Churg-Strauss Research Articles

B-112 Routine Application of PR3- and MPO-ANCA Chemiluminescence Immunoassays Demonstrates Enhanced Detection Rates

Abstract Background Sensitive and accurate PR3- and MPO-ANCA detection are crucial in the diagnosis and monitoring of patients with ANCA-associated vasculitides (AAV) and the specific diseases categorised thereof, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Chemiluminescence immunoassays (ChLIA) and bead technology have emerged as promising tools for fast, sensitive and accurate autoantibody detection. Applied to PR3- and MPO-ANCA, they could improve limitations in sensitivity, narrow measuring range and level of quantification seen in other assay formats. Here, we examined the routine performance of ChLIAs using human native MPO as well as human recombinant PR3 antigens. Methods The Anti-PR3 ChLIA (IgG) and prototype Anti-Myeloperoxidase ChLIA (IgG) were processed on the RA Analyzer 10 (EUROIMMUN) and the EliA PR3S and EliA MPOS on the Phadia250 (Thermo-Fisher Scientific), both in accordance to the recommendations by the manufacturers. For a comparative analysis of the routine performance, 675 sera from 615 individuals requested for PR3-ANCA, MPO-ANCA or both at the Central Diagnostic Laboratory at Maastricht University Medical Center were measured with the respective assays from both automation systems. The results were compared in respect to the qualitative outcome and numerical correlation. Results Of the total 675 samples, 585 and 556 were subjected to PR3-ANCA and MPO-ANCA analysis, respectively. For both ANCA types, all samples found positive with EliAs were also positive in the corresponding ChLIAs. 24 and 26 samples resulted positive for PR3- and MPO-ANCA by ChLIA, respectively, but were below cut-off in the relevant EliA test. Of those, 50.0% (n = 12 for PR3) and 96.2% (n = 25 for MPO) were from individuals in follow-up after AAV diagnosis, in the remaining cases an ANCA involvement was suspected based on symptoms of the patients. The overall concordance between the two assay systems was 96.0% for PR3-ANCA and 95.4% for MPO-ANCA detection. Conclusion In a routine scenario, the ChLIAs fully covered the PR3- and MPO-ANCA detection by the compared reference test system. Moreover, further positive results in samples found negative by EliA demonstrated enhanced detection rates by both ChLIAs, predominantly in samples from individuals with a known history of AAV. The clinical relevance will be subject to further studies.

Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Renal involvement in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis, which typically affects small-to medium-sized blood vessels. It is characterized by the presence of tissue infiltrates rich in eosinophils, along with the formation of granulomatous lesions. About 40% of cases have positive anti-neutrophil cytoplasm antibodies (ANCA), with predominant perinuclear staining, and anti-myeloperoxidase (anti-MPO) specificity in about 65% of cases. Typical manifestations of EGPA include the late onset of asthma, nasal and sinus-related symptoms, peripheral neuropathy, and significant eosinophilia observed in the peripheral blood. In contrast to granulomatosis with polyangiitis and microscopic polyangiitis, renal involvement in EGPA is less frequent (about 25%) and poorly studied. Necrotizing pauci-immune crescentic glomerulonephritis is the most common renal presentation in patients with ANCA-positive EGPA. Although rarely, other forms of renal involvement may also be observed, such as eosinophilic interstitial nephritis, mesangial glomerulonephritis, membranous nephropathy, or focal sclerosis. A standardized treatment for EGPA with renal involvement has not been defined, however the survival and the renal outcomes are usually better than in the other ANCA-associated vasculitides. Nonetheless, kidney disease is an adverse prognostic factor for EGPA patients. Larger studies are required to better describe the renal involvement, in particular for patterns different from crescentic glomerulonephritis, and to favor the development of a consensual therapeutic approach. In this article, in addition to personal data, we will review recent findings on patient clinical phenotypes based on ANCA, genetics and the impact of biological drugs on disease management.

Eosinophilic Granulomatosis with Polyangiitis: Latest Findings and Updated Treatment Recommendations.

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.

Cluster Analysis To Explore Clinical Subphenotypes Of Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss).

Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA) could be determined by presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal, mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central or peripheral neurological involvement); a second model also included ANCA results. The analyses included 489 patients diagnosed in 1984-2015. ANCA were detected in 37.2% of patients, mostly P-ANCA (85.4%) and/or anti-myeloperoxidase (87.0%). Compared with ANCA-negative patients, those with ANCA had more renal (P<0.001) and peripheral neurological involvement (P=0.04), fewer cardiovascular signs (P<0.001) and fewer biopsies with eosinophilic tissue infiltrates (P=0.001). The cluster analyses generated four (model without ANCA) and five clusters (model with ANCA). Both models identified three identical clusters of 34, 39 and 40 patients according to the presence or absence of ENT, CNS and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

Real-world characteristics of "super-responders" to mepolizumab and benralizumab in severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.

The current definition of severe eosinophilic asthma (SEA) super-responders to biologic treatment does not include patients with other eosinophil-based comorbidities. Although eosinophilic granulomatosis with polyangiitis (EGPA) is frequently associated with SEA, we lack data on a possible super-response to biologic treatments in patients suffering from these two diseases. We aim to assess super-responder features in real-life patients with SEA and EGPA treated with mepolizumab and benralizumab. We enrolled 39 patients with SEA and EGPA eligible for treatment with mepolizumab or benralizumab. Super-responder assessment was performed considering oral corticosteroid (OCS) cessation, lack of exacerbations, forced expiratory volume in 1 s and Asthma Control Test (ACT) improvement. Super-responders showed worse clinical baseline characteristics than non-super-responder patients, with a greater improvement in severe asthma exacerbations, OCS dose reduction and ACT score increase. Definition of super-responders was consistent only considering a 12-month course of monoclonal antibody, lacking sensitivity in earlier evaluations. Mepolizumab and benralizumab are safe and effective in patients with EGPA and SEA, since a consistent proportion of patients show a super-response after 12 months of treatment. Further studies will address specific criteria for super-responder assessment in these patients.

Changes in Peripheral Blood Eosinophil Counts and Risk of Eosinophilic Granulomatosis with Polyangiitis Onset after Initiation of Dupilumab Administration in Adult Patients with Asthma.

The purpose of this study is to clarify the changes in peripheral blood eosinophil (PBE) counts and eosinophilic granulomatosis with polyangiitis (EGPA) onset in patients with asthma who were treated with dupilumab in clinical practice. The primary outcome of this study is to determine the onset of EGPA in patients whose PBE counts continued to rise within 6 months of dupilumab initiation (rising group) and in patients whose PBE counts peaked and subsequently declined within 6 months (peaked and declined group). As a secondary outcome, the incidence of developing EGPA in patients with PBE counts greater than 1500 cells/μL at 3 or 6 months after dupilumab administration is investigated. A total of 37 individual were enrolled (male/female = 14/23, median age = 57.0 years old). The development of EGPA was significantly more frequent in the rising group compared with the peaked and declined group (p = 0.042, effect size = 0.455, moderate association). Patients with PBE counts greater than 1500 cells/μL showed a significantly higher risk of developing EGPA (p = 0.017, effect size = 0.678, strong association). Physicians should check for the onset of EGPA by monitoring the elevation of eosinophils within 6 months after dupilumab administration, especially in patients with PBE counts greater than 1500 cells/μL at 3 months.

Racial and Ethnic Distribution of Rheumatic Diseases in Health Systems of the National Patient-Centered Clinical Research Network.

To evaluate the relative prevalence of 8 rheumatic and musculoskeletal diseases (RMDs) across racial and ethnic groups within the National Patient-Centered Clinical Research Network (PCORnet). Electronic health records from participating PCORnet institutions and systems from January 1, 2013, to December 31, 2018, were used to identify adult patients with ≥ 2 diagnosis codes for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoporosis (OP), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), giant cell arteritis (GCA), and Takayasu arteritis (TAK). Among those with race and ethnicity data available, we compared prevalence of RMDs by race and ethnicity. Data from 28,059,546 patients were available for analysis. RA was more common in patients who were American Indian or Alaska Native vs White, with a prevalence of 11.57 vs 10.11/1000 (odds ratio [OR] 1.15, 95% CI 1.09-1.22). SLE was more common in patients who were Black or African American (6.73/1000), American Indian or Alaska Native (3.82/1000), and Asian (3.39/1000) vs White (2.80/1000; OR 2.43, 95% CI 2.39-2.46; OR 1.39, 95% CI 1.25-1.53; OR 1.26, 95% CI 1.21-1.31, respectively). SLE was more common in patients who were Hispanic vs non-Hispanic (prevalence 3.93 vs 3.45/1000, OR 1.14, 95% CI 1.12-1.16). TAK was more common in patients who were Asian vs White (prevalence 0.05 vs 0.04/1000, OR 1.43, 95% CI 1.00-2.03). OP, RA, and the vasculitides were all more common in patients who were White vs Black or African American. These data provide important information on the prevalence of RMDs by race and ethnicity in the United States. PCORnet can be used as a reliable data source to study RMDs within a large representative population.

ANCA-Associated Vasculitis For the Allergist and Immunologist

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of multisystemic, relapsing, autoimmune diseases that include eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). While rare, with incidences between 1 and 25 per 100,000 individuals/year, these are diagnoses that should not be missed, as unrecognized, they are associated with significant morbidity and mortality. Despite their infrequency, international collaborative research has resulted in multiple new therapeutic strategies across all three diseases.

Benralizumab for eosinophilic granulomatosis with polyangiitis

BackgroundBenralizumab is effective in the treatment of eosinophilic asthma and is being investigated for the treatment of other eosinophil-associated diseases. Reports on the use of benralizumab for the treatment of...

Eosinophilic myocarditis: from etiology to diagnostics and therapy.

Eosinophilic myocarditis (EM) is a rare, potentially life-threatening, form of inflammatory heart disease characterized by eosinophilic infiltration of the myocardium. Different diseases are involved in its etiopathogeneses, such as eosinophilic granulomatosis with polyangiitis (or Churg-Strauss Syndrome), hypereosinophilic syndromes, parasitic infections, drug reactions, paraneoplastic syndromes and primary immunodeficiencies (e.g. Omenn Syndrome). There is a wide spectrum of clinical pictures at presentation ranging from chronic restrictive cardiomyopathy (Loeffler cardiomyopathy) to acute necrotizing myocarditis with cardiogenic shock. The genetic contribution and the environmental interplay, such as SARS-CoV-2 infection and related vaccines, are fields not well studied yet. Many non-invasive tools, mainly echocardiography and cardiac magnetic resonance imaging, along with invasive procedures, such as endomyocardial biopsy, are the crucial steps in the diagnostic workup. The correct diagnosis is a challenge but mandatory for timely and appropriate immunosuppressive therapy.

Retrospective Analysis of the Burden of Illness of Eosinophilic Granulomatosis With Polyangiitis (EGPA) Versus Asthma in Commercially Insured US Patients.

Background andaim Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder associated with the presence of blood and tissue eosinophilia, extravascular granulomas, and asthma. Currently, the burden of EGPA on the patient and the healthcare system is not well characterized. This study aimed to assess the real-world clinical and economic burden of disease in adult patients with EGPA compared with matched patients with asthma without EGPA. Methods This retrospective cohort study used medical, pharmacy, enrolment, and demographic data from a US administrative claims database (PharMetrics Plus). Patients ≥18 years old, with ≥six months of continuous health plan enrolment in the baseline period, and ≥12 months of continuous health plan enrolment in the follow-up period were eligible for this analysis. Patients with EGPA and patients with asthma without EGPA were identified using diagnosis codes and were subsequently matched 1:5 (e.g., one patient with EGPAmatched with five patients with asthma, without EGPA) based on baseline characteristics. The primary outcome measure was all-cause healthcare costs; secondary outcomes included healthcare resource utilization, medication usage, and clinical characteristics. Results In the final matched cohorts, there were 7183 patients with EGPA and 35,915 patients with asthma without EGPA. During the follow-up period, mean total all-cause healthcare costs were significantly higher in patients with EGPA than in those with asthma without EGPA (mean {standard deviation}: $44,405 {$82,060} vs $24,487 {$54,691}; p<0.0001). Patients with EGPA had mean total all-cause healthcare costs that were 73.9% greater than those in patients with asthma without EGPA, even after applying a multivariable analysis to adjust for differences in demographic and clinical characteristics. Medication usage was consistently higher in the EGPA population than in the asthma population (excepting short-acting β2-agonists). The majority of patients in the EGPA population (83.1%) also experienced ≥one relapse during the study period, with 26.3% of patients in the EGPA population experiencing a major relapse. Conclusions There is a significantly greater economic and clinical burden associated with EGPA compared with asthma without EGPA in adults. These results underscore the unmet need in this patient population for improved disease control strategies that will reduce the burden of EGPA on patients and the healthcare system.

Increased factor XI but not factor XII is associated with enhanced inflammation and impaired fibrin clot properties in patients with eosinophilic granulomatosis with polyangiitis.

In eosinophilic granulomatosis with polyangiitis (EGPA) a prothrombotic state, including formation of denser fibrin networks with reduced lysability has been observed. Little is known about the intrinsic pathway in EGPA. We investigated whether coagulation factors (F)XI and FXII are associated with eosinophil-driven prothrombotic state. In 34 consecutive EGPA patients with remission we assessed FXI and FXII levels along with plasma fibrin clot permeability (Ks), fibrin clot morphology using scanning electron microscopy, and efficiency of fibrinolysis, expressed as lysis time (t50%) and maximum rate of increase in D-dimer levels (D-Drate). Increased FXI level (>130%, the upper reference limit) was found in 8 (23.5%) patients. Compared to patients with FXI levels ≤130%, those with increased FXI had higher eosinophil count (+365%) and reduced percentage of neutrophils (-20.4%), along with reduced Ks (-20.5%). In patients with FXI>130% clots were composed of thinner fibrin fibers (-17.5%). FXI was not associated with C-reactive protein and fibrinogen levels or anti-neutrophil cytoplasmic antibodies titers. There were no correlations between FXI and FXII levels as well as between FXII and eosinophil count (all p>0.05). To our knowledge, this study is the first to show association between FXI and a prothrombotic state in EGPA. Given clinical trials on FXI inhibition as an antithrombotic option, our findings suggest that this therapeutic approach could be useful in diseases with hypereosinophilia.

Subclinical microvascular changes in ANCA-vasculitides: the role of optical coherence tomography angiography and nailfold capillaroscopy in the detection of disease-related damage

BackgroundBoth cardiovascular and complement-mediated disorders might lead to microvascular damages in anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAV). We aimed at investigating, for the first time, subclinical microvascular abnormalities with non-invasive techniques in AAV patients by analyzing both retinal and nailfold capillary changes. Retinal plexi were investigated using optical coherence tomography angiography (OCT-A), while nailfold capillary changes by video-capillaroscopy (NVC). Potential correlations between microvessels’ abnormalities and disease damage were also explored.MethodsAn observational study was conducted on consecutive patients who met the inclusion criteria of defined diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA), age ≥ 18 ≤ 75 yrs, and no ophthalmological disorders. Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS), damage by Vasculitis Damage Index (VDI), and poorer prognosis by the Five Factor Score (FFS). Quantitative analysis of vessel density (VD) was performed by OCT-A in both superficial and deep capillary plexi. Figures and detailed analysis from NVC were performed for all subjects in the study.ResultsIncluded AAV patients (n = 23) were compared with 20 age/sex-matched healthy controls (HC). Retinal VD in superficial whole and parafoveal plexi resulted significantly decreased in AAV compared to HC (P = 0.02 and P = 0.01, respectively). Furthermore, deep whole and parafoveal vessel density was strongly reduced in AAV than HC (P ≤ 0.0001 for both). In AAV patients, significant inverse correlations occurred between VDI and OCTA-VD in both superficial (parafoveal, P = 0.03) and deep plexi (whole, P = 0.003, and parafoveal P = 0.02). Non-specific NVC pattern abnormalities occurred in 82% of AAV patients with a similar prevalence (75%) in HC. In AAV, common abnormalities were edema and tortuosity in a comparable distribution with HC. Correlations between NVC changes and OCT-A abnormalities have not been described.ConclusionSubclinical microvascular retinal changes occur in patients with AAV and correlate with the disease-related damage. In this context, the OCT-A can represent a useful tool in the early detection of vascular damage. AAV patients present microvascular abnormalities at NVC, whose clinical relevance requires further studies.

Childhood-Onset ANCA- Associated Vasculitis: single center experience from Central California

BackgroundChildhood-onset ANCA-associated vasculitides (AAV) are characterized by necrotizing inflammation and include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Pediatric data is scare and there have been no prior studies examining the characteristics of pediatric AAV in Central California.MethodsThis retrospective study comprised AAV patients ≤18 years of age, diagnosed between 2010 and 2021, in Central California. We analyzed initial presentation including demographics, clinical, laboratory characteristics, treatment, and initial outcomes.ResultsOf 21 patients with AAV, 12 were categorized as MPA and 9 with GPA. Median age at diagnosis was 13.7 years in MPA cohort and 14 years in GPA. MPA cohort were majority females (92% versus 44%). 57% of the cohort were racial/ethnic minority including Hispanics (n = 9), Asians (n = 2), multiracial (n = 1) and 43% were white (n = 9). MPA patients were more frequently Hispanic (67%), meanwhile GPA patients were frequently white (78%). Median duration of symptoms prior to diagnosis was 14 days in MPA cohort and 21 days in GPA cohort. Renal involvement was frequent (100% in MPA and 78% in GPA). GPA cohort had frequent ear, nose and throat (ENT) involvement (89%). All patients were ANCA positive. All Hispanic patients were MPO positive, meanwhile 89% of white patients were PR3 positive. MPA cohort tended towards more severe disease with 67% requiring ICU admission and 50% requiring dialysis. Two deaths were reported in MPA cohort, related to Aspergillus pneumonia and pulmonary hemorrhage. In MPA cohort, 42% received cyclophosphamide in combination with steroids and 42% received rituximab in combination with steroids. GPA patients received cyclophosphamide, either with steroids alone (78%) or in combination with steroids and rituximab (22%).ConclusionsMicroscopic polyangiitis was the most frequent AAV subtype with female preponderance, shorter duration of symptoms at onset and higher proportion of racial/ ethnic minority patients. Hispanic children demonstrated frequent MPO positivity. Trends towards higher rates of ICU requirement and need for dialysis upon initial presentation was noted in MPA. Patients with MPA received rituximab more frequently. Future prospective studies are needed to understand differences in presentation and outcomes in childhood onset AAV between diverse racial-ethnic groups.

Mepolizumab exerts crucial effects on glucocorticoid discontinuation in patients with eosinophilic granulomatosis with polyangiitis: a retrospective study of 27 cases at a single center in Japan

ObjectivesTo investigate the efficacy of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and factors contributing to glucocorticoid (GC) discontinuation.MethodsWe retrospectively studied EGPA patients treated with mepolizumab who were on GC at the time of induction of mepolizumab, at Japanese single center as of January 2023.Patients were classified into those who were able to discontinue GC at the time of the investigation (GC-free group) and those who continued (GC-continue group). Patient characteristics at the time of EGPA diagnosis (age, gender, absolute eosinophil counts, serum CRP level, serum IgE level, Rheumatoid factor (RF) / anti-neutrophil cytoplasmic antibody (ANCA) positivity, presence of asthma, affected organ, Five factor score (FFS), Birmingham Vasculitis Activity Score (BVAS) and characteristics at the time of mepolizumab induction (daily prednisolone dose, concomitant immunosuppressive maintenance therapy at the mepolizumab induction, prior history of GC pulse therapy, concomitant immunosuppressive therapy for remission induction,), history of relapse before mepolizumab induction and the duration of mepolizumab treatment were compared.We also followed the clinical indicators (absolute eosinophil counts, CRP and IgE levels, BVAS, Vascular Damage Index (VDI)) and daily prednisolone dosage at the EGPA diagnosis, at the mepolizumab induction and at the survey.ResultsTwenty-seven patients were included in the study. At the time of the study, patients had received mepolizumab for median 31 months (IQR, 26 to 40), the daily prednisolone dose was median 1 mg (IQR, 0 to 1.8) and GC-free was achieved in 13 patients (48%). Among clinical indicators that have improved by conventional therapy before the induction of mepolizumab, eosinophil counts, GC doses and BVAS have successively shown significant reductions throughout the observation period both GC-free and GC-continue. Of the GC-free patients, 7 were ANCA positive and 12 had FFS1 or more. Univariate analysis showed that the absolute eosinophil counts at diagnosis was significantly higher in the GC-free group (median 8165/µl (IQR, 5138 to 13,409) vs. 4360/µl (IQR, 151 to 8380), P = 0.037) and significantly fewer patients presented with gastrointestinal lesions (2 (15%) vs. 8 (57%), P = 0.025), while multivariate analysis showed no significant differences. Mepolizumab treatment significantly improved VDI in the GC-continue group (P = 0.004).ConclusionsAfter three years of treatment with mepolizumab, approximately 50% of patients with EGPA achieved GC-free status. GC could be discontinued even in severe cases and ANCA-positive cases. Although multivariate analysis did not extract any significant factors contributing to achieving GC-free, we found that improvement in eosinophil counts and BVAS led to GC reduction, resulted in protection of organ damages in both the GC-free and continuation groups. The significance of achieving GC-free remission in EGPA patients was demonstrated.

CPC03 Triad of generalized rash, peripheral eosinophilia and coexisting obstructive airway disease

Abstract An 87-year-old woman was referred to the acute dermatology service with a 1-week history of a generalized painful rash. She was under the care of the medical team for treatment of pneumonia with symptoms of a cough, fevers and shortness of breath. Her past medical history included adult-onset asthma, hyponatraemia and hypertension. She had never smoked. On examination, she had erythematous smooth papules and plaques on her limbs and torso with palmoplantar involvement, alongside purple macules and patches where older lesions were present. There was no lymphadenopathy and no mucosal involvement. She had an oxygen requirement of 2 L per minute via nasal cannula. Initial blood tests showed eosinophils of 2.8 × 109 cells L−1 and a C-reactive protein (CRP) of 77 mg L−1. A chest radiograph showed bilateral ill-defined shadowing. Two skin punch biopsies were performed for histology and immunofluorescence. Vasculitis screen identified positive antinuclear antibodies (anti-Ro) and reduced complement C4 with negative antineutrophil cytoplasmic antibody (ANCA). The patient remained unwell with increasing CRP and peripheral eosinophilia (up to 9.2 × 109 cells L−1) with rash progressing to exhibit a reticular pattern. Alongside bilateral patchy ground glass opacification on chest computed tomography, a clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was made. Differential diagnoses included viral exanthem, erythema multiforme and urticarial vasculitis. Screening for cardiac, renal and sinus involvement was undertaken. The patient improved clinically following the initiation of systemic steroids and the peripheral eosinophilia returned to baseline. Skin histology reinforced the clinical diagnosis of EGPA, demonstrating a dermal and perivascular eosinophilic infiltrate with focal extension into vessel walls. EGPA is a rare small- to medium-sized vessel vasculitis with an annual incidence of 0.9–2.4 per million and a median age at diagnosis of 49–59 years. The clinicopathological hallmarks, as in this case, are asthma with peripheral eosinophilia and pulmonary eosinophilic infiltrates. Median time from onset of asthma to presentation with EGPA is 5–9 years. EGPA remains a clinical diagnosis, reinforced by serological and histological findings, although ANCA is reported to be negative in 60–70% of cases. Systemic steroids are the first-line therapy, with a role for second-line immunosuppressants such as methotrexate and rituximab. The key learning points from this case are to keep an open mind in considering a systemic cause for cutaneous manifestations, especially when the patient does not fulfil the usual demographic picture.

Wells Syndrome with Generalized Oedema.

Biopsies are essential to establish a diagnosis in unusual cases of cellulitis.COVID-19 vaccination is a putative trigger for Wells syndrome.There is significant overlap between Wells and Churg-Strauss syndromes.

#5034 ANCA ASSOCIATED VASCULITIS AFTER COVID-19

Abstract Background and Aims ANCA associated vasculitis (AAV) is a group of systemic autoimmune diseases characterized by inflammation of small and medium sized vessels. The three main types of AAV are granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Similar pathways are involved mechanisms of disease involving COVID-19 and ANCA-associated vasculitis. For instance, neutrophil extracellular traps (NETs) are induced in both entities. Method We describe 3 cases reports of patients with ANCA associated vasculitis after COVID19. Results Case 1: A 46-year-old female patient was hospitalized in intensive care unit for COVID19 pneumonia. She has fever, cough and dyspnea. A few days before, the SARS-CoV-2 polymerase chain reaction(PCR) was positive on nasopharyngeal swab. She received high flu nasal canula. She presented a pneumo-renal syndrome with intra-alveolar hemorrhage and acute kidney injury. Chest scanner shows lesions on bilateral lung parenchyma, and an acute kidney injury (AKI) on admission. Urinalysis revealed an active sediment with dysmorphic erythrocytes and signifcant proteinuria. Renal function gradually deteriorated. So intermittent hemodialysis treatment was initiated. Serological evaluation showed negative antinuclear antibody, and anti-dsDNA, normal serum complements, and an elevated MPO. In kidney biopsy, pauci-immune necrotizing GN with cellular crescents was detected. The patient received pulse dose corticosteroids and subsequently, she was transitioned to oral prednisone. She underwent 2 sessions of plasmapheresis, which were stopped in the absence of confirmation of pulmonary involvement. She received cyclophosphamide during the hospitalization. While hematuria and proteinuria were persistant in the most recent urinalysis, the sCr level decreased to 159 µmol/L. In addition, she developed adrenal insufficiency after stopping corticosteroid therapy, requiring her to be put on Cortef. Case 2: A 63-year-old female patient with past medical history of hypertension, was hospitalized in intensive care unit for dyspnea and hemoptysis. A few months before, the SARS-CoV-2 polymerase chain reaction(PCR) was positive on nasopharyngeal swab. She received high flu nasal canula (HFNC). At this moment, she had acute kidney injury with a sCr level of 165µmol/L that was not explored. Currently she presented a pneumo-renal syndrome with a rapidly progressive glomerulonephritis and intra-alveolar hemorrhage. Renal function gradually deteriorated and peak sCr level of 308µmol/L. Chest scanner shows ground glass lesions of bilateral lung parenchyma, and hemoglobin at 4.9 g/dL. Urinalysis revealed an active sediment with dysmorphic erythrocytes and signifcant proteinuria. So intermittent hemodialysis treatment was initiated. The patient received pulse dose corticosteroids and subsequently, she was transitioned to oral prednisone. She received cyclophosphamide during the hospitalization. Serological evaluation showed negative antinuclear antibody, and anti-dsDNA, normal serum complements, and an elevated MPO. She underwent 6 sessions of plasmapheresis, for intra-alveolar hemorrhage. There was an improvement in respiratory and renal function Case 3: 57 years old, with a history of functional colopathy, covid infection 1 month before her hospitalization in nephrology department for kidney injury. Currently she presented a pneumo-renal syndrome with a rapidly progressive glomerulonephritis and intra-alveolar hemorrhage. Urinalysis revealed an active sediment with dysmorphic erythrocytes and signifcant proteinuria. Serological evaluation showed negative antinuclear antibody, and anti-dsDNA, normal serum complements, an elevated MPO and positive anti GBM. She was treated with plasmapheresis and cyclophosphamide. Conclusion SARS-CoV-2 infection can be a 'trigger factor' for vasculitis. ANCA-associated vasculitis should be kept in mind in patients who develop acute kidney injury after COVID-19.

#6567 ANCA ASSOCIATED VASCULITIS AND COVID

Abstract Background and Aims The coronavirus 2019 (COVID-19) pandemic has brought on challenges not only to acute care, but also chronic care of patients. Patients with ANCA-associated vasculitis (AAV) frequently require immunosuppression and may be at increased risk for developing COVID-19. The incidence and impact of COVID-19 on patients with AAV is currently not well known. We collected the data of patients with AAV infected with SARS-CoV-2, focused on the relationship with the employed immunosuppressants and the stage of chronic kidney disease. Method A retrospective study of AAV patients was conducted. Data regarding demographics, disease characteristics and therapy were confirmed by review of the electronic medical record. Information regarding current and previous therapies was collected. Results In our center there were 110 AAV patients who had data in the pandemic period. The majority was diagnosed with microscopic polyangiitis (MPA, n=61) or with granulomatosis with polyangiitis (GPA, n=44), there was 5 patients with eosinophilic granulomatosis with polyangiitis (EGPA). Seventy pts (77%) were receiving immunosuppression treatment, sixteen (17.6%) of these patients employing rituximab during the pandemic period. Twelve patients on immunosuppression treatment for AAV was diagnosed with COVID infection. Eight pts had kidney transplantation, no one had positive PCR test. Thirty-two pts of the 110 pts with AAV was on chronic dialyisis treatment, (29 pts on haemodialysis, 3 pts on peritoneal dialysis), eleven of them had positive PCR test for COVID-19. Among the 110 pts with AAV eighteen pts (19%) had positive PCR test for COVID-19. Seven pts had mild disease (with no or mild pneumonia), no specific therapy was applied. Five of them received immunosuppression (rituximab combinated with azathioprine or micophenolate mofetil), two pts was on haemodialysis. Severe disease (dyspnea, hypoxia, or &amp;gt;50 percent lung involvement on imaging within 48 hours) was reported in 7 pts. Five pts was on immunosuppression treatment (2 rituximab, 2 azathioprin, 1 leflunomide), 2 of them was on haemodialysis as well, 2 pts on HD without ISU. In the hospital four patients received favipiravir and prednisolone, no one of them died. Four pts was treated with critical disease (respiratory failure, shock, or multiorgan dysfunction). Two of them was on chronic haemodialysis, and received rituximab with azathioprine, one of them died. The other two pts was without immunosuppression, unfortunately both of them died. Conclusion The incidence of COVID infection is higher among pts with AAV. The pts treated with immunosuppression has higher risk for COVID infection, but the mortality was not significantly higher than in other pts groups. The highest incidence of the COVID infection was in the pts on chronic dialysis treatment, mostly due to the infection during the transfer to the HD Unit.