OBJECTIVES:To investigate the impact of sustained C reactive protein (CRP) elevation on cardiovascular (CV) risk factors, particularly endothelial dysfunction and atherosclerosis, in axial spondyloarthritis (axSpA) patients and to explore the underlying molecular mechanisms. METHODS:245 axSpA patients were enrolled. Carotid intima-media thickness (CIMT) and microvascular endothelial function (post-ischaemic reactive hyperaemia) were measured. Retrospective CRP measurements from the past 5 years classified patients as having sustained high CRP if >50% of readings were elevated. Serum levels of 184 inflammation and CV disease-related proteins were analysed using a proximity extension assay, and in vitro studies were conducted in human umbilical vein endothelial cells. RESULTS:40% of axSpA patients had sustained CRP elevation, showing increased metabolic comorbidities, higher prevalence of atherosclerotic plaques and worse microvascular endothelial function compared with those with intermittent CRP elevations. Proteomic analysis identified 10 altered proteins, with interleukin 6 (IL-6) and CUB domain-containing protein 1 (CDCP-1) linked to endothelial dysfunction, higher CIMT and metabolic disturbances. Paraoxonase 3 (PON-3), the only downregulated protein, showed anti-inflammatory, antioxidant and antiatherogenic properties, restoring endothelial function in vitro. CDCP-1 was associated with atherosclerotic plaques and promoted endothelial adhesion, oxidative stress and inflammation in vitro. Anti-TNF-α therapy reduced inflammatory markers, complement components and the atherogenic index, while increasing high density lipoprotein, apolipoprotein A and PON-3 levels and decreasing IL-6 and CDCP-1 levels. CONCLUSIONS:Sustained CRP elevation in axSpA is strongly linked to increased CV risk, endothelial dysfunction and atherosclerosis. IL-6, CDCP-1 and PON-3 emerge as key mediators connecting inflammation to CV risk. Anti-tumour necrosis factor-α therapy improved the metabolic and inflammatory profile and modulated IL-6, CDCP-1 and PON-3 levels, supporting its role in managing CV risks in axSpA.

1 Abstract Background Systemic autoimmune diseases (SADs) are characterized by internal heterogeneity, overlapping clinical symptoms, and shared molecular pathways. Therefore, they are difficult to diagnose and new tools allowing precise diagnosis are needed. Molecular-based reclassification studies enable to find patterns in a diagnosis-independent way. Objective To evaluate the possibility of using high-content immunophenotyping for detecting patient subgroups in the context of precise treatment. Methods Whole blood high-content immunophenotyping of 101 patients with 7 systemic autoimmune diseases and 22 controls was performed using 36-plex mass cytometry panel. Patients were compared across diagnostic entities and re-classified using Monte Carlo reference-based consensus clustering. Levels of 45-plex multiplexed cytokine were measured and used for cluster characterization. Results Differential analysis by diagnosis did not reveal any disease-specific pattern in the cellular compositions and phenotypes but rather their relative similarities. Accordingly, patients were classified into phenotypically distinct groups composed of different diagnostic entities sharing common immunophenotypes and cytokine signatures. These features were mainly based on granulocyte activation and CD38 expression in discrete lymphocyte populations and were related to Th17 or IFN-dependent cytokines. Conclusions Our data indicate that specific individuals could potentially benefit from the same line of treatment independently of their diagnosis and emphasize the possibility of using immunophenotyping as a stratification tool in precision rheumatology. 2 Graphical abstract Key messages Whole blood immmunophenotyping could be used to stratify systemic autoimmune patients, thus it is a useful tool in precision medicine. Patients’ groups could benefit from the same line of treatment.

Background and objective: Axial spondyloarthritis (axSpA) are musculoskeletal diseases with different manifestations. In clinical practice, variability, and limitations in the collection of the outcomes required for follow-up have been observed. The objective of the CREA project was to agree on improvement strategies for the initial assessment and follow-up of patients with axSpA in Spain. Materials and methods: A survey with 33 questions was conducted by a representative sample of rheumatologists on clinical practice, resources, and present limitations in the follow-up of patients with axSpA. The results of the survey were discussed in 10 regional meetings, and 105 strategies were proposed and evaluated through a Delphi consensus in which 85 experts participated.Results: The lack of time for clinical visits, the lack of nurses and/or support staff and the delay in performing the imaging tests were the most prominent limitations in the follow-up of patients with axSpA. One hundred and five strategies were proposed related to the evaluation of disease activity, physical function, quality of life and disease impact, to the evaluation of comorbidities and extra-articular manifestations, laboratory tests; imaging tests, physical examination and metrology. Of the total, 85 were considered highly advisable. No regional differences were found.Conclusions: The proposals agreed upon as highly advisable in the present study are applicable to the entire national territory, allow tighter and more homogeneous monitoring of the patients with axSpA, facilitate more comprehensive management of the disease, and respond to the unmet needs detected in the initial survey.& COPY; 2022 Elsevier Espana, S.L.U. and Sociedad Espanola de Reumatologia y Colegio Mexicano de Reumatologia. All rights reserved.

La espondiloartritis axial (EspAax) es una enfermedad musculoesquelética con manifestaciones diversas. En la práctica clínica se ha observado variabilidad y limitaciones en la recogida de las variables necesarias para su seguimiento. El objetivo del proyecto CREA fue consensuar estrategias de mejora para la valoración inicial y el seguimiento de los pacientes con EspAax en España. Se realizó una encuesta con 33 preguntas a una muestra representativa de reumatólogos expertos del territorio español sobre la práctica clínica, los recursos y las limitaciones actuales en el seguimiento de los pacientes con EspAax. En 10 reuniones regionales se discutieron los resultados de la encuesta y se propusieron 107 estrategias que fueron valoradas mediante un consenso Delphi en el que participaron 85 expertos. La falta de tiempo en consulta, de personal de enfermería y/o de apoyo, y el retraso en la realización de pruebas de imagen fueron las limitaciones más destacadas en el seguimiento de los pacientes con EspAax. Se propusieron 202 estrategias relacionadas con la evaluación de los índices de calidad de vida e impacto de la enfermedad; las comorbilidades y manifestaciones extraarticulares; las pruebas de laboratorio; las pruebas de imagen; la exploración física y metrología; y los índices de actividad y función. De todas, 54 se consideraron altamente aconsejables. No se encontraron diferencias regionales en los valores de consenso. Las propuestas consensuadas como altamente aconsejables en el estudio actual son aplicables a todo el territorio nacional, permiten realizar un seguimiento y control más estrecho y homogéneo de los pacientes con EspAax, facilitar un manejo integral y responden a las necesidades no cubiertas detectadas en la encuesta inicial. Axial spondyloarthritis (axSpA) are musculoskeletal diseases with different manifestations. In clinical practice, variability, and limitations in the collection of the outcomes required for follow-up have been observed. The objective of the CREA project was to agree on improvement strategies for the initial assessment and follow-up of patients with axSpA in Spain. A survey with 33 questions was conducted by a representative sample of rheumatologists on clinical practice, resources, and present limitations in the follow-up of patients with axSpA. The results of the survey were discussed in 10 regional meetings, and 105 strategies were proposed and evaluated through a Delphi consensus in which 85 experts participated. The lack of time for clinical visits, the lack of nurses and/or support staff and the delay in performing the imaging tests were the most prominent limitations in the follow-up of patients with axSpA. One hundred and five strategies were proposed related to the evaluation of disease activity, physical function, quality of life and disease impact, to the evaluation of comorbidities and extra-articular manifestations, laboratory tests; imaging tests, physical examination and metrology. Of the total, 85 were considered highly advisable. No regional differences were found. The proposals agreed upon as highly advisable in the present study are applicable to the entire national territory, allow tighter and more homogeneous monitoring of the patients with axSpA, facilitate more comprehensive management of the disease, and respond to the unmet needs detected in the initial survey.

La artritis psoriásica (APs) es una enfermedad inflamatoria crónica mediada por el sistema inmune que afecta al sistema musculoesquelético y la piel, y se manifiesta de forma heterogénea y con un curso variable. En la práctica clínica habitual se ha observado variabilidad y limitaciones en su seguimiento. El objetivo del proyecto CREA fue consensuar estrategias de mejora para la valoración inicial y el seguimiento de los pacientes con APs en España. Se realizó una encuesta a una muestra representativa de reumatólogos expertos del territorio español, que contenía 33 preguntas sobre la práctica clínica habitual, los recursos disponibles y las limitaciones actuales en el seguimiento de los pacientes con APs. Se discutieron los resultados en reuniones regionales y se propusieron 105 estrategias que, finalmente, fueron valoradas por 85 expertos en un consenso Delphi. Las limitaciones destacadas en el seguimiento de la APs fueron la falta de tiempo en consulta, de personal de enfermería, y el retraso en la realización de pruebas de imagen. Se propusieron 108 estrategias relacionadas con la evaluación de los índices de calidad de vida e impacto de la enfermedad; las comorbilidades y las manifestaciones extraarticulares; las pruebas de laboratorio; las pruebas de imagen; la exploración física y metrología y los índices de actividad y función. Entre todas, 53 se consideraron altamente aconsejables, sin diferencias regionales en los valores de consenso. Las propuestas ofrecidas en el estudio actual son aplicables a todo el territorio nacional, responden a las necesidades no cubiertas detectadas en la encuesta inicial, conforman un cuadro de actuación mínimo y aseguran un seguimiento óptimo de los pacientes con APs. Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that affects the musculoskeletal system and skin, and manifests heterogeneously, with a variable course. In current clinical practice, variability and limitations in its follow-up have been observed. The aim of the CREA project was to agree on strategies to improve the initial assessment and follow-up of patients with PsA in Spain. A survey was conducted among a representative sample of expert rheumatologists in Spain, containing 33 questions on current clinical practice, available resources, and current limitations in the follow-up of patients with PsA. The results were discussed in regional meetings and 105 strategies were proposed and finally evaluated by 85 experts in a Delphi consensus. The most important limitations in the follow-up of PsA were lack of consultation time, lack of nursing staff, and delays in performing imaging tests. A total of 108 strategies were proposed related to the assessment of quality of life and disease-impact indices; comorbidities and extra-articular manifestations; laboratory tests; imaging tests; physical examination and metrology; and activity and function indices. Of the total, 53 were considered highly advisable, with no regional differences in consensus values. The proposals offered in the current study are applicable to the entire country, respond to the unmet needs detected in the initial survey, form a minimum action framework, and ensure optimal follow-up of patients with PsA.

BackgroundSpondyloarthritis, (axial (axSpA), peripheral (pSpA)) and psoriatic arthritis (PsA)) share enthesitis as a hallmark clinical feature. Reliable clinical instruments have been developed to assess enthesitis: Spondyloarthritis Research Consortium of Canada Enthesitis (SPARCC), Leeds Enthesitis Index (LEI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and MEI (Mander Enthesitis Index). Since these four indexes include different enthesis locations, they may capture a different number of patients with enthesitis in the different SpA entities.Objectivesa) To describe the individual locations of enthesitis in axSpA, pSpA and PsA; b) to evaluate whether the prevalence of patients with at least one enthesitis across the three groups differs depending on the use of SPARCC, LEI, MASES and MEI indexes; c) to evaluate the level of agreement between these indexes for detecting patients with at least one enthesitis in axSpA, pSpA and PsA populations.MethodsPerSpA was a multinational observational, cross-sectional study with 24 participating countries worldwide. A total of 4185 patients with a diagnosis of axSpA (2719), pSpA (433) and PsA (1033) according to the Rheumatologist’s opinion were included in this analysis. Information on the location of enthesitis collected during the study visit was used according to the SPARCC, LEI, MASES and MEI indexes.The prevalence of patients with at least one enthesitis according to the different indexes were compared across the diseases (axSpA, PsA and pSpA), and pair-wise agreement between indexes were evaluated using the Cohen’s kappa in the global population and in the three groups.ResultsOut of 36 locations, the most prevalent enthesitis in the overall population were the lumbar spinous processes (6.5%), the thoracic spinous processes (4.9%) and the insertion of the Achilles tendon right (4.8%) and left (3.9%). A total of 10.7%, 8.3%, 13.5% and 17.2% of patients in the overall population showed at least one enthesitis according to the SPARCC, LEI, MASES and MEI indexes, respectively. Figure 1 shows that, among patients with axSpA, MEI and MASES indexes capture the majority of patients with at least one enthesitis (98.7% and 82.4%, respectively), while in pSpA and PsA, MEI and SPARCC are the indexes which capture the majority of patients with enthesitis (100% and 84.6% for MEI and SPARCC in pSpA, and 97.3% and 77% for MEI and SPARCC in PsA, respectively). In PsA, the LEI only captured 57.2% of the patients with at least one enthesitis. In the total population, MASES and MEI showed the strongest agreement for patients with at least one enthesitis (absolute agreement 96.3%; Cohen’s kappa: 0.86). Similarly, among axSpA patients, MASES and MEI showed an almost perfect agreement (97.3%; 0.90), while LEI and MEI showed a moderate agreement (90.4%; 0.54). In pSpA patients, SPARCC and MEI showed the strongest agreement (97.2%; 0.90), as well as among PsA patients (95.4%; 0.82). However, MASES and SPARCC showed a less agreement in PsA patients (94.2%; 0.67).Figure 1.Prevalence of enthesitis captured by different indexes.ConclusionThe most prevalent locations of enthesitis on the global SpA population are the lumbar spinous processes, the thoracic spinous processes and Achilles tendon. MEI and MASES are the two index that capture more patients with enthesitis in axSpA, while MEI and SPARCC are the two index that capture more patients in pSpA and PsA. The LEI index may underestimate the prevalence of enthesitis in these patients. MASES and MEI showed the largest level of agreement in the overall population and in axSpA, while MEI and SPARCC showed the largest level of agreement in pSpA and PsA. These results suggest that the prevalence of enthesitis across entities differs depending on the disease and on the use of the different index.References[1]Heuft-Dorenbosch L, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis 2003;62:127-132Disclosure of InterestsNone declared

Background and aim: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that affects the musculoskeletal system and skin, and manifests heterogeneously, with a variable course. In current clinical practice, variability and limitations in its follow-up have been observed. The aim of the CREA project was to agree on strategies to improve the initial assessment and follow-up of patients with PsA in Spain.Materials and methods: A survey was conducted among a representative sample of expert rheumatologists in Spain, containing 33 questions on current clinical practice, available resources, and current limitations in the follow-up of patients with PsA. The results were discussed in regional meetings and 105 strategies were proposed and finally evaluated by 85 experts in a Delphi consensus. Results: The most important limitations in the follow-up of PsA were lack of consultation time, lack of nursing staff, and delays in performing imaging tests. A total of 108 strategies were proposed related to the assessment of quality of life and disease-impact indices; comorbidities and extra-articular manifestations; laboratory tests; imaging tests; physical examination and metrology; and activity and function indices. Of the total, 53 were considered highly advisable, with no regional differences in consensus values. Discussion and conclusions: The proposals offered in the current study are applicable to the entire country, respond to the unmet needs detected in the initial survey, form a minimum action framework, and ensure optimal follow-up of patients with PsA.(c) 2022 Elsevier Espana, S.L.U. and Sociedad Espanola de Reumatologia y Colegio Mexicano de Reumatologia. All rights reserved.

Aims To explore the clinical and radiographical characteristics of axial psoriatic arthritis (PsA) and to compare it with ankylosing spondylitis (AS) with psoriasis. Methods Cross-sectional study from the national multicentre registry REGISPONSER where participants fulfilled the European Spondyloarthropathy Study Group spondyloarthritis criteria at entry. Clinical, laboratory and radiographical characteristics between patients classified as axial PsA and AS with psoriasis by their rheumatologist are compared according to HLA-B27 status. Results Of 2367 patients on REGISPONSER, n=405 had PsA, of whom 27% (n=109) had axial involvement as per the treating rheumatologist. 30% (n=26/86) of axial PsA were HLA-B27 positive. In the AS group, 9% (127/1422) had a history of psoriasis and were more frequently male, with longer diagnostic delay and more anterior uveitis than those with axial PsA who had more peripheral involvement and nail disease. Patients with HLA-B27-negative axial PsA reported less inflammatory pain and structural damage compared with AS with psoriasis. By contrast, HLA-B27-positive axial PsA shared clinical characteristics similar to AS and psoriasis although with a lower BASRI score. In the multivariable analysis, patients with AS and psoriasis were independently associated with HLA-B27 positivity (OR 3.34, 95% CI 1.42 to 7.85) and lumbar structural damage scored by BASRI (OR 2.14, 95% CI 1.4 to 3.19). Conclusion The more prevalent axial PsA phenotype is predominantly HLA-B27 negative and presents different clinical and radiological manifestations when compared with AS with psoriasis. There is great heterogeneity in what rheumatologists consider axial PsA from a clinical and imaging perspective, highlighting the need for research into possible genetic drivers and a consensus definition.

An amendment to this paper has been published and can be accessed via the original article.