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 Contribution of Innate Immunity in Large-Vessel Vasculitis: Detangling New Pathomechanisms beyond the Onset of Vascular Inflammation.

Large-vessel vasculitis (LVV) are autoimmune and autoinflammatory diseases focused on vascular inflammation. The central core of the intricate immunological and molecular network resides in the disruption of the "privileged immune state" of the arterial wall. The outbreak, initially primed by dendritic cells (DC), is then continuously powered in a feed-forward loop by the intimate cooperation between innate and adaptive immunity. If the role of adaptive immunity has been largely elucidated, knowledge of the critical function of innate immunity in LVV is still fragile. A growing body of evidence has strengthened the active role of innate immunity players and their key signaling pathways in orchestrating the complex pathomechanisms underlying LVV. Besides DC, macrophages are crucial culprits in LVV development and participate across all phases of vascular inflammation, culminating in vessel wall remodeling. In recent years, the variety of potential pathogenic actors has expanded to include neutrophils, mast cells, and soluble mediators, including the complement system. Interestingly, new insights have recently linked the inflammasome to vascular inflammation, paving the way for its potential pathogenic role in LVV. Overall, these observations encourage a new conceptual approach that includes a more in-depth study of innate immunity pathways in LVV to guide future targeted therapies.

Effectiveness and safety of filgotinib in rheumatoid arthritis: a real-life multicentre experience.

OBJECTIVES: We investigated the effectiveness and safety of filgotinib in a real-life multicentre cohort of rheumatoid arthritis (RA) patients. METHODS: RA patients were evaluated at baseline and after 12 and 24 weeks and were stratified based on previous treatments as biologic disease-modifying anti-rheumatic drug (bDMARD)-naive and bDMARD-insufficient responders (IR). Concomitant usage of methotrexate (MTX) and oral glucocorticoids (GC) was recorded. At each timepoint we recorded disease activity, laboratory parameters and adverse events. RESULTS: 126 patients were enrolled. 15.8% were bDMARD-naive (G0), while 84% were bDMARD-IR (G1). In G0, 45% of patients were in monotherapy (G2) and 55% were taken MTX (G3). In G1, 50% of patients were in monotherapy (G4) and 50% used MTX (G5).A significant reduction in all parameters at 12 weeks was observed; in the extension to 24 weeks the significant reduction was maintained for patient global assessment (PGA), examiner global assessment (EGA), visual analogue scale (VAS) pain, VAS fatigue, disease activity score (DAS)28- C-reactive protein (CRP) and CRP values. Filgotinib in monotherapy showed better outcomes in bDMARD-naive patients, with significant differences for patient reported outcomes (PROs) and DAS28-CRP. At 12 weeks, low disease activity (LDA) and remission were achieved in a percentage of 37.2 % and 10.7 % by simplified disease activity index (SDAI), 42.6 % and 5.7 % by clinical disease activity index (CDAI), 26.8 % and 25.2 % by DAS28-CRP, respectively. A significant decrease in steroid dose was evidenced in all patients. We observed a major adverse cardiovascular event in one patient and an increase in transaminase in another. No infections from Herpes Zoster were reported. CONCLUSIONS: Our real-world data confirm the effectiveness and safety of filgotinib in the management of RA, especially in bDMARD-naive patients.

Characterising oesophageal motility disorders by high-resolution impedance manometry in dermatomyositis patients.

OBJECTIVES: We studied high-resolution impedance manometry (HRiM) findings in dermatomyositis (DM) to detect oesophageal dysmotility, even in asymptomatic patients, and correlated the alterations to clinical and serological disease domains. METHODS: We performed a cross-sectional study of DM patients, enrolled between December 2021 and December 2022. All patients underwent rheumatological, laboratory and HRiM assessment. HRiM findings were compared with different clinical and serological profiles. RESULTS: The study population consisted of 15 DM patients (13 women and 2 men, age 54±15.2 years). The mean disease duration was 6.6 years. According to HRiM findings, three different groups of oesophageal disease severity were identified (in order of severity G0, G1 and G>1, 5 patients per group). G>1 group was significantly associated with MDA5 antibodies (80% vs. 20%, p<0.05). Interstitial lung disease (ILD) did not show any significant association with HRiM findings. However, a diffusing lung capacity for carbon oxide (DLCO) < 80% was present in 100% of G>1 (p<0.05). No associations between dysphagia, creatine kinase (CK) level, muscle weakness, skin, articular involvement and treatment were found. CONCLUSIONS: Oesophageal involvement is frequent and should be evaluated in the comprehensive work-up of DM. We used for the first time HRiM in DM, which proved to be an accurate and objective technique in assessing oesophageal disease, even in the subclinical stage. Interestingly, the MDA5-positive group had a higher burden of HRiM pathological findings, suggesting a greater severity of oesophageal involvement, often asymptomatic.

JAK/STAT inhibition modifies the ILC1 immune response in patients with rheumatoid arthritis.

OBJECTIVES: Recent evidence suggests that innate lymphoid cells (ILCs) might be involved in rheumatoid arthritis (RA) pathogenesis and individuals at risk of RA exhibited an increased frequency of ILC1. JAK3 participates in ILC1 and ILC3 differentiation. Tofacitinib and the Janus Kinase (JAK) 3 inhibitor, PF-06651600, impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ and the proliferation of ILC1 and ILC3. Our study aims to evaluate the ex vivo effects of tofacitinib in RA patients and to investigate if ILC1s and ILC3s are specific targets of tofacitinib in RA. METHODS: Twenty RA patients starting tofacitinib and 10 RA patients starting anti-TNFα were enrolled. Peripheral blood mononuclear cells (PBMCs) from RA patients, collected before and three months after therapy, were cultured to evaluate ILC1 and ILC3 frequencies and the respective production of IFN-γ and IL-17 by flow cytometry analysis. PBMCs of RA patients were in vitro cultured with tofacitinib to evaluate the dose effects on ILC frequencies. RESULTS: RA patients showed a significant expansion of ILC1 but not ILC3. Unlike anti-TNFα treated patients, in whom no reduction in ILCs was reported, after three months of tofacitinib therapy the overall ILC frequency was reduced, as well as the ILC1 ability to release IFN-γ. In vitro treatment of PBMCs with tofacitinib demonstrated a dose-dependent reduction in the frequency of ILCs compared to untreated cells. CONCLUSIONS: Our preliminary results demonstrate that tofacitinib modulates the innate immune response by reducing the frequency of ILC1 cells and their production of IFN-γ.

Severe case of rhabdomyolysis following jellyfish envenomation in the Mediterranean Sea.

Jellyfish envenomation is a common problem in coastal areas all over the world; usually symptoms are self-limited with no long-lasting complications. Despite that, some jellyfish species, mainly populating the Indian Ocean, are renown to be potentially lethal and in some cases may cause severe myopathy. We report the first case of rhabdomyolysis following a jellyfish sting in the Mediterranean Sea. A 17-year-old patient was admitted to the intensive care unit of our hospital in life-threatening conditions. He was dyspnoeic and dysphagic with pain and functional impairment of upper and lower limbs. The evidence of a red mark in his face and the clinical presentation, coupled with the diagnostic test performed, allowed the diagnosis of toxidrome from jellyfish venom. Treatment with hydration, ventilatory support and steroids led to a progressive improvement of patient conditions. Our case report stresses the importance of prompt identification and treatment of potential rhabdomyolysis determined by jellyfish and rises awareness on the presence of such venomous species in the Mediterranean Sea.

Avoidant Restrictive Food Intake Disorder: A Narrative Review of Types and Characteristics of Therapeutic Interventions.

The diagnosis of avoidant/restrictive food intake disorder (ARFID) was added to the diagnostic and statistical manual of mental disorders (DSM-5) just 10 years ago. This disorder consists of the failure to meet one's nutritional and/or energy needs, which may result in significant weight loss, significant nutritional deficit or functioning dependent on enteral nutrition or oral supplements. In children with this disorder, development is often problematic, and there is also marked interference with psychosocial functioning at all ages. The causes leading to food avoidance in these patients may be related to a lack of interest, to the sensory properties of the food or to the possible adverse consequences associated with it. Given the multitude of aspects involved in this disorder and the impact it has especially on younger patients, more and more studies are addressing treatments and related benefits and/or complications. A narrative review of currently published studies was performed for articles published before 5 March 2023 on therapeutic interventions in patients with ARFID. Because of the large number of results obtained, this review was conducted only via PubMed in order to analyze and discuss children and adolescent ARFID treatments reported in literature. The treatments most often referred to in the literature are cognitive behavioral therapy, family-based therapy and pharmacological treatment. All the data on these treatments are promising. However, due to the recent introduction of this disorder and the limited data still available, a multidisciplinary approach seems to be the best option.

Possible role for IL-40 and IL-40-producing cells in the lymphocytic infiltrated salivary glands of patients with primary Sjögren's syndrome.

OBJECTIVES: Aim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in pSS-associated lymphomas. METHODS: 29 patients with pSS and 24 controls were enrolled. Minor salivary gland (MSG) biopsies from patients, controls and parotid gland biopsies from pSS-associated lymphoma were obtained. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-40 were performed on MSG. MSG cellular sources of IL-40 were determined by flow-cytometry and immunofluorescence. Serum concentration of IL-40 was assessed by ELISA and cellular sources of IL-40 were determined by flow-cytometry. An in vitro assay with recombinant IL-40 (rIL-40) was performed to detect the effect on cytokine production from peripheral blood mononuclear cells (PBMCs). RESULTS: IL-40 was significantly increased in the lymphocytic infiltrated MSG of patients with pSS and correlated with focus score and with IL-4 and transforming growth factor-ß expression. In addition, IL-40 was increased in the serum of pSS and its levels correlated with the EULAR Sjögren's Syndrome Disease Activity Index score. B cells from patients were shown to be the major source of IL-40 at both tissue and peripheral level. PBMCs from patients, exposed to rIL-40 in vitro, released proinflammatory cytokines, specifically interferon-γ from B cells and T-CD8+ and tumour necrosis factor-α and IL-17 from both T-CD4+ and T-CD8+. IL-40 expression in parotid glands of pSS-associated lymphomas was also increased. Moreover, IL-40-driven NETosis was evidenced in neutrophils obtained from pSS. CONCLUSION: Our results suggest that IL-40 may play a role in pSS pathogenesis and pSS-associated lymphomas.

Rituximab-induced hypogammaglobulinaemia in patients affected by idiopathic inflammatory myopathies: a multicentre study.

OBJECTIVES: Rituximab (RTX) is an anti-CD20 chimeric monoclonal antibody recommended as off-label treatment in patients with idiopathic inflammatory myopathies (IIM). The present study aimed to evaluate changes in immunoglobulin (Ig) levels during RTX-treatment and their potential association with infections in a cohort of IIM patients. METHODS: Patients evaluated in the Myositis clinic belonging to the Rheumatology Units of Siena, Bari and Palermo University Hospitals, and treated for the first time with RTX were enrolled. Demographic, clinical, laboratory and treatment variables, including previous and concomitant immunosuppressive drugs and glucocorticoid (GC) dosage were analysed before (T0) and after 6 (T1) and 12 (T2) months of RTX treatment. RESULTS: Thirty patients (median age, IQR 56 (42-66); 22 female) were selected. During the observational period, low levels of IgG (<700 mg/dl) and IgM (<40 mg/dl) occurred in 10% and 17% of patients, respectively. However, no one showed severe (IgG<400 mg/dl) hypogammaglobulinaemia. IgA concentrations were lower at T1 than T0 (p=0.0218), while IgG concentrations were lower at T2 compared to those at baseline (p=0.0335). IgM concentrations were lower at T1 and T2 than T0 (p<0.0001), as well at T2 than T1 (p=0.0215). Three patients suffered major infections, two others had paucisymptomatic COVID-19, one suffered from mild zoster. GC dosages at T0 were inversely correlated with IgA T0 concentrations (p=0.004, r=- 0.514). No correlation was found between demographic, clinical and treatment variables and Ig serum levels. CONCLUSIONS: Hypogammaglobulinaemia following RTX is uncommon in IIM and is not related to any clinical variables, including GC dosage and previous treatments. IgG and IgM monitoring after RTX treatment does not seem useful in stratifying patients who require closer safety monitoring and prevention of infection, due to the lack of association between hypogammaglobulinaemia and the onset of severe infections.

Focus on Liability of Residences for Elderly and Sick People: A Case Series and Medico-Legal Issues.

Residences for elderly and sick people, self-sufficient or dependent, are varied. To date, the liability profiles of these structures are not clearly delineated, and increasingly often, their operating and organization criteria are entrusted to subnational, regional, or local regulations. Among the various deficits, there is the keeping of a complete and detailed documentation/diary of the patient, the lack of which can generate medico-legal problems. In this paper, we present three cases of guests in residences for a dependent person brought to the attention of the Institute of Forensic Medicine of the University Hospital of Palermo due to criminal proceedings, where the lack of existing documentation in the structure and, in some cases, the behavior of the professionals working there, led the evaluator to deduce the organization's culpability.

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.

The role of bDMARDs in idiopathic inflammatory myopathies: A systematic literature review.

Idiopathic inflammatory myopathies (IIM) are a group of different conditions typically affecting striate muscle, lung, joints, skin and gastrointestinal tract. Treatment typically relies on glucocorticoids and synthetic immunosuppressants, but the occurrence of refractory, difficult to treat, manifestations, may require more aggressive treatment, borrowed from other autoimmune diseases, including biologic disease modifying drugs (bDMARDs). In this regard, we conducted a systemic literature review in order to depict the current evidence about the use of bDMARDs in IIM. A total of 78 papers, published during the last 21 years, were retrieved. The majority of patients was treated with TNF-α inhibitors, whose effectiveness was assessed particularly in recalcitrant striate muscle, skin and joints involvement. Rituximab, whose evidence is supported by a large number of real-life studies and trials, seems to be an excellent option in case of ILD and anti-synthetase syndrome, while Tocilizumab, despite not meeting primary and secondary endpoints in a recently published clinical trial, proved its effectiveness in rapidly progressing ILD. Similarly, Abatacept, studied in a phase IIb clinical trial with conflicting evidence, was reported to be effective in some case reports of refractory dermatomyositis. Less data exist for anti-IL1 and anti-IL23 agents, which were employed particularly for inclusion body myositis and severe skin disease, respectively. This study provides an organ-focused assessment of bDMARDs in IIM, which display encouraging results in the treatment of refractory subsets of disease.

Relapses of idiopathic inflammatory myopathies after vaccination against COVID-19: a real-life multicenter Italian study.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination plays a crucial role as pivotal strategy to curb the coronavirus disease-19 (COVID-19) pandemic. The present study described the clinical status of patients affected by idiopathic inflammatory myopathies (IIM) after COVID-19 vaccination to assess the number of relapses. We included all patients affected by IIM and followed by Myositis Clinic, Rheumatology and Respiratory Diseases Units, Siena University Hospital, Bari University Hospital, Policlinico Umberto I, Sapienza University, Rome, and Policlinico Paolo Giaccone, Palermo. They underwent a telephone survey. A total of 119 IIM patients (median, IQR 58 (47-66) years; 32males; 50 dermatomyositis, 39 polymyositis and 30 anti-synthetase syndrome) were consecutively enrolled. Except four patients who refused the vaccination, 94 (81.7%) received Comirnaty, 16 (13.9%) Spikevax, 5 (4.4%) Vaxzevria. Seven (6.1%) patients had flare after vaccination. One of them had life-threatening systemic involvement and died two months after second dose of COVID-19 vaccination. From logistic regression analysis, Chi2-log ratio = 0.045,the variable that most influences the development of flare was the number of organs involved (p = 0.047). Sixty-eight patients received the third dose of COVID-19 vaccination: 51(75%) Comirnaty and 17 (25%) Moderna. No patients had flares after third dose. Our study represents the largest cohort of IIM patients in which the incidence of recurrence after anti-SARS-CoV-2 vaccine was assessed. In line with real-life data from other diseases, we found a clinical non-statistically significant risk of relapse in our patients, which occurred seldom, usually mild and in patients with a more severe and aggressive course of disease.

Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity.

Immune cells undergo different metabolic pathways or immunometabolisms to interact with various antigens. Immunometabolism links immunological and metabolic processes and is critical for innate and adaptive immunity. Although metabolic reprogramming is necessary for cell differentiation and proliferation, it may mediate the imbalance of immune homeostasis, leading to the pathogenesis and development of some diseases, such as autoimmune diseases. Here, we discuss the effects of metabolic changes in autoimmune diseases, exerted by the leading actors of innate immunity, and their role in autoimmunity pathogenesis, suggesting many immunotherapeutic approaches.

Metabolomics: An Emerging Approach to Understand Pathogenesis and to Assess Diagnosis and Response to Treatment in Spondyloarthritis.

Spondyloarthritis (SpA) is a group of rheumatic diseases whose pathogenesis relies on a complex interplay between genetic and environmental factors. Over the last several years, the importance of the alteration of the gut microbiota, known as dysbiosis, and the interaction of bacterial products with host immunity have been highlighted as intriguing key players in SpA development. The recent advent of the so called "-omics" sciences, that include metabolomics, opened the way to a new approach to SpA through a deeper characterisation of the pathogenetic mechanisms behind the disease. In addition, metabolomics can reveal potential new biomarkers to diagnose and monitor SpA patients. The aim of this review is to highlight the most recent advances concerning the application of metabolomics to SpA, in particular focusing attention on Ankylosing Spondylitis and Psoriatic Arthritis.

Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview.

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases.

Primary Sjogren Syndrome: Focus on Innate Immune Cells and Inflammation.

Primary Sjogren Syndrome (pSS) is a complex, multifactorial rheumatic disease that mainly targets salivary and lacrimal glands, inducing epithelitis. The cause behind the autoimmunity outbreak in pSS is still elusive; however, it seems related to an aberrant reaction to exogenous triggers such as viruses, combined with individual genetic pre-disposition. For a long time, autoantibodies were considered as the hallmarks of this disease; however, more recently the complex interplay between innate and adaptive immunity as well as the consequent inflammatory process have emerged as the main mechanisms of pSS pathogenesis. The present review will focus on innate cells and on the principal mechanisms of inflammation connected. In the first part, an overview of innate cells involved in pSS pathogenesis is provided, stressing in particular the role of Innate Lymphoid Cells (ILCs). Subsequently we have highlighted the main inflammatory pathways, including intra- and extra-cellular players. A better knowledge of such processes could determine the detection of new therapeutic targets that are a major need for pSS.