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    High Dimensional Analyses of Circulating Immune Cells in Psoriatic Arthritis Detects Elevated Phosphorylated STAT3. Macaubas Claudia,Rahman Shamma S,Lavi Idit,Haddad Amir,Elias Muna,Sengupta Deepanwita,Zisman Devy,Mellins Elizabeth D Frontiers in immunology Psoriatic arthritis (PsA) is a chronic inflammatory arthritis, affecting up to 40% of patients with psoriasis. Constitutive expression by CD4+ T cells of an active form of STAT3, a signal transducer and transcription factor, has been shown to induce many of the major features of PsA in an animal model. We used high dimensional mass cytometry (CyTOF) to probe levels of phosphorylated STAT3 (pSTAT3) in circulating immune cell subpopulations from PsA patients during active and inactive states. We evaluated the frequency of 16 immune cell populations and the levels of the activated forms of STAT3 (pSTAT3) and, for comparison, STAT1 (pSTAT1) and Src (pSrc) in whole blood fixed shortly after collection. In addition to PsA patients, we studied active rheumatoid arthritis (RA) patients. Increased levels of pSTAT3 were found in all the CD4+ T cell subsets analyzed, specifically, Th1, Th2, Th17, T follicular helper (Tfh) and T regulatory (Treg) as well as in CD14+CD16- (classical) monocytes from active PsA patients compared to inactive patients. After correcting for body mass index (BMI), smoking and conventional disease modifying antirheumatic drugs (c-DMARDs), levels of pSTAT3 levels remained increased in Th1 and Tfh CD4+ T cells, and in CD14+CD16- monocytes from active patients compared to inactive patients. No differences between the patient groups were observed for pSTAT1 or pSrc. No differences were found between the active PsA and active RA groups after correction for multiple testing. During active PsA, circulating Th1 and Tfh CD4+ T cells, and CD14+CD16- monocytes expressing high levels of pSTAT3 may play a role in PsA pathophysiology, perhaps by migration to inflamed sites. 10.3389/fimmu.2021.758418
    CD209/CD14 Dendritic Cells Characterization in Rheumatoid and Psoriatic Arthritis Patients: Activation, Synovial Infiltration, and Therapeutic Targeting. Marzaioli Viviana,Canavan Mary,Floudas Achilleas,Flynn Keelin,Mullan Ronan,Veale Douglas J,Fearon Ursula Frontiers in immunology Dendritic cells (DC) have a key role in the initiation and progression of inflammatory arthritis (IA). In this study, we identified a DC population that derive from monocytes, characterized as CD209/CD14 DC, expressing classical DC markers (HLADR, CD11c) and the Mo-DC marker (CD209), while also retaining the monocytic marker CD14. This CD209/CD14 DC population is present in the circulation of Healthy Control (HC), with increased frequency in Rheumatoid Arthritis (RA) and Psoriatic arthritic (PsA) patients. We demonstrate, for the first time, that circulatory IA CD209/CD14 DC express more cytokines (IL1β/IL6/IL12/TNFα) and display a unique chemokine receptor expression and co-expression profiles compared to HC. We demonstrated that CD209/CD14 DC are enriched in the inflamed joint where they display a unique inflammatory and maturation phenotype, with increased CD40 and CD80 and co-expression of specific chemokine receptors, displaying unique patterns between PsA and RA. We developed a new protocol of magnetic isolation and expansion for CD209 DC from blood and identified transcriptional differences involved in endocytosis/antigen presentation between RA and PsA CD209 DC. In addition, we observed that culture of healthy CD209 DC with IA synovial fluid (SF), but not Osteoarthritis (OA) SF, was sufficient to induce the development of CD209/CD14 DC, leading to a poly-mature DC phenotype. In addition, differential effects were observed in terms of chemokine receptor and chemokine expression, with healthy CD209 DC displaying increased expression/co-expression of CCR6, CCR7, CXCR3, CXCR4 and CXCR5 when cultured with RA SF, while an increase in the chemokines CCR3, CXCL10 and CXCL11 was observed when cultured with PsA SF. This effect may be mediated in part by the observed differential increase in chemokines expressed in RA PsA SF. Finally, we observed that the JAK/STAT pathway, but not the NF-κB pathway (driven by TNFα), regulated CD209/CD14 DC function in terms of activation, inflammatory state, and migratory capacity. In conclusion, we identified a novel CD209/CD14 DC population, which is active in the circulation of RA and PsA, an effect potentiated once they enter the joint. Furthermore, we demonstrated that JAK/STAT inhibition can be used as a therapeutic strategy to decrease the inflammatory state of the pathogenic CD209/CD14 DC. 10.3389/fimmu.2021.722349
    Predicting the Risk of Psoriatic Arthritis in Plaque Psoriasis Patients: Development and Assessment of a New Predictive Nomogram. Liu Panpan,Kuang Yehong,Ye Li,Peng Cong,Chen Wangqing,Shen Minxue,Zhang Mi,Zhu Wu,Lv Chengzhi,Chen Xiang Frontiers in immunology Objective:This study aimed to develop a risk of psoriatic arthritis (PsA) predictive model for plaque psoriasis patients based on the available features. Methods:Patients with plaque psoriasis or PsA were recruited. The characteristics, skin lesions, and nail clinical manifestations of the patients have been collected. The least absolute shrinkage was used to optimize feature selection, and logistic regression analysis was applied to further select features and build a PsA risk predictive model. Calibration, discrimination, and clinical utility of the prediction model were evaluated by using the calibration plot, C-index, the area under the curve (AUC), and decision curve analysis. Internal validation was performed using bootstrapping validation. The model was subjected to external validation with two separate cohorts. Results:Age at onset, duration, nail involvement, erythematous lunula, onychorrhexis, oil drop, and subungual hyperkeratosis were presented as predictors to perform the prediction nomogram. The predictive model showed good calibration and discrimination (C-index: 0.759; 95% CI: 0.707-0.811). The AUC of this prediction model was 0.7578092. Excellent performances of the C-index were reached in the internal validation and external cohort validation (0.741, 0.844, and 0.845). The decision curve indicated good effect of the PsA nomogram in guiding clinical practice. Conclusion:This novel PsA nomogram could assess the risk of PsA in plaque psoriasis patients with good efficiency. 10.3389/fimmu.2021.740968
    Safety of JAK inhibitors: focus on cardiovascular and thromboembolic events. Expert review of clinical immunology INTRODUCTION:To date, four Janus kinase inhibitors (JAKis) are licensed for the treatment of rheumatoid arthritis (RA) and/or psoriatic arthritis (PsA) in North America and/or Europe: tofacitinib, baricitinib, upadacitinib, and filgotinib. Most DMARDs have cardioprotective potential, yet for some of them, including JAKi, the modulatory effect on cardiovascular risk remains undetermined. Since their commercialization, the risk of venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is taking on a relevant role in RA patients. AREAS COVERED:In this article, we will review the effect of JAKi on CV risk and atherosclerosis process as major contributor to MACE. Furthermore, we will present the effect of JAKi on thromboembolic risk. EXPERT OPINION:Although the effect of JAKi on CV and thrombosis is one of the most relevant topic regarding RA patients, it is necessary to underline that these patients have an increased risk of these comorbidities due to the inflammation process, and further study are needed in order to understand the real role of JAKi in controlling or inducing these complications. 10.1080/1744666X.2022.2039630
    Reliability assessment of the definition of ultrasound enthesitis in SpA: results of a large, multicentre, international web-based study. Di Matteo Andrea,Cipolletta Edoardo,Destro Castaniti Giulia Maria,Smerilli Gianluca,Airoldi Carla,Aydin Sibel Zehra,Becciolini Andrea,Bonfiglioli Karina,Bruns Alessandra,Carrara Greta,Cazenave Tomas,Ciapetti Alessandro,Cosatti Micaela Ana,de Agustin Juan Josè,Di Carlo Marco,Di Donato Eleonora,Di Geso Luca,Duran Emine,Elliott Ashley,Estrach Cristina,Farisogulları Bayram,Fiorenza Alessia,Fodor Daniela,Gabba Alessandra,Hernández-Díaz Cristina,Huang Feng,Hurnakova Jana,Li Ling,Jesus Diogo,Karadag Omer,Martire Maria Victoria,Massarotti Marco,Michelena Xabier,Musca Alice Andreea,Nair Jagdish,Okano Tadashi,Papalopoulos Ioannis,Rosemffet Marcos,Rovisco João,Rozza Davide,Salaffi Fausto,Satulu Iulia,Scioscia Crescenzio,Scirè Carlo Alberto,Sun Fei,Tamas Maria-Magdalena,Tanimura Shun,Ventura-Rios Lucio,Voulgari Paraksevi V,Vreju Florentin Ananu,Vukatana Gentiana,Wong Ernest,Yang Jinshui,Zacariaz Hereter Johana,Zanetti Anna,Grassi Walter,Filippucci Emilio Rheumatology (Oxford, England) OBJECTIVES:To investigate the reliability of the OMERACT ultrasound (US) Task Force definition of US enthesitis in spondyloarthritis (SpA). METHODS:In this web exercise, based on the evaluation of 101 images and 39 clips of the main entheses of the lower limbs, the elementary components included in the OMERACT definition of US enthesitis in SpA [hypoechoic areas, entheseal thickening, power Doppler signal (PD) at the enthesis, enthesophytes/calcifications, bone erosions] were assessed by 47 rheumatologists from 37 rheumatology centres in 15 countries.Inter and intra-observer reliability of the US components of enthesitis was calculated using Light's kappa, Cohen's kappa, Prevalence and Bias Adjusted Kappa (PABAK) and their 95% confidence intervals. RESULTS:Bone erosions and PD showed the highest overall inter-reliability [Light's kappa: 0.77 (0.76-0.78), 0.72 (0.71-0.73), respectively; PABAK: 0.86 (0.86-0.87), 0.73 (0.73-0.74), respectively], followed by enthesophytes/calcifications [Light's kappa: 0.65 (0.64-0.65), PABAK: 0.67 (0.67-0.68)]. This was moderate for entheseal thickening [Light's kappa: 0.41 (0.41-0.42), PABAK: 0.41 (0.40-0.42)], and fair for hypoechoic areas [Light's kappa: 0.37 (0.36-0.38); PABAK: 0.37 (0.37-0.38)]. A similar trend was observed in the intra-reliability exercise, although this was characterized by an overall higher degree of reliability for all US elementary components compared with the inter-observer evaluation. CONCLUSIONS:The results of this multicentre, international, web-based study show a good reliability of the OMERACT US definition of bone erosions, PD, and enthesophytes/calcifications. The low reliability of entheseal thickening and hypoechoic areas raises questions about the opportunity to revise the definition of these two major components for the US diagnosis of enthesitis. 10.1093/rheumatology/keac162
    Does SAPHO syndrome exist in dermatology? Journal of the European Academy of Dermatology and Venereology : JEADV In the late 1960s, palmoplantar pustulosis (PPP) with sternocostoclavicular arthropathy was first described in Japan, predominantly affecting women in the perimenopausal age. In the 1970s, the chronic non-bacterial osteomyelitis and chronic recurrent multifocal osteomyelitis were initially observed in paediatric patients with approximately 70% girls. Acne fulminans accompanied by polyarthralgia have been observed since early 1970s, which almost exclusively occurs in adolescent boys. Report on spondyloarthropathy associated with hidradenitis suppurativa can be traced back to 1982. The SAPHO syndrome was coined in 1987 to lump together synovitis, acne, pustulosis, hyperostosis and osteitis to conceptualize a group of inflammatory osteocutaneous diseases of unclear etiopathogenesis and ill-defined associations spanning disparate age and gender groups. From historical view, Sasaki syndrome is proposed to replace SAPHO syndrome to represent PPP with sternocostoclavicular arthropathy in the absence of other skin manifestations. Hidradenitis suppurativa is folliculitis in pathogenesis and no longer classified as acne. PPP accompanied by psoriasis vulgaris is more likely psoriasis pustulosa palmoplantaris in dermatological aspect, and the associated arthritis is part of psoriatic arthropathy. Pathophysiology of these disorders is incompletely understood. To echo the advancement of high-throughput sequencing, splitting but not lumping of clinical findings would be a better strategy to decipher these multigenic complex inflammatory disorders. 10.1111/jdv.18172
    Dactylitis is associated with more severe axial joint damage and higher disease activity in axial psoriatic arthritis. The Journal of rheumatology OBJECTIVE:To investigate the association of dactylitis with disease activity and the severity of radiological damage in patients with axial psoriatic arthritis (AxPsA). METHODS:Patients with AxPsA met the classification criteria (CASPAR) were recruited. Clinical data, radiographic changes and disease activity in AxPsA patients with or without dactylitis were compared using t-tests, Mann-Whitney U test or Kruskal-Wallis test for continuous variables, Ⲭ or Fisher exact tests for categorical variables and logistic regression analysis for the association between dactylitis and radiographic damage. RESULTS:A total of 186 AxPsA patients were analysed and dichotomized by the presence or absence of dactylitis. Patients with dactylitis had higher levels of CRP, ESR, NLR and PLR than those who did not have (P=0.004; P=0.006; P=0.035; PPLR=0.020). In addition, dactylitic AxPsA patients also had higher TJC, SJC, DAPSA and HAQ (P<0.001), and higher score of DAS28, ASDAS, BASFI and BASDAI (P<0.05), while less patients met MDA and DAPSA-LDA criteria (P<0.05). Consistently, they had more severe radiological damage (P< 0.05), higher sacroiliac scores (OR 2.076, 95%CI 1.137 to 3.791, P=0.017) and more significant reduction in BMD (OR 2.422, 95%CI 1.342 to 4.372, P=0.003). No statistical differences were observed for HLA-B27 and LEI between these two group patients. Notably, only half of dactylitic AxPsA patients had inflammatory back pain. CONCLUSION:Our study demonstrated that dactylitic AxPsA patients had higher disease activity and more severe joint damage compared those without dactylitis. Careful examination of axial involvements and proper management are recommended. 10.3899/jrheum.220098
    Effectiveness and safety of combined biological therapy in patients with refractory multidomain spondyloarthritis. Annals of the rheumatic diseases 10.1136/annrheumdis-2021-221812
    HIPPOCRATES: improving diagnosis and outcomes in psoriatic arthritis. FitzGerald Oliver,Pennington Stephen R Nature reviews. Rheumatology 10.1038/s41584-022-00748-w
    Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Annals of the rheumatic diseases OBJECTIVE:To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS:In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS:ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. CONCLUSIONS:Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. TRIAL REGISTRATION NUMBER:NCT03881059. 10.1136/annrheumdis-2021-221664
    Effects of targeted therapies on bone in rheumatic and musculoskeletal diseases. Nature reviews. Rheumatology Generalized bone loss (osteoporosis) and fragility fractures can occur in rheumatic and musculoskeletal diseases including rheumatoid arthritis and spondyloarthritis (SpA; including ankylosing spondylitis and psoriatic arthritis). In addition, rheumatoid arthritis can involve localized, periarticular bone erosion and, in SpA, local (pathological) bone formation can occur. The RANK-RANKL-osteoprotegerin axis and the Wnt-β-catenin signalling pathway (along with its inhibitors sclerostin and Dickkopf 1) have been implicated in inflammatory bone loss and formation, respectively. Targeted therapies including biologic DMARDs and Janus kinase (JAK) inhibitors can stabilize bone turnover and inhibit radiographic joint damage, and potentially also prevent generalized bone loss. Targeted therapies interfere at various points in the mechanisms of local and generalized bone changes in systemic rheumatic diseases, and they effect biomarkers of bone resorption and formation, bone mass and risk of fragility fractures. Studies on the effects of targeted therapies on rates of fragility fracture are scarce. The efficacy of biologic DMARDs for arresting bone formation in axial SpA is debated. Improved understanding of the most relevant therapeutic targets and identification of important targeted therapies could lead to the preservation of bone in inflammatory rheumatic and musculoskeletal diseases. 10.1038/s41584-022-00764-w
    EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases. Annals of the rheumatic diseases OBJECTIVE:To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs). METHODS:The points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale. RESULTS:Six overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals. CONCLUSION:These points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM. 10.1136/annrheumdis-2022-222155
    Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis. Annals of the rheumatic diseases OBJECTIVES:Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. METHODS:Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. RESULTS:Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor-ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPαTHY1 invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA. 10.1136/annrheumdis-2021-221761
    Treat-to-target dose reduction and withdrawal strategy of TNF inhibitors in psoriatic arthritis and axial spondyloarthritis: a randomised controlled non-inferiority trial. Annals of the rheumatic diseases OBJECTIVES:Tumour necrosis factor inhibitors (TNFi) are effective in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), but are associated with a small (0.6%) increase in serious infection risk, patient burden due to need for self-injection and high costs. Treat-to-target (T2T) tapering might ameliorate these drawbacks, but high-quality evidence on T2T tapering strategies is lacking in PsA and axSpA. METHODS:We performed a pragmatic open-label, monocentre, randomised controlled non-inferiority (NI) trial on T2T tapering of TNFi. Patients with PsA and axSpA using a TNFi with ≥6 months stable low disease activity (LDA) were included. Patients were randomised 2:1 to disease activity-guided T2T with or without tapering until withdrawal and followed-up to 12 months. Primary endpoint was the difference in proportion of patients having LDA at 12 months between groups, compared with a prespecified NI margin of 20%, estimated using a Bayesian prior. RESULTS:122 patients (64 PsA and 58 axSpA) were randomised to a T2T strategy with (N=81) or without tapering (N=41). The proportion of patients in LDA at 12 months was 69% for the tapering and 73% for the no-tapering group: adjusted difference 5% (Bayesian 95% credible interval: -10% to 19%) which confirms NI considering the NI margin of 20%. The mean percentage of daily defined dose was 53% for the tapering and 91% for the no-tapering group at month 12. CONCLUSIONS:A T2T TNFi strategy with tapering attempt is non-inferior to a T2T strategy without tapering with regard to the proportion of patients still in LDA at 12 months, and results in a substantial reduction of TNFi use. TRIAL REGISTRATION NUMBER:NL 6771. 10.1136/annrheumdis-2022-222260