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SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still’s disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

Sjögren Syndrome (SS) seems to be associated with a greater “overall risk” of cardiovascular (CV) and cerebrovascular events. Although not conventionally considered a feature of the disease, CV events represent a major burden in SS patients. CV risk is the consequence of a complex combination of multiple factors, including traditional risk factors and disease-related mechanisms. A complex relationships between disease-related features, endothelial dysfunction and traditional risk factor has been suggested. Several drugs are available for treating the systemic manifestations of SS, however they have shown positive effects on different outcomes of the disease, but until today the data on the role of these drugs on CV events are scarse. Given these data, the aim of this review was to evaluate the risk of CV risk in primary SS and the effect of the drugs on this manifestation.

Janus-kinase (JAK) and signal transduction activator of transcription (STAT) signal transduction pathway is involved in a wide range of physiological and pathological processes, including in the pathogenesis of several autoimmune diseases. Data supporting the role of JAK/STAT in the development of vasculitis are limited and mostly focused on large vessel vasculitis and Behçet’s disease. In this review, we provide a thorough picture of currently available evidence on the topic, gathered from in vitro experiments, animal models and human real-life data, analyzing the rationale for the use of JAK inhibitors for the management of vasculitis. Overall, despite a very strong biological and pathogenic basis, data are too few to recommend this therapeutic approach, beyond very severe and refractory forms of vasculitis. However, for the same reasons, a strong scientific effort in this direction is indeed worthwhile.

Sjögren's syndrome (SS) is a systemic autoimmune disease mainly characterized by inflammatory involvement of exocrine gland. Atherosclerosis is a complex process leading to plaque formation in arterial wall with subsequent cardiovascular (CV) events. Recently, numerous studies demonstrated that SS patients bear an increased CV risk. Since activation of immune system is a key element in atherosclerosis, it is interesting to analyze whether and how the autoimmune and inflammatory events characterizing SS pathogenesis directly or indirectly contribute to atherosclerosis risk in these patients. An increase in circulating endothelial microparticles and integrins, which may be a consequence of endothelial damage and impaired repair mechanisms, has been demonstrated in SS. Increased endothelial expression of adhesion molecules with subsequent infiltration of inflammatory cells into arterial wall is also a critical event in atherosclerosis. The early inflammatory events taking place in the atherosclerotic plaque cause an increase in alarmins, such as S100A8/A9, which seems to be associated with SS disease activity and, in turn, induce up-regulation of interleukin (IL)-1β and other pro-atherogenic cytokines. Interestingly, increased IL-1β levels were also detected in tertiary lymphoid structures developing in vessel adventitia adjacent to the atherosclerotic plaque, suggesting a direct role of IL-1β in this process. Similar to these structures, germinal center-like structures arising in SS exocrine glands are also tertiary lymphoid systems where T-helper (Th) cell subsets govern the adaptive immune response. Th1 cells are the most prevalent subtype and have been shown to be strongly involved in both SS pathogenesis and atherosclerosis. Th17 cells are attracting great interest and few studies showed its importance in SS development. Albeit in low amounts, a Th17 signature was also detected in atherosclerotic plaques and some animal models demonstrated a significant pro-atherogenic role and positive effects of IL-17A blockade. Despite the fact that T cells have a pivotal role in the inflammatory process that ultimately leads to atherosclerosis, B cells have also been detected in atherosclerotic plaques, although their exact role is still mostly unknown with studies showing contrasting results. In this scenario, the role of inflammation in atherosclerosis pathogenesis in patients with SS needs to be further explored.

Background Endothelial dysfunction contributes to increased cardiovascular (CV) disease in rheumatoid arthritis (RA). Angiogenic T cells (Tang) are a key regulator of vascular function via their interaction with endothelial progenitor cells (EPCs). Methotrexate (MTX) has been associated to reduced CV disease risk, but its effects on endothelial homeostasis have been poorly explored. We investigated MTX effects on endothelial homeostasis in early, treatment-naïve RA patients. Methods Fifteen untreated, early RA patients and matched healthy controls (HC) were enrolled. RA patients with long-standing disease in remission or low disease activity treated with MTX for at least 6 months were selected as controls. Circulating CD28 + and CD28 null Tang cell, endothelial microparticle (EMP), EPC and soluble vascular cell adhesion molecule (sVCAM)-1 levels were measured. Results Tang percentage was higher in early RA than in HCs and significantly increased after 3-month MTX treatment. Tang cells in RA were characterized by higher percentage of CD28 null and lower CD28-positive cells than HCs. MTX restored a Tang cell phenotype similar to HCs. Altered sVCAM-1, EMP and EPC were restored to levels similar to HCs after a 3-month MTX. Biomarker levels after 3 months of MTX were not different to those of patients with long-standing treatment. Conclusions MTX has a positive effect on Tang, sVCAM-1, EPCs and EMPs in RA. Restoration of imbalance between CD28 + and CD28 null Tang by MTX may be one of the mechanisms underlying its favourable effects on endothelial dysfunction. These effects seem to be long-lasting and independent from systemic inflammation reduction, suggesting a direct effect of MTX on the endothelium.

This pilot study investigates distinctive features within the nail-enthesis complex among Psoriatic arthritis (PsA), Psoriasis (PSO), Rheumatoid Arthrit is (RA), and Healthy Control (HC) groups, utilizing a combined approach of ultrasound (US) and nailfold videocapillaroscopy (NVC). Clinical assessments and comprehensive US and NVC evaluations of the nail-enthesis complex were conducted on 72 subjects (18 PsA, 16 PSO, 19 RA, 19 HC). Unsupervised clustering models and factor analysis were employed to identify patterns and interrelationships between US and NVC parameters. Significant structural differences were detected, emphasizing the discriminatory power of semiquantitative US scores (GS BUNES, Wortsman type). Trends in vascularization aligned with literature, showcasing dysregulated angiogenesis in PsA and PSO. The clustering model effectively distinguished HC from PsA subjects, revealing a potential continuum between PSO and PsA. RA subjects exhibited subsets with features akin to both HC and PsA/PSO, underscoring the complexity of its manifestations. This study provides insights into nail-enthesis complex alterations, highlighting distinctions among PsA, PSO, RA, and HC subjects. The clustering model emphasizes potential overlap between PSO and PsA. Factor analysis elucidates collinearity in US-detected characteristics, while suggesting limited discriminative power of some quantitative parameters. These findings advocate for further exploration in prospective trials, potentially predicting the evolution of undifferentiated early arthritis and arthritis onset in PSO patients.

The prevalence of peripheral nervous system (PNS) involvement in primary Sjögren's syndrome (pSS) has been reported to range from 2% to over 50%. Bias in study designs, including low number of patients and unclearly defined rheumatological and neurological diagnosis could explain such variability. Consequently, the exact depiction of PNS involvement in pSS is still lacking. This study aimed at analyzing the prevalence and the clinical and laboratory factors associated with PNS involvement in a very large cohort of well-characterized pSS patients with a clearly defined neurological diagnosis. Clinical and serological data of 1,695 pSS patients with specific and accurate information on PNS involvement were analyzed. Comparisons between patients with and without PNS involvement and between patients with distinct subsets of PNS manifestations were performed. Prevalence of PNS involvement was 3.7%. The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants. Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype. Our results highlight that PNS involvement is rather rare, but prognostically relevant in pSS. Main adverse prognostic features characterize patients with SMP, while pure sensory neuropathies are usually associated with a mild clinical picture. These findings, useful for patient stratification, may suggest protean pathogenic pathways underlying different types of PNS manifestations in pSS.

Background: Reliable biomarkers are urgently needed to aid in the differential diagnosis, prognosis, disease progression monitoring, and prediction of therapeutic response in patients with systemic sclerosis (SSc). This study aimed to evaluate a panel of potentially pathogenic circulating cytokines and chemokines in a cohort of SSc patients. Methods: Serum samples were obtained from 35 SSc patients and 40 age- and sex-matched healthy controls. Twenty-three cytokines/chemokines were quantified using a Luminex® multiplex immunoassay (BioRad-BioPlex 200 System-Lumine x-Map technology R&D Systems, USA) following the manufacturer’s instructions and customized procedures. Data were acquired using Bioplex manager v 6.1. Data analysis was performed using GraphPad Prism v.8 (GraphPad Software, Inc.), with significance defined as p ≤ 0.05. V.8 Results: Levels of TNFRII and MMP-8 were significantly higher in SSc patients compared to healthy controls, while IL-1RII levels were significantly elevated in healthy individuals (p < 0.001 for all comparisons). Patients with elevated ESR at baseline (>30 mm/h) showed higher IL-15 levels (p = 0.019). A strong positive correlation was found between MCP-1 and the modified Rodnan skin score (mRSS) (p = 0.009, r = 0.740), and a moderate correlation between TNFRII and diffusing capacity for carbon monoxide (p = 0.046, r = 0.339). PLS regression identified MMP-8, MCP-1, TNFRII, IL-15, and IL-1RII as key predictors of SSc, with MMP-8 having the strongest influence. The logistic regression model showed high performance (AUC = 0.93, accuracy = 87.5%). Conclusions: TNFRII, MMP-8, and IL-1RII may play a pathogenic role in SSc. TNFRII, in particular, may serve as a biomarker for pulmonary involvement, aligning with its known role in pro-fibrotic pathways. These findings support their utility in diagnosis and disease profiling.

The treatment of patients with rheumatoid arthritis (RA) has dramatically changed in the past 30 years. Currently, numerous conventional, biologic, and targeted synthetic DMARDs have been licensed and used following recommendations provided by international and national scientific societies. However, the availability of biosimilars and the increasing necessity of savings impacted on the local/national prescription of these drugs. The information provided by data sheet of every single drug is a decisive factor on the choice of a certain treatment merged with the patient’s profile. Thus, our purpose was to construct a rational algorithm for the treatment strategy in RA according to costs and the product leaflet of the biologic and targeted-synthetic DMARDs currently licensed in Italy. We used the most recent available recommendations and then we performed a review of the literature considering all the factors that are known to influence drug safety/effectiveness. All these factors were considered in the context of the data sheets of currently available originators and biosimilars.

Intravenous immunoglobulins (IVIG) are blood preparations pooled from the plasma of donors that have been first employed as replacement therapy in immunodeficiency. IVIG interact at multiple levels with the different components of the immune system and exert their activity against infections. Passive immunotherapy includes convalescent plasma from subjects who have recovered from infection, hyperimmune globulin formulations with a high titer of neutralizing antibodies, and monoclonal antibodies (mAbs). IVIG are used for the prevention and treatment of several infections, especially in immunocompromised patients, or in case of a poorly responsive immune system. The evolution of IVIG from a source of passive immunity to a powerful immunomodulatory/anti-inflammatory agent results in extensive applications in autoimmune diseases. IVIG composition depends on the antibodies of the donor population and the alterations of protein structure due to the processing of plasma. The anti-viral and anti-inflammatory activity of IVIG has led us to think that they may represent a useful therapeutic tool even in COVID-19. The human origin of IVIG carries specific criticalities including risks of blood products, supply, and elevated costs. IVIG can be useful in critically ill patients, as well as early empirical treatment. To date, the need for further well-designed studies stating protocols and the efficacy/tolerability profile of IVIG and convalescent plasma in selected situations are awaited.