Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis with hypereosinophilia that is preceded by asthma and chronic rhinosinusitis with nasal polyps. Since multiple organs may be involved in this disease, early treatment is required. In this regard, glucocorticoid (GC) therapy is often initiated before a definitive diagnosis is made. A biopsy of an injured organ is useful for a diagnosis but is not performed in all cases due to its invasiveness and, at times, diagnostic accuracy. Therefore, a comprehensive diagnosis is often made based on symptoms and clinical course of disease. However, it is sometimes difficult to distinguish EGPA from other hypereosinophilic diseases or vasculitides. In recent years, in addition to GC and immunosuppressive agents, anti-interleukin (IL)-5/IL-5 receptor alpha (IL-5Rα) antibodies targeting eosinophils have become increasingly important in the treatment of EGPA. However, accumulating data suggest that such anti-IL-5/IL-5Rα antibody therapy may have effects beyond those observed in eosinophils. This paper outlines the clinical features, diagnosis, pathogenesis, and current treatment of EGPA, a hypereosinophilic disease.

Type 2 inflammation in the airways and lungs is inflammation induced by type 2 cytokines such as IL-4, IL-5, and IL-13, produced primarily by type 2 helper T cells and type 2 innate lymphoid cells, and causes changes in the physiology and structure of the airways. Type 2 inflammation is currently in the spotlight because of its direct link to the treatment of several airway and lung diseases. Abundant evidences have accumulated that inflammatory biomarkers such as blood eosinophils, fractional exhaled nitric oxide, and IgE are essential clinical tools in the diagnosis and management of asthma and COPD. It is well known that asthma and COPD have diverse inflammatory phenotypes even when clinical features are similar, and it has been demonstrated that assessment of airway inflammation with biomarkers can improve diagnostic accuracy, determine safer and more effective treatment strategies, and predict future risks such as exacerbations and lung function decline. The Japanese Respiratory Society has published clinical practice guidelines for the evaluation of type 2 inflammation in the airways and lungs. In addition to asthma and COPD, the guide covers a wide range of airway and lung diseases, including interstitial lung disease, allergic bronchopulmonary mycosis, allergic rhinitis, and eosinophilic chronic rhinosinusitis. It also provides comprehensive guidelines covering a variety of clinical biomarkers. The purpose of this guidance is to provide evidences for the interpretation of type 2 inflammation measurements and to promote the widespread use of inflammation assessment to further improve the efficiency of airway and respiratory disease management.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and intractable chronic disease. Glucocorticoids are the mainstay of treatment for EGPA. The drugs that target interleukin (IL)-5 signaling have also been marketed or developed in recent years. While no animal model can completely recapitulate EGPA, the ovalbumin (OVA)-induced eosinophilic vasculitis mouse model exhibits pathological similarities in the lungs. However, the effect of an anti-IL-5 drug has not yet been investigated using this model. This study used the OVA-induced eosinophilic vasculitis model to evaluate and characterize its usefulness, focusing on the effects of an anti-IL-5 antibody.

Female C57BL/6NCrSlc mice were intraperitoneally immunized on days 0 and 14 with OVA adsorbed onto an aluminum gel. From days 26-32, the mice were exposed to aerosolized 1% OVA daily for 1 h. Anti-IL-5 antibody or vehicle was injected intravenously or intraperitoneally once on the first day of aerosol exposure (day 26). On day 33, the eosinophil and lymphocyte counts in the blood and bronchoalveolar lavage fluid (BALF) were measured. Lung specimens were used to assess the vascular lesions formed in the pulmonary arteries. Plasma cytokine levels were measured on day 28.

The anti-IL-5 antibody significantly reduced eosinophil counts in the blood and BALF. In contrast, it did not inhibit the lymphocyte counts in BALF or vascular lesion formation. The anti-IL-5 antibody significantly blocked the plasma level of IL-5 on day 28. However, the levels of other cytokines (i.e., IL-2, IL-6, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-12, IL-4, IL-13, and IL-17) were not altered.

In the investigated model, lymphocyte infiltration in lung tissue and cytokines other than or in addition to IL-5 were suggested to have contributed to the development of vasculitis. IL-5 signaling has a potential impact on EGPA pathogenesis via a different mechanism or in addition to the mechanism demonstrated in the OVA-induced eosinophilic vasculitis mouse model. The model may be useful for drug discovery targeting both eosinophilic and non-eosinophilic aspects of EGPA pathogenesis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is an immune-mediated, inflammatory, multisystemic disease that is considered a form of ANCA-associated vasculitis and whose association with asthma and blood and tissue eosinophilia differentiate it from other types of vasculitis. Nevertheless, diagnosis of EGPA may be difficult or delayed not only because of the rarity of the disease, but also because other diseases can present with similar manifestations.

We review a series of key areas in EGPA, namely, laboratory and clinical indicators of disease, diagnosis, role of biomarkers, induction and maintenance therapy, and use of traditional and novel drugs. This narrative review was based on a thorough search of PubMed.

Clinicians should be aware of the limitations of available tools for diagnosing EGPA, and more efforts should be made to identify clinical and laboratory red flags, with the purpose of achieving an early diagnosis before irreversible damage occurs. New effective therapies are available, although future research should target an approach that spares glucocorticoids, reduces the risk of flares and organ damage, and maintains long-term remission with minimum adverse effects.

Eosinophilic granulomatosis with polyangiitis (EGPA), as a heterogeneous component of antineutrophil cytoplasmic antibody-associated vasculitis, may be induced by a series of environmental and genetic factors, involved with a variety of immune cells and immune components, and presented with various clinical manifestations, with multiple organs and systems (respiratory, skin, heart, kidney, nerve, etc.) involved. The choice of glucocorticoid (GC) dosage and immunosuppressant in traditional treatment strategies varies greatly from individual to individual and is not universally applicable in all the EGPA phenotype spectrum, especially in relapsing or refractory diseases. With the understanding of the heterogeneity of EGPA, a variety of therapeutic approaches are emerging and improving the traditional treatment model. In this review, we summarized the heterogeneity of EGPA etiology and pathogenesis. Clinical and pathological manifestations of the same organ involved also show significant differences and there are even gender differences. Biological treatments that mainly target type 2 inflammatory pathways are widely used in clinical practice for remission induction and maintenance of EGPA. Targeted biological therapy has shown excellent performance in reducing GC dosage and controlling symptoms and recurrence. However, a large number of high-quality randomized controlled studies are still under research for relapsing or refractory EGPA with special organ involvement. We believe that EGPA has a highly heterogeneous phenotype spectrum, and the treatment patterns targeting key molecules in the pathogenesis are of great value for individual treatment of EGPA.

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations. Historically, the mainstay of therapy for both conditions has been systemic glucocorticoids. However, recent availability of biologics that directly or indirectly target eosinophils has provided new avenues to pursue improved outcomes with decreased toxicity. In this article, we summarize the evidence supporting the use of specific biologics in HES and/or EGPA and provide a framework for their clinical use in patients.

Conventional immunosuppressants are ineffective for the management of EGPA-related asthma. Tezepelumab is a human monoclonal antibody that inhibits thymic stromal lymphopoietin (TLSP) that has proven efficacy in several phase 3 studies for the treatment of asthma. We treated with off-label tezepelumab the first two patients with severe refractory EPGA-related asthma. These preliminary findings suggest that targeting upstream signaling of the T2 inflammatory pathway can improve symptoms, reduce BVAS and increase Asthma Control Test scores, even in patients with refractory asthma who have failed several previous lines of treatment. Nevertheless, by analogy with dupilumab-induced IL-4/13 blockade, the persistence of sputum eosinophilia (reported in both patients) raises questions as to whether TSLP inhibition could lead to a rebound of eosinophilia and potentially to eosinophil-related symptoms in patients with EGPA.

The activities, ontogeny, and mechanisms of lineage expansion of eosinophils are less well resolved than those of other immune cells, despite the use of biological therapies targeting the eosinophilia-promoting cytokine interleukin (IL)-5 or its receptor, IL-5Rα. We combined single-cell proteomics and transcriptomics and generated transgenic IL-5Rα reporter mice to revisit eosinophilopoiesis. We reconciled human and murine eosinophilopoiesis and provided extensive cell-surface immunophenotyping and transcriptomes at different stages along the continuum of eosinophil maturation. We used these resources to show that IL-5 promoted eosinophil-lineage expansion via transit amplification, while its deletion or neutralization did not compromise eosinophil maturation. Informed from our resources, we also showed that interferon response factor-8, considered an essential promoter of myelopoiesis, was not intrinsically required for eosinophilopoiesis. This work hence provides resources, methods, and insights for understanding eosinophil ontogeny, the effects of current precision therapeutics, and the regulation of eosinophil development and numbers in health and disease.

Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. Furthermore, the impact of genetic predisposition and environmental factors on disease susceptibility and severity was considered, and the current treatment options were presented. Understanding the mechanisms involved in the pathogenesis of pulmonary vasculitis is crucial for developing targeted therapies and improving clinical outcomes in affected individuals.

Eosinophilic granulomatosis with polyangiitis (EGPA) causes necrotizing vasculitis and eosinophil-rich granulomatous inflammation in small- to medium-sized vessels, resulting in multiple organ damage. EGPA is classified as an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, with myeloperoxidase-ANCA detected in approximately one-third of the patients. Conventional treatment of EGPA relies on systemic glucocorticoids (GCs) in combination with cyclophosphamide when poor prognostic factors are present; however, the dilemma between disease control and drug-related adverse effects has long been a challenge. Recent studies have revealed that the genetic background, pathophysiology, and clinical manifestations differ between ANCA-positive and ANCA-negative patients; however, mepolizumab, an interleukin (IL)-5 inhibitor, is effective in both groups, suggesting that the IL-5-eosinophil axis is deeply involved in the pathogenesis of both ANCA-positive and ANCA-negative EGPA. This review summarizes the latest knowledge on the pathophysiology of EGPA and focuses on the roles of eosinophils and ANCA. We then introduce the current treatment recommendations and accumulated evidence for mepolizumab on EGPA. Based on current unmet clinical needs, we discuss potential future therapeutic strategies for EGPA.

Kawasaki disease (KD) is a form of idiopathic vasculitis frequently accompanied by coronary artery lesions, which involves endothelial dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are implicated in many cardiovascular diseases. However, few studies have examined the role of circRNAs on endothelial dysfunction in KD. In this study, we investigated the role of circ7632 on endothelial-mesenchymal transition (EndoMT) in KD and then explored the underlying mechanism. Children diagnosed with KD and age-matched healthy controls (HC) were included. Sera samples were collected. Primary human umbilical vein endothelial cells (HUVECs) were obtained and incubated with 15% HC and KD serum for 48 h. The mRNA and protein expression of mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) and endothelial marker zonula occludens-1 (ZO-1) in HUVECs transfected with plasmid-circ7632 and si-circ7632 were detected by RT-qPCR and Western blot analysis. CCK8, scratch test, and migration test were performed to examine the effect of circ7632 on the cell proliferation and migration. The circ7632 level was higher in HUVECs treated by KD serum than in HUVECs treated with HC serum. Overexpression of circ7632 significantly increased vimentin and α-SMA expression, decreased ZO-1 expression, and also decreased cell proliferation. Down-regulation of circ7632 expression got the opposite results. RNA-seq analysis, and confirmatory experiment displayed that down-regulation of circ7632 decreased IL-33 expression, and IL-33 silencing mitigated KD serum-mediated EndoMT. Our study revealed that circ7632 level was elevated in KD serum-treated HUVECs. Circ7632 down-regulation could alleviate EndoMT likely through decreasing IL-33 expression. The circ7632 may become a potential therapeutic target for KD.

The mainstay of treatment for eosinophilic granulomatosis with polyangiitis (EGPA) is systemic corticosteroid therapy; some patients also receive intravenous immunoglobulins, other immunosuppressive agents, and biologics. Mepolizumab, an anti-interleukin-5 monoclonal antibody, induces remission and decreases the daily corticosteroid dose; however, the clinical efficacy of mepolizumab in EGPA and the prognosis with long-term treatment with this drug are unknown.

Seventy-one EGPA patients were treated at Hiratsuka City Hospital, Japan, between April 2018 and March 2022. We administered mepolizumab for a mean of 2.8 ± 1.7 years to 43 patients in whom remission could not be induced by conventional treatment. After excluding 18 patients who had received mepolizumab for less than 3 years, we classified 15 patients into a "super-responder group" (the daily dose of corticosteroids or other immunosuppressant could be decreased, or the interval between IVIG treatments could be prolonged) and 10 patients into a "responder group" (neither of these changes was achievable). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and other immunosuppressants, Birmingham Vasculitis Activity Score (BVAS), and relapse frequency before and after mepolizumab initiation were determined.

Blood eosinophil count at diagnosis and the lowest serum IgG level before mepolizumab treatment were significantly higher in super-responders than in responders (p < 0.05). In super-responders, the prednisolone dose at last visit on mepolizumab treatment was lower than that before treatment (p < 0.01) and lower than that at last visit in the responders (p < 0.01). In both groups, peripheral blood eosinophil numbers and BVAS were lower after starting mepolizumab than before (p < 0.01). BVAS before mepolizumab (p < 0.05) and at last visit (p < 0.01) were lower in super-responders than in responders. Relapse rates every year after the start of mepolizumab were lower in super-responders than in responder groups (p < 0.01). In super-responders, relapse rates were lower during the 3 years following mepolizumab initiation (p < 0.01) and at last visit (p < 0.01) were significantly lower than after 1 year of treatment.

Mepolizumab treatment of super-responders sustainably reduced the relapse rate.

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. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but potentially lethal systemic vasculitis. Only a few prospective therapeutic trials had been conducted in EGPA, and its treatment was mostly adapted from other vasculitides. Monoclonal antibodies inhibiting various pathways (e.g. interleukin-5 [IL5] or B cells) have been investigated.

Published studies on treatments for EGPA using glucocorticoids, conventional immunosuppressants (such as cyclophosphamide or azathioprine), antiIL5 pathway agents (mepolizumab, approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for EGPA; benralizumab and reslizumab), other and future possible treatments [PubMed search, 01/1990-02/2023] are reviewed.

With advances made in the pharmacotherapeutic management of EGPA, the prognosis has gradually shifted from a potentially fatal to a more chronic course, for which more targeted and safer treatments can be used. However, glucocorticoids remain central. Rituximab is now a possible alternative to cyclophosphamide for induction, although data are still limited. AntiIL5 pathway therapies have been shown to be safe and effective in relapsing patients with EGPA, who often experience asthma and/or ears, nose, and throat (ENT) manifestations, but long-term data are needed. Treatment strategies need to be optimized based on individual patient characteristics, likely with sequential, combination-based approaches, while topical airway treatments should not be forgotten.

The link between severe asthma and eosinophilic granulomatosis with polyangiitis (EGPA) in terms of pathophysiological background, clinical manifestations and disease evolution has leaded to investigate the relevance of anti T2 monoclonal antibodies licensed for severe asthma patients as a treatment option for EGPA. The present review aimed to provide un update on EGPA pathophysiology and to critically summarize the most robust evidence coming from trials and real-life setting on the use of anti T2 biologics in EGPA patients.

Mepolizumab, an anti-interleukin-5 monoclonal antibody, is the only biologic drug targeting eosinophilic inflammation currently approved for EGPA treatment at the dose of 300 mg/4 weeks. Its use is restricted by the American College of Rheumatology guidelines to specific diseases phases and severity grades. However the most appropriate mepolizumab positioning and dose is still under investigation in the real life practice, which is providing an increasing amount of evidence confirming its efficacy, alone or in combination with other options in different disease stages. The relevance of other monoclonal antibodies interfering with T2 inflammation, including omalizumab and benralizumab, is under investigation but the evidence is still scarce.

Taking into account the suboptimal medium-long term safety profile of conventional EGPA treatments, the opportunity of selectively targeting eosinophilic inflammation certainly represents a revolutionary approach. However, further real-word evidence is required to effectively position the new treatments in the light of the disease complexity, including different immunological drivers, and individual variability.

Alarmins are endogenous, constitutively expressed, chemotacting and immune activating proteins or peptides released because of non-programmed cell death (i.e. infections, trauma, etc). They are considered endogenous damage-associated molecular patterns (DAMPs), able to induce a sterile inflammation. In the last years, several studies highlighted a possible role of different alarmins in the pathogenesis of various autoimmune and immune-mediated diseases. We reviewed the relevant literature about this topic, for about 160 articles. Particularly, we focused on systemic autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, idiopathic inflammatory myopathies, ANCA-associated vasculitides, Behçet's disease) and cutaneous organ-specific autoimmune diseases (vitiligo, psoriasis, alopecia, pemphigo). Finally, we discussed about future perspectives and potential therapeutic implications of alarmins in autoimmune diseases. In fact, identification of receptors and downstream signal transducers of alarmins may lead to the identification of antagonistic inhibitors and agonists, with the capacity to modulate alarmins-related pathways and potential therapeutic applicability.

Vasculitis describes a wide spectrum of rare, inflammatory, multisystem disorders. These heterogenous diseases all have inflammation of blood vessels as a central feature. However, they differ in terms of their genetic and environmental risk factors, disease pathogenesis, clinical presentations and treatment strategies. Many animal models of vasculitis exist, each resembling a different human clinical phenotype. This review provides an overview of recently published findings from experimental animal models of vasculitis.

Several new animal models have been described during the review period. New insights gleaned from existing animal models regarding cause, disease effector mechanisms and novel treatments identified in established animal models are discussed.

Animal models continue to be an important tool for understanding disease pathogenesis, especially in rare and complex diseases such as vasculitis. They also provide an invaluable platform for development and preclinical testing of new treatments.