Head and Neck Manifestations of Eosinophilic Granulomatosis with Polyangiitis: A Systematic Review.

OBJECTIVE: To conduct the first and only systematic review of the existing literature on head and neck manifestations of eosinophilic granulomatosis with polyangiitis to guide clinical decision making for the otolaryngologist. DATA SOURCES: PubMed, Cochrane Library, Scopus, and LILACS. REVIEW METHODS: A systematic review of the aforementioned sources was conducted per the PRISMA guidelines. RESULTS: From an initial 574 studies, 28 trials and reports were included, accounting for a total of 1175 patients with eosinophilic granulomatosis with polyangiitis. Among clinical and cohort studies, 48.0% to 96.0% of all included patients presented with head and neck manifestations. In a distinct group of patients detailed in case reports describing patients presenting with head and neck manifestations, patients on average fulfilled 4.6 diagnostic criteria per the American College of Rheumatology. Furthermore, 95.8% of reported cases were responsive to steroids, and 60% required additional therapy. CONCLUSION: Otolaryngologists are in a unique position for the early diagnosis and prevention of late complications of eosinophilic granulomatosis with polyangiitis. The American College of Rheumatology criteria should be relied on in the diagnostic workup. Close surveillance of these patients in a multidisciplinary fashion and with baseline complete blood counts, chest radiographs, and autoimmune laboratory tests is often necessary. Such patients with head and neck manifestations of the disease are nearly always responsive to steroids and often require additional immunosuppressive therapy or surgical intervention in cases of cranial neuropathies, temporal bone involvement, and refractory symptoms

Eosinophilic granulomatosis with polyangiitis (EGPA) and PRES: a case-based review of literature in ANCA-associated vasculitides

Eosinophilic granulomatosis with polyangiitis (EGPA) is a small-sized vessel systemic necrotizing vasculitis and belongs to the family of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. The involvement of central nervous system in this condition is pretty rare. Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity described for the first time by Hinchey et al. (N Engl J Med 334(8):494-500, 1996) and characterized by MRI findings of reversible subcortical vasogenic edema predominantly in the white matter of posterior cerebral lobes. There are few case reports describing the concurrence of PRES with ANCA-associated vasculitides. We describe a case of PRES in a patient with a diagnosis of EGPA with a concise review of the literature. The exact cause of this syndrome is unknown. It has been related to eclampsia, drug-induced hypertension, renal insufficiency and also to rheumatologic diseases. Endothelial injury, hypertension and immunosuppressive medications can compromise the regulation of cerebral blood flow. In ANCA-associated vasculitides, patients presenting with symptoms of PRES represent a challenge to treatment with immunosuppressive medications. However, since an inflammatory process might be implicated, judicious use of these agents along with tight control of blood pressure and a supportive therapy may contribute to the resolution of the encephalopathic syndrome treating at the same time other manifestation related to the rheumatologic disease. Larger clinical studies are warranted to optimize the management of vasculitis-associated PRES

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+\u2009ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+\u2009ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6,809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA

Governance of regional innovations towards sustainability

This paper addresses the governance of regional innovations towards sustainability. From the literature it is clear that variety is a major source of innovations: innovations come into being in interplay between a variety of public and private actors who bring with them a large variety of identities, values, realities and practices. In this context, traditional concepts of governance such as planning and control, formalized processes and top–down steering are less appropriate. Yet some stability and structures are needed to create common understandings and mutual trust

Model-Checking of Ordered Multi-Pushdown Automata

We address the verification problem of ordered multi-pushdown automata: A multi-stack extension of pushdown automata that comes with a constraint on stack transitions such that a pop can only be performed on the first non-empty stack. First, we show that the emptiness problem for ordered multi-pushdown automata is in 2ETIME. Then, we prove that, for an ordered multi-pushdown automata, the set of all predecessors of a regular set of configurations is an effectively constructible regular set. We exploit this result to solve the global model-checking which consists in computing the set of all configurations of an ordered multi-pushdown automaton that satisfy a given w-regular property (expressible in linear-time temporal logics or the linear-time \mu-calculus). As an immediate consequence, we obtain an 2ETIME upper bound for the model-checking problem of w-regular properties for ordered multi-pushdown automata (matching its lower-bound).Comment: 31 page

Management of Severe Asthma in Eosinophilic Granulomatosis with Polyangiitis with Interleukin-5-Targeted Therapies: Current Status and Report of Two Cases

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disorder characterized by peripheral eosinophilia, severe eosinophilic asthma, sinusitis, transient pulmonary infiltrates, and features of medium/small-vessel vasculitis. EGPA belongs to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides, although only 30 to 40% of patients display ANCA positivity, which is mainly of myeloperoxidase (MPO) specificity. Particularly, ANCA-positive patients typically show vasculitic features. Interleukin (IL)-5 has been demonstrated to play a crucial role in determining eosinophilic airway inflammation in EGPA patients. Specifically, maturation, activation, and survival of eosinophils especially depend on IL-5 availability. Therefore, blocking IL-5 biological activity may be a rewarding strategy for control of eosinophilic inflammation. Several monoclonal antibodies with the ability to interfere with the biological activity of IL-5 have been developed, namely, mepolizumab, reslizumab, and benralizumab. Here, we discuss the role of these drugs in the management of severe eosinophilic asthma in the context of EGPA and report the outcome of two EGPA patients with severe eosinophilic asthma treated at our outpatient clinic

A role for IL-33-activated ILC2s in eosinophilic vasculitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here, we report that patients with EGPA have elevated levels of TSLP, IL-25, and soluble ST2, which are well-characterized cytokine alarmins that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage were induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis was dependent on ILC2s and signaling through IL4Rα. In the absence of IL4Rα or STAT6, IL-33-treated mice had less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and they suggest that IL-33, ILC2s, and IL4Rα signaling may be potential targets for further study and therapeutic targeting in patients with EGPA

Familial vasculitides: granulomatosis with polyangitis and microscopic polyangitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases. Although the aetiology of AAV is uncertain, it is likely that genetic and environmental factors contribute. We report the unusual case of two brothers presenting with AAV with differing clinical pictures and differing ANCA specificity. There is a recently identified difference in genetic risk factors associated with ANCA specificity, making it surprising that first-degree relatives develop AAV with differing clinical and serological features. Our report illustrates the complex aetiology of AAV and suggests that further research on the interaction of genetic and environmental factors is needed