Intensive training programme for ultrasound-guided minimally invasive synovial tissue biopsy on knees and wrists in different phases of inflammation.

OBJECTIVES: To develop an intensive training programme for ultrasound (US)-guided synovial tissue (ST) biopsy on knees and wrists in inflammatory arthritis and to assess the learning curve, patient tolerability, sample quality and trainees' expectations. METHODS: Active or remission rheumatoid arthritis patients were enrolled. Nine trainees joined the 4-month programme in a centre experienced in performing US-guided ST biopsies consisting of four sequential phases: (1) observation, (2) performance of guided step-by-step phases, (3) execution of the whole procedure on paired joints (knees or wrists) of the same patient in parallel with the trainer and (4) performance of the procedure autonomously. Sample representativity was assessed by histology, and procedure-related adverse events were recorded. Before and after the programme, trainees' expectations and perceptions were collected. RESULTS: 328 ST biopsy procedures were included. The rate of trainees' informative samples was: (1) comparable to the trainers in active and remission knees, but lower in active wrists (70% for trainees vs 100% for trainers, p=0.06) in phase 3; (2) excellent on active knees and wrists (91.9% and 90.9% respectively) but lower (77.6%, p=0.0089) on remission knees in phase 4. Procedures performed by trainees did not affect patient tolerability. Trainees' expectations about procedure-related invasiveness and pain infliction decreased while the difficulty of procedure execution on active wrists and remission knees remained perceived as moderately difficult. CONCLUSIONS: This intensive training programme develops advanced skills in the performance of US-guided ST biopsy on knees and wrists, yielding high-quality specimens available for basic and translational studies on inflammatory joint diseases.

The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations.

Spondyloarthritis (SpA) contemplates the inflammatory involvement of the musculoskeletal system, gut, skin, and eyes, delineating heterogeneous diseases with a common pathogenetic background. In the framework of innate and adaptive immune disruption in SpA, neutrophils are arising, across different clinical domains, as pivotal cells crucial in orchestrating the pro-inflammatory response, both at systemic and tissue levels. It has been suggested they act as key players along multiple stages of disease trajectory fueling type 3 immunity, with a significant impact in the initiation and amplification of inflammation as well as in structural damage occurrence, typical of long-standing disease. The aim of our review is to focus on neutrophils' role within the spectrum of SpA, dissecting their functions and abnormalities in each of the relevant disease domains to understand their rising appeal as potential biomarkers and therapeutic targets.

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans.

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules' interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.

Impact of low-dose acetylsalicylic acid on pregnancy outcome in systemic lupus erythematosus: results from a multicentre study.

OBJECTIVE: It is still a matter of debate whether low-dose acetylsalicylic acid (LDASA) should be prescribed to all patients with SLE during pregnancy. This study aimed at investigating the impact of LDASA on pregnancy outcomes in patients with SLE without history of renal involvement and without antiphospholipid antibodies (aPL). METHODS: This is a retrospective analysis of prospectively monitored pregnancies at seven rheumatology centres. Previous/current renal involvement and aPL positivity were the exclusion criteria. Adverse pregnancy outcome (APO) is the composite outcome of the study and included proteinuric pre-eclampsia, preterm delivery <37 weeks, small-for-gestational age infant, low birth weight <2500 g, intrauterine growth restriction and intrauterine fetal death after 12 weeks of gestation of a morphologically normal fetus. RESULTS: 216 pregnancies in 187 patients were included; 82 pregnancies (38.0%) were exposed to LDASA treatment. No differences in terms of age at conception, disease duration, clinical manifestations, comorbidities and disease flare during pregnancy were observed between patients taking LDASA and those who did not take LDASA during pregnancy. APO was observed in 65 cases (30.1%), including 13 cases (6.1%) of pre-eclampsia. The incidence of all complications was similar in the two groups. However, it is interesting to note that pre-eclampsia had lower frequency in patients taking LDASA versus those not taking LDASA (2.4% vs 8.3%, p=0.14). CONCLUSIONS: In pregnant patients with SLE without renal involvement and were aPL-negative, there is a low risk of severe obstetric complications, such as early pre-eclampsia. LDASA treatment does not provide a statistically significant advantage over these complications. However, a careful individual risk-benefit balance is warranted.

Myocardial involvement in anti-phospholipid syndrome: Beyond acute myocardial infarction.

Anti-phospholipid antibodies (aPL) are the serological biomarkers of anti-phospholipid syndrome (APS), an autoimmune disorder characterized by vascular events and/or pregnancy morbidity. APS is a unique condition as thrombosis might occur in arterial, venous or capillary circulations. The heart provides a frequent target for circulating aPL, leading to a wide variety of clinical manifestations. The most common cardiac presentation in APS, valvular involvement, acknowledges a dual etiology comprising both microthrombotic and inflammatory mechanisms. We describe the cases of 4 patients with primary APS who presented a clinically manifest myocardiopathy without epicardial macrovascular distribution. We propose that microthrombotic/inflammatory myocardiopathy might be an overlooked complication of high-risk APS. As extensively hereby reviewed, the literature provides support to this hypothesis in terms of anecdotal case-reports, in some cases with myocardial bioptic specimens. In aPL-positive subjects, microthrombotic/inflammatory myocardial involvement might also clinically manifest as dilated cardiomyopathy, a clinical entity characterized by ventricular dilation and reduced cardiac output. Furthermore, microthrombotic/inflammatory myocardial involvement might be subclinical, presenting as diastolic dysfunction. Currently, there is no single clinical or imaging finding to firmly confirm the diagnosis; an integrated approach including clinical history, clinical assessment, laboratory tests and cardiac magnetic resonance should be pursued in patients with suggestive clinical presentation.

The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How?

In the majority of joint diseases, changes in the organization of the synovial architecture appear early. Synovial tissue analysis might provide useful information for the diagnosis, especially in atypical and rare joint disorders, and might have a value in case of undifferentiated inflammatory arthritis, by improving disease classification. After patient selection, it is crucial to address the dialogue between the clinician and the pathologist for adequately handling the sample, allowing identifying histological patterns depending on the clinical suspicion. Moreover, synovial tissue analysis gives insight into disease progression helping patient stratification, by working as an actionable and mechanistic biomarker. Finally, it contributes to an understanding of joint disease pathogenesis holding promise for identifying new synovial biomarkers and developing new therapeutic strategies. All of the indications mentioned above are not so far from being investigated in everyday clinical practice in tertiary referral hospitals, thanks to the great feasibility and safety of old and more recent techniques such as ultrasound-guided needle biopsy and needle arthroscopy. Thus, even in rheumatology clinical practice, pathobiology might be a key component in the management and treatment decision-making process. This review aims to examine some essential and crucial points regarding why, when, where, and how to perform a synovial biopsy in clinical practice and research settings and what information you might expect after a proper patient selection.

Clinical pharmacology of filgotinib in the treatment of rheumatoid arthritis: current insights.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis. AREAS COVERED: This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology. EXPERT OPINION: The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.

Psychosocial burden in young patients with primary anti-phospholipid syndrome: an Italian nationwide survey (The AQUEOUS study).

OBJECTIVES: The AQUEOUS (Anti-phospholipid syndrome: a QUEstionnaire for yOUng patientS) study aimed to assess how the diagnosis of primary anti-phospholipid syndrome (PAPS) affects the psychosocial status of young patients. METHODS: Subjects with PAPS aged 18-45 years were invited to compile an ad hoc designed questionnaire and the Short Form-12 to assess quality of life (QoL). RESULTS: Ninety-two patients (83.7% females) were recruited in 10 Italian centres. Vascular and obstetric manifestations were equally represented. Nearly half of the patients perceived the need for psychological support, 89.2% when considering women after pregnancy complications. Social activities and working efficiency were reduced in APS patients, also intimacy was threatened. In all cases, fatigue appeared to be the main determinant. PAPS affected family planning, due to fears of treatment side-effects, disease hereditariness, inability to care for the newborn child. Fertility appeared to be conserved: the median time to pregnancy was 2 months; assisted reproduction techniques were pursued by 5 women. Our survey documented significantly lower rates of hospitalisation and learning disabilities in 51 children born after APS diagnosis as compared to 48 children born before. PAPS patients displayed lower QoL in physical and, to a greater extent, mental scores compared to the general Italian population. Both components were significantly lower in women and in patients with fatigue. CONCLUSIONS: The AQUEOUS study assessed for the first time the unmet needs of young PAPS patients, enabling the development of a future "youth-focused" strategy to reduce disease burden.

The Link Between Autonomic Nervous System and Rheumatoid Arthritis: From Bench to Bedside.

Neuronal stimulation is an emerging field of research focused on the management and treatment of various diseases through the reestablishment of physiological homeostasis. Electrical vagus nerve stimulation has recently been proposed as a revolutionary therapeutic option for rheumatoid arthritis (RA) in combination with or even as a replacement for conventional and biological drugs. In the past few years, disruption of the autonomic system has been linked to RA onset and activity. Novel research on the link between the autonomic nervous system and the immune system (immune-autonomics) has paved the way for the development of innovative RA management strategies. Clinical evidence supports this approach. Cardiovascular involvement, in terms of reduced baroreflex sensitivity and heart rate variability-derived indices, and mood disorders, common comorbidities in patients with RA, have been linked to autonomic nervous system dysfunction, which in turn is influenced by increased levels of circulating pro-inflammatory cytokines. This narrative review provides an overview of the autonomic nervous system and RA connection, discussing most of the common cardiac and mental health-related RA comorbidities and their potential relationships to systemic and joint inflammation.