Identification of the central tolerance checkpoint for autoreactive proteinase 3 B cells in human bone marrow.

Major target antigens of ANCA-associated vasculitis (AAV) are myeloperoxidase (MPO) and proteinase 3 (PR3). High-affinity MPO- and PR3-ANCA immunoglobulins are produced by antigen-experienced, class-switched autoreactive B cells. To prevent autoreactivity, B cells are subjected to several self-tolerance checkpoints, from the early immature stages in the bone marrow (BM), collectively called "central tolerance", to late mature stages, collectively called "peripheral tolerance"; the latter was recently elucidated for autoreactive PR3 B cells.

Very long-term data on patients with severe eosinophilic asthma treated with mepolizumab: a case series.

Background: Patients with severe asthma are often dependent on oral corticosteroids (OCS) and have frequent exacerbations. This article aims to report very long-term data of patients with severe eosinophilic asthma assessing asthma control, lung function, inhaled corticosteroid (ICS) dose reduction, and clinical and biological parameters of patients treated with mepolizumab.

Methods: Four cases of adult patients with severe eosinophilic asthma who were treated for 60 months or more with mepolizumab 100 mg/4 weeks, leading to the stable discontinuation of OCS, are presented.

Anti-IL-5 Pathway Agents in Eosinophilic-Associated Disorders Across the Lifespan.

Monoclonal antibodies targeting interleukin (IL)-5 pathways have revolutionized the treatment expectations for eosinophilic-associated conditions, particularly in patients with respiratory involvement. Mepolizumab (IL-5 antagonist monoclonal antibody), benralizumab (IL-5 receptor blocker monoclonal antibody), and reslizumab (IL-5 antagonist monoclonal antibody) have collectively contributed to the overall improvement of the disease burden in various conditions. Eosinophilic asthma currently boasts the most robust evidence across all age groups: all three biologics are approved for adults (aged ≥18 years); mepolizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also in children (aged ≥ 6 years), while bernalizumab was recently approved by the FDA for patients aged ≥6 years in the USA.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response.

Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire.

Objectives: The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients.

Methods: The study design took a prospective cohort study approach.

Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis.

Introduction: Combinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs.

Using the 6-min walk test to assess the clinical response to mepolizumab and conventional therapy in severe eosinophilic asthma.

Background: Severe asthma limits exercise to avoid respiratory symptoms. The objective of the present study was to investigate the role of the 6-min walk test (6MWT) in severe asthma.

Methods: Consecutive patients with severe eosinophilic asthma were enrolled.

Impulse oscillometry defined small airway dysfunction in asthmatic patients with normal spirometry: Prevalence, clinical associations, and impact on asthma control.

Background: The small-airway dysfunction (SAD), detected with impulse oscillometry (IOS) methods, has been recently better characterized in patients with asthma. However, little is known about SAD in asthmatic patients with normal spirometry (NS).

Objective: In this study, we aimed to investigate, in an unselected sample of 321 patients with physician-diagnosed asthma and NS, prevalence, clinical characterization, and impact on asthma control of IOS-defined SAD.

Anti-Tumor Efficacy of In Situ Vaccination Using Bacterial Outer Membrane Vesicles.

In situ vaccination (ISV) is a promising cancer immunotherapy strategy that consists of the intratumoral administration of immunostimulatory molecules (adjuvants). The rationale is that tumor antigens are abundant at the tumor site, and therefore, to elicit an effective anti-tumor immune response, all that is needed is an adjuvant, which can turn the immunosuppressive environment into an immunologically active one. Bacterial outer membrane vesicles (OMVs) are potent adjuvants since they contain several microbe-associated molecular patterns (MAMPs) naturally present in the outer membrane and in the periplasmic space of Gram-negative bacteria.

Treatment Approaches to Granulomatosis with Polyangiitis and Microscopic Polyangiitis.

We have made significant headway in our ability to induce and maintain remission in patients with granulomatosis with polyangiitis and microscopic polyangiitis. With increased understanding of the pathogenesis of antineutrophilic cytoplasmic antibody-associated vasculitides (AAV), therapeutic targets have been identified and studied in clinical trials. From initial induction strategies including glucocorticoids and cyclophosphamide, we have discovered effective induction regimens with rituximab and complement inhibition that can significantly decrease the glucocorticoid cumulative doses in patients with AAV.

Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients.

Background: Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce.

Methods: Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021.

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA.

EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update.

Background: Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update.

Methods: Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations.

Small airway dysfunction in asthmatic patients treated with as-needed SABA monotherapy: A perfect storm.

Background: Short-acting beta agonist (SABA)-only treatment is associated with poor asthma control and adverse clinical outcomes. The importance of small airway dysfunction (SAD) is increasingly recognized in asthma, but less is known in patients using SABA-only therapy. We aimed to investigate the impact of SAD on asthma control in an unselected cohort of 60 adults with physician-diagnosed intermittent asthma treated with as-needed SABA monotherapy.

Targeting the interleukin-5 pathway in EGPA: evidence, uncertainties and opportunities.

Only a minority of patients with eosinophilic granulomatosis with polyangiitis (EGPA) can be weaned-off glucocorticoids (GC) using conventional treatment strategies. The development of biological agents specifically inhibiting the IL-5 pathway provided the opportunity to treat EGPA by targeting one of the crucial regulators of eosinophils, reducing the GC dose required to control the disease.The anti-IL-5 antibody mepolizumab at the dose of 300 mg/4 weeks has proven to be safe and effective in EGPA.

A glance into the future of anti-neutrophil cytoplasmic antibody-associated vasculitis.

In the past decade, unprecedented progress has been made in understanding the pathogenesis, diagnosis, assessment, and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). International collaborations and input from several fields (e.g.

Measurement Properties of Outcome Instruments for Large-Vessel Vasculitis: A Systematic Literature Review.

Objective: To systematically review the measurement properties of outcome instruments used in large-vessel vasculitis (LVV).

Methods: MEDLINE, Embase, Cochrane, and Scopus databases were searched for studies published from inception to July 14, 2020, that addressed measurement properties of instruments used in giant cell arteritis (GCA) and Takayasu arteritis (TA). The measurement properties of the instruments identified were collected following the Outcome Measures in Rheumatology (OMERACT) and Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) frameworks.

Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice.

ANCA-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80-90% of all AAV. Exposure to silica dust, farming and chronic nasal Staphylococcus aureus carriage are associated with increased risk of developing AAV.

Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Objective: Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA-associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.

Monoclonal antibodies targeting small airways: a new perspective for biological therapies in severe asthma.

Small airway dysfunction (SAD) in asthma is characterized by the inflammation and narrowing of airways with less of 2 mm in diameter between generations 8 and 23 of the bronchial tree. It is now widely accepted that small airways are involved in the pathogenesis of asthma and are a major determinant of airflow obstruction in this disease. In recent years, specialized tests have been developed, such as Impulse Oscillometry (IOS) and Multiple Breath Nitrogen Washout (MBNW) tests, which have been deemed more accurate in detecting SAD than conventional spirometry.

Interstitial lung disease in microscopic polyangiitis and granulomatosis with polyangiitis: demographic, clinical, serological and radiological features of an Italian cohort from the Italian Society for Rheumatology.

Objectives: Interstitial lung disease (ILD) has been described as a possible pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Aim of this cross-sectional Italian national study was to describe demographic, clinical and serological profile of ILD related to MPA and GPA and investigate possible correlations between radiologic patterns of ILD and vasculitis features.

Methods: We enrolled 95 consecutive patients with AAV-ILD, 56 affected by MPA (58.