Pros and cons of TNF inhibitors and tocilizumab in the treatment of large-vessel vasculitis.

Large-vessel vasculitides (LVVs) include giant cell arteritis (GCA) and Takayasu's arteritis (TAK). Even if similar, these two entities differ in terms of treatment and outcomes.High doses of glucocorticoids (GCs) are still the first choice for the treatment of both conditions. However, adjunctive therapies are recommended in selected patients in order to decrease the risk of relapse and the amount of side effects related to GCs. Tumour necrosis factor α inhibitors (TNFis) and tocilizumab (TCZ) are used for the treatment of LVVs, with some differences. In GCA, TCZ has been proved to be effective and safe in inducing remission with some open questions still remaining, whereas data about TNFis are scarce and non-conclusive. On the contrary, in TAK either TNFis or TCZ seem to be able to control symptoms and angiographic progression in refractory forms.However, their place in the management of treatment must still be clarified, and as a result the American College of Rheumatology and EULAR guidelines slightly differ in the recommendations about when and what treatment to start. Thus, the aim of this review is to look at the evidence on the use of TNFis and TCZ in LVVs, outlining the pros and cons of both therapies.

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.

Pathogenesis of primary Sjögren's syndrome beyond B lymphocytes.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting exocrine glands of the body, prevalently lacrimal and salivary glands. The pSS pathogenesis has been thought to be B-cell-centric and several clinical trials have been carried out in order to clarify the therapeutic role of B-cell depletion in patients with pSS. Unfortunately, however, B-cell depletion with rituximab has failed in demonstrating any significant results in pSS patients. Besides the contribution of B cells in the pathogenesis of pSS, effector Tfh, Th17 and Th22 cells, follicular dendritic cells (DCs), innate cells (ICs) and several cytokines, chemokines and miRNA have been proved to participate to the development of this systemic disease. Understanding these molecular processes may help guide research into resistant diseases and highly targeted therapeutic strategies. This review aims to discuss important pathogenetic mechanisms involved in the initiation and perpetuation of pSS behind the established role of B cells.

ILC3 in Axial Spondyloarthritis: the Gut Angle.

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. 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.

The Craniovertebral Junction in Rheumatoid Arthritis: State of the Art.

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.

Comparing treatment options for large vessel vasculitis.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

New insights into the pathogenesis of giant cell arteritis: are they relevant for precision medicine?

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.

Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor-Like Molecule 1A+Interleukin-23+ Monocytes Are Expanded in Patients With Ankylosing Spondylitis and Modulate Innate Lymphoid Cell 3 Immune Functions.

OBJECTIVE: Gut-derived innate lymphoid cell 3 (ILC3) has been shown to participate in the pathogenesis of ankylosing spondylitis (AS). CX3 CR1+ mononuclear phagocytes (MNPs) have been demonstrated to modulate ILC3 function in the gut. This study was undertaken to investigate the role of proinflammatory CX3 CR1+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 CX3 CR1+CD59+ cells in tissue was confirmed by confocal microscopy. Expression of the proinflammatory chemokines CX3 CL1 and CCL2 and decoy receptor 6 (DcR-6) was analyzed. Peripheral CX3 CR1+CD59+ cells were cocultured with ILC3, and changes in their frequency were evaluated by flow cytometry. Transcriptome analysis of circulating CX3 CR1+ monocytes was also performed. RESULTS: DcR-6 deficiency and CCL2 overexpression were observed in inflamed tissues from AS patients. In the gut, the proinflammatory CX3 CR1+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 CX3 CR1, were also expanded in the small intestines of treatment-naive SKG relative to BALB/c mice. The frequency of gut-derived CX3 CR1+CD59+CCR9+TL1A+IL-23+ MNPs was significantly higher in the peripheral blood and synovial fluid of AS patients than controls. CCR9+CX3 CR1+CD59+ monocytes were also expanded in AS synovial and bone marrow samples. Transcriptome analysis of isolated CX3 CR1+CD59+ monocytes demonstrated a specific proinflammatory profile in AS. Isolated proinflammatory CX3 CR1+CD59+ MNPs from AS patients induced the expansion and activation of ILC3. CONCLUSION: Proinflammatory CX3 CR1+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.

Subclinical atherosclerosis and history of cardiovascular events in Italian patients with rheumatoid arthritis: Results from a cross-sectional, multicenter GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) study.

Several studies have pointed out a significant association between rheumatoid arthritis (RA) and accelerated atherosclerosis. At the best of our knowledge, no such study has been carried out in a large Italian series and, in this study, we aimed to investigate the prevalence of both subclinical atherosclerosis and history of cardiovascular events (CVEs), in patients consecutively admitted from January 1, 2015 to December 31, 2015 to Rheumatology Units throughout the whole Italy.Centers members of GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) were invited to enrol patients consecutively admitted from January 1, 2015 to December 31, 2015 and satisfying American College of Rheumatology/ European League Against Rheumatism criteria for RA and to investigate each of them for: traditional cardiovascular risk factors: sex, age, smoking habit, total cholesterol, triglycerides, glycaemia, high blood pressure, metabolic syndrome (MS), type 2 diabetes (T2D); RA features: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage as assessed by hands and feet x-ray, and previous joint surgery; prevalence of both subclinical atherosclerosis and history of CVEs.Eight centers participated to the study. From January 1, 2015 to December 31, 2015, the 1176 patients, who had been investigated for all the items, were enrolled in the study. They were mostly women (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.Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, and 7 stroke). This figure appears to be lower than that reported worldwide (8.5%). After excluding the 82 patients with a history of CV events, subclinical atherosclerosis was detected in 16% of our patients, (176 patients), a figure lower than that reported worldwide (32.7%) and in previous Italian studies.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.