Genetic and Non-Genetic Contributions to Eosinophilic Granulomatosis with Polyangiitis: Current Knowledge and Future Perspectives.

In this work, we present a comprehensive overview of the genetic and non-genetic complexity of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a rare complex systemic disease that occurs in people presenting with severe asthma and high eosinophilia. After briefly introducing EGPA and its relationship with the anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAVs), we delve into the complexity of this disease. At first, the two main biological actors, ANCA and eosinophils, are presented. Biological and clinical phenotypes related to ANCA positivity or negativity are explained, as well as the role of eosinophils and their pathological subtypes, pointing out their intricate relations with EGPA. Then, the genetics of EGPA are described, providing an overview of the research effort to unravel them. Candidate gene studies have investigated biologically relevant candidate genes; the more recent genome-wide association studies and meta-analyses, able to analyze the whole genome, have confirmed previous associations and discovered novel risk loci; in the end, family-based studies have dissected the contribution of rare variants and the heritability of EGPA. Then, we briefly present the environmental contribution to EGPA, reporting seasonal events and pollutants as triggering factors. In the end, the latest omic research is discussed and the most recent epigenomic, transcriptomic and microbiome studies are presented, highlighting the current challenges, open questions and suggesting approaches to unraveling this complex disease.

Azathioprine vs methotrexate in eosinophilic granulomatosis with polyangiitis: a monocentric retrospective study.

OBJECTIVES: To analyse the effectiveness, safety and steroid-sparing effect of AZA and MTX as induction of remission and maintenance treatment in eosinophilic granulomatosis with polyangiitis. METHODS: We retrospectively collected data from 57 patients divided into four groups according to treatment: MTX/AZA as first-line agents (MTX1/AZA1) in non-severe disease or as second-line maintenance therapy (MTX2/AZA2) in severe disease previously treated with CYC/rituximab. During the first 5 years of treatment with AZA/MTX we compared the groups according to: remission rate [defined as R1: BVAS = 0; R2: BVAS = 0 with prednisone ≤5 mg/day; R3 (MIRRA definition): BVAS = 0 with prednisone ≤3.75 mg/day], persistence on therapy, cumulative glucocorticoid (GC) dose, relapse and adverse events (AEs). RESULTS: There were no significant differences in remission rates (R1) in each group (63% in MTX1 vs 75% in AZA1, P = 0.53; 91% in MTX2 vs 71% in AZA2, P = 0.23). MTX1 allowed R2 more frequently in the first 6 months compared with AZA1 (54% vs 12%, P = 0.04); no patients receiving AZA1 achieved R3 up to the first 18 months (vs 35% in MTX1, P = 0.07). The cumulative GC dose was lower for MTX2 vs AZA2 (6 g vs 10.7 g at 5 years, P = 0.03). MTX caused more AEs compared with AZA (66% vs 30%, P = 0.004), without affecting the suspension rate. No differences emerged in time-to-first relapse, although fewer patients treated with AZA2 had asthma/ENT relapses (23% vs 64%, P = 0.04). CONCLUSION: A significant proportion of patients achieved remission with both MTX and AZA. MTX1 had an earlier remission on a lower GC dose but MTX2 had a better steroid-sparing effect.

Real-world safety and effectiveness of mepolizumab for patients with eosinophilic granulomatosis with polyangiitis in Japan: A 48-week interim analysis of the MARS study.

OBJECTIVES: The objective of the study is to assess real-world, long-term safety/effectiveness of mepolizumab for eosinophilic granulomatosis with polyangiitis (EGPA) in Japan. METHODS: The Mepolizumab long-term study to Assess Real-world Safety and effectiveness of EGPA in Japan (MARS) (GSK ID: 213684/NCT04551989) is an ongoing 96-week study of patients with EGPA who received four-weekly mepolizumab 300 mg subcutaneously for ≥96 weeks before study entry (baseline) and continued treatment. This interim analysis included safety from baseline to Week 48 (observation period) and clinical outcomes before mepolizumab and during the observation period. RESULTS: Of 118 patients enrolled, 29% (34/118) experienced adverse events (AEs), of which 13% (15/118) experienced serious AEs; none were considered mepolizumab related. The median oral corticosteroid (OCS) dose decreased from 6.9 (pre-mepolizumab) to 3.0 (baseline) and 2.0 mg/day (Weeks 45-48); the proportion of patients receiving no OCS increased from 8% to 32% and 38%, respectively. Patients experiencing clinical symptoms decreased from 94% (pre-mepolizumab) to 73% (baseline) and 67% (Week 48). During the observation period, 5% of patients experienced EGPA relapse; the rates of EGPA-related hospitalisations, EGPA-related emergency room/unscheduled visits, and asthma exacerbations were 0.05, 0.09, and 0.08 event/person-year, respectively. CONCLUSIONS: The results of mepolizumab treatment for ≥144 weeks (before baseline plus observation) were consistent with the known safety profile and allowed OCS dose reduction while improving disease control versus pre-treatment among patients with EGPA.

Diagnostic challenge of Creutzfeldt-Jakob disease in a patient with multimorbidity: a case-report.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal neurodegenerative condition caused by prions. The clinical symptoms of CJD vary with its subtype, and may include dementia, visual hallucinations, myoclonus, ataxia, (extra)pyramidal signs and akinetic mutism. In the early course of disease however, several clinical symptoms of CJD may mimic those of co-existing morbidities. CASE PRESENTATION: We report a male in his 60s with a history of situs inversus totalis and Churg Strauss syndrome, who presented with speech fluency disturbances, neuropsychiatric symptoms and allodynia, a few months after becoming a widower. Initially presumed a bereavement disorder along with a flare-up of Churg Strauss, his symptoms gradually worsened with apraxia, myoclonic jerks and eventually, akinetic mutism. MRI revealed hyperintensities at the caudate nucleus and thalami, while the cerebrospinal fluid was positive for the 14-3-3 protein and the real-time quick test, making the diagnosis of CJD highly probable. This case illustrates the complexities that may arise in diagnosing CJD when pre-existing multimorbidity may cloud the clinical presentation. We also discuss the potential mechanisms underlying the co-occurrence of three rare conditions (situs inversus totalis, Churg Strauss syndrome, CJD) in one patient, taking into consideration the possibility of coincidence as well as common underlying factors. CONCLUSIONS: The diagnosis of CJD may be easily missed when its clinical symptoms are obscured by those of pre-existing (rare) multimorbidity. This case highlights that when the multimorbidity has neurological manifestations, an extensive evaluation remains crucial to establish the diagnosis, minimize the risk of prion-transmission and provide appropriate guidance to patients and their caregivers.

Eosinophilic Granulomatosis With Polyangiitis Following COVID-19 Vaccination: A Case Report.

The current emergence of the coronavirus disease 2019 (COVID-19) pandemic and the possible side effects of COVID-19 mRNA vaccination remain worrisome. Few cases of vaccination-related side effects, such as vasculitis, have been reported. Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a type of vasculitis characterized by the histological richness of eosinophils, asthma, polyneuropathy, sinusitis, and skin or lung involvement. Here, we report the first case of new onset EGPA following COVID-19 vaccination in Korea. A 71-year old woman developed a skin rash and presented with progressive weakness of the upper and lower extremities after the BNT162b2 vaccination (Pfizer-BioNTech). She was diagnosed with EGPA and her symptoms improved after systemic steroid and immunosuppressant therapy. Although it is very rare, clinicians should be aware that EGPA may occur after COVID-19 vaccination.

Trends in prevalence, treatment use, and disease burden in patients with eosinophilic granulomatosis with polyangiitis in Japan: real-world database analysis.

OBJECTIVES: Report the prevalence of eosinophilic granulomatosis with polyangiitis (EGPA) and describe oral corticosteroid (OCS) use and disease burden before and after mepolizumab approval in 2018 for EGPA in Japan. METHODS: Two retrospective studies (GSK IDs: 218083; 218084) used two databases: 1) the JMDC insurer database (Japanese health insurer claims) was used to report annual EGPA prevalence and OCS use in mepolizumab-treated patients; 2) Medical Data Vision database was used to report annual treatment use, OCS dose, relapses, and healthcare resource utilization (HCRU) in patients with EGPA. RESULTS: EGPA prevalence (95% confidence interval) increased from 4.2 (0.1, 23.4) in 2005 to 58.6 (53.2, 64.5) per 1,000,000 in 2020. Median OCS dose (mg/day) decreased from a range of 4.8-7.7 during 2010-2017 to 4.5-4.8 during 2018-2020 (lowest dose in 2020). The proportion of patients with prednisolone-equivalent daily OCS dose >10 mg decreased from 2017 (11.9%) to 2020 (10.3%), while the median dose halved. The proportion of patients with EGPA relapses (64.3% to 41.6%) and hospitalisation (27.8% to 23.6%) decreased from 2010 to 2020. CONCLUSIONS: EGPA prevalence increased between 2005 and 2020. With the introduction of mepolizumab for EGPA in 2018, real-world OCS use, relapses and HCRU decreased.

Systemic bevacizumab to facilitate anticoagulation in antiphospholipid syndrome and bleeding gastrointestinal angiodysplasia.

Bleeding gastrointestinal angiodysplasia may occur in patients with vasculitis and can be challenging to treat. We describe the novel use of bevacizumab therapy to treat bleeding gastrointestinal angiodysplasia and severe anemia in a patient with eosinophilic granulomatosis with angiitis complicated by antiphospholipid antibody syndrome requiring indefinite warfarin therapy. Studies confirmed multiple bleeding jejunal angiodysplasias unamenable to endoscopic intervention, and the patient required ongoing support with iron infusions and blood transfusions to maintain a minimally acceptable hemoglobin. Given the severe anemia, need for continued, indefinite antiplatelet and anticoagulation therapy, and failure of standard treatment approaches, the patient was initiated on systemic bevacizumab therapy, on the basis of prior documented success of bevacizumab to manage gastrointestinal telangiectasias in patients with hereditary hemorrhagic telangiectasia. Bevacizumab was highly effective, with rapid resolution of bleeding, normalization of hemoglobin, liberation from hematologic support and no adverse events, including no thromboembolic events. Vascular endothelial growth factor (VEGF-A) rose paradoxically after initiation of bevacizumab and normalized after its discontinuation. Given these findings, use of systemic bevacizumab to manage bleeding angiodysplasia in patients with acquired vascular disorders merits further study.

Muscle biopsy in anti-neutrophil cytoplasmic antibody-associated vasculitis: diagnostic yield depends on anti-neutrophil cytoplasmic antibody type, sex and neutrophil count.

OBJECTIVES: This study aimed to examine the sensitivity of muscle biopsy (MB) in ANCA-associated vasculitis (AAV), identify factors predicting MB positivity and assess the prognostic value of a positive MB. METHODS: We conducted a single-centre retrospective study of AAV with an MB performed at diagnosis. AAV classification [granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA)] followed the European Medicines Agency algorithm. A logistic regression model was used to identify the factors associated with MB positivity. Survival curves were generated using the Kaplan-Meier method. RESULTS: Among 276 AAV patients (1995-2018), 101 had an MB. Seventy-eight patients were included: 33 with GPA, 25 with MPA and 20 with EGPA. MB samples were positive in 45 cases (58%): 17 GPA, 16 MPA and 12 EGPA. Univariate analysis focussed on GPA and MPA, revealed that the MB yield was higher in females [22/31 (71%) vs 11/27 (41%); P = 0.02] and in anti-MPO patients [25/37 (68%) vs 6/19 (32%) for anti-PR3; P = 0.01]. By multivariate analysis, three factors predicted MB positivity: anti-MPO ANCA [odds ratio (OR) 10.67 (CI 2.09, 81.68)], female sex [OR 5.3 (CI 1.16, 32.35)] and neutrophil count [OR 1.33 (CI 1.07, 1.8)]. MB positivity had no impact on relapse, death or end-stage renal disease-free survival. CONCLUSIONS: MB is a safe and efficient diagnostic tool for AAV. Predictors of MB yield include ANCA type, sex and neutrophil count. MB cannot substitute for kidney biopsy when indicated, but should be considered in other cases.

Clinical Features of Patients with Active Eosinophilic Granulomatosis with Polyangiitis Successfully Treated with Mepolizumab.

BACKGROUND: In some patients with eosinophilic granulomatosis with polyangiitis (EGPA), remission cannot be induced, despite treatment with corticosteroids and immunosuppressants. We evaluated the clinical features of patients with EGPA in whom mepolizumab was effective. METHODS: There were 59 EGPA patients treated at Hiratsuka City Hospital, Japan, between April 2018 and September 2020, and 30 of them received mepolizumab. Twenty (66.7%) experienced a "marked effect" (the daily dose of corticosteroid or immunosuppressant could be decreased, or the interval between intravenous immunoglobulin (IVIG) treatments could be prolonged) and 10 (33.3%) experienced a "weak effect" (these measures were not achieved). Eosinophil numbers, serum IgG levels, daily doses of corticosteroids and immunosuppressants, and the interval between IVIG treatments at diagnosis and before and after mepolizumab initiation were determined. RESULTS: Eosinophil numbers at diagnosis were significantly higher in the marked-effect group than in the weak-effect group (p < 0.05) but not before mepolizumab initiation or at the last visit. Birmingham Vasculitis Activity Scores (BVASs) before mepolizumab initiation (p < 0.05) and at last visit (p < 0.01), and frequency of relapse before treatment initiation (p < 0.05) were significantly higher, and the serum IgG level before mepolizumab treatment was significantly lower in the weak-effect group than in the marked-effect group. The weak-effect group received higher doses of corticosteroids, even if the corticosteroid dose could be reduced for a while after mepolizumab initiation. CONCLUSION: High peripheral blood eosinophil numbers at EGPA diagnosis were suggestive of a positive clinical response to mepolizumab.

Presence of purpura is related to active inflammation in association with IL-5 in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a relatively rare necrotizing vasculitis that causes asthma, nasal involvement, peripheral nerve disturbance, renal disorder, and cutaneous lesions like purpura and is characterized by eosinophil infiltration into the damaged tissue. Purpura is the most common cutaneous lesion, but it remains unknown whether this skin lesion is associated with disease activity of EGPA and laboratory data including interleukin (IL)-5, a target cytokine of this disease. We conducted a search of our hospital electronic records for cases of EGPA from the last 10 years. Symptoms related to EGPA (fever, asthma, nasal and cutaneous manifestations, neuropathy), the Birmingham Vasculitis Activity Score (BVAS), and laboratory parameters, such as eosinophil count, urinalysis, antineutrophil cytoplasmic antibody (ANCA), CRP, IgE and IL-5, before and during treatment were compared among the eligible cases. A total of 28 EGPA patients (21 females and 7 males) were selected. Almost all developed peripheral neuropathy. Fever occurred in 25%, nasal symptoms in 38.1% and purpura in 44%. Glomerulonephritis developed in 7.7%. One patient had cardiac involvement (3.6%). The laboratory data showed a marked increase in peripheral eosinophil count, CRP, serum IgE and serum IL-5. ANCA was positive in 15.4%. In the univariate analysis, presence of purpura was associated with increased CRP and IL-5, and high BVAS score. Multivariate analysis revealed a robust relationship between purpura and CRP. Our findings showed that presence of purpura was associated with increased CRP and IL-5, and high disease activity in EGPA.

COVID-19 and eosinophilic granulomatosis with polyangiitis or COVID-19 mimicking eosinophilic granulomatosis with polyangiitis?

Coronavirus disease 2019 (COVID-19) and eosinophilic granulomatosis with polyangiitis (EGPA) share similarities in clinical, imaging findings and may present with respiratory distress. Differentiating a new-onset EGPA from COVID-19 during the current pandemic is a diagnostic challenge, particularly if other EGPA symptoms are overlooked. Here in this study we reviewed the literature regarding EGPA patients with COVID-19 and patients who diagnosed with EGPA or suffered an EGPA flare mimicking COVID-19. We conducted a literature survey in PUBMED database using meshed keywords "COVID-19" and "EGPA", "COVID-19" and "eosinophilic granulomatosis with polyangiitis", "COVID-19" and "Churg Strauss Syndrome", to reveal previously reported cases involving EGPA patients who had COVID-19 infection, patients who suspected to have COVID-19 but eventually diagnosed with EGPA and patients with a known diagnosis of EGPA who suffered a flare but a COVID-19 infection was suspected initially. A total of 11 cases (6 literature cases, 5 cases from our clinic) were included in our study. Seven (63.6%) of the cases were defined as COVID-19 mimicker and 4 (36.4%) were EGPA with COVID-19. All of the cases in EGPA with COVID-19 group had a history of asthma. All of them had a positive PCR result and ground-glass opacities in thorax CT. In COVID-19 mimicker group, six (85.7%) patients had a history of asthma and other EGPA features that were observed were eosinophilia in 6 (85.7%). Our study provided clues regarding the EGPA/COVID-19 diagnostic challenge which may be useful in the current pandemic. Since none of the findings in COVID-19 are disease-specific, other conditions like EGPA should not be overlooked particularly in PCR negative patients and clinical, laboratory and imaging findings should be interpreted carefully. Furthermore, we did not observe poor outcomes in EGPA patients who had COVID-19.

Pharmacogenetic investigation of efficacy response to mepolizumab in eosinophilic granulomatosis with polyangiitis.

Treatment of patients with the rare disease eosinophilic granulomatosis with polyangiitis (EGPA) with mepolizumab, a monoclonal antibody to interleukin-5 (IL-5) that reduces blood eosinophil counts, as an add-on therapy to glucocorticoid treatment, results in more accrued weeks in remission, reductions in glucocorticoid use and reductions in relapse rate. However, treatment response varies across a continuum. Therefore, to investigate if large genetic effects could identify responders, the impact of genetic variants on efficacy in EGPA subjects taking mepolizumab and glucocorticoids was assessed in this post hoc study. Using linear regression and a negative binomial model, genetic variant association with three endpoints (accrued duration of remission, average oral glucocorticoid dose, and frequency of relapse) was tested in 61 EGPA subjects dosed with mepolizumab from MIRRA, a phase 3 trial. Candidate gene and genome-wide approaches were used. The candidate gene analysis was designed to investigate drug target effects with eight gene regions selected that were focused on the intersection of the glucocorticoid response (steroidal response) and IL-5 response mechanisms and recognizing potential overlap between EGPA and severe eosinophilic asthma diseases for which mepolizumab is used. The sample size was insufficient to enable testing of rare variants for effects. No genetic variant from either the candidate gene analysis or the GWAS associated with any endpoint. Thresholds to declare significance were p < 0.0008 (candidate variant) and p < 2.5 × 10-8 (genome-wide) analyses. Large genetic effects on mepolizumab-treatment response were not identified which could help differentiate responders from non-responders.

Cutaneous manifestations of childhood Eosinophilic Granulomatosis with Polyangiitis (cEGPA): A case-based review.

BACKGROUND/OBJECTIVES: This study seeks to better define the clinical presentation and histopathology of cutaneous manifestations in childhood eosinophilic granulomatosis with polyangiitis (cEGPA). METHODS: Case reports were collected from Ovid Medline Database and PubMed using keyword identifiers from 1946 to 2017. Adult patients ≥ 18 years and cases not diagnosed with EGPA by the author were excluded. Sixty-five case reports of cEGPA were initially identified. These were reviewed individually, and fifty cases were determined to meet the American College of Rheumatology criteria for EGPA. No case series examining the cutaneous morphology and histopathology were identified. Cutaneous morphology, lesion location, and cutaneous histopathology results were recorded. Results were analyzed using summary statistics. RESULTS: Sixty-four percent (32/50) of cEGPA patients presented with cutaneous manifestations. Twenty-nine cases provided specific morphological descriptions and lesion location. Common manifestations included purpura (15/29), subcutaneous nodules (8/29), and a macular/papular/maculopapular rash (8/29). However, twelve different cutaneous morphologies were identified in this review. Lesions occurred most commonly on the extremities (26/29). Twenty-two cases reported corresponding cutaneous histopathology, which revealed extravascular eosinophils (15/22), vasculitis (13/22), and granulomas (5/22). Only one biopsy sample (1/22) had all three classical EGPA characteristics of granulomas, extravascular eosinophils, and vasculitis. CONCLUSION: With nearly two-thirds of cEGPA patients presenting with cutaneous manifestation, this study highlights the importance of clinical recognition of this disease by dermatologists. While the varied morphology of skin lesions and rarity of this disease makes cEGPA a difficult diagnosis, prompt recognition and treatment will improve outcomes in this patient population.

Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis.

BACKGROUND: In a recent phase III trial (NCT02020889) 53% of mepolizumab-treated versus 19% of placebo-treated patients with eosinophilic granulomatosis with polyangiitis (EGPA) achieved protocol-defined remission. OBJECTIVE: We sought to investigate post hoc the clinical benefit of mepolizumab in patients with EGPA using a comprehensive definition of benefit encompassing remission, oral glucocorticoid (OGC) dose reduction, and EGPA relapses. METHODS: The randomized, placebo-controlled, double-blind, parallel-group trial recruited patients with relapsing/refractory EGPA receiving stable OGCs (prednisolone/prednisone, ≥7.5-50 mg/d) for 4 or more weeks. Patients received 300 mg of subcutaneous mepolizumab or placebo every 4 weeks for 52 weeks. Clinical benefit was defined post hoc as follows: remission at any time (2 definitions used), 50% or greater OGC dose reduction during weeks 48 to 52, or no EGPA relapses. The 2 remission definitions were Birmingham Vasculitis Activity Score of 0 plus OGC dose of 4 mg/d or less (remission 1/clinical benefit 1) or 7.5 mg/d or less (remission 2/clinical benefit 2). Clinical benefit was assessed in all patients and among subgroups with a baseline blood eosinophil count of less than 150 cells/µL, baseline OGC dosage of greater than 20 mg/d, or weight of greater than 85 kg. RESULTS: With mepolizumab versus placebo, 78% versus 32% of patients experienced clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both P < .001). Significantly more patients experienced clinical benefit 1 with mepolizumab versus placebo in the blood eosinophil count less than 150 cells/µL subgroup (72% vs 43%, P = .033) and weight greater than 85 kg subgroup (68% vs 23%, P = .005); in the OGC greater than 20 mg/d subgroup, results were not significant but favored mepolizumab (60% vs 36%, P = .395). CONCLUSION: When a comprehensive definition of clinical benefit was applied to data from a randomized controlled trial, 78% to 87% of patients with EGPA experienced benefit with mepolizumab.

Updates in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for the ENT surgeon.

ENT involvement is common in ANCA-associated vasculitis (AAV), particularly in GPA and EGPA. Early recognition and treatment is important for good outcomes, yet evidence suggests that UK ENT surgeons may not consistently recognise the early features of AAV, despite a similar incidence to vestibular schwannoma. AAV is a rapidly advancing field, with significant developments in the understanding of its pathogenesis, classification and treatment over the past decade. Relevant vasculitis mimics are also discussed with a particular focus on the increasing prevalence of vasculitis mimics driven by an increase in recreational cocaine use, as well as the emergence and reclassification of several other vasculitis mimics in the head and neck. This article reviews key recent updates in the vasculitis literature, with a particular focus on those relevant to recognition and diagnosis of AAV for the ENT surgeon. Strengths and limitations of relevant diagnostic testing are discussed, and a method of evaluation of patients with features of AAV presenting to ENT services is outlined.

Heart disease in a mutant mouse model of spontaneous eosinophilic myocarditis maps to three loci.

BACKGROUND: Heart disease (HD) is the major cause of morbidity and mortality in patients with hypereosinophilic diseases. Due to a lack of adequate animal models, our understanding of the pathophysiology of eosinophil-mediated diseases with heart complications is limited. We have discovered a mouse mutant, now maintained on an A/J inbred background, that spontaneously develops hypereosinophilia in multiple organs. Cellular infiltration into the heart causes an eosinophilic myocarditis, with affected mice of the mutant line (i.e., A/JHD) demonstrating extensive myocardial damage and remodeling that leads to HD and premature death, usually by 15-weeks old. RESULTS: Maintaining the A/JHD line for many generations established that the HD trait was heritable and implied the mode of inheritance was not too complex. Backcross and intercross populations generated from mating A/JHD males with females from four different inbred strains produced recombinant populations with highly variable rates of affected offspring, ranging from none in C57BL/6 J intercrosses, to a few mice with HD using 129S1/SvImJ intercrosses and C57BL/6 J backcrosses, but nearly 8% of intercrosses and > 17% of backcrosses from SJL/J related populations developed HD. Linkage analyses of these SJL/J derived recombinants identified three highly significant loci: a recessive locus mapping to distal chromosome 5 (LOD = 4.88; named Emhd1 for eosinophilic myocarditis to heart disease-1); and two dominant variants mapping to chromosome 17, one (Emhd2; LOD = 7.51) proximal to the major histocompatibility complex, and a second (Emhd3; LOD = 6.89) that includes the major histocompatibility region. Haplotype analysis identified the specific crossovers that defined the Emhd1 (2.65 Mb), Emhd2 (8.46 Mb) and Emhd3 (14.59 Mb) intervals. CONCLUSIONS: These results indicate the HD trait in this mutant mouse model of eosinophilic myocarditis is oligogenic with variable penetrance, due to multiple segregating variants and possibly additional genetic or nongenetic factors. The A/JHD mouse model represents a unique and valuable resource to understand the interplay of causal factors that underlie the pathology of this newly discovered eosinophil-associated disease with cardiac complications.

Anti-Neutrophil Cytoplasmic Antibodies Positivity and Anti-Leukotrienes in Eosinophilic Granulomatosis with Polyangiitis: A Retrospective Monocentric Study on 134 Italian Patients.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis associated with asthma, anti-neutrophil cytoplasmic antibodies (ANCA) positivity, and tissue eosinophilia. OBJECTIVE: To describe the presenting clinical features, significant biochemical alterations, and also potential pathogenic factors in adult patients diagnosed in our Center over a period of >20 years. METHOD: A retrospective study of EGPA patients diagnosed from 1994 to 2019 at ASST Grande Ospedale Metropolitano Niguarda Ca' Granda, Milan (Italy), which was performed according to the 1990 American College of Rheumatology criteria and Chapel Hill Consensus Conference definition. A dataset was compiled, registering demographic and clinical features, biochemical analysis at onset, and also the therapies received 3 months prior to EGPA diagnose. Statistical analyses were subsequently conducted dividing patients in 2 groups based on ANCA positivity and comparing them. RESULTS: Two groups were clearly identified by ANCA serology and specific organ involvement in accordance with literature reports; however, our data underline for the first time the association between anti-leukotriene receptor antagonists (LTRAs) and ANCA positivity. The group of previously treated patients presents an OR of 6.42 to be ANCA positive. This finding could be attributed to an imbalanced stimulation of leukotriene receptors, inducing both mast cells activation and an increased neutrophil extracellular traps release from neutrophils. CONCLUSION: Despite the limitations of this retrospective study, the association between LTRAs and ANCA antibodies elucidates the mechanism by which innate immunity is directly involved in tolerance breakdown and autoantibodies production. Validation of our results with targeted studies could clarify the differences between ANCA-positive and ANCA-negative patients with important consequences on the use of some drug classes in the treatment of EGPA and asthmatic subjects.

Churg-strauss syndrome: clinical case and its feautures.

OBJECTIVE: Introduction: The article describes the clinical case devoted to the features of the clinical course of Churg-Strauss syndrome (eosinophilic granulomatous with systemic necrotizing vasculitis). Churg-Strauss syndrome is a disease that is rarely diagnosed because of presenting by high-variability clinical syndromes, that causes difficulties in diagnostic process, especially on the first visit of patient to the general practioner. The aim of the article is to show the clinical course feautures of the Churg-Strauss syndrome in the time of disease progression, as well as pecullarities and possibilities of in-time diagnosis of this disease. RESULTS: Clinical case: It was described a clinical case of Churg-Strauss syndrome in a 46-year-old woman, presenting with successively appeared signs of the disease that resulted in some difficulties of making in-time diagnosis. CONCLUSION: Conclusions: As Churg-Strauss syndrome is a low-spread disease presenting with high-variety of clinical signs and despite of the presence of clear diagnostic criterias Churg-Stross syndrome was diagnosed with delay in this clinical setting. General practitioner should remember that if the disease debuts by the signs of pneumonia with further appearance of signs of bronchial obstruction and eosinophilia, its necessary to perform diagnostic approaches with the aim to carry out the presence of the Churg-Strauss syndrome.

Innate immune response reflects disease activity in eosinophilic granulomatosis with polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a disease characterized by allergic granulomatosis, necrotizing vasculitis, and peripheral blood eosinophilia. Interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), and type 2 innate lymphoid cells (ILC2) are involved in the innate and type 2 immune responses in EGPA. However, the relationships among these molecules and the mechanisms underlying the development of EGPA remain unknown. OBJECTIVE: We investigated the relationships among peripheral blood eosinophil count, serum IL-33 and TSLP concentration, and peripheral blood ILC2 count in patients with EGPA, chronic eosinophilic pneumonia (CEP), or bronchial asthma (BA). METHODS: We recruited 86 patients with EGPA in three groups (remission, relapse, and onset), 25 patients with CEP at active or inactive stages of disease, and 11 patients with BA. In patients with EGPA, CEP, or BA, serum IL-33, sST2, and TSLP concentrations were determined using ELISA and peripheral blood ILC2 counts (as Lin-1- CD127+ CRTH2+ cells) were determined using flow cytometry. RESULTS: Peripheral blood eosinophil count or ILC2 count, and serum sST2 or TSLP concentration were higher in patients with EGPA at onset than in those with EGPA at relapse or remission, or in those with BA or CEP. Serum IL-33 concentration was higher in patients with EGPA at relapse than in those with EGPA at onset or remission, or in those with BA or CEP. In a logistic regression model, EGPA disease activity was correlated with serum IL-33 concentration and peripheral blood ILC2 count, but not daily systemic and inhaled corticosteroid dose or immunosuppressant use. Eosinophil count was correlated with peripheral blood ILC2 count and serum TSLP concentration, but not serum IL-33 concentration. CONCLUSIONS: Increased peripheral blood ILC2 count and serum IL-33 concentration were associated with disease activity in EGPA. Increases in serum IL-33 concentration may indicate the presence of active vasculitis rather than peripheral or tissue eosinophilia.

Focus on the Involvement of the Nose and Paranasal Sinuses in Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss Syndrome): Nasal Cytology Reveals Infiltration of Eosinophils as a Very Common Feature.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis that predominantly affects small- to medium-sized vessels. It is characterized by a wide spectrum of extrapulmonary symptoms, including sinonasal and paranasal sinus abnormalities. These are the most common features of this disease, constituting diagnostic criteria for EGPA. However, the actual clinical features, cellular mechanisms and impact on patients' quality of life (QoL) are still a matter of study. METHODS: Thirty-nine EGPA patients underwent multidimensional rhinological evaluations, including rhinofibroscopy, nasal cytology, and QoL questionnaires. This was coupled with respiratory and rheumatological assessments. RESULTS: Twenty-eight patients were diagnosed with chronic rhinosinusitis (CRS). Of these, 18 had nasal polyposis (NP). Chronic rhinitis was diagnosed in 10 patients. Of these, 3 had allergic rhinitis (AR) and seven had non-AR (NAR). Overall, only 1 patient (2.6%) was normal. Nasal cytology showed that hypereosinophilia was present in 17/28 patients with CRS, 4/7 patients with NAR and all patients with AR. SNOT-22 and SF-36 showed a severe impact of nasal symptoms on QoL. No differences in asthma control or rheumatological patterns for EGPA were observed among patients with or without NP. CONCLUSIONS: Even when the rheumatological assessment scored EGPA "under control" according to the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, sinonasal diseases and related nasal inflammatory processes were not controlled. Therefore, there is a need for clinical monitoring and targeted treatment to control the inflammatory processes and improve the QoL of EGPA patients.