Bosentan effect on echocardiographic systolic pulmonary arterial pressure in systemic sclerosis-related pulmonary hypertension: a systematic review and metanalysis.

OBJECTIVES: Bosentan is a dual endothelin receptor antagonist approved for the treatment of SSc digital ulcers (DU) and pulmonary arterial hypertension (PAH). Systolic pulmonary arterial pressure (sPAP) is a relevant parameter for the follow-up and prognosis of SSc-PAH. The therapeutic magnitude of bosentan in SSc-PAH is not fully understood, thus we aim to establish the degree of sPAP reduction in bosentan treated SSc-PAH patients. METHODS: We performed a systematic literature review in three databases from January 2000 to June 2023, involving sPAP measurement at transthoracic echocardiography of SSc patients before and after starting bosentan. Following the study quality assessment and data extraction, we performed random-effects meta-analysis and Egger's test for publication bias. Stratified analysis was performed for mono-/combination therapy, follow up duration (≤1 year), indication for bosentan therapy (PAH or DU/mixed). RESULTS: In the 11 selected manuscripts, sPAP mean difference before and after bosentan therapy was - 5.63mmHg (CI95% -9.79 to -1.48, p=0.0078). In stratified analysis, sPAP mean was significantly different before and after bosentan therapy only for studies considering < 1 year of follow-up (p=0.0020), monotherapy (p=0.0140) and the strict indication for PAH (p=0.0002). CONCLUSIONS: Bosentan significantly decreases sPAP, a relevant prognostic marker, especially in overt SSc-PAH. However, bosentan did not decrease sPAP when started for DU/mixed indication nor for follow-up>1 year. The burden of publication bias was significant. Therefore, further studies are required to assess bosentan's haemodynamic effect in high-risk patients for SSc-PAH.

Increased Prevalence of Headaches and Migraine in Patients with Psoriatic Arthritis and Axial Spondyloarthritis: Insights from an Italian Cohort Study.

BACKGROUND: Psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) are inflammatory diseases with shared genetic backgrounds and clinical comorbidities. Headache, a common global health issue, affects over 50% of adults and encompasses various types, including migraine, tension-type, and cluster headaches. Migraine, the most prevalent, recurrent, and disabling type, is often associated with other medical conditions such as depression, epilepsy, and psoriasis, but little is known about the relationship between autoimmune disease and the risk of migraine. METHODS: A cross-sectional study was conducted from July to November 2022, enrolling 286 participants, including 216 with PsA, 70 with axSpA, and 87 healthy controls. RESULTS: Headache prevalence was significantly higher in the PsA (39.81%) and axSpA (45.71%) patients compared to the healthy controls. The prevalence of migraine without aura was also significantly higher in both the PsA (18.52%) and axSpA (28.57%) groups compared to the healthy controls. CONCLUSIONS: These findings underscore the high burden of headache and migraine in PsA and axSpA participants, highlighting the need for improved management and treatment strategies for these patients.

Association between Patient Acceptable Symptom State and disease activity in psoriatic arthritis is disrupted by confounders, including comorbid fibromyalgia.

OBJECTIVES: Due to the prevalence of fibromyalgia in psoriatic arthritis (PsA) patients, any evaluation about PsA-specific patient-reported outcomes (PROs) should take in account the possible bias related to this comorbidity. Patient acceptable symptom state (PASS) is a patient-reported measure evaluating the acceptable and/or satisfactory level of symptoms in rheumatic diseases, which has been proposed as a disease activity index, in patients with PsA. Thus, this study was designed to analyse if the association between PASS and PsA disease activity may be biased by the presence of comorbid fibromyalgia. METHODS: A multi-centre, cross-sectional, observational study enrolling consecutive PsA participants has been conducted from July 2021 to November 2021. The Disease Activity for Psoriatic Arthritis (DAPSA) was collected; the following formulation of PASS question: 'Think about all the ways your PsA has affected you during the last 48 hours. If you were to remain in the next few months as you were during the last 48 hours, would this be acceptable to you?', was submitted to our participants. RESULTS: Multivariable logistic regressions, adjusted for the presence of fibromyalgia, did not show any significant association between PASS and DAPSA low disease activity, DAPSA as nominal variable (remission, low disease activity, moderate disease activity, high disease activity) and DAPSA as continuous variable. CONCLUSIONS: Our data suggest that fibromyalgia influences the patient's perception of the disease and has a negative impact on PASS status independently of disease activity, thus limiting the utility of this Patient reported outcome in real world clinical practice.

The assessment of atlantoaxial joint involvement in patients with rheumatoid arthritis, results from an observational "real-life" study.

Atlantoaxial joint is a possible affected site during rheumatoid arthritis (RA) and, in this work, we evaluated its occurrence and associated characteristics in a "real-life" cohort. By a medical records review study of RA patients longitudinally followed-up, the occurrence of severe atlantoaxial joint involvement was estimated (incidence proportion and incidence rate per 1000 person-years at risk). Regression analyses were also exploited to evaluate possible associated factors. Based on these findings, a prospective recruitment was performed to build a descriptive cross-sectional study in evaluating a subclinical atlantoaxial joint involvement in patients with the same clinical characteristics. Retrospectively, 717 patients (female 56.6%, age 64.7 ± 12.3 years) were studied. The incidence proportion of severe atlantoaxial joint involvement was 2.1% [1.5-2.5], occurring in 15 out of 717 patients, and identified by both MRI and CT scan. Considering over 3091 person-years, an incidence rate of 5.2 × 1000 [2.9-8.3] person-years was estimated. Regression analyses suggested that male gender, a longer disease duration, ACPA positivity and extra-articular manifestations resulted to be significantly associated with a severe atlantoaxial joint involvement. Given these findings, 30 asymptomatic patients were selected according to these clinical characteristics and underwent MRI of cervical spine. To date, almost 50% of these asymptomatic patients showed a subclinical atlantoaxial joint involvement. The occurrence of the severe atlantoaxial joint involvement in RA patients was estimated in a "real-life" setting. Male gender, ACPA positivity, long disease duration, and extra-articular manifestations could be associated with the severe atlantoaxial joint involvement in RA. MRI could provide a useful clinical tool to early evaluate the atlantoaxial joint involvement in RA, also in asymptomatic patients.

The specialized pro-resolving lipid mediator Protectin D1 affects macrophages differentiation and activity in Adult-onset Still's disease and COVID-19, two hyperinflammatory diseases sharing similar transcriptomic profiles.

Introduction: COVID-19 and autoinflammatory diseases, such as Adult-onset Still's Disease (AOSD), are characterized by hyperinflammation, in which it is observed massive production and uncontrolled secretion of pro-inflammatory cytokines. The specialized pro-resolving lipid mediators (SPMs) family is one the most important processes counteracting hyperinflammation inducing tissue repair and homeostasis restoration. Among SPMs, Protectin D1 (PD1) is able to exert antiviral features, at least in animal models. The aim of this study was to compare the transcriptome of peripheral blood mononuclear cells (PBMCs) from patients with AOSD and COVID-19 and to evaluate the role of PD1 on those diseases, especially in modulating macrophages polarization. Methods: This study enrolled patients with AOSD, COVID-19, and healthy donors HDs, undergoing clinical assessment and blood sample collection. Next-generation deep sequencing was performed to identify differences in PBMCs transcripts profiles. Plasma levels of PD1 were assessed by commercial ELISA kits. Monocyte-derived macrophages were polarized into M1 and M2 phenotypes. We analyzed the effect of PD1 on macrophages differentiation. At 10 days, macrophages were analyzed for surface expression of subtypes markers by flow cytometry. Cytokines production was measured in supernatants by Bio-Plex Assays. Results: In the transcriptomes from AOSD patients and COVID-19 patients, genes involved in inflammation, lipid catabolism, and monocytes activation were specifically dysregulated in AOSD and COVID-19 patients when compared to HDs. Patients affected by COVID-19, hospitalized in intensive care unit (ICU), showed higher levels of PD1 when compared to not-ICU hospitalized patients and HDs (ICU COVID-19 vs not-ICU COVID-19, p= 0.02; HDs vs ICU COVID-19, p= 0.0006). PD1 levels were increased in AOSD patients with SS ≥1 compared to patients with SS=0 (p=0.028) and HDs (p=0.048). In vitro treatment with PD1 of monocytes-derived macrophages from AOSD and COVID-19 patients induced a significant increase of M2 polarization vs control (p<0.05). Furthermore, a significant release of IL-10 and MIP-1ß from M2 macrophages was observed when compared to controls (p<0.05). Discussion: PD1 is able to induce pro-resolutory programs in both AOSD and COVID-19 increasing M2 polarization and inducing their activity. In particular, PD1-treated M2 macrophages from AOSD and COVID-19 patients increased the production of IL-10 and enhanced homeostatic restoration through MIP-1ß production.

Interstitial Lung Disease and Pulmonary Damage in Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary lung involvement is the most common extra-glandular manifestation in patients with primary Sjögren's syndrome (pSS), leading to a worsening of the patient's prognosis. To date, different studies have assessed the prevalence of pulmonary involvement and interstitial lung disease (ILD) in pSS patients with different results. METHODS: We performed a systematic literature review and meta-analysis on ILD pooled prevalence in pSS according to the PRISMA and MOOSE guidelines. Furthermore, we explored the pooled prevalence of the two main presentations of pSS-ILD, nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). RESULTS: We analysed the pSS-ILD prevalence in 30 studies including 8255 pSS patients. The pSS-ILD pooled prevalence was 23% (95% CI: 16-30). For NSIP, we found a pooled prevalence of 52% (CI 41-64), and for UIP we found a pooled prevalence of 44% (CI: 32-55). Regarding the meta-regression analysis, male gender, DLco value, country, and HRCT seem to contribute to the ILD presence. CONCLUSIONS: At least 20% of pSS patients have a comorbid ILD, usually NSIP. Male gender and alteration in DLco value may be considered the most important independent factors supporting an active search of lung complications during the clinical history of pSS patients.

Cardiometabolic multimorbidity may identify a more severe subset of rheumatoid arthritis, results from a "real-life" study.

This "real-life" cross-sectional study has been designed to describe disease features of rheumatoid arthritis (RA) participants affected by cardiometabolic multimorbidity than those without. Our purpose was also the identification of possible associations between these cardiometabolic diseases and RA clinical characteristics. Consecutive RA participants with and without cardiometabolic multimorbidity were assessed and their clinical characteristics were recorded. Participants were grouped and compared by the presence or not of cardiometabolic multimorbidity (defined as ≥ 2 out of 3 cardiovascular risk factors including hypertension, dyslipidemia, and type 2 diabetes). The possible influence of cardiometabolic multimorbidity on RA features of poor prognosis was assessed. The positivity of anti-citrullinated protein antibodies, presence of extra-articular manifestations, lack of clinical remission, and biologic Disease-Modifying anti-Rheumatic Drugs (bDMARDs) failure were considered as RA features of poor prognosis. In the present evaluation, 757 consecutive RA participants were evaluated. Among them, 13.5% showed cardiometabolic multimorbidity. These were older (P < .001) and characterized by a longer disease duration (P = .023). They were more often affected by extra-articular manifestations (P = .029) and frequently displayed smoking habit (P = .003). A lower percentage of these patients was in clinical remission (P = .048), and they showed a more frequent history of bDMARD failure (P < .001). Regression models showed that cardiometabolic multimorbidity was significantly correlated with RA features of disease severity. They were predictors of anti-citrullinated protein antibodies positivity, of extra-articular manifestations, and of lack of clinical remission, in both univariate and multivariate analyses. Cardiometabolic multimorbidity was significantly associated with a history of bDMARD failure. We described disease features of RA participants with cardiometabolic multimorbidity, identifying a possible more difficult to treat subset, which may need a new management approach to achieve the treatment goal.

The negative impact of pain catastrophising on disease activity: analyses of data derived from patient-reported outcomes in psoriatic arthritis and axial spondyloarthritis.

OBJECTIVES: Psychosocial factors are recognised as important determinants of pain experience in patients with inflammatory arthritides. Among them, pain catastrophising, a maladaptive cognitive style, observed in patients with anxiety and depressive disorders, garnered specific attention. Here, we evaluated pain catastrophising (PC) and its related domains (Rumination, Magnification, and Helplessness), in psoriatic arthritis (PsA) and axial spondyloarhtiritis (axSpA) participants, to assess its impact on disease activity. Furthermore, we analysed possible correlations of PC-Scale (PCS) with those psychometric domains which have been already related to catastrophisation in patients with chronic pain. Lastly, we aimed to define the relationship between PCS and the different variables included in the composite indices of disease activity. METHODS: A multi-centre, cross-sectional, observational study has been conducted on 135 PsA (age 56 (47-64) years, males/females 40.74/59.26%; Disease Activity in Psoriasic Arthritis (DAPSA) 13.34 (5.21-22.22)) and 71 axSpA (age 49 (37-58) years, males/females 56.34/43.66%; Bath Ankylosing Spondylitis Arthritis Activity (BASDAI) 4.17 (2.1-6.3)) participants. Multivariable regressions and correlations were performed to evaluate the relationship between pain catastrophising and both disease activity and patient-reported outcomes. RESULTS: The adjusted linear regression model showed a positive association between PCS and DAPSA as well as between PCS and BASDAI; PCS negative impacts on the subjective domains of disease activity scores. CONCLUSIONS: This study suggests the role of PC, independently of inflammation, in disease perception and achievement of remission or low disease activity in chronic arthritides.

The similar expression of both ferritin and scavenger receptors activation genes in patients with COVID19 and AOSD support their role in the pathogenesis of these diseases and identify a common mechanism at the basis of the "hyperferritinemic syndromes".

A role for COVID19 in "hyperferritinemic syndromes" has been proposed based on its clinical and serological characteristics and its similarities with AOSD. To better understand the molecular pathways responsible of these similarities, we evaluated in the PBMCs of 4 active AOSD patients, 2 COVID19 patients with ARDS, and 2 HCs the expression of genes associated with iron metabolisms, with monocyte/macrophages activation, and finally with NETs formation.

2-Arachidonoylglycerol Reduces the Production of Interferon-Gamma in T Lymphocytes from Patients with Systemic Lupus Erythematosus.

Background: the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a pivotal role in immune cells regulation. The plasma levels of 2-AG are increased in patients with systemic lupus erythematosus (SLE) and correlate with disease activity. Moreover, in plasmacytoid dendritic cells from SLE patients, 2-AG is able to control the production of type 1 interferon (IFN) through CB2 activation. The aim of this study was to evaluate the potential role of 2-AG on T lymphocytes from SLE patients. Methods: peripheral blood mononuclear cells (PBMCs) from SLE participants and age- and sex-matched healthy donors (HD) were isolated by Ficoll-Hypaque density-gradient centrifugation. The PBMCs were treated with increasing concentrations of 2-AG, and AM251 and AM630 were used to antagonize CB1 and CB2, respectively. Flow cytometry was used to assess the expression of CD3, CD4, CD8, CD25, IFN-É£, IL-4, and IL-17A. Results: 2-AG (1 µM) decreased IFN-É£ expression (p = 0.0005) in the Th1 lymphocytes of SLE patients. 2-AG did not modulate the cytokine expression of any other T lymphocyte population from either SLE or HD. Treatment with both 2-AG and AM630 increased the IFN-É£ expression in Th1 lymphocytes of SLE patients (p = 0.03). Discussion: 2-AG is able to modulate type 2 IFN production from CD4+ T lymphocytes from SLE patients through CB2 activation.

Persistence of C-reactive protein increased levels and high disease activity are predictors of cardiovascular disease in patients with axial spondyloarthritis.

An accurate prediction of cardiovascular (CV) risk in patients with Axial Spondyloarthritis (axSpA) is a strong unmet need, as CV risk algorithms poorly perform in these subjects. The aim of this study was to establish whether the persistence of high C-reactive protein (CRP) and high disease activity may be considered predictive factors of CVD in axSpA. 295 patients without personal history of CVD, were consecutively enrolled in this study. To evaluate the relationship between CV events occurrence (fatal and non-fatal) and the persistence of increased CRP levels, ASDAS (Ankylosing Spondylitis Disease Activity Score) > 2.1, and BASDAI (Bath Ankylosing Spondylitis Disease Activity) > 4 during the follow-up, univariable and multivariable Cox Proportional Hazard Models have been performed. During follow-up (we analyzed 10-years retrospective data), 23 patients had a CV event. Multivariable Cox Proportional Hazard Models showed a strong association between CV event and the persistency of increased CRP levels (namely, percentage of visits in which CRP levels were increased) (HR = 1.03; 95%CI 1.015-1.045; p < 0.001), of ASDAS > 2.1 (HR = 1.014, 95%CI 1.000-1.028, p = 0.047), and of BASDAI > 4 (HR 1.019, 95%CI 1.006-1.033, p = 0.006) during follow-up, after adjustment for age, sex, and diabetes. This study suggests that persistence of increased CRP levels and high disease activity may be considered biomarkers to identify those axSpA patients at higher risk of CVD. Innovative axSpA-specific CV risk score, including these variables, have to be developed.

Duration of clinical remission and low disease activity impacts on quality of life and its domains in psoriatic arthritis patients: results from an Italian multicentre study.

OBJECTIVES: Long-term quality of life (QoL) is significantly compromised in patients with psoriatic arthritis (PsA) and only partially improves achieving remission or low disease activity. The main aim of this study is to evaluate the QoL in PsA patients and to investigate their possible relationship with clinical remission and low disease activity, and with its duration over time. METHODS: A multicentre cross-sectional observational study has been performed. QoL domains considered were analysed through PROs. Chi2 test was used for analysis of contingency tables, while Mann-Whitney test and Kruskal-Wallis test with Holm's pairwise comparison corrections were used to compare ranks. To evaluate variables associated to the different QoL domains, univariate and multiple linear regressions were used. RESULTS: 143 participants were included in this study. The physical component of the Short Form-36 or Functional Assessment of Chronic Illness Therapy-Fatigue tends to improve with short duration of low or minimal disease activity. However, this is not confirmed for the mental component of SF-36 (MCS), which improved only with longer duration of low/minimal disease activity. CONCLUSIONS: This study proves the existence of an inverse relation between disease activity and QoL domains. Apart from low or minimal disease activity, also its persistence over time has a great influence on the patient's perception of their clinical condition; therefore, persistence over time of clinical remission/low disease activity should be added to the latest definition of treat-to-target in PsA.

Experimental and Investigational Pharmacotherapy for Psoriatic Arthritis: Drugs of the Future.

In recent years, different studies have shown in psoriatic arthritis (PsA), the pathogenetic role of multiple cytokines other than tumor necrosis factor-α, such as interleukin-17 (IL-17), and IL-23 and dysfunction of Janus kinase (JAK)-signal family pathway. These molecules also represent the target of recently developed biologic (bDMARDs) and targeted synthetic disease modifying antirheumatic drugs (DMARDs) (tsDMARDs) currently investigated in several Phase II and III randomized controlled trials (RCTs). This review examines the therapeutic efficacy and safety of most recent developed IL-17, IL-23 and JAK inhibitors and highlights how these new PsA therapies are going to revolutionize the management of PsA in the next few years. Ongoing RCTs of these molecules in PsA are also described. Available literature on new anti-IL-17 and anti-IL-23 agents and JAK inhibitors demonstrates the potential role of these molecules as effective therapeutic strategies across multiple PsA clinical domains, along with an acceptable tolerability and safety profile, thus expanding the treatment options available for PsA patients. Of note, other molecules are under investigation, and among those, potential therapeutic strategies seem to be represented by single antibodies blocking simultaneously two cytokines, the agents inhibiting mammalian target of rapamycin (mTOR), receptor retinoic acid receptor-related orphan receptor gamma (RORγt), A3 adenosine receptor (A3 AR), and K+ channel voltage channel inhibitors. Remarkable progress has been made in PsA pharmacotherapy, and novel bDMARDs targeting IL17A and tsDMARDs (JAK-inhibitors) represent promising therapies. More clinical trials are needed to better characterize the efficacy and safety profile of these therapeutic agents in PsA treatment.

Cardiovascular Risk Prediction in Ankylosing Spondylitis: From Traditional Scores to Machine Learning Assessment.

INTRODUCTION: The performance of seven cardiovascular (CV) risk algorithms is evaluated in a multicentric cohort of ankylosing spondylitis (AS) patients. Performance and calibration of traditional CV predictors have been compared with the novel paradigm of machine learning (ML). METHODS: A retrospective analysis of prospectively collected data from an AS cohort has been performed. The primary outcome was the first CV event. The discriminatory ability of the algorithms was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC), which is like the concordance-statistic (c-statistic). Three ML techniques were considered to calculate the CV risk: support vector machine (SVM), random forest (RF), and k-nearest neighbor (KNN). RESULTS: Of 133 AS patients enrolled, 18 had a CV event. c-statistic scores of 0.71, 0.61, 0.66, 0.68, 0.66, 0.72, and 0.67 were found, respectively, for SCORE, CUORE, FRS, QRISK2, QRISK3, RRS, and ASSIGN. AUC values for the ML algorithms were: 0.70 for SVM, 0.73 for RF, and 0.64 for KNN. Feature analysis showed that C-reactive protein (CRP) has the highest importance, while SBP and hypertension treatment have lower importance. CONCLUSIONS: All of the evaluated CV risk algorithms exhibit a poor discriminative ability, except for RRS and SCORE, which showed a fair performance. For the first time, we demonstrated that AS patients do not show the traditional ones used by CV scores and that the most important variable is CRP. The present study contributes to a deeper understanding of CV risk in AS, allowing the development of innovative CV risk patient-specific models.

Homocysteinylated alpha 1 antitrypsin as an antigenic target of autoantibodies in seronegative rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic autoimmune disease and rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are the most frequently detected autoantibodies (autoAbs). To date, more than 20% of RA cases are still defined as seronegative forms (seronegative RA, SN-RA). The aim of this study was to identify new antigenic targets of autoAbs in RA patients, which can also be recognized in SN-RA. Using a proteomic approach, we tested sera from SN-RA patients by analyzing synovial fluid (SF) proteins from these patients. Sera from SN-RA patients revealed a strong reactive spot, corresponding to alpha 1 antitrypsin (A1AT). Reverse-phase nanoliquid chromatography and tandem mass spectrometry (Matrix Assisted Laser Desorption/Ionization-Time Of Flight, MALDI-TOF/TOF) confirmed the presence of A1AT in SF and showed that homocysteinylation was one of the post-translational modifications of A1AT. Homocysteinylated (Hcy)-A1AT immunoprecipitated from SN-RA patients' SFs and in vitro modified Hcy-A1AT were used as antigens by Enzyme-Linked ImmunoSorbent Assay (ELISA) to test the presence of specific autoAbs in sera from 111 SN-RA patients, 132 seropositive (SP)-RA patients, and from 95 patients with psoriatic arthritis, 40 patients with osteoarthritis, and 41 healthy subjects as control populations. We observed that a large portion of SN-RA patients (75.7%), and also most of SP-RA patients' sera (87.1%) displayed anti-Hcy-A1AT autoAbs (anti-HATA). Native A1AT was targeted at a lower rate by SP-RA patients autoAbs, while virtually no SN-RA patients' sera showed the presence of anti-native A1AT autoAbs. In conclusion, anti-HATA can be considered potential biomarkers for RA, also in the SN forms. The discovery of novel autoAbs targeting specific autoantigens can represent higher clinic significance for all RA patients' population.