Higher Synovial Immunohistochemistry Reactivity of IL-17A, Dkk1, and TGF-ß1 in Patients with Early Psoriatic Arthritis and Rheumatoid Arthritis Could Predict the Use of Biologics.

BACKGROUND: Delay in diagnosis and therapy in patients with arthritis commonly leads to progressive articular damage. The study aimed to investigate the immunohistochemical reactivity of synovial cytokines associated with inflammation and the bone erosives/neoformatives processes among individuals diagnosed with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and radiographic axial spondyloarthritis (r-axSpA), with the intention of identifying potential biomarkers. METHODS: Specimens were collected from the inflamed knee joints of patients referred for arthroscopic procedures, and the synovial tissue (ST) was prepared for quantifying protein expression through immunohistochemical analysis (% expressed in Ratio_Area-Intensity) for TGF-ß1, IL-17A, Dkk1, BMP2, BMP4, and Wnt5b. The collected data underwent thorough analysis and examination of their predictive capabilities utilising receiver operating characteristic (ROC) curves. RESULTS: Valid synovial tissue samples were acquired from 40 patients for IHC quantification analysis. Initially, these patients had not undergone treatment with biologics. However, after 5 years, 4 out of 13 patients diagnosed with PsA and two out of nine patients diagnosed with RA had commenced biologic treatments. Individuals with early PsA who received subsequent biologic treatment exhibited significantly elevated IHC reactivity in ST for TGF-ß1 (p = 0.015). Additionally, patients with both PsA and RA who underwent biologic therapy displayed increased IHC reactivity for IL-17A (p = 0.016), TGF-ß1 (p = 0.009), and Dkk1 (p = 0.042). ROC curve analysis of IHC reactivity for TGF-ß1, Dkk1, and IL-17A in the synovial seems to predict future treatment with biologics in the next 5 years with the area under the curve (AUC) of a combined sum of the three values: AUC: 0.828 (95% CI: 0.689-0.968; p 0.005) S 75% E 84.4%. CONCLUSIONS: Higher synovial immunohistochemistry reactivity of IL-17A, Dkk1, and TGF-ß1 in patients with early psoriatic arthritis and rheumatoid arthritis may serve as potential indicators for predicting the necessity of utilising biologic treatments.

Increased synovial immunohistochemistry reactivity of TGF-ß1 in erosive peripheral psoriatic arthritis.

BACKGROUND: Immune and non-immune cells contribute to the pathology of chronic arthritis, and they can contribute to tissue remodeling and repair as well as disease pathogenesis. The present research aimed to analyze inflammation and bone destruction/regeneration biomarkers in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS). METHODS: Samples were obtained from the inflamed knee of patients with knee arthritis who had been referred for undergoing arthroscopies. The synovial membrane was processed for pathological description, IHC analysis, and quantification of mRNA expression ratio by qRT-PCR. Serum levels of TGF-ß1, IL-23, IL-6, IL-17 A, IL-22, Dkk1, Sclerostin, BMP2, BMP4, Wnt1, and Wnt5a were measured by ELISA. All these data were analyzed and compared with the demographic, clinical, blood tests, and radiological characteristics of the patients. RESULTS: The synovial membrane samples were obtained from 42 patients for IHC, extraction, and purification of RNA for synovial mRNA expression analysis, and serum for measuring protein levels from 38 patients. IHC reactivity for TGF-ß1 in the synovial tissue was higher in patients with psoriatic arthritis (p 0.036) and was positively correlated with IL-17 A (r = 0.389, p = 0.012), and Dkk1 (r = 0.388, p = 0.012). Gene expression of the IL-17 A was higher in PsA patients (p = 0.018) and was positively correlated with Dkk1 (r = 0.424, p = 0.022) and negatively correlated with BMP2 (r = -0.396, p = 0.033) and BMP4 (r = -0.472, p = 0.010). It was observed that IHC reactivity for TGF-ß1 was higher in patients with erosive PsA (p = 0.024). CONCLUSIONS: The IHC reactivity of TGF-ß1 in synovial tissue was higher in patients with erosive psoriatic arthritis, and TGF-ß1 was in relation to higher levels of gene expression of IL-17 A and Dkk1.

Confounders contributing to explain the association between sex and disease impact in patients with recent-onset psoriatic arthritis.

OBJECTIVES: To evaluate the effect of potential confounders on the association between sex and disease impact in recent-onset psoriatic arthritis. METHODS: We performed a multicentre observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset was generated using data for each patient at the 3 visits (baseline, first year, and second year of follow-up) matched with the PsAID values at each of the 3 visits. Once variables associated with both PsAID ≥4 and sex were selected, those that led to a difference of >10% between the adjusted and crude estimations were identified as potential confounders in the association between sex and PsAID. Lastly, the final multivariate logistic regression model estimating the association between sex and PsAID was defined. RESULTS: The dataset contained 418 observations (158 at baseline, 135 at the first follow-up visit, and 125 at the second visit). The confounders identified in the multivariate model were HAQ, global pain, level of physical activity, and joint pattern at diagnosis. After adjustment for these variables, no statistically significant association was observed between female sex and PsAID ≥4. CONCLUSIONS: The association between female sex and greater disease impact could be explained by the influence of other variables, specifically higher HAQ score, greater intensity of pain, differences in the level of physical activity and in the joint pattern at diagnosis (lower frequency of the spondylitis pattern in women).

Characteristics associated with the perception of high-impact disease (PsAID ≥4) in patients with recent-onset psoriatic arthritis. Machine learning-based model.

OBJECTIVES: To evaluate which patient and disease characteristics are associated with the perception of high-impact disease (PsAID ≥4) in recent-onset psoriatic arthritis. METHODS: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset was generated using data for each patient at the 3 visits (baseline, first year, and second year of follow-up) matched with the PsAID values at each of the 3 visits. PsAID was categorized into two groups (<4 and ≥4). We trained a logistic regression model and random forest-type and XGBoost machine learning algorithms to analyze the association between the outcome measure and the variables selected in the bivariate analysis. A k-fold cross-validation with k = 5 was performed. RESULTS: The sample comprised 158 patients. Of the patients who attended the clinic, 45.8% scored PsAID ≥4 at baseline; 27.1%, at the first follow-up visit, and in 23.0%, at the second follow-up visit. The variables associated with PsAID ≥4 were, in decreasing order of importance: HAQ, pain, educational level, and physical activity. Higher HAQ (logistic regression coefficient 10.394; IC95% 7.777,13.011), higher pain (5.668; 4.016, 7.320), lower educational level (-2.064; -3.515, -0.613) and high level of physical activity (1.221; 0.158, 2.283) were associated with a higher frequency of PsAID ≥4. The mean values of the measures of validity of the algorithms were all ≥85%. CONCLUSIONS: Despite the higher weight given to pain when scoring PsAID, we observed a greater influence of physical function on disease impact.

Minimal disease activity (MDA) in patients with recent-onset psoriatic arthritis: predictive model based on machine learning.

BACKGROUND: Very few data are available on predictors of minimal disease activity (MDA) in patients with recent-onset psoriatic arthritis (PsA). Such data are crucial, since the therapeutic measures used to change the adverse course of PsA are more likely to succeed if we intervene early. In the present study, we used predictive models based on machine learning to detect variables associated with achieving MDA in patients with recent-onset PsA. METHODS: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset contained data for the independent variables from the baseline visit and from follow-up visit number 1. These were matched with the outcome measures from follow-up visits 1 and 2, respectively. We trained a random forest-type machine learning algorithm to analyze the association between the outcome measure and the variables selected in the bivariate analysis. In order to understand how the model uses the variables to make its predictions, we applied the SHAP technique. We used a confusion matrix to visualize the performance of the model. RESULTS: The sample comprised 158 patients. 55.5% and 58.3% of the patients had MDA at the first and second follow-up visit, respectively. In our model, the variables with the greatest predictive ability were global pain, impact of the disease (PsAID), patient global assessment of disease, and physical function (HAQ-Disability Index). The percentage of hits in the confusion matrix was 85.94%. CONCLUSIONS: A key objective in the management of PsA should be control of pain, which is not always associated with inflammatory burden, and the establishment of measures to better control the various domains of PsA.

Severe Disease in Patients With Recent-Onset Psoriatic Arthritis. Prediction Model Based on Machine Learning.

Objectives: To identify patient- and disease-related characteristics that make it possible to predict higher disease severity in recent-onset PsA. Methods: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥ 18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. Severe disease was defined at each visit as fulfillment of at least 1 of the following criteria: need for systemic treatment, Health Assessment Questionnaire (HAQ) > 0.5, polyarthritis. The dataset contained data for the independent variables from the baseline visit and follow-up visit number 1. These were matched with the outcome measures from follow-up visits 1 and 2, respectively. We trained a logistic regression model and random forest-type and XGBoost machine learning algorithms to analyze the association between the outcome measure and the variables selected in the bivariate analysis. Results: The sample comprised 158 patients. At the first follow-up visit, 78.2% of the patients who attended the clinic had severe disease. This percentage decreased to 76.4% at the second visit. The variables predicting severe disease were patient global pain, treatment with synthetic DMARDs, clinical form at diagnosis, high CRP, arterial hypertension, and psoriasis affecting the gluteal cleft and/or perianal area. The mean values of the measures of validity of the machine learning algorithms were all ≥ 80%. Conclusion: Our prediction model of severe disease advocates rigorous control of pain and inflammation, also addressing cardiometabolic comorbidities, in addition to actively searching for hidden psoriasis.

Secukinumab como tratamiento biológico en la artritis psoriásica en práctica clínica real / Secukinumab as Biological Treatment for Psoriatic Arthritis in Real Clinical Practice

Introducción: Los ensayos clínicos de secukinumab han demostrado su eficacia y seguridad en la artritis psoriásica como biológico de primera opción o tras respuesta inadecuada a otros tratamientos biológicos. Objetivo: Analizar la eficacia y seguridad de secukinumab en la artritis psoriásica periférica durante 12 meses en práctica clínica real. Material y métodos: Se incluyó a pacientes con artritis psoriásica periférica activa que iniciaron tratamiento con secukinumab según ficha técnica. Se evaluó la eficacia y seguridad desde la situación basal hasta los 12 meses, comparando la respuesta de pacientes naive y no naive al biológico. Resultados: Se incluyó a 76 pacientes (22 naive y 54 no naive al biológico) con una edad de 51,9 años (10,3) y una duración de la enfermedad de 9,5 años (7,1). El 31,6% con dactilitis, el 51,3% con entesitis y el índice DAPSA basal fue 19 (9,8). La tasa de retención fue elevada: 90,9% en naive y 81,5% en no naive, y el porcentaje de pacientes con un DAPSA menor o igual a 14 fue mayor en pacientes naive, incluso después de ajustar por edad, sexo y fármacos modificadores del curso de la enfermedad (p=0,016). Los datos de seguridad fueron similares a los descritos en los ensayos clínicos. Conclusiones: Secukinumab es eficaz y seguro en el tratamiento a 12 meses en la artritis psoriásica periférica activa en la práctica clínica real, tras respuesta inadecuada a los iTNF o como primer biológico.(AU)

Introduction: Clinical trials of secukinumab have demonstrated their efficacy and safety in psoriatic arthritis as biological first choice or after inadequate response to other biological treatments. Objective: To analyze the efficacy and safety of secukinumab in peripheral psoriatic arthritis over 12 months in real clinical practice. Material and methods: Patients with active peripheral psoriatic arthritis who started treatment with secukinumab according to the technical specifications were included. Efficacy and safety were evaluated from baseline to 12 months comparing naive and non-naive to biological therapy patients. Results: A total of 76 patients were included (22 naive and 54 non-naive to biological) with an age of 51.9 years (10.3) and duration of the disease of 9.5 years (7.1). Of them, 31.6% with dactylitis, 51.3% with enthesitis and the baseline DAPSA was 19.0 (9.8). The retention rate was high, 90.9% in naive and 81.5% in non-naïve patients, and the percentage of patients with a DAPSA less than or equal to 14 was higher in the naive patients even after adjusting for age, sex and FAMEsc (P=.016). The safety data were similar to those described in the clinical trials. Conclusions: Secukinumab is effective and safe in 12-month treatment in peripheral active psoriatic arthritis in real clinical practice, after inadequate response to TNF or as first biological treatment.(AU)

Secukinumab as Biological Treatment for Psoriatic Arthritis in Real Clinical Practice. / Secukinumab como tratamiento biológico en la artritis psoriásica en práctica clínica real.

INTRODUCTION: Clinical trials of secukinumab have demonstrated their efficacy and safety in psoriatic arthritis as biological first choice or after inadequate response to other biological treatments. OBJECTIVE: To analyze the efficacy and safety of secukinumab in peripheral psoriatic arthritis over 12 months in real clinical practice. MATERIAL AND METHODS: Patients with active peripheral psoriatic arthritis who started treatment with secukinumab according to the technical specifications were included. Efficacy and safety were evaluated from baseline to 12 months comparing naive and non-naive to biological therapy patients. RESULTS: A total of 76 patients were included (22 naive and 54 non-naive to biological) with an age of 51.9 years (10.3) and duration of the disease of 9.5 years (7.1). Of them, 31.6% with dactylitis, 51.3% with enthesitis and the baseline DAPSA was 19.0 (9.8). The retention rate was high, 90.9% in naive and 81.5% in non-naïve patients, and the percentage of patients with a DAPSA less than or equal to 14 was higher in the naive patients even after adjusting for age, sex and FAMEsc (P=.016). The safety data were similar to those described in the clinical trials. CONCLUSIONS: Secukinumab is effective and safe in 12-month treatment in peripheral active psoriatic arthritis in real clinical practice, after inadequate response to TNF or as first biological treatment.

Registro Español de Artritis Psoriásica de Reciente Comienzo (estudio REAPSER). Objetivos y metodología / Spanish Registry of Recent-onset Psoriatic Arthritis (REAPSER study): aims and methodology

OBJETIVOS: Describir la metodología del Registro Español de Artritis Psoriásica de reciente comienzo de la Sociedad Española de Reumatología (REAPSER), así como sus fortalezas y limitaciones. El objetivo principal del proyecto es identificar factores pronósticos de la evolución clínica y radiográfica en una cohorte de pacientes que padecen artritis psoriásica (APs) diagnosticada con menos de 2 años de evolución. MATERIAL Y MÉTODO: Estudio observacional, prospectivo (2 años de seguimiento; periodicidad anual de las visitas), multicéntrico. La intención en la visita basal fue reflejar la situación del paciente antes de que la evolución de la enfermedad se viese modificada por los tratamientos pautados en los servicios de reumatología. Los pacientes fueron invitados a participar consecutivamente en una de sus visitas habituales al reumatólogo. El tamaño muestral finalmente alcanzado fue de 211 pacientes. Se recogen datos sociodemográficos; de situación laboral; historia familiar; antecedentes personales y comorbilidad; antropométricos; estilo de vida; uso de los servicios de salud; situación clínica al diagnóstico de APs; afectación articular y dolor espinal; dolor y valoración global de la enfermedad; entesitis, dactilitis y uveítis; afectación cutánea y ungueal; situación funcional y calidad de vida; evaluación radiográfica; determinaciones analíticas; tratamiento; brotes en esqueleto axial y periférico. CONCLUSIONES: El estudio REAPSER incluye una cohorte de pacientes con APs de inicio reciente reclutados antes de que la evolución de la enfermedad se viese modificada por la prescripción de FAME en los servicios de reumatología. Se espera que la información exhaustiva recogida en las visitas suponga una amplia fuente de datos para futuros análisis

AIMS: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2 years of symptom evolution. METHODS: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. CONCLUSIONS: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis

Incidence of first cardiovascular event in Spanish patients with inflammatory rheumatic diseases: prospective data from the CARMA project.

OBJECTIVES: To determine the incidence and risk factors of first cardiovascular event (CVE) in patients with chronic inflammatory rheumatic diseases (CIRD). METHODS: Analysis of data after 2.5 years of follow-up from the prospective study CARMA project, that includes patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and matched individuals without CIRD from 67 hospitals in Spain. CVE cumulative incidence per 1000 patients was calculated after 2.5 years from the start of the project. Weibull proportional hazard model was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI) of the risk factors. RESULTS: 2595 (89.1%) patients completed the 2.5 years of follow-up visit. Cumulative incidence of CVE in patients with CIRD was 15.30 cases per 1000 patients (95% CI: 12.93-17.67), being higher in the subgroup with AS; 22.03 (95% CI: 11.01-33.04). Patients with AS (HR: 4.11; 95% CI: 1.07-15.79), those with older age (HR: 1.09; 95% CI: 1.05-1.13), systolic hypertension (HR: 1.02; 95% CI: 1.00-1.04) and long duration of the disease (HR: 1.07; 95% CI: 1.03-1.12) were at higher risk of first CVE during the 2.5 years of follow-up. In contrast, female gender was a protective factor (HR: 0.43; 95% CI: 0.18-1.00). CONCLUSIONS: Among CIRD patients prospectively followed-up at rheumatology outpatient clinics, those with AS show higher risk of first CVE. Besides cardiovascular risk factors, such as hypertension, being a man and older as well as having a long disease duration increase the risk of CVE in patients with CIRD.

Spanish Registry of Recent-onset Psoriatic Arthritis (REAPSER study): Aims and methodology. / Registro Español de Artritis Psoriásica de Reciente Comienzo (estudio REAPSER). Objetivos y metodología.

AIMS: To describe the methodology of REAPSER (Spanish Registry of Recent-onset Psoriatic Arthritis), its strengths and limitations. The aim of this study is to identify prognostic factors for the clinical and radiographic course in a cohort of patients with psoriatic arthritis (PsA) diagnosed within 2years of symptom evolution. METHODS: Multicenter, observational and prospective study (with 2-year follow-up including annual visits). Baseline visit intended to reflect patient situation before the disease course was modified by treatments prescribed in rheumatology departments. Patients were invited to participate consecutively in one of their routine visits to the rheumatologist. 211 patients were included. Following data were collected: sociodemographic variables; employment situation; family history; personal history and comorbidities; anthropometric data; lifestyle; use of healthcare services; clinical situation at the time of PsA diagnosis; joint involvement and spinal pain; pain and overall assessment; enthesitis, dactylitis and uveitis; skin and nail involvement; functional situation and quality of life; radiographic evaluation; analytical determinations; treatment; axial and peripheral flare-ups. CONCLUSIONS: The REAPSER study includes a cohort of patients with recent-onset PsA, before the disease course was modified by disease-modifying antirheumatic drugs prescribed in rheumatology departments. Exhaustive information collected in each visit is expected to be an important data source for future analysis.

A reduced 12-joint ultrasound examination predicts lack of X-ray progression better than clinical remission criteria in patients with rheumatoid arthritis.

To study the predictive value of clinical remission definitions and ultrasound (US) examination on X-ray progression in rheumatoid arthritis (RA). This was an observational prospective multicenter 1-year follow-up cohort of RA patients with moderate disease activity (3.2 < DAS28 ≤ 5.1) who started anti-TNF therapy. DAS28ESR, DAS28CRP, SDAI, CDAI, and ACR/EULAR remission criteria were applied and reduced 12-joint US examination was performed at baseline and at 6 and 12 months. At baseline and month 12, radiographs of hands and feet were obtained in a subset of patients. A blind independent reader scored radiographs. X-ray progression was defined as Sharp van der Heijde change score >1 and no progression was defined as ≤0. 319 of 357 patients completed the study; patients had a mean (SD) age of 53.5 (13.1) years, with a disease duration of 7.5 (7.1) years. Laboratory, clinical, and US values significantly improved at month 6, except CRP, with additional improvement at month 12. Remission and low disease activity rates increased at follow-up. In the subset of 115 patients with radiological studies, clinical remission by any definition was not significantly associated with X-ray progression. Patients without PD signal at baseline and month 6 were a lower risk of X-ray progression than patients with PD signal, OR 0.197 (95% CI 0.046-0.861) and 0.134 (95% CI 0.047-0.378), respectively. Absence of PD signal, but not clinical remission predicts lack of X-ray progression. A feasible 12-joint US examination may add relevant information to RA remission criteria.

Urine metabolome profiling of immune-mediated inflammatory diseases.

BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are a group of complex and prevalent diseases where disease diagnostic and activity monitoring is highly challenging. The determination of the metabolite profiles of biological samples is becoming a powerful approach to identify new biomarkers of clinical utility. In order to identify new metabolite biomarkers of diagnosis and disease activity, we have performed the first large-scale profiling of the urine metabolome of the six most prevalent IMIDs: rheumatoid arthritis, psoriatic arthritis, psoriasis, systemic lupus erythematosus, Crohn's disease, and ulcerative colitis. METHODS: Using nuclear magnetic resonance, we analyzed the urine metabolome in a discovery cohort of 1210 patients and 100 controls. Within each IMID, two patient subgroups were recruited representing extreme disease activity (very high vs. very low). Metabolite association analysis with disease diagnosis and disease activity was performed using multivariate linear regression in order to control for the effects of clinical, epidemiological, or technical variability. After multiple test correction, the most significant metabolite biomarkers were validated in an independent cohort of 1200 patients and 200 controls. RESULTS: In the discovery cohort, we identified 28 significant associations between urine metabolite levels and disease diagnosis and three significant metabolite associations with disease activity (P FDR < 0.05). Using the validation cohort, we validated 26 of the diagnostic associations and all three metabolite associations with disease activity (P FDR < 0.05). Combining all diagnostic biomarkers using multivariate classifiers we obtained a good disease prediction accuracy in all IMIDs and particularly high in inflammatory bowel diseases. Several of the associated metabolites were found to be commonly altered in multiple IMIDs, some of which can be considered as hub biomarkers. The analysis of the metabolic reactions connecting the IMID-associated metabolites showed an over-representation of citric acid cycle, phenylalanine, and glycine-serine metabolism pathways. CONCLUSIONS: This study shows that urine is a source of biomarkers of clinical utility in IMIDs. We have found that IMIDs show similar metabolic changes, particularly between clinically similar diseases and we have found, for the first time, the presence of hub metabolites. These findings represent an important step in the development of more efficient and less invasive diagnostic and disease monitoring methods in IMIDs.