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.

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.

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.

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.

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.

Microbiome Changes in Connective Tissue Diseases and Vasculitis: Focus on Metabolism and Inflammation.

The microbial community acts as an active player in maintaining homeostasis and immune functions through a continuous and changeable cross-talk with the host immune system. Emerging evidence suggests that altered microbial composition, known as dysbiosis, might perturb the delicate balance between the microbiota and the immune system, triggering inflammation and potentially contributing to the pathogenesis and development of chronic inflammatory diseases. This review will summarize the current evidence about the microbiome-immunity cross-talk, especially focusing on the microbiota alterations described in patients with rheumatic diseases and on the recent findings concerning the interaction between microbiota, metabolic function, and the immune system.

Immunity and Nutrition: The Right Balance in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is an increasingly urgent medical problem that strongly impairs quality of life for patients. A global rise in incidence has been observed over the last few decades, with the highest incidence rates recorded in North America and Europe. Still, an increased incidence has been reported in the last ten years in newly industrialized countries in Asia, including China and India, both with more than one billion inhabitants. These data underline that IBD is an urgent global health problem. In addition, it is estimated that between 20% and 30% of IBD patients will develop colorectal cancer (CRC) within their lifetime and CRC mortality is approximately 50% amongst IBD patients. Although the exact etiology of IBD is still being defined, it is thought to be due to a complex interaction between many factors, including defects in the innate and adaptive immune system; microbial dysbiosis, i.e., abnormal levels of, or abnormal response to, the gastrointestinal microbiome; a genetic predisposition; and several environmental factors. At present, however, it is not fully understood which of these factors are the initiators of inflammation and which are compounders. The purpose of this review is to analyze the complex balance that exists between these elements to maintain intestinal homeostasis and prevent IBD or limit adverse effects on people's health.

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.

Invariant NKT Cells and Rheumatic Disease: Focus on Primary Sjogren Syndrome.

Primary Sjogren syndrome (pSS) is a complex autoimmune disease mainly affecting salivary and lacrimal glands. Several factors contribute to pSS pathogenesis; in particular, innate immunity seems to play a key role in disease etiology. Invariant natural killer (NK) T cells (iNKT) are a T-cell subset able to recognize glycolipid antigens. Their function remains unclear, but studies have pointed out their ability to modulate the immune system through the promotion of specific cytokine milieu. In this review, we discussed the possible role of iNKT in pSS development, as well as their implications as future markers of disease activity.