grifols, Gabriele De Marco: None declared, Laura Mason: None declared, Jenny Emmel: None declared, Dennis McGonagle Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, Pedro M Machado Speakers bureau: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, Consultant of: Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB.

Background & Aim Synovial fluid contains resident mesenchymal stem cells (SF-MSCs) that are derived from the synovial membrane and may interact with superficial cartilage injury sites . We previously reported novel methodology for increasing the number of MSC in knee joints using synovial brushing and of platelet lysate (PL) as chondrogenic inducer [1, 2]. The purpose of this study was to evaluate autologous and allogenic PL as chondrogenic inducer and the chondrogenic potential of the mobilised MSCs without resort to in vitro expansion. Methods, Results & Conclusion SF-MSCs were derived from joint cavity of patients undergoing arthroscopy procedures.Autologous blood was processed through platelet concentrating device HemaTrate (HT) to produce platelets concentrate (PC). For the mechanical release of MSCs‘before’ and ‘after’ brusing samples of irrigation fluid were collected and MSCs numbers were evaluated CFU-F assay and flow cytomery.Standard chondrogenic assay was performed on uncultured and cultured synovial cells. Pellet cultures were maintained in complete chondrogenic media (CCM), DMEM+50% of autologous PC,50% Stemulate (allogeneic PL) or expansion media (control). Chondrogenesis was assessed by Glycosaminoglycan (GAG) and Toluidine blue staining. The HT device significantly concentrated platelets and WBCs by 6 P 0.5. Unculturedsynovial cells produced significantly more GAG when cultured in CCM or DMEM+50% autologous PC compared to control P Conclusion: Autologous PC can be used as chondrogenic inducer for uncultured SF-MSCs. Sufficient cells can be released mechanically to be subjected to chondrogenic induction with significant chondrogenic activity without the need of culture expansion. This suggests possibility of one stage arthroscopy procedures for cartilage repair.

Background:Upadacitinib (UPA), an oral JAK inhibitor selective for JAK1, demonstrated efficacy in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to nonsteroidal anti-inflammatory drugs (NSAID) therapy in the SELECT-AXIS 11 trial.Objectives:To identify pathways modulated by UPA in AS patients with emphasis on those associated with response to treatment.Methods:A subgroup of patients from the SELECT-AXIS 1 study, with available baseline and at least one follow up plasma sample during the placebo-controlled period, were selected for analysis (PBO, n= 65; UPA 15 mg QD, n=63). The levels of 92 inflammation related protein biomarkers (BioMs) were analyzed using the Olink® platform; change from baseline were expressed as Log2 Fold Change; a repeated measure mixed linear model identified BioMs differentially modulated by UPA. Relationship between change in BioMs and change in clinical disease activity measures were derived using Pearson’s correlation (ASDAS-CRP, BASDAI, and CRP) and Spearman’s correlation (MRI Spine SPARCC). Pathway analysis was performed with Ingenuity® Pathway Analysis (Qiagen Inc.).Results:Treatment with UPA 15 mg QD reduced the levels of BioMs associated with IFN, IL6, T Cells, M1 or “inflammatory” Macrophages, and Dendritic Cells (DC); and increased those of BioMs associated with tissue repair and hematopoiesis. The type of pathways, inferred in silico based on BM data, suggests that UPA exerts broad inhibitory activity directly on multiple JAK1-dependent (IFNα/β, IFNγ, IL6, IL2, IL5, IL7, and OSM) and indirectly on JAK1-independent upstream pathways (IL1, IL23, IL17, IL18, and TNFα), resulting in the inhibition of key functional pathways such as leukocyte activation and mobility, inflammatory response, and damage to connective tissue. Improvement in ASDAS-CRP, BASDAI, and MRI spine SPARCC correlated with increase in BioMs associated with tissue repair (FGF5, DNER [Delta/Notch Like EGF Repeat Containing]) and hematopoiesis (FLT3LG,and SCF/KITLG), while improvement in ASDAS-CRP and CRP correlated with decrease in CCL23, CSF1, IL-6, and MMP1; and reduction in only CRP correlated with decrease in IFN- and of TNFα-related BioMs (Data tables will be presented).Conclusion:Treatment of NSAID-IR AS patients with UPA 15 mg QD resulted in the coordinated decrease in multiple BioMs associated with the innate and adaptive immune responses, and in the increase in BioMs generally associated with tissue repair and hematopoiesis. In silico pathway prediction indicates that treatment with UPA directly inhibits JAK1-dependent and indirectly JAK1-independent pathways, resulting in the down modulation of functional pathways related to inflammation and tissue damage which are known to be dysregulated in AS2. Based on this observation and on the correlation of change in BioMs with change in clinical measures, we hypothesize that both increase in BioMs associated with tissue repair and hematopoiesis, and decrease in BioMs associated with inflammation may contribute to the clinical activity of UPA in AS patients.References:[1]van der Heijde, D. et al. Lancet 394, 2108-2117 (2019).[2]Stoll, M.L. Clin Exp Rheumatol 29, 322-330 (2011).Acknowledgements:AbbVie, Inc was the study sponsor, contributed to the study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of the final versionDisclosure of Interests:Thierry Sornasse Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie, Timothy Radstake Shareholder of: AbbVie, Employee of: AbbVie, Dennis McGonagle Speakers bureau: AbbVie, Grant/research support from: AbbVie

Background:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, a deleterious aberrant non-effective host immune response plays an important role especially in severe forms of COVID-19. There is intense investigation to explore the utility of immunomodulatory drugs commonly used in the Rheumatology arena as agents that may mitigate against COVID-19 to improve disease prognosis. Rheumatologists are used to the utilization of these immune targeted therapies.Objectives:To summarize the available information on the use of immunomodulatory agents in severe COVID-19.Methods:As part of a EULAR taskforce, a systematic literature search was conducted from January 2019 up to December 11, 2020. Two reviewers independently identified eligible studies according to the PICO framework P (population): patients with SARS-CoV-2 infection; I (intervention): any immunomodulator agent/strategy; C (comparator): any comparator; O (outcome) any clinical outcome including but not limited to mortality, admission to intensive care unit and clinical improvement. Data on efficacy and safety of immunomodulatory agents utilized therapeutically in SARS-CoV-2 infection at any stage were extracted. The risk of bias was assessed using validated tools.Results:Of 60372 records, 401 articles were eligible for inclusion. Studies were at variable risk of bias. Randomised controlled trials (RCTs) were available for the following drugs: hydroxychloroquine (N=12), glucocorticoids (N=6), tocilizumab (N= 4), convalescent plasma (N=4), interferon beta (N=2), IVIg (N=2) and N=1 each for anakinra, baricitinib, colchicine, leflunomide, ruxolitinib, interferon kappa, and vilobelimab. For glucocorticoids, dexamethasone reduced mortality only in patients requiring respiratory support; while methylprednisolone reduced mortality in patients aged 60 years or over. Data from RCTs on tocilizumab are conflicting and definite conclusions cannot be drawn at this point in time, but recent studies suggest possible benefit in patients requiring respiratory support. Hydroxychloroquine was not beneficial at any disease stage, one RCT with anakinra was negative, one RCT with baricitinib+remdesivir was positive, and individual trials testing some other compounds provided interesting, albeit preliminary, results.Conclusion:Although there is emerging evidence about immunomodulatory therapies for the management of COVID-19, conclusive data is scarce with some conflicting data. Since glucocorticoids seem to improve survival in some subsets of patients, RCTs comparing glucocorticoids alone versus glucocorticoids plus anti-cytokine/immunomodulatory treatment are warranted. This SLR informed the initiative to formulate EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.Figure 1.Forest plots showing the risk ratio (RR) and 95% confidence interval for mortality in randomized controlled trials divided by intervention. The latest follow-up available is reported in the timing column.Disclosure of Interests:None declared

Background:Guselkumab (GUS), a novel monoclonal antibody that specifically binds to the p19-subunit of IL-23, demonstrated efficacy in the Ph 3 DISCOVER-1 (D1) & DISCOVER-2 (D2) trials of pts with active psoriatic arthritis (PsA).1,2Dactylitis & enthesitis, key PsA clinical manifestations, can be difficult to treat and may portend more significant disease burden.3,4Objectives:In pts with dactylitis or enthesitis at baseline, assess: 1) changes in symptoms over time and 2) relationships between improvements in dactylitis or enthesitis and other PsA domains.Methods:Adults with active PsA despite standard therapies were eligible for D1 & D2. Approx. 30% of D1 pts previously received 1-2 TNF inhibitors; D2 pts were biologic-naïve. Pts were randomized 1:1:1 to GUS 100mg Q4W; GUS 100mg at W0, W4, Q8W; or PBO. Independent assessors evaluated dactylitis (total score: 0-60) & enthesitis (Leeds Enthesitis Index [LEI]; total score 0-6). Dactylitis and enthesitis findings through W24 were prespecified to be pooled across D1 & D2. P-values are unadjusted. We assessed changes in dactylitis and LEI scores over time (ANCOVA); associations between dactylitis or enthesitis resolution and ACR/PASI responses at W24 (Chi-square); and correlations between dactylitis or LEI and HAQ-DI/SF-36 change scores at W24 (Spearman’s correlation). AEs through W24 were reported.1,2Results:At W0, 42% of pooled D1+D2 pts had dactylitis; 65% had enthesitis. GUS improved dactylitis and LEI scores vs PBO at W8, W16, W24. GUS vs PBO differences were significant for dactylitis changes at W16 & W24 and LEI changes at W8 (Q4W only), W16 & W24; no dose response was observed (Fig). Rates of dactylitis or enthesitis resolution by W24 were consistently significantly (pTable). In GUS-treated pts at W24, significant correlations were observed between dactylitis change scores and PASI (pConclusion:In PsA pts with dactylitis or enthesitis at W0, GUS improved dactylitis or LEI scores vs PBO by W8; treatment differences were significant at W16 & W24. Resolution of dactylitis or enthesitis was significantly associated with clinically meaningful improvements in PsA joint & skin symptoms. Improved dactylitis scores correlated with improved skin symptoms and mental health; improved LEI scores correlated with improved physical function.References:[1]Deodhar A (A#807),[2]Mease P (A#L13), Arthritis Rheumatol 2019;71(suppl 10);[3]DOI: 10.1186/s13075-017-1399-5;4DOI: 10.1016/j.semarthrit.2018.02.002Table.Pooled DISCOVER-1&2: associations between dactylitis/enthesitis resolution and joint/skin responseACR20ACR50ACR70PASI75aPASI90aDactylitis resolutionbN%pts%pts%ptsN%pts%pts Q4W37355*34*16*12178*55* Q8W37553*31*16*11680*65* PBO37226*12*5*11519*10*Enthesitis resolutionc Q4W24334*31*11*18782*63* Q8W23040*7*12*16277*62* PBO25514*13*5*18219*9** p < 0.001 (Chi-square)aIn pts with ≥3% BSA psoriasis & IGA ≥2 at W0bIn pts with D at W0cIn pts with E at W0Acknowledgments:NoneDisclosure of Interests:Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Atul Deodhar Grant/research support from: AbbVie, Eli Lilly, GSK, Novartis, Pfizer, UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myer Squibb (BMS), Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, May Shawi Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shelly Kafka Employee of: Janssen Scientific Affairs, LLC, Chetan Karyekar Shareholder of: Johnson & Johnson, Consultant of: Janssen, Employee of: Janssen Global Services, LLC. Previously, Novartis, Bristol-Myers Squibb, and Abbott Labs., Alexa Kollmeier Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shihong Sheng Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Prasheen Agarwal Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Bei Zhou Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Christopher T. Ritchlin Grant/research support from: UCB Pharma, AbbVie, Amgen, Consultant of: UCB Pharma, Amgen, AbbVie, Lilly, Pfizer, Novartis, Gilead, Janssen, Proton Rahman Grant/research support from: Janssen and Novartis, Consultant of: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, and Pfizer., Speakers bureau: Abbott, AbbVie, Amgen, BMS, Celgene, Lilly, Janssen, Novartis, Pfizer

Background IL-23 is a cytokine heavily implicated in the immunopathology of both psoriasis and psoriatic arthritis. Emerging evidence suggest IL-36λ, a novel inflammatory cytokine which has been heavily implicated in psoriatic immunopathology, is able to stimulate the release of IL-23.1–3 PDE4 inhibitors, which elevate cyclic AMP (cAMP) are known to exert anti-inflammatory effects by regulating transcription factors such as NF-κB. The PDE4 inhibitor, Apremilast has proved successful in treating both psoriasis and psoriatic arthritis with patients showing a decrease in inflammatory cytokine levels, including IL-23.4 However, the ability and mechanism of PDE4 inhibitors to lower IL-23 secretion from immune cells induced by disease relevant stimuli is presently unknown. Additionally, any potential relationship between IL-36λ driven inflammation and potential PDE4 inhibition is yet to be determined. Methods Blood mononuclear cells from healthy patients, (n=5) were pre-treated with either the PDE4 inhibitor Rolipram or other compounds known to elevate cAMP levels, such as histamine and 8-bromo-cAMP. Cells were subsequently treated with either bacterial or fungal toll like receptor adjuvants (LPS and Mannan) or the novel psoriatic cytokine IL-36λ. IL-23 was subsequently measured in culture supernatants by ELISA and by intracellular IL-23p19 flow cytometry. Results LPS, Mannan and IL-36λ all induced IL-23 secretion which could be attenuated in a dose dependent manner by the PDE4 inhibitor, Rolipram. Other compounds also known to increase cAMP levels, histamine and 8-bromo-cAMP similarly were able to reduce IL-23 secretion from all stimuli. Conclusions This data suggests a direct link between PDE4 inhibition and reduced IL-23 secretion in circulating immune cells. Additionally, it provides insight into of how IL36/IL-23/IL-17 driven inflammation may be reduced by PDE4 inhibitors in psoriasis and psoriatic arthritis. References [1] Gabay C, Towne JE. Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J Leukoc Biol2015;97(4):645–652. [2] Chi HH, et al. IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis. J Am Soc Nephrol2017;28(7):2022–2037. [3] Bridgewood C, et al. IL-36γ is a strong inducer of IL-23 production and angiogenesis in psoriasis. Frontiers in Immunology2018;9:200. [4] Keating GM. Apremilast: A Review in Psoriasis and Psoriatic Arthritis. Drugs2017;77(4):459–472. Disclosure of Interest None declared

Background The Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) share common aetiopathogenetic and clinical manifestations. Vedolizumab, a humanised IgG1 monoclonal antibody to α4β7 integrin, has been approved for the treatment of inflammatory bowel disease (IBD) and inhibits α4β7 integrin at the gut level. Vedolizumab therapy for IBD has been associated with mild SpA related features including sacroiliitis and synovitis. Herein, we report the emergence of severe SpA under therapy with Vedolizumab. Objectives We conducted a clinical evaluation of 7 vedolizumab treated patients with IBD that developed severe active SpA and/or enthesopathy with the aim of characterising the vedolizumab associated SpA/entheseal flares. Methods Vedolizumab treated IBD patients with SpA/enthesopathy were identified across four hospitals. We identified clinical, biochemical and imaging characteristics within routine case records as part of a clinical evaluation. Results We identified 6/7 subjects that developed de novo SpA/enthesopathy and 1/7 (subject 1) with a severe flare of pre-existing SpA. There were 3/7 patients hospitalised due to the severity of skeletal disease. The median time from vedolizumab initiation to flare was 10 weeks (table 1 below). Subject 4 developed new-onset SpA with severe spinal vertebral end-plate oedema (T6–12) and inflammatory Romanus lesions (L3–4) (image below). Acute sacroiliitis was identified on MRI in 3 subjects, one of which showed evidence of radiographic bilateral grade 2 sacroiliitis. In at least 4 cases the IBD disease activity was considered to be low or well controlled. Following vedolizumab discontinuation, so far 3 patients have switched to alternative biologic therapies including certolizumab pegol, golimumab, and 1 subject to sulphasalazine. cpd=cigarettes per day, MTX=methotrexate, AZA=azathioprine, OC=oral corticosteroid, Pred=prednisolone, nr=non radiographic, MRI+ve= MRI positive, XR +ve = radiograph positive, NA=not available. Conclusions This case series demonstrates severe vedolizumab associated SpA/enthesopathy that resulted in hospitalised cases. The severity of vedolizumab related SpA flares is relatively severe disease in comparison to the literature. We recognise that vedolizumab is efficacious in IBD, however our observations highlight the need to monitor symptoms to identify patients that develop axial or peripheral SpA several weeks from commencing vedolizumab. Disclosure of Interest None declared

Background The use of magnetic resonance imaging (MRI) has been instrumental in the early recognition and characterisation of axial spondyloarthritis (axSpA). However, a recent survey in the UK showed that there is diverse practice in the use of MRI and limited knowledge of MRI features suggestive of axSpA among radiologists.1 Objectives To develop clinical practice recommendations for the acquisition and interpretation of MRI of the spine and sacroiliac joints (SIJs) in the investigation of axSpA through a collaboration between rheumatologists and radiologists. Methods A working group comprising 9 rheumatologists and 9 musculoskeletal radiologists with an interest in axSpA was established. The EULAR standardised operating procedures were followed.2 Two working group meetings were held, the first to define the scope of the exercise and the second to review the results of the Systematic Literature Review that informed the recommendations. An anonymised Delphi process was used to formulate the final set of recommendations. The level of evidence and strength of recommendation was added to the recommendations. The level of agreement by working group members was assessed using a numerical rating scale. Results A total of 2 overarching principles and 7 recommendations were formulated (figure 1). The first 3 recommendations address the MRI acquisition protocol, namely anatomical areas to be scanned and sequences to be used. The remaining 4 recommendations address the interpretation of active and structural lesions of the spine and SIJs. Conclusions A UK joint rheumatology and radiology consensus on the most appropriate MRI acquisition protocol and interpretation of images in the investigation of axSpA was achieved. This consensus will help standardise practices and ensure prompt and effective patient management in the diagnosis and treatment of axSpA. References [1] Bennett, et al. J Rheumatol2017. [2] van der Heijde, et al. Ann Rheum Dis2015. Acknowledgements This work was financially supported by the British Society for Spondyloarthritis (BRITSpA). Disclosure of Interest None declared

Background: Recently Ustekinumab, an IL12/23 p40 monoclonal antibody that is licensed for Psoriatic Arthritis and Psoriasis, showed promising results in phase II trials in SLE- a prototype IFN mediated disease. We previously confirmed a novel IFN gene scoring system associated with the different SLE symptoms (manuscript in review). Additionally, we also recently validated in two independent cohorts the value of BST2/ tetherin as IFN-I biomarker assay correlates with clinical activity and predicts clinical flare in SLE. Given that psoriasis has several SNPs in the IFN pathway; Thus mechanistic studies of the effect of Ustekinumab on the IFN pathway can be explored in this disease setting. Objectives: This work tested the hypothesis that a novel interferon type I (IFN-I) status markers in the blood and skin of Ustekinumab treated psoriasis patients might correlate with therapy responses and provide insights into how p40 blockers may affect IFN pathways in a relevant human disease model. Methods: Skin biopsies and peripheral blood at baseline (before therapy, 24weeks, 54 weeks) from 23 Ustekinumab patients with psoriasis who had ultrasound imaging confirmed subclinical enthesopathy) were recruited. Cellular immunophenotyping was performed using multi-parameter flow cytometry to detect tetherin on (Monocyte, B cells, T cells and neutrophils). All data was compared to age-matched samples from healthy controls (HC). Skin biopsies were digested and RNA extracted, qPCR of common ISGs genes were analysed in lesional and peri-lesional at corresponding time points. Results: Tetherin showed a higher level of expression on blood subsets of psoriasis compared to HC at baseline on Monocytes, T cells, NK cells and B cells (p=0.003, =0.005, =0.035, =0.002) compared to the baseline. No significant changes observed between baseline and 2nd visit 24 weeks. Interestingly, a substantial reduction in tetherin expression at (52 weeks) in psoriasis was observed in all subsets in Monocytes, T cells, NK cells and B cells (all p Conclusions: Psoriasis which is genetically and mechanistically linked to IFN-I signatures shows responses to Ustekinumab therapy that correlate with improvement in IFN-I signatures in blood and tissues. Given that whole blood ISG signatures were complex and weakly correlating with disease activity. We provide a convenient, validated method to analyse IFN pathway in routine clinical practice using tetherin which could be a future research tool for the cell-specific IFN-I response. These studies support the idea that p40 efficacy in psoriasis is associated with IFN-I pathway modulation and relevant for exploring how p40 blockers may exert potential benefit in SLE. References 1. Krueger, et al. N Engl J Med. 2007Feb 8;356(6):580–92. Disclosure of Interest: None declared

Background Many patients with hand osteoarthritis (OA) have little symptoms. Bone oedema and synovitis have been associated to pain in OA, but inflammation involving ligaments has not been studied, likely limited by inadequate MRI resolution. We have previously found significant ligament pathology in early and established hand OA (HOA) [1]. Objectives We hypothesise that the well innervated ligaments are key to a better understanding of the relationship between joint structure and pain in HOA. This research aims to see if small joint collateral ligament abnormalities are worth exploring further in relationship to pain in HOA. Methods High-resolution contrast enhanced MRI of 26 joints in 15 patients (mean (SD) age 58.3 (8.2), 13F:2M) and 10 in 5 healthy controls (age 38 (5.6); 4F:1M) were scanned using a microscopy MRI coil. 15 joints in 8 patients were painful [median (IQR) pain VAS 4 (3, 7)). Joints were scored blinded to clinical data for joint fluid, capsule/synovitis, extracapsular oedema, collateral ligament thickening/oedema/degeneration, extensor and flexor tendons, bone oedema and cysts. All structures were graded 0–3 for normal, mild, moderate, severe, as defined in OMERACT HOAMRIS where available [2]. Proportions of joints with any level of abnormality (score>0) were calculated according to pain status (present/absent). Results All OA patients with and without pain had ligament abnormalities. Substantive differences in proportion of joints between healthy controls and OA patients were seen for all pathologies except tendons (no tendon abnormalities were found in all groups). Proportions of joints with capsular/synovium, extra capsular changes and proximal cysts differed between OA joints with and without pain but no substantive differences in pathology score were found. Of painful joints, 93% (14) had both ligament and capsular/synovium or extracapsular abnormality present, compared to 45% (5) of non-painful joints. Conclusions Modifiable abnormalities involving capsular/synovium and extracapsular areas may be more frequently seen in painful OA joints. The presence of collateral ligament abnormalities in HOA joints, whether painful or not, suggest that the severity of ligament abnormalities in small joint OA and the degree of pain may be an important area to investigate further. References Tan AL, et al. Ann Rheum Dis. 2006 Oct;65(10):1267–72. Haugen IK, et al. J Rheumatol. 2014 Feb;41(2):386–91. Acknowledgements Funded by NIHR. Disclosure of Interest None declared

Background Nerve growth factor (NGF) is a key regulator of pain and anti-NGF therapy reduces osteoarthritis (OA) associated pain. However, anti-NGF therapy is associated with rapidly progressive OA (RPOA) [1]. In hip OA there is a 5-fold increase in mesenchymal stem cells (MSCs) from MRI bone marrow (BM) lesions, areas associated with OA progression [2]. MSCs in such lesions are uniformly positive for the NGF receptor, p75, which is also linked to chemotaxis and proliferation in other stromal cell compartments [3]. Objectives Evaluate anti-NGF treatment in monoiodoacetate (MIA) induced OA and test whether NGF influences human BM-MSC function. Methods Human tibial plateau (TP) bone was isolated from patients undergoing total knee replacement. OA was induced in male Wistar rats (n=6) by intra-articular injection of 0.3 mg MIA. Each animal was treated with subcutaneous injection of control human IgG or anti-NGF (3 mg/kg) at Days 5, 10 and 15. Human and animal tissues sections were prepared for histological analysis using H&E staining and immunohistochemistry (IHC) using anti-p75 and anti-NGF antibodies. BM-MSCs were isolated from iliac crest aspirates and cultured under normal conditions. Expression of p75 was induced following overnight incubation with 400mM ethanol (EtOH) and confirmed by flow cytometry. Proliferation was assessed ± EtOH and 0–1 μg/ml NGF. Results Regions adjacent to cartilage loss in human TP showed abundant stromal proliferation, NGF and p75 immunoreactivity. In MIA model, by Day 18 there was substantial loss of cartilage, bone remodelling and stromal proliferation mimicking human disease. By Week 4 animals demonstrated unequal weight-bearing (p To investigate increased p75 positivity in knee OA, we restored p75 expression loss in expanded cell, to 97% of BM-MSCs (n=3) using EtOH. Increased MSC proliferation was seen at Days 6 and 9 (26%, p=0.03 and 30%, p=0.01 increase respectively, n=7) for 1 μg/ml NGF in the presence of EtOH compared to control (no NGF). In cultures without EtOH induction (absent p75) NGF had no effect. Conclusions TP bone from OA patients and rat MIA-treated subchondral bone contains p75 positive staining in regions of cartilage destruction and associated NGF positivity. Anti-NGF treatment exacerbated MIA-induced OA and reduced NGF and p75 expression. In vitro, NGF increased BM-MSC proliferation, suggesting NGF may be involved in the stromal proliferation seen at sites of OA damage. Thus, NGF may regulate MSC function. Complete blockade represents a novel mechanism for accelerated joint destruction in OA. References Hochberg MC et al. Arthritis Rheumatol 2016. Campbell TM et al Arthritis Rheumatol 2016. Jiang Y, et al. Cartilag Arthritis Res Ther 2015. Disclosure of Interest T. Baboolal: None declared, S. Al Hinai: None declared, E. Jones: None declared, J. Reckless Employee of: Rxcelerate Ltd, M. Foster Consultant for: Levicept Ltd, R. Doyle Employee of: Tetrad Discovery Ltd, K. af Forselles Consultant for: Levicept Ltd, S. Westbrook Shareholder of: Levicept Ltd, Employee of: Levicept Ltd, D. McGonagle: None declared

Background Both synovial and related synovial fluid-derived mesenchymal stem cells (SF-MSC) are highly proliferative and chondrogenic and have direct access to superficial cartilage injuries [1]. Human platelet lysate (PL) is being increasingly used for joint regenerative approaches [2,3] but the biological basis for in vivo effect, if any is lacking. Objectives The study evaluated the effect of PL on adhesion, proliferation, migration and trilineage differentiation of synovial cavity derived MSCs in comparison to “gold standard” foetal calf serum (FCS) based stem cell media. Methods MSCs were derived from joint cavity washout in patients undergoing anterior cruciate ligament reconstruction or meniscal repairs. Cells were plated in StemMACS (FCS media) or with DMEM Supplemented with 10% Stemulate (PL media, Cook Regentec). Standard MSC proliferation, trilineage differentiation assays, and transwell migration assays were performed for both conditions. Results PL enhanced MSC colonies sizes (CFU-F) by 2.5 folds compared to FCS (p=0.0023, n=5). PL shortened MSC doubling times (p=0.0411, n=6). However, PL had no impact on CFU-F numbers (p=0.5973, n=5). In transwell migration assays, MSC migration was significantly increased toward 10%PL compared to 10%FCS (p=0.0286, n=6). Under standard chondrogenic induction conditions, PL-expanded MSC showed 30% more sulphated GAG (sGAG) production compared to FCS-expanded cells (n=4). In osteogenic and adipogenic induction, Alizarin red staining Ca++ assay and Nile Red showed no significant difference compared to FCS expanded cells (p=0.3429, n=4). Interestingly, replacing TGFbβ with 20% PL was as good as standard chondrogenic media and with increasing PL percentage sGAG production increased (n=4). In same time using PL with high glucose media in 1:1 ratio was efficient to produced sGAG as compared to negative control (media only) (p=0.0286, n=4, figure 1). Moreover, substituting FCS with PL in the osteogenic media resulted in increased Ca++ deposition in both PL and FCS expanded cells by 90% and 100% compared standard osteogenic media. Conclusions This is the first study that assessed joint cavity MSC responses to PL. All aspects of joint cavity derived MSC biology towards cartilage repair were augmented in vitro with PL based media over “gold standard” MSC media. This work provides biological plausibility for the combination of PL with joint resident MSC towards endogenous joint repair strategies. References Jones, E.A., et al., Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level. Arthritis Rheum, 2008. 58(6): p. 1731–40. Morito, T., et al., Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford), 2008. 47(8): p. 1137–43. Ben Azouna, N., et al., Phenotypical and functional characteristics of mesenchymal stem cells from bone marrow: comparison of culture using different media supplemented with human platelet lysate or fetal bovine serum. Stem Cell Res Ther, 2012. 3(1): p. 6. Disclosure of Interest None declared

Background Ustekinumab1 targets the common p40 sub-unit of interleukin-12 (IL-12/interleukin-23 (IL-23). In patients treated with Ustekinumab for psoriasis where patients were selected on the basis of subclinical imaging enthesopathy, we have noted an improvement in subclinical imaging enthesopathy (Savage LJ et al submitted), raising the possibility that it may be possible to find a biomarker for predicting response to therapy in psoriatic disease. Innate lymphoid cells may be centrally involved in the pathogenesis of psoriatic skin and joints disease2, since they express IL-23R receptor and are associated with IL-17/IL-22 production. Objectives This work was performed to test the hypothesis that peripheral blood ILC perturbations may be useful in defining response in psoriasis cases with imaging confirmed subclinical enthesopathy. Methods Peripheral blood collected at baseline (before therapy, 24weeks, 54 weeks) from patients in the MUSTEK trial (Ustekinumab in psoriasis cases who had ultrasound imaging confirmed subclinical enthesopathy) (n=23). Cellular immunophenotyping was performed density gradient separated PBMCs. Innate lymphoid cells were identified as lineage negative (CD3- TCRγδ- TCRαβ- CD19- CD14- CD11c- CD1a- CD303- FcɛRI- CD34- CD123-) with positive expression of CD45, CD127. ILC2 cells were identified as Lineage- CD127+ and CRTH2 positive, while ILC3 were identified as Lineage- CD127+, CRTH2 – and CD117 (c-Kit) positive and further subdivided of NKp44+ and NKp44-. ILC1 were identified as lineage- CD127+ CD117-and CRTH2-. For data analysis we separated cases into PASI>90% or PASI Results No correlation was found with total ILCs (ILC1,2, AND 3) (R=0.104, p=321, Spearman R) and therapy response. While, The absolute numbers of baseline ILC3s was inversely correlated in with the reduction in the PASI score (R -0.404, p=0308, Spearman R). The ILC3s also fell progressively under therapy. All the patients respond with reduction of PASI score mean 92.6% (range 65.8–100%), Interestingly, those patients with reduction below 90% of PASI score has a significantly higher absolute numbers of ILC3+ cells in peripheral blood at the baseline than PASI (n=6/23) than super-responder group (n=17/23) Conclusions Only peripheral blood ILC3s, but not other ILCs changes, correlate with the PASI score (disease activity), Furthermore, excellent responders (PASI reduction >90%) showed strong correlated with higher ILC3 population at the baseline. This may help to use ILC3 enumeration as predictive parameter for ustekinamab clinical therapeutic response and may be relevant to assessing novel biomarkers for subclincal arthropathy in psoriasis. References Kreuger et al. N Engl J Med. 2007 Feb 8; 356(6):580–92. Vallinova et al. 2014 Apr;134(4):984–91. Disclosure of Interest None declared

Background Recent animal studies have suggested that γδT-cells accumulate at enthesis, secrete IL-17 and are responsible for driving the spondyoarthritis (SpA) phenotype resulting from IL-23 overexpression in mice (1, 2). In humans examination of the immunological profile of enthesis has been hampered by lack of tissue. Recently, we used a novel strategy to show that group 3 innate lymphoid cells are present at the human enthesis (3). Here we extend our methodology to examine the broader immunological profile of human enthesis and to determine if γδT-cells are also present. Objectives To characterise γδT-cells at human enthesis and adjacent peri-entheseal bone Methods Human etheseal soft tissue (EST) and peri-entheseal bone (PEB) was harvested from normal spinous process in patients undergoing elective spinal orthopaedic procedures. Interspinous EST was dissected from PEB and enzymatically digested, followed by isolation of mononuclear cells. Flow cytometry was then used to determine the proportion of B-cells (CD45+, CD19+) NK cells (CD45+, CD3-, CD56+) and T-cells (CD45+, CD3+). T-cells were then sub divided based on expression of CD4 (T-helper cells), CD8 (Cytotoxic T-cells) and TCRγδ (γδT-cells). All entheseal data was compared to age-matched peripheral blood from healthy controls. Results Entheseal digests contained on average a lower proportion of T-cells compared to peripheral blood (p=0.018). However, the proportion of T-cells not expressing either CD4 or CD8 was greater in entheseal tissues (p=0.021), this population was largely composed of γδT-cells. As a proportion of T-cells γδT-cells were 6 fold more numerous in EST compared to peripheral blood (p=0.024), and PEB had 3 fold more. 37% of EST γδT-cells expressed CCR6 this compared to 26% and 34% in PEB and peripheral blood respectively. Conclusions γδT-cells are present in normal human enthesis and γδT-cells constitute a greater proportion of the T-cell pool compared to peripheral blood, making it likely that they represent a tissue resident population. Additionally, we observed a very similar proportion γδT-cells that expressed CCR6, a functional marker for IL-17 production, as was observed in mice (2). This is the first description of γδT-cells at the human enthesis and offers tentative confirmation of findings in mouse models where these cells play a key role in SpA pathogenesis. References Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012 Jul;18(7):1069–76. PubMed PMID: 22772566. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Oberdorfer L, et al. IL-23-dependent γδT cells produce IL-17 and accumulate in enthesis, aortic valve, and ciliary body. Arthritis & Rheumatology. 2016. Cuthbert R, Fragkakis E, Dunsmuir R, Millner P, El-Sherbiny Y, McGonagle D. AB0028 Innate Lymphoid Cells Are Present at Normal Human Enthesis Providing A Potential Mechanism for Spondyloarthropathy Pathogenesis. Annals of the Rheumatic Diseases. 2016;75(Suppl 2):906-. Disclosure of Interest None declared

Background Tumour necrosis factor inhibitors (TNFi) are highly efficacious in axial spondyloarthritis (axSpA) with significant clinical responses mirrored in resolution of MRI determined bone marrow oedema (BMO) lesions representative of active inflammation in the sacroiliac joints (SIJ) and spine. However, symptom flare suggesting loss of response is common with many patients reporting deterioration days or weeks prior to the next dose. We hypothesised that intermittent suppression of inflammation with longer acting TNFis such as adalimumab or infliximab may be associated with a greater likelihood of recurrence of MRI determined BMO lesions than shorter acting agents such as etanercept. Objectives To explore the relationship between symptom flare immediately prior to next treatment dose and recurrence of MRI determined BMO lesions with different TNFi in axSpA. Methods Proof-of-concept, single centre study. Eligible participants were adults with axSpA established on adalimumab, etanercept or infliximab describing loss of response immediately prior to next treatment dose. Loss of response was defined as subjective “flare” or “wearing off” of drug effect before the expected duration of treatment effect. Participants attended at three points: Baseline: first day of treatment cycle (day of drug dose); Endpoint 1: 3–4 days after dose; and Endpoint 2: within 48 hours of next dose. ASDAS-CRP and whole spine and SIJ MR imaging utilising 3T MRI scanner were performed at each visit. Images were scored according to the semi-quantitative Leeds MRI scoring system by two observers blinded to participant identity and date of scan. Results 38 participants (16 adalimumab; 12 etanercept; 10 infliximab) with a total 113 MRI scans were analysed. 71% (n=27) male; 60% (n=23) HLA-B27+ with no differences between the groups; 73.7% (n=28) fulfilled mNYC for AS; the remainder were classified as nr-axSpA. 58% (n=22) had at least 1 Grade 1 BMO lesion at baseline with lesions more commonly seen with longer acting drugs (5/12 in etanercept group; 9/16 in adalimumab group; 8/10 in infliximab group) and 11 (50%) had at least 1 Grade ≥2 lesion (Table 2). There was a trend towards number and severity of BMO lesions fluctuating through the treatment cycle (Figure 1) mimicking subjective loss of response, also reflected on the ASDAS-CRP (Table 1) but this did not reach statistical significance. Conclusions This small proof-of-concept study shows subtle fluctuations on MRI changes of BMO and ASDAS-CRP corresponding to time of subjective “flare” before next scheduled TNFi dose in subjects with axSpA. Although these changes may be more common with the longer acting TNFi our data are not confirmatory. Larger studies are required to explore this concept further as these observations are potentially relevant for disease progression since cycles of inflammation and its subsequent suppression could theoretically increase the risk of new bone formation. Acknowledgements This study was sponsored by Pfizer. Disclosure of Interest R. Ansell Grant/research support from: Pfizer, H. Mathieson: None declared, M. Merashli: None declared, N. Busquets-Perez: None declared, D. McGonagle Grant/research support from: Celgene, Janssen & Pfizer, Consultant for: AbbVie, Celgene, Janssen, Novartis, UCB, Speakers bureau: Abbvie, Celgene, Janssen, UCB., H. Marzo-Ortega Grant/research support from: Janssen & Pfizer., Consultant for: AbbVie, Celgene, Janssen, Novartis, UCB. S, Speakers bureau: Abbvie, Celgene, Janssen, UCB.

The Early Arthritis for Psoriatic patients (EARP) questionnaire is a screening tool for psoriatic arthritis. The original Italian version has good measurement properties but the EARP required translation and adaptation for use in Spain. This article describes the cultural adaptation process as a step prior to validation.We used the principles of good practice for the cross-cultural adaptation of patient-reported outcomes measurement established by the International Society Pharmacoeconomics and Outcome Research. The steps in this process were preparation, forward translation, reconciliation, back-translation and review, harmonization, cognitive debriefing and review, and proofreading. During preparation the developers of the original questionnaire were asked for their permission to adapt the EARP for use in Spain and to act as consultants during the process.The original questionnaire was translated into Spanish by native Spanish translators, who made slight changes that were approved by the questionnaire's developers. The Spanish version was then back-translated into Italian; that version was reviewed to confirm equivalence with the original Italian text. The reconciled Spanish EARP was then tested for comprehensibility and interpretation in a group of 35 patients. All the patients answered all items without making additional comments.This cultural adaptation of the EARP questionnaire for Spanish populations is the first step towards its later use in routine clinical practice. The application of a cross-cultural adaptation method ensured equivalence between the original and Spanish versions of the EARP. The Spanish questionnaire will be validated in a second stage.

Background Up to 20% of inflammatory bowel diseases (IBD) cases may have an associated form of Spondyloarthropathy (SpA). Axial disease in SpA may vary from sporadic back pain to advanced spinal fusion, undistinguishable from Ankylosing Spondylitis (AS). Magnetic resonance imaging (MRI) is well established in the assessment of spinal disease in SpA, but axial MRI data in IBD are still sparse. In AS and axial Psoriatic Arthritis (PsA), it has previously been shown that the extent and severity of inflammatory changes of bone marrow oedema (BMO) on MRI is related to HLA-B27. Objectives The aims of this study were to describe the prevalence and extent of BMO lesions and their relationship with HLA-B27 status in IBD-related SpA with axial symptoms. Methods Consecutive MRI scans [thoracic spine (TS), lumbar spine (LS) and sacroiliac joints (SIJs)], from patients attending the Leeds Combined Rheumatology and Gastroenterology service between 2005–2015, were assessed retrospectively. Scans had been performed as part of clinical assessment for inflammatory back pain. All subjects had histological diagnosis of IBD and fulfilled ASAS classification criteria for SpA, HLA-B27 status and demographics were also collected. MRI scans were scored by consensus by two expert readers, blinded to the clinical characteristics of the patients. We used the semiquantitative (0–3) Leeds MRI Scoring System for BMO lesions representative of inflammation in the spine and SIJs, whereby a lesion graded as moderate (grade 2) is considered clinically significant. Concordant data from the two readers were used to report on definite lesions. Results MRI scans from 43 patients were available for analysis; mean age 43.4 yrs (SD 13.2, range 18.1–80.9), 25 were females (58.1%). Mean age at SpA diagnosis was 37.1 yrs (SD 11.9, range 17.1–63). HLA-B27 was positive in 15 subjects (34.9%) and was associated with younger age at SpA diagnosis (p=0.015). The median MRI score and number of BMO lesions were 2 (IQR 0–7 and 0–5, respectively), 13 patients (30.2%) scored zero, 14 subjects (32.6%) showed at least 1 clinically relevant lesion (grade ≥2). Gender, current age or age at MRI scan were not associated with HLA-B27. MRI total (whole axial skeleton) and partial (TS, LS and SIJs single analysis) score, number of BMO lesions and severe lesions (total axial skeleton and TS-LS-SIJs single analysis) were not different according to HLA B27 status. Conclusions Although the majority of IBD-related SpA do not carry HLA B27, diagnosis at a younger age was related to HLA-B27 status. Axial BMO lesions in IBD disease showed the whole spectrum of changes noted in AS. Unlike AS and axial PsA, no association was found between the extent and severity of MRI-determined axial disease and HLA-B27. Disclosure of Interest None declared

To test the hypothesis that CD45(low)CD271+ bone marrow multipotential stromal cells (MSCs) are abundant in the trabecular bone niche and to explore their functional "fitness" in health and osteoarthritis (OA).Following enzymatic extraction, MSC release was evaluated using colony-forming unit-fibroblast (CFU-F) and colony-forming unit-osteoblast assays, flow cytometry, and confocal microscopy. CD45(low)CD271+ cells isolated by fluorescence-activated cell sorting were enumerated and expanded under standard and clonal conditions. Their proliferative and osteogenic potencies were assessed in relation to donor age and compared with those of aspirated CD45(low)CD271+ cells. In vitro and in vivo MSC "aging" was measured using quantitative polymerase chain reaction-based telomere length analysis, and standard differentiation assays were utilized to demonstrate multipotentiality.Cellular isolates from trabecular bone cavities contained approximately 65-fold more CD45(low)CD271+ cells compared with aspirates (P0.0001) (median 1.89% [n = 39] and 0.029% [n = 46], respectively), concordant with increased CFU-F release. Aspirated and enzymatically released CD45(low)CD271+ cells had identical MSC phenotypes (approximately 100% CD73+CD105+CD13+, approximately 50-60% CD146+CD106+CD166+) and contained large proportions of highly clonogenic multipotential cells. In vitro osteogenic potency of freshly isolated CD45(low)CD271+ cells was comparable with, and often above, that of early-passage MSCs (8-14%). Their frequency and in vivo telomere status in OA bone were similar to those in bone from age-matched controls.Our findings show that CD45(low)CD271+ MSCs are abundant in the trabecular bone cavity and indistinguishable from aspirated CD45(low)CD271+ MSCs. In OA they display aging-related loss of proliferation but no gross osteogenic abnormality. These findings offer new opportunities for direct study of MSCs in musculoskeletal diseases without the requirement for culture expansion. They are also relevant for direct therapeutic exploitation of prospectively isolated, minimally cultured MSCs in trauma and OA.

At the 2008 meeting of GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis), the primary focus of the imaging session was the enthesis. Presentations from Dennis McGonagle (Leeds, UK), Richard Hodgson (Leeds, UK), and Paolo Gisondi (Verona, Italy) elaborated on this theme and prepared the meeting attendees for group discussions of further work in this area. Imaging, notably magnetic resonance imaging (MRI) and ultrasonography, provides evidence of pathological change at the enthesis in psoriatic arthritis (PsA). Further, imaging abnormalities are found at sites that are asymptomatic in both PsA and psoriasis. The role of newer imaging modalities, such as ultra-short echo time (UTE) MRI, is promising but remains to be fully elucidated. The implication of these findings in relation to subclinical and predisease status is intriguing and requires further study in longitudinal studies. Further work is also required to examine the proposed common biomechanical basis between joint and skin, the mechanism of the resulting inflammation, and how these mechanisms differ from those seen in rheumatoid arthritis.

We are mapping 29 rotational transitions of 21 chemical and isotopic molecular species in the central Orion molecular ridge with Nyquist sampling using the new 15-element focal plane array receiver QUARRY on the FCRAO 14 m telescope. Our goal is to obtain complete, unbiased data sets for a study of the interrelated physics and chemistry in GMC cores.

The seronegative spondyloarthropathies (SpAs) are associated both with clinical and subclinical colitis. Recently biological blockade with the tumour necrosis factor alpha (TNFalpha) antagonists infliximab and etanercept has been shown to be effective in the treatment of SpA. However, only infliximab is efficacious in the treatment of colitis in patients with Crohn's SpA. We report on two patients with SpA and associated Crohn's disease treated with etanercept whose arthritis showed an excellent response with complete resolution of spinal pathology, whereas their Crohn's disease persisted or flared. These findings suggest that the effect of TNFalpha blockade in SpA differs between the joint and the bowel.

Biologic blockade of tumour necrosis factor alpha is an exciting new development in the treatment of the spondyloarthropathies (SpA). Recent reports suggest that both infliximab and etanercept are potent suppressors of inflammation in SpA and this has been confirmed by studies showing suppression of inflammatory indices as well as complete regression or improvement in the inflammatory lesions as shown by magnetic resonance imaging (MRI). Whilst limited follow up data have been reported in the case of infliximab there are no data on how patients on etanercept fare after a years' treatment.

To determine areas of agreement and disagreement among experts in the interpretation of the published criteria for RA (ACR) and spondylarthropathies ( ESSG).Thirty-two experts (16 from France and 16 from 10 other countries) replied anonymously to a mailed questionnaire.Tenosynovitis and 'sausage-like' painless swelling of the toes were considered as criteria for RA by 18 and 14 experts, respectively. The definition of symmetry differed widely among experts (symmetry of only one group of joints was sufficient for 13). Twenty-five experts considered erosions of other joints than the wrists and fingers as a criterion for RA, 17 thought that fulfilment of criteria could be achieved cumulatively, and 19 would appreciate clarifications of the current criteria. Among possible clarifications for RA, it was frequently recommended that morning stiffness and nodules be eliminated and that new marker antibodies, X-rays of the feet, and exclusion criteria be added. Twenty-three of the 29 experts who gave an opinion (79%) agreed with the notion of SP in the absence of axial signs and sacroiliitis, 26/31 (84%) indicated that a patient can have both RA and SP, and 19/30 (63%) thought that RA and SP could be regarded as syndromes more than diseases. Only 5/32 experts relied more on the criteria than on their clinical judgement in diagnosing RA.There would seem to be a needfor the optimisation of RA and ESSG criteria, particularly within the context of early arthritis.

Polymyalgia rheumatica (PMR) is an inflammatory condition of the aging population characterised by pain, stiffness, and symmetrical involvement of shoulder and pelvic girdles. It has been proposed that the primary site of disease may reside outside the synovial joint,1 2 but its aetiopathogenesis remains ill understood. There is good indirect evidence that vasculitis is important in the pathogenesis of PMR, based on observations from the closely related disease, giant cell arteritis (GCA).3 Many patients with GCA have PMR-like symptoms and the converse is also true. One of the characteristics of PMR is its dramatic response to moderate doses of corticosteroid treatment. However, a subset of patients responds inadequately to treatment or has difficulty with dose reduction, the basis for which is not well defined. We report here the case of a patient with PMR which was difficult to treat who was found to have underlying vasculitis on magnetic resonance imaging (MRI), a finding which explains the requirement for the …

The pathogenesis of human immunodeficiency virus (HIV) associated spondyloarthropathy (SpA) is poorly understood. In this case report a patient is described with severe HIV associated reactive arthritis, who on magnetic resonance imaging and sonographic imaging of inflamed knees had extensive polyenthesitis and adjacent osteitis. The arthritis deteriorated despite conventional antirheumatic treatment, but improved dramatically after highly active antiretroviral treatment, which was accompanied by a significant rise in CD4 T lymphocyte counts. The implications of the localisation of pathology and effect of treatment for pathogenic models of SpA and rheumatoid arthritis in the setting of HIV infection are discussed.

The ability to make an early, accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important with the availability of new, expensive, and targeted therapies. However, plain radiography, the traditional method of detecting the characteristic bone erosions and an important adjunct in establishing a diagnosis of RA, is known to be insensitive. This study compared sonography, a modern imaging technique, with conventional radiography for the detection of erosions in the metacarpophalangeal (MCP) joints of patients with RA.One hundred RA patients (including 40 with early disease) underwent posteroanterior radiography and sonography of the MCP joints of the dominant hand. Twenty asymptomatic control subjects also underwent sonography. Erosion sites were recorded and subsequently compared using each modality. Magnetic resonance imaging (MRI) was performed on the second MCP joint in 25 patients with early RA to confirm the pathologic specificity of sonographic erosions. Intraobserver reliability of sonography readings was assessed using video recordings of 55 MCP joint scans of RA patients, and interobserver reliability was assessed by comparing 160 MCP joint scans performed sequentially by 2 independent observers.Sonography detected 127 definite erosions in 56 of 100 RA patients, compared with radiographic detection of 32 erosions (26 [81%] of which coincided with sonographic erosions) in 17 of 100 patients (P0.0001). In early disease, sonography detected 6.5-fold more erosions than did radiography, in 7.5-fold the number of patients. In late disease, these differences were 3.4-fold and 2.7-fold, respectively. On MRI, all sonographic erosions not visible on radiography (n = 12) corresponded by site to MRI abnormalities. The Cohen-kappa values for intra- and interobserver reliability of sonography were 0.75 and 0.76, respectively.Sonography is a reliable technique that detects more erosions than radiography, especially in early RA. Sonographic erosions not seen on radiography corresponded to MRI bone abnormalities. This technology has potential in the management of patients with early RA/inflammatory arthritis and is likely to have major implications for the future practice of rheumatology.

Conventional radiology (CR) is a major tool for the diagnosis and assessment of early arthritis. However, CR does not image the primary pathology of rheumatoid arthritis (RA), i.e. the synovium, and is insensitive for radiological erosions. New techniques, particularly magnetic resonance imaging (MRI) and ultrasonography (US) have shown their potential to improve on the sensitivity of CR. This article reviews the current status of this approach in early disease.

The interrelationship between synovitis and bone damage in rheumatoid arthritis (RA) is a subject of controversy. Using magnetic resonance imaging (MRI), this study followed the bone changes in early RA and determined their relationship to synovitis.Thirty-one patients with early RA who had swelling of the metacarpophalangeal (MCP) joints and 31 healthy control subjects with no clinical evidence of arthritis underwent MRI of the second through fifth MCP joints of the dominant hand by use of a 1.5T scanner. Coronal T1-weighted and T2-fat suppressed (FS) sequences were performed to evaluate bone edema, and gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) pulse sequences were obtained to evaluate synovitis. Bony abnormalities were described as bone edema (low signal on T1-weighted sequences and intermediate/high signal on T2 FS sequences adjacent to the bone cortex) or as bone cysts (circular juxtacortical abnormalities with low signal on T1-weighted images and with very high signal on T2 FS sequences). Contrast and noncontrast MRI films were scored in a blinded manner, and Fisher's exact probability test was used to determine differences between groups.Twenty-one of the 31 RA patients (68%) had bone edema, which was seen in 43 of 124 joints (35% of joints) and 3 of the 31 control subjects had bone edema seen in 3 of 124 joints (2% of joints) (P0.0001). Thirty RA patients (97%) had Gd-DTPA-confirmed MCP joint synovitis, and bone edema was seen in 40 of the 75 joints with Gd-DTPA-proven synovitis (53%), but in only 3 of 49 without (6%) (P0.0001).MCP joint bone edema is present in the majority of patients with RA at presentation, but is seen only occasionally in normal control subjects. The fact that bone edema occurred rarely in the absence of synovitis in patients with RA suggests that bony changes in RA are secondary to synovitis.

To use magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA) and spondylarthropathy (SpA) to determine if the primary site of abnormality differs.Twenty patients with recent-onset knee effusion (10 with SpA and 10 with RA) were evaluated using fat-suppressed MRI. Knee joint effusion and synovitis were confirmed using ultrasonography. MRI scans were independently scored by 2 observers who were blinded to the patient's diagnosis.All 10 of the SpA patients, but only 4 of the 10 RA patients, had focal peri-entheseal high signal (compatible with fluid or edema) outside the joint (P = 0.01). Six of the SpA patients had bone marrow edema that was maximal at entheseal insertions; in 4 cases this was multifocal. No RA patients showed such an abnormality (P = 0.01).Prominent entheseal abnormalities on MRI are a consistent feature of new-onset synovitis in SpA, but are a minor feature of RA. This finding has important implications for the diagnosis, classification, and mechanisms of synovitis in patients with SpA.

We report a survey for nitrogen sulfide (NS) toward regions of massive star formation. NS was observed by means of its 2 pi 1/2, J = 3/2 --> 1/2, J = 5/2 --> 3/2, and J = 7/2 --> 5/2 transitions at 69, 115, and 161 GHz, respectively, and was detected toward 12 of 14 giant molecular clouds (GMCs) observed. Analysis of the hyperfine component relative line strengths suggests that NS emission is optically thin toward these sources, with the possible exception of Sgr B2(M). The fractional abundance of NS relative to molecular hydrogen is best defined for the Orion molecular cloud, where it is typically (1-4) x 10(-10), which is about an order of magnitude larger than found by some recent gas-phase chemistry models developed for quiescent clouds. Toward OMC-1, the NS integrated intensity is strongly peaked toward KL, but also extends all along the Orion ridge, resembling the distribution of SO and CH3OH. We have identified a spectral feature seen toward several sources as the ortho-NKK = 4(04) --> 3(13) J = 3 --> 2, fine-structure component of methylene (CH2; cf. Hollis, Jewell, & Lovas). We also report the first detection of the SO+ 2 pi 1/2, J = 3/2 --> 1/2, parity-e transition toward W51(MS) and L134N.

We have detected a new interstellar molecule, H2CN (methylene amidogen), in the cold, dark molecular cloud TMC-1. The column density of H2CN is estimated to be approximately 1.5 x 10(exp 11) cm(exp -2) by assuming an excitation temperature of 5 K. This column density corresponds to a fractional abundance relative to H2 of approximately 1.5 x 10(exp -11). This value is more than three orders of magnitude less than the abundance of the related molecule HCN in TMC-1. We also report a tentative detection of H2CN in Sgr B2(N). The formation mechanism of H2CN is discussed. Our detection of the N2CN molecule may suggest the existence of a new series of carbon-chain molecules, CH2C(n)N (N = 0, 1, 2, ...).

We report the first detection of interstellar nitrogen sulfide (NS) in cold dark clouds. Several components of the (2)Pi(sub 1/2), J = 3/2 to 1/2 and J = 5/2 to 3/2 transitions were observed in TMC-1 and L134N. The inferred column density for TMC-1 is N(sub NS) approximately 8 x 10(exp 12)/sq cm toward the NH3 peak in that cloud, and in L134N is N(sub NS) approximately 3 x 10(exp 12)/sq cm toward the position of peak NH3 emission. These values correspond to fractional abundances relative to molecular hydrogen of f(sub NS) approximately 8 x 10(exp -10) for TMC-1, and f(sub NS) approximately 6 x 10(exp -10) for L134N. The NS emission is extended along the TMC-1 ridge and is also extended in L134N. The measured abundances are significantly higher than those predicted by some recent gas phase ion-molecule models.

Nitric oxide has been newly detected towards several star-forming clouds, including Orion-KL, Sgr B2(N), W33A, W51M, and DR21(OH) via its J = 3/2 --1/2 transitions near 150 GHz, using the FCRAO 14 m telescope. Both lambda-doubling components of NO were observed towards all sources. Column densities derived for nitric oxide in these clouds are N approximately 10(15)-10(16) cm-2, corresponding to fractional abundances of f approximately 0.5-1.0 x 10(-8), relative to H2. Towards Orion-KL, the NO line profile suggests that the species arises primarily from hot, dense gas. Nitric oxide may arise from warm material toward the other clouds as well. Nitric oxide in star-forming regions could be synthesized by high-temperature reactions, although the observed abundances do not disagree with values predicted from low-temperature, ion-molecule chemistry by more than one order of magnitude. The abundance of NO, unlike other simple interstellar nitrogen compounds, does appear to be reproduced by chemical models, at least to a good approximation. Regardless of the nature of formation of NO, it appears to be a common constituent of warm, dense molecular clouds. N-O bonds may therefore be more prevalent than previously thought.

Interstellar hydrogen sulfide (H2S) and its isotopic variant H2 34S have been observed toward several star-forming regions via their 1(10)-1(01) transitions at 2 mm, using the FCRAO telescope. In sources where both isotopic species H2S and H2 34S were observed, column densities of approximately 10(16) cm-2 were measured. Column density lower limits of approximately 10(14) cm-2 for H2S were found for other sources, where only the main isotopic line was observed. The fractional abundances of H2S relative to molecular hydrogen appear to be enhanced by at least an order of magnitude relative to quiescent cloud values (approximately 10(-9)) for many of the observed sources. Such enhancement toward star-forming clouds suggests that some process involving elevated temperature aids in producing this species; this could be gas-phase reactions, grain-related processes, or both.