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Autoimmunity Reviews Jan 2023Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, multi-system, inflammatory disease, belonging to the group of anti-neutrophil cytoplasmic antibody... (Review)
Review
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, multi-system, inflammatory disease, belonging to the group of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Previously known as Churg-Strauss syndrome, EGPA is characterised by late-onset asthma, eosinophilia and vasculitis affecting small-to-medium vessels. This disease behaves differently in many aspects to the other AAV and is often excluded from AAV studies. The disease is poorly understood and, due to it rarity and unique manifestations, there has been limited research progress to optimise our understanding of its complex pathogenesis and ability to develop management options - although the success of interleukin-5 inhibitors such as Mepolizumab has been a welcome development. The pathophysiology also appears to be different to other forms of AAV and hence management strategies that work for AAV may not fully apply to this condition. There is no current standard therapy for EGPA although corticosteroids are almost universally used for treatment alongside other agents and encouraging modes of treatment continue to evolve beyond glucocorticoid immunosuppression (including interleukin-5 inhibition). There is therefore a significant ongoing unmet need for efficacious steroid-sparing immunosuppressing agents. The prognosis also diverges from other forms of AAV, and we discuss the pathophysiology, clinical features and diagnosis, management and prognosis in this article.
Topics: Humans; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Interleukin-5; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Prognosis; Antibodies, Antineutrophil Cytoplasmic
PubMed: 36283646
DOI: 10.1016/j.autrev.2022.103219 -
International Journal of Molecular... Oct 2020Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels.... (Review)
Review
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Prognosis; Serogroup
PubMed: 33023023
DOI: 10.3390/ijms21197319 -
European Journal of Rheumatology Jul 2022Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's...
Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg - Strauss syndrome). Renal-limited AAV can be considered a fourth entity. Despite their rarity and still unknown cause(s), research into AAV has been very active over the past decades and has allowed for the development of new therapeutic regimens. The pathogenesis is a complex process of immune dysregulations with genetic and environmental influences. Recent genome-wide association studies have identified multiple genetic predisposing variants, especially at the major histocompatibility complex region. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) is well supported by several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) is not as strongly demonstrated. B cells likely play a major role in the pathogenesis because they produce ANCAs, as do neutrophil abnormalities, imbalances in T-cell subtypes, and/or cytokine - chemokine networks. The role of the alternative complement pathway was established more recently, and studies of the antagonist of human C5a receptor (avacopan) in AAV have just been completed, with promising results. The current standard management of severe AAV still consists of remission induction therapy with glucocorticoids combined with rituximab or, less often now, cyclophosphamide. Several studies showed that reduced-dose regimens of glucocorticoids are noninferior to the previously used heavier regimens, for therefore less cumulative exposure to glucocorticoids. Avacopan use may even lead to new steroid-free therapeutic approaches, at least for some selected patients. Several trials and studies have now shown the superiority of rituximab over azathioprine or methotrexate as maintenance therapy. However, the optimal dosing regimen and duration for maintenance remain to be better defined, at the individual patient level. Many changes have occurred in the standard of care for AAV over the past decades, and more are expected soon, including with use of avacopan, but also, likely, a few other agents under investigation or development.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Genome-Wide Association Study; Granulomatosis with Polyangiitis; Humans; Remission Induction; Rituximab
PubMed: 35156630
DOI: 10.5152/eujrheum.2022.20248 -
Autoimmunity Reviews Jun 2021The primary vasculitides constitute a heterogeneous group of immune mediated diseases of incompletely understood pathogenesis currently classified by the size of blood... (Review)
Review
The primary vasculitides constitute a heterogeneous group of immune mediated diseases of incompletely understood pathogenesis currently classified by the size of blood vessels affected (Chapel Hill classification). In recent years, several drugs with well-characterized immunological targets have been tested in clinical trials in large vessel vasculitis and small vessel vasculitis. Such trials provide "reverse translational" or bedside to bench information about underlying pathogenic mechanisms. Therefore, the aim of this systematic literature review was to examine the evidence base for a more refined mechanistic immunological classification of vasculitis. A total of 40 studies (20 randomized controlled trials (RCTs), 16 prospective studies, 1 retrospective cohort study and 3 case series) were included for full qualitative assessment. RCTs concerning biologic therapy for large vessel vasculitis mainly supports interleukin 6 receptor inhibition (tocilizumab). RCTs concerning biologic therapy for granulomatosis with polyangiitis and microscopic polyangiitis mainly support anti-CD20 treatment (rituximab) and complement inhibition with a small molecule C5a receptor antagonist (avacopan) is an emerging treatment option. The biologic treatment of eosinophilic granulomatosis with polyangiitis is centered around interleukin 5 inhibition (mepolizumab). Studies on tumor necrosis factor alpha inhibition (adalimumab, infliximab, and etanercept) showed negative results in giant cell arteritis but some effect in Takayasu arteritis. Taken together, clinical studies with cytokine and cell specific drugs are dissecting the heterogeneous immunopathogenic mechanisms of vasculitis and support a mechanistic immunological classification. Especially, cytokine antagonism is pointing towards immunological distinctions between eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis/microscopic polyangiitis and differences between giant cell arteritis and Takayasu arteritis.
Topics: Churg-Strauss Syndrome; Etanercept; Giant Cell Arteritis; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Randomized Controlled Trials as Topic; Rituximab; Takayasu Arteritis
PubMed: 33872767
DOI: 10.1016/j.autrev.2021.102829 -
Allergology International : Official... Oct 2019Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis... (Review)
Review
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future.
Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Biopsy; Diagnosis, Differential; Disease Susceptibility; Eosinophilia; Eosinophils; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Phenotype
PubMed: 31266709
DOI: 10.1016/j.alit.2019.06.004 -
Yonsei Medical Journal Jan 2023Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises group of small vessel vasculitides, including granulomatosis with polyangiitis (GPA),... (Review)
Review
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises group of small vessel vasculitides, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In 2022, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) jointly proposed new classification criteria for AAV (the 2022 ACR/EULAR criteria). In this review, we briefly summarize the 2022 ACR/EULAR criteria for GPA, MPA, and EGPA, and introduce our clinical experience with applying them to patients who were previously diagnosed with AAV based on three criteria: firstly, the classification criteria for GPA and EGPA proposed by the ACR in 1990; secondly, the algorithm for the classification of AAV and polyarteritis nodosa proposed by the European Medicines Agency algorithm in 2007 (the 2007 EMA algorithm); and thirdly, the revised International Chapel Hill Consensus Conference nomenclature of vasculitides in 2012 (the 2012 CHCC definitions). We found that concordance rate was highest in patients with MPA (96.6%), followed by those with EGPA (86.3%) and GPA (73.8%). In addition, compared to previous criteria, we noted several issues of the undervalued or overvalued items in the 2022 ACR/EULAR criteria for classifying AAV and provided several suggestions. To increase the diagnostic accuracy and reduce the discordance rate among the new and previous criteria for AAV, we suggest that the previous criteria should be considered together with the 2022 ACR/EULAR criteria when applying the classification criteria for AAV to patients suspected of AAV.
Topics: Humans; United States; Granulomatosis with Polyangiitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Rheumatology; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Microscopic Polyangiitis
PubMed: 36579374
DOI: 10.3349/ymj.2022.0435 -
European Respiratory Review : An... Mar 2022The functions ascribed to eosinophils have classically been limited to host defence against certain parasitic infections and potentially deleterious effects in the... (Review)
Review
The functions ascribed to eosinophils have classically been limited to host defence against certain parasitic infections and potentially deleterious effects in the setting of specific diseases that are associated with elevated eosinophil counts in blood and/or tissue. The ability to induce eosinophil depletion either experimentally in animal models or through targeted therapies in humans has extended our understanding of the roles played by eosinophils in health and homeostasis as well as in disease pathogenesis. When associated with human disease aetiology, the eosinophil takes on a pathogenic rather than a protective role. This maladaptive response, called "eosinophilic immune dysfunction" herein, appears central to exacerbation pathogenesis and disease control in severe asthma and may be involved in the aetiology of other eosinophil-related conditions ranging from organ-system-limited diseases such as phenotypic subsets of chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyposis to more broadly systemic diseases such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. In this review, we describe the evidence supporting eosinophilic functions related to health and homeostasis and explore the contribution of eosinophilic immune dysfunction to human disease.
Topics: Animals; Asthma; Churg-Strauss Syndrome; Eosinophilia; Eosinophils; Granulomatosis with Polyangiitis; Humans
PubMed: 35082127
DOI: 10.1183/16000617.0150-2021 -
Allergy Mar 2022Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is... (Review)
Review
Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.
Topics: Adrenal Cortex Hormones; Anti-Asthmatic Agents; Antibodies, Monoclonal, Humanized; Asthma; Churg-Strauss Syndrome; Eosinophils; Granulomatosis with Polyangiitis; Humans; Pulmonary Eosinophilia; Treatment Outcome
PubMed: 34402066
DOI: 10.1111/all.15056 -
Mayo Clinic Proceedings Jul 2023Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare... (Review)
Review
Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare multisystem disorders such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with these multisystem diseases, often associated with markedly elevated eosinophil counts, have a substantial risk of morbidity and mortality due to delayed diagnosis or inadequate treatment. A thorough workup of symptomatic patients presenting with elevated eosinophil counts is essential, although in some cases the differential diagnosis may remain difficult because of overlapping presentations between HES and EGPA. Notably, first- and second-line treatment options and response to therapy may differ for specific HES and EGPA variants. Oral corticosteroids are the first line of treatment for HES and EGPA, except when HES is the result of specific mutations driving clonal eosinophilia that are amenable to targeted treatment with a kinase inhibitor. Cytotoxic or immunomodulatory agents may be required for those with severe disease. Novel eosinophil-depleting therapies, such as those targeting interleukin 5 or its receptor, have shown great promise in reducing blood eosinophil counts, and reducing disease flares and relapses in patients with HES and EGPA. Such therapies could reduce the side effects associated with long-term oral corticosteroids or immunosuppressant use. This review provides a pragmatic guide to approaching the diagnosis and clinical management of patients with systemic hypereosinophilic disorders. We highlight practical considerations for clinicians and present cases from real-world clinical practice to show the complexity and challenges associated with diagnosing and treating patients with HES and EGPA.
Topics: Humans; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Eosinophilia; Eosinophils; Antineoplastic Agents; Adrenal Cortex Hormones; Asthma
PubMed: 37419574
DOI: 10.1016/j.mayocp.2023.02.013 -
The European Respiratory Journal Jan 2023The enduring view of eosinophils, as immune effector cells whose primary function is host defence against infection by helminths and other microbial pathogens, sets the... (Review)
Review
The enduring view of eosinophils, as immune effector cells whose primary function is host defence against infection by helminths and other microbial pathogens, sets the stage for a fundamental question regarding the safety of therapeutic eosinophil depletion. If eosinophils are significantly reduced or altogether depleted in an effort to alleviate the negative effects of tissue eosinophilia and eosinophilic inflammation in conditions such as asthma, COPD, chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome, would these patients become susceptible to infection or another illness? Development of mouse models in which the eosinophil lineage has been ablated, observations in patients naturally lacking eosinophils and data from studies of eosinophil-depleting medical therapies indicate that the absence of eosinophils is not detrimental to health. The evidence available to date, as presented in this review, supports the conclusion that even if certain homeostatic roles for the eosinophil may be demonstrable in controlled animal models and human settings, the evolution of the human species appears to have provided sufficient immune redundancy such that one may be hale and hearty without eosinophils.
Topics: Animals; Humans; Eosinophils; Rhinitis; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Eosinophilia; Nasal Polyps
PubMed: 35953100
DOI: 10.1183/13993003.01217-2022