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Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are the major forms of large vessel vasculitis (LVV). Glucocorticoids represent the cornerstone of LVV treatment, however, relapses and recurrences frequently occur when they are tapered or stopped, determining a prolonged exposure to glucocorticoids and a subsequent increased risk of glucocorticoid-related side effects. Therefore, conventional and biologic immunosuppressive drugs have been proposed to obtain a glucocorticoid-sparing effect.We searched PubMed® using the keywords 'giant cell arteritis/drug therapy' and 'Takayasu Arteritis/drug therapy' OR 'Takayasu Arteritis/surgery' This review focuses on the management of LVV, based on the current evidence while highlighting the differences in terms of therapeutic management of TAK and GCA.Conventional disease modifying anti-rheumatic drugs, such as methotrexate or azathioprine, are recommended in association to glucocorticoids for selected GCA and all TAK patients. Two randomized placebo-controlled trials recently demonstrated the efficacy of tocilizumab in reducing relapses and cumulative prednisone dosage in GCA patients with newly diagnosed or relapsing disease. Observational evidence and two small randomized controlled trials support the use of TNF-alpha inhibitors and tocilizumab as glucocorticoid-sparing agents in relapsing TAK, albeit high-quality evidence regarding the management of TAK is still lacking.

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.

Summary Giant cell arteritis is a primary granulomatous vasculitis characterised by a strict tissue tropism for large and medium-size vessels, occurring in people older than 50 years. Although considerable progress in understanding some of the pathophysiological mechanisms involved in the pathogenesis of giant cell arteritis has been made in the past 10 years, specific triggers of disease and mechanisms of chronic damage have not yet been identified. The definition of a specific pro-inflammatory hierarchy between the multiple cell types and the different cytokines or chemokines involved in the inflammatory process are still unexplored areas of study. The overall goal of precision medicine is to identify the best possible therapeutic approach for an individual or group of individuals with a given disease. The fundamental prerequisite of this approach is the identification, at baseline, of clinical and imaging findings and of molecular biomarkers that allow a precise stratification of patients and an adequate prediction of the therapeutic response. In this regard, the possibility of obtaining temporal artery biopsies for diagnostic purposes offers incredible exploratory possibilities to define different disease pathotypes potentially susceptible to different therapeutic interventions. In this Series paper, we will describe the most recent evidence relating to the pathogenesis of giant cell arteritis, trying to define, if possible, a new pathogenetic-centred approach to patients with giant cell arteritis.

Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.

Purpose of Review: A growing body of evidence supports the relevance of the interleukin-23/interleukin-17 (IL-23/IL-17) pathway for the pathogenesis of axial spondyloarthritis (axSpA) and its treatment. Recently, innate lymphoid cells (ILC), a heterogeneous family of immune effector cells, have been identified as a relevant contributor in tissue homeostasis, partially via IL-23/IL-17 axis. This review describes the biology and the origins of the group 3 ILCs (ILC3s) in humans, focusing on their role in the pathogenesis of axSpA. Recent Findings: Clinical trials showed the effectiveness of IL23/IL-17 axis inhibition in both spondyloarthritis (SpA) and Inflammatory Bowel Disease (IBD). Recent findings confirm the high prevalence of subclinical gut inflammation in patients with SpA. Translational data in humans have demonstrated an increase in the number of ILC3s responsive to IL-23 and producing either IL-22 or IL-17 in the gut of SpA patients. The observation of gut-derived ILC3s in circulation and at inflamed tissues in patients with SpA suggest a recirculation of ILCs from mucosal site to lymphoid tissues and possibly enthesis and joints. Summary: Multiple observations demonstrate the expansion of IL-17- and IL-22-producing ILC3 in the subclinically inflamed gut of SpA patients. These innate immune cells, also observed in normal entheses, seem to be able to re-circulate from the gut to inflamed tissues of SpA patients, thus contributing to the disease perpetuation. The development of tools that can provide access to diseased tissue from sacroiliac joint and spinal entheses will provide valuable knowledge on the role of ILC3 in axSpA pathogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder, characterized by polyarticular inflammation causing progressive joint damage and disability. The mechanisms underlying its pathogenesis involve activation of innate and adaptive immunity, microvascular endothelial cell activation, and inflammatory infiltration of lymphocytes and monocytes into the synovium. Spinal involvement in RA is not typical; when it occurs, the main radiological features are (1) atlantoaxial subluxation (AAS), which is the most typical form of cervical spine involvement; (2) cranial settling—also known as basilar impression, atlantoaxial impaction or superior migration of the odontoid—which is the most severe form of associated spinal instability; and (3) subaxial subluxation. A combination of these alterations may occur. Synovitis is characterized by infiltration of innate and adaptive immune cells; joint destruction is a consequence of activation of synovial fibroblasts, which acquire aggressive, inflammatory, invasive features, associated with increased chondrocyte catabolism and synovial osteoclastogenesis. Neck pain is the most frequent symptom of spinal involvement in RA; it occurs in 40–80% of patients and is mostly localized at the craniocervical junction. Other symptoms—caused by compression of neural structures such as the greater occipital nerve (at C2), the nucleus of the spinal trigeminal tract and the greater auricular nerve—are occipital neuralgia, facial pain and ear pain, respectively. Irritation of the lesser occipital nerve (at C1) can cause pain in the suboccipital region. Sometimes patients may complain of a sensation of their head falling down with flexion, weakness, reduced endurance, loss of ability, gait alterations, paraesthesias or other symptoms due to cord and medullary compression, and upper or lower motor neuron signs, or both. Surgical management of RA remains a challenging field.

Background A growing body of evidences indicate that the aberrant activation of innate immune systems, occurring in genetically predisposed patients, drives inflammatory processes in Ankylosing Spondylitis (AS).1 Objectives Aim of this study was to evaluate the activation and the functional relevance of inflammasome pathways in patients with AS. Methods Intestinal, synovial and bone marrow expression of inflammasome pathways, pyroptosis and IL-1b and IL-18 was evaluated in AS patients. Organic acid extraction was performed on ileal samples as previously described on.2 The expression of the metabolite-sensing receptors GPR43 and GPR109A involved in the regulation of the intestinal inflammasome was also assessed. The role of intestinal dysbiosis in modulating inflammasome activation was also studied in AS patients and HLA-B27 transgenic rats. Inflammasome activation was evaluated in isolated peripheral AS monocytes. The role of LPS, PGE2 and nicotine in inducing monocyte inflammasome activation and the role of inflammasome in modulating IL-23 production was also evaluated. Results Activation of inflammasomes was observed in the inflamed gut, synovial and bone marrow samples of AS patients and associated with an increased expression of caspase-1, IL-1b and IL-18. In AS, AIM2 expression was observed in the context of tuft cells and of adherent ileal bacteria. Inflammasome activation in AS gut, was associated with the occurrence of dysbiosis and increased pyroptosis as demonstrated by the membrane localization of Gasdermin D. Isolated intestinal bacteria from AS ileal samples, significantly modulated inflammasome activation in isolated monocytes. Reduced Short-chain fatty acids concentrations and increased expression of GPR43 and GPR109 were demonstrated in the AS ileal samples. Inflammasome activation was also observed in the inflamed gut of HLA-B27 TG rats and suppressed by antibiotics treatment. Increased expression of NLRP3, NLRC4 and AIM2 was confirmed in AS isolated peripheral monocytes. Serum levels of IL-1b and IL-18 were increased in AS patients, especially in smoker patients, and directly correlated with the ASDAS-CRP. In in vitro studies, LPS and nicotine strongly activated NLRP3, NLRC4 and AIM2 pathways in AS monocytes. The CC genotype of PTGER4 SNP rs6896969 was associated with a significantly increased activation of inflammasome in AS. Finally, inflammasome activation in AS monocytes was required for the induction of IL-23p19 expression in an IL-1b-dependent way. Conclusions Inflammasome activation occurs in AS patients being modulated by a plethora of different stimuli. Inflammasome drives IL-23 production in an IL-1b-dependent mechanism in AS patients supporting the auto-inflammatory nature of the disease and possibly representing a future therapeutic target in AS. References [1] Ciccia F, et al. Intestinal dysbiosis and innate immune responses in axial spondyloarthritis. Curr Opin Rheumatol2016. [2] Fuller M, et al. The short chain fatty acid receptor, FFA2, contributes to gestional glucose homeostasis. American Journal of Physiology – Endocrinology and Metabolism2015. [3] Macia L, et al. Metabolite-sensing receptors GPR43 and GPR109 facilitate dietary fibre-induced gut homeostasis through the regulation of the inflammasome. Nat Commun2015. Disclosure of Interest None declared

Background Several studies showed a close relationship between Rheumatoid Arthritis (RA) and accelerated atherosclerosis [1,2]. At the best of our knowledge, no such study has been carried out in a large Italian series. Objectives To investigate the prevalence of presence of subclinical atherosclerosis and history of cardio-cerebrovascular events (CVEs), in 1266 patients consecutively admitted to Rheumatology Units throughout the whole Italy. Methods From 01/01/2015 to 31/12/2015, 1266 consecutive patients admitted to GIRRCS centres, satisfying ACR/EULAR criteria for RA were investigated for: i. traditional cardiovascular risk factors: gender, age, smoking habit, cholesterol, triglycerides, glycemia, systemic arterial hypertension (SAH), metabolic syndrome (MS), type 2 diabetes (T2D); ii. RA aspects: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage by joint X-ray, and joint surgery; iii. subclinical atherosclerosis, as assessed by ultrasound technique and/or atherosclerotic peripheral lesions; iv. history of CVEs. Results We evaluated 1176 patients out of 1266, that were investigated for both CVEs and subclinical atherosclerosis. They were mostly females (80.52%), with a median age of 60 years (range 18–91 years), a median disease duration of 12 years (range 0.8–25 years), seropositive in 69.21%. Nineteen percent were in remission; 17.51% presented low disease activity; 39.45% moderate disease activity, 22.61% high disease activity. Out of 1176 patients, 217 (18%) showed evidence of subclinical atherosclerosis: a figure lower than that reported worldwide (32.7%) [2]. Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, 7 Stroke), too this figure is lower than that reported worldwide (8.5%) [3,4]. In multivariate analysis, older age (p=0.0001, OR:1.069, CI95%:1.05–1.09), MS (p=0.0001, OR:3.417, CI95%:2.16–5.40) and SAH (p=0.0001, OR:3.714, CI95%:2.23–6.17) and high disease activity (p=0.001, OR:2.117, CI95%:1.35–3.32) were significantly associated with the presence of subclinical atherosclerosis. Male gender (p=0.0001, OR:3.465, CI95%:1.94–6.185), MS (p=0.005, OR:2.542, CI95%:1.29–4.52), T2D (p=0.007, OR:2.324, CI95%:1.29–4.29) and SAH (p=0.001, OR:4.921, CI95%:2.14–11.45) and higher disease activity (p=0.003, OR:1.316, CI95%:1.15–1.68) were significantly associated with a history of CVEs. Conclusions This is the first Italian multicenter study on subclinical and clinical atherosclerosis in patients with RA. We pointed out a low prevalence of both subclinical atherosclerosis and history of CV events. Nonetheless, a high disease activity and presence of cardiovascular risk factors were found to play a role, similarly to other countries. References Ruscitti P, et al. PLoS One. 2017;12:e0170108. Ambrosino P, et al. Thromb Haemost. 2015;113:916–30. Solomon D et al. Ann Rheum Dis. 2010;69:1920–5. Avina-Zubieta JA, et al. Ann Rheum Dis. 2012;71:1524–9. Disclosure of Interest None declared

Objective: Gut-derived innate lymphoid cell 3 (ILC3) has been shown to participate in the pathogenesis of ankylosing spondylitis (AS). CX3CR1+ mononuclear phagocytes (MNPs) have been demonstrated to modulate ILC3 function in the gut. This study was undertaken to investigate the role of proinflammatory CX3CR1+CD59+ MNPs in modulating ILC3 function in AS patients. Methods: MNP subsets in the blood of AS patients and controls were analyzed by flow cytometry. The presence of CX3CR1+CD59+ cells in tissue was confirmed by confocal microscopy. Expression of the proinflammatory chemokines CX3CL1 and CCL2 and decoy receptor 6 (DcR-6) was analyzed. Peripheral CX3CR1+CD59+ cells were cocultured with ILC3, and changes in their frequency were evaluated by flow cytometry. Transcriptome analysis of circulating CX3CR1+ monocytes was also performed. Results: DcR-6 deficiency and CCL2 overexpression were observed in inflamed tissues from AS patients. In the gut, the proinflammatory CX3CR1+CD59+ MNP population was expanded, correlated with the presence of bacteria, and produced high levels of tumor necrosis factor–like molecule 1A (TL1A) and interleukin-23 (IL-23). MNPs positive for CD11b, CD11c, and major histocompatibility complex class II, predominantly expressing CX3CR1, were also expanded in the small intestines of treatment-naive SKG relative to BALB/c mice. The frequency of gut-derived CX3CR1+CD59+CCR9+TL1A+IL-23+ MNPs was significantly higher in the peripheral blood and synovial fluid of AS patients than controls. CCR9+CX3CR1+CD59+ monocytes were also expanded in AS synovial and bone marrow samples. Transcriptome analysis of isolated CX3CR1+CD59+ monocytes demonstrated a specific proinflammatory profile in AS. Isolated proinflammatory CX3CR1+CD59+ MNPs from AS patients induced the expansion and activation of ILC3. Conclusion: Proinflammatory CX3CR1+CD59+TL1A+IL-23+ MNPs are expanded in AS patients and display a specific proinflammatory transcriptome profile. Given the ability of these cells to support ILC3 expansion, they may promote a sustained proinflammatory status in AS.

No abstract available