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 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.

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.

Multiparametric autoantibody analysis: a new paradigm for the diagnosis of connective tissue diseases.

BACKGROUND: In patients affected by connective tissue diseases (CTDs), the identification of wide autoantibody profiles may prove useful in early diagnosis, in the evaluation of prognosis (risk stratification), and in predicting response to therapy. The aim of the present study was to evaluate the utility of multiparametric autoantibody analysis performed by a new fully automated particle-based multi-analyte technology (PMAT) digital system in a large multicenter cohort of CTD patients and controls. METHODS: Serum samples from 787 patients with CTD (166 systemic lupus erythematosus; 133 systemic sclerosis; 279 Sjögren's syndrome; 106 idiopathic inflammatory myopathies; 103 undifferentiated CTD), 339 patients with other disorders (disease controls) (118 infectious diseases, 110 organ-specific autoimmune diseases, 111 other rheumatic diseases), and 121 healthy subjects were collected in 13 rheumatologic centers of the FIRMA group. Sera were analyzed with the Aptiva-PMAT instrument (Inova Diagnostics) for a panel of 29 autoantibodies. RESULTS: Multiparametric logistic regression showed that enlarged antibody profiles have a higher diagnostic efficiency than that of individual antibodies or of antibodies that constitute classification criteria for a given disease and that probability of disease increases with multiple positive autoantibodies. CONCLUSIONS: This is the first study that analyzes the clinical and diagnostic impact of autoantibody profiling in CTD. The results obtained with the new Aptiva-PMAT method may open interesting perspectives in the diagnosis and sub-classification of patients with autoimmune rheumatic diseases.

Effectiveness of Golimumab as Second Anti-TNFα Drug in Patients with Rheumatoid Arthritis, Psoriatic Arthritis and Axial Spondyloarthritis in Italy: GO-BEYOND, a Prospective Real-World Observational Study.

In this prospective observational study, data were collected from 34 rheumatology clinics in Italy in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) who started golimumab (GLM) as a second anti-TNFα drug. The primary objective was to evaluate the effectiveness of GLM after 6 months. Changes in quality of life using the EQ-5D-5L were also assessed. A total of 194 patients aged 53.2 ± 12 years started GLM as a second anti-TNF drug: 39 (20.1%) with RA, 91 (46.9%) with PsA and 64 (32.9%) with axSpA. After 6 months of GLM treatment, 68% of RA patients achieved low disease activity (LDA; DAS28-CRP ≤ 3.2), 31.9% of PsA patients achieved minimal disease activity and 32.5% of axSpA patients achieved LDA (ASDAS-CRP < 2.1). Good/moderate EULAR response was achieved in 61.9% and 73.8% of patients with RA and PsA, respectively, and 16% of axSpA patients achieved a 50% improvement in BASDAI. Across all indications, improvements in disease activity measures and EQ-5D-5L domains were observed over 6 months. The main reasons for GLM interruption were lack/loss of efficacy (7.2%) or adverse events (2%). This study confirms the effectiveness of GLM as a second-line anti-TNF for the treatment of RA, PsA and axSpA in a real-world setting in Italy.

Ultrasound detection of subclinical synovitis in rheumatoid arthritis patients in clinical remission: a new reduced-joint assessment in 3 target joints.

OBJECTIVES: The ability of ultrasound (US) to identify subclinical joint inflammation in rheumatoid arthritis (RA) patients in remission has been already reported. Nonetheless, current studies present a lack of homogeneity in patient's characteristics and number of joints assessed by US. The aim of this study was to identify a reduced set of target joints to be scanned in RA patients in clinical remission in order to detect subclinical synovitis. METHODS: Forty RA patients in clinical remission (DAS28 ≤2.6) for at least 3 months underwent an US examination of 18 joints: wrist, II-III-IV-V metacarpophalangeal (MCP) and II-III-IV-V metatarsophalangeal joints bilaterally. The presence of synovial hypertrophy (SH) and power-Doppler (PD) signal was registered following the OMERACT definitions and was graded according to a 4-point scale (0-3). Then, by applying a process of data reduction based on the frequency of joint involvement, a reduced assessment was obtained. RESULTS: Twenty (50%) subjects had at least one joint affected by active synovitis; 17.5% presented grade 1 PD and 32.5% grade 2 PD. The joints most frequently affected by active synovitis were the wrists (75%) and the II MCP joints (55%). After data reduction, the evaluation of 3 joints (both wrists and the II MCP of the dominant hand) obtained a sensitivity of 90% for the detection of subclinical synovitis. CONCLUSIONS: The US scan of 3 target joints showed a high sensitivity in detecting subclinical active synovitis in RA patients in clinical remission and can be feasible in the routine assessment of these patients.

The use of an interferon-gamma release assay as a biomarker of response to anti-TNF-alpha treatment.

Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine that plays a central role in the immune system functioning and in the pathogenesis of rheumatoid arthritis (RA). TNF-α inhibition has been demonstrated effective to treat RA; however, response to anti-TNF-α therapies is heterogeneous, with roughly one-third of patients not achieving disease control. Identification of a biological marker to assess the effectiveness of TNF-α inhibition may help to discriminate patients with a reduced response to anti-TNF-α agents. The aim of this study was to assess whether anti-TNF-α treatment was able to modify the cytokine network interfering with interferon gamma (INFγ) release after phytohemagglutinin (PHA) stimulation of peripheral blood mononuclear cells (PBMCs) from RA patients, according to disease activity. We found that RA patients with active disease had low release of INFγ after PHA stimulation, but anti-TNF-α agents were able to modify INFγ production. In anti-TNF-α responders, we observed a higher release of INFγ, achieving levels comparable with those seen in healthy subjects. The ability of PBMCs from RA patients to release INFγ may serve as a biomarker of disease activity and response to anti-TNF-α. Larger studies are needed to validate these data.

The classification of Crithidia luciliae immunofluorescence test (CLIFT) using a novel automated system.

INTRODUCTION: In recent years, there has been an increased demand for computer-aided diagnosis (CAD) tools to support clinicians in the field of indirect immunofluorescence. To this aim, academic and industrial research is focusing on detecting antinuclear, anti-neutrophil, and anti-double-stranded (anti-dsDNA) antibodies. Within this framework, we present a CAD system for automatic analysis of dsDNA antibody images using a multi-step classification approach. The final classification of a well is based on the classification of all its images, and each image is classified on the basis of the labeling of its cells. METHODS: We populated a database of 342 images--74 positive (21.6%) and 268 negative (78.4%)-- belonging to 63 consecutive sera: 15 positive (23.8%) and 48 negative (76.2%). We assessed system performance by using k-fold cross-validation. Furthermore, we successfully validated the recognition system on 83 consecutive sera, collected by using different equipment in a referral center, counting 279 images: 92 positive (33.0%) and 187 negative (67.0%). RESULTS: With respect to well classification, the system correctly classified 98.4% of wells (62 out of 63). Integrating information from multiple images of the same wells recovers the possible misclassifications that occurred at the previous steps (cell and image classification). This system, validated in a clinical routine fashion, provides recognition accuracy equal to 100%. CONCLUSION: The data obtained show that automation is a viable alternative for Crithidia luciliae immunofluorescence test analysis.

Leptin, adiponectin and vascular stiffness parameters in women with systemic lupus erythematosus.

The purpose of the present study was to determine levels of adipokines and their relationship with stiffness parameters and disease activity index in SLE patients in comparison with healthy controls. Sixty SLE patients and 29 control subjects were enrolled in the study. Serum leptin and adiponectin levels were determined by commercial sandwich ELISA kits. Colour-coded carotid duplex sonography was performed using a Siemens SONOLINE Antares machine equipped with linear 5-13 MHz. SLEDAI, ECLAM and SLICC were evaluated in all patients. Data were analysed by software for statistical analysis (Prism 5.0). Median leptin is higher among SLE patients compared with controls (p 0.035). Median values of vascular stiffness and PSEM are increased in SLE compared with controls (p = 0.0003 and p = 0.007). Vascular strain and vascular distensibility are lower in SLE patients in comparison with controls (p = 0.0001 and p = 0.0006, respectively). Considering SLE patients, leptin levels correlate with vascular stiffness (r = 0.64, p < 0.0001) and PSEM (r = 0.63, p < 0.0001). Adiponectin levels correlate with vascular strain (r = 0.28, p 0.039) and negatively correlate with vascular stiffness (r = -0.38, p 0.039). Leptin levels correlate with disease activity (SLEDAI and ECLAM) and cumulative damage (SLICC) indexes. This study demonstrates higher values of leptin in SLE patients. Moreover, SLE patients show increased levels of vascular stiffness and PSEM and reduced values of vascular strain and distensibility. These results globally indicate a decline in arterial elasticity. We find a positive correlation of leptin with stiffness parameters. According to its atheroprotective action, adiponectin inversely correlates with stiffness parameters.

Novel opportunities in automated classification of antinuclear antibodies on HEp-2 cells.

The recommended method for antinuclear antibodies (ANA) detection is IIF but it is influenced by many different factors. In order to pursue a high image quality without artefacts and to reduce inter-observer variability, this study aims to evaluate the reliability of using automatically acquired digital images for diagnostic purposes. In this paper we present SLIM-system a comprehensive system that supports the two sides of IIF tests classification. It is based on two systems: the first labels the fluorescence intensity, whereas the second recognizes the staining pattern of positive wells. We populated a dataset of 600 images obtained from sera screened for ANA by IIF on Hep-2 cells. The error rate has been evaluated according to eight-fold cross validation method; the rates reported in the following are the mean of the tests. Performance of the system in positive/negative recognition ranges from 87% up to more than 94%. Staining pattern classification accuracy of main classes ranges from 71% to 74%. The system provides high and reliable identification of negative samples and a flexibility that permits to use this application for different purposes. The analysis of its perspective performance shows the system potential in lowering the method variability, in increasing the level of standardization and in reducing the specialist workload of more than 80%. Our data represent a first step to validate the use of Computer Aided Diagnosis (CAD), thus offering an opportunity for standardizing and automatizing the detection of ANA by IIF.