Eosinophilic Granulomatosis With Polyangiitis Patients Research Articles

Mepolizumab as the first targeted treatment for eosinophilic granulomatosis with polyangiitis: a review of current evidence and potential place in therapy.

Mepolizumab is an anti-interleukin-5 (IL-5) humanized monoclonal antibody that binds to free IL-5. It induces bone marrow eosinophil maturation arrest and decreases eosinophil progenitors and subsequent maturation in the blood and bronchial mucosa. Its use has been extensively studied in severe eosinophilic asthma at a dose of 100 mg subcutaneously (SC) every 4 weeks and, more recently, in other hypereosinophilic syndromes. Eosinophilic granulomatosis with polyangiitis (EGPA) is an eosinophilic vasculitis that may involve multiple organs. Characteristic clinical manifestations are asthma, sinusitis, transient pulmonary infiltrates and neuropathy. Among the numerous pathways involved in the pathogenesis of EGPA, the Th-2 phenotype has a main role, as suggested by the prominence of the asthmatic component, in triggering the release of key cytokines for the activation, maturation and survival of eosinophils. In particular, IL-5 is highly increased in active EGPA and its inhibition can represent a potential therapeutic target. In this scenario, mepolizumab may play a therapeutic role. After some positive preliminary observations on the use of mepolizumab in small case series of EGPA patients with refractory or relapsing disease despite standard of care treatment, a randomized controlled trial was published in 2017. Mepolizumab at a dose of 300 mg administered by SC injection every 4 weeks proved effective in prolonging the period of remission of the disease, allowing for reduced steroid use. The positive results of this study, which met both of the primary endpoints, led to the approval in the USA of mepolizumab in adult patients with EGPA by the Food and Drug Administration in 2017. Therefore, mepolizumab can be officially considered as an add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. However, the most appropriate dose and duration of therapy still need to be determined. Future studies on larger multinational populations with prolonged follow-up are warranted.

Endothelial dysfunction in patients with eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of vasculitis associated with asthma and eosinophilia. Endothelial dysfunction has been well documented in other types of vasculitis but not in EGPA. Thirty patients (10 men and 20 women) diagnosed with EGPA and remaining in a remission, and 58 controls (24 men and 34 women) matched for age, sex, and body mass index, were enrolled in the study. We assessed each participants for typical risk factors of cardiovascular diseases and measured serum levels of vascular cell adhesion molecule-1 (VCAM-1), interleukin 6 (IL-6), and thrombomodulin. We also measured flow-mediated dilatation (FMD) of the brachial artery and intima-media thickness (IMT) of the common carotid artery using ultrasonography. Patients with EGPA had 20% higher serum level of VCAM-1 (p < 0.001) and 41.9% of thrombomodulin (p < 0.001). They also had 38.8% lower relative increase of FMD (FMD%) (p < 0.001), indicating endothelial dysfunction. These differences remained significant also after adjustment for potential confounders. Laboratory and ultrasonographic parameters of endothelial injury were correlated to the markers of inflammation and impaired kidney function. Determinants of lower FMD% in a simple regression model were pack-years of smoking (β = − 0.3 [95% confidence interval (CI) − 0.5 to − 0.1]), serum level of IL-6 (β = − 0.36 [95% CI − 0.62 to − 0.1]), and thrombomodulin (β = − 0.34 [95% CI − 0.6 to − 0.08]). EGPA patients are characterized by inflammatory endothelial injury that is likely related to the pathogenesis of the disease. Proper immunosuppressive treatment is the best method to prevent atherosclerosis and future cardiovascular events, the patients may also benefit from additional preventive interventions.

Overall Disability Sum Score for Clinical Assessment of Neurological Involvement in Eosinophilic Granulomatosis With Polyangiitis.

The aim of this study was to verify the application of Overall Disability Sum Score (ODSS) for standardized clinical assessment of neurological involvement in patients with eosinophilic granulomatosis with polyangiitis (EGPA) and its correlation with treatment response and long-term outcomes. Consecutive EGPA patients referred to our tertiary vasculitis center were retrospectively evaluated. Patients' neurological damage and disability were systematically assessed with Vasculitis Damage Index and ODSS. Fifty EGPA patients were included in the study with a median follow-up of 75 months (9-180 months). Twenty-five (50%) developed peripheral neuropathy, 17 (68%) presented mononeuritis multiplex, whereas 8 (32%) had symmetric polyneuropathy. Patients with neurological involvement were older (56.3 ± 13.4 vs. 44.4 ± 12.1 years, P < 0.0009), more frequently antineutrophil cytoplasmic antibody positive (48% vs. 16%, P = 0.015), and were more likely to have renal involvement (24% vs. 0%, P = 0.022). An early clinical response to therapy was observed within 6 months of treatment, resulting in a significant decrease in ODSS, which fell from the baseline value of 4.2 ± 2.4 to 2.9 ± 1.5 (P = 0.0001), whereas only a slow decreasing pattern was noted over the long-term period. However, all subjects developed neurological impairment and disability despite remission from active vasculitis. Patients with ODSS of greater than 3 at baseline (n = 13 [52%]) retained a higher score at the last examination (P < 0.001), predicting a low therapeutic response. Furthermore, ODSS of greater than 3 was found associated with more neurological relapses (53.8% vs. 0%, P = 0.027). Overall Disability Sum Score could be a rapid, simple, reliable instrument to evaluate the severity of disability and nerve damage due to neurological involvement caused by vasculitis and to predict, at presentation, improvement and risk of neurological worsening.

Revision endoscopic sinus surgery rates by chronic rhinosinusitis subtype.

Revision surgery rates following endoscopic sinus surgery (ESS) range between 7% and 50% and are influenced by many factors. This study investigates ESS outcomes for chronic rhinosinusitis (CRS) subtypes. Retrospective review of adult CRS patients undergoing ESS with a single surgeon (2010-2015) was conducted. Outcomes were analyzed by CRS subtypes. ESS was performed in 424 CRS patients (CRS with nasal polyps [CRSwNP], n = 170; CRS without polyps [CRSsNP], n = 254). Most patients (309; 72.9%) could not be specifically subtyped; 115 (27.1%) were subtyped as follows: aspirin-exacerbated respiratory disease (AERD), n = 47 (11.1%); allergic fungal sinusitis (AFS), n = 39 (9.2%); immunodeficiency, n = 21 (5.0%); granulomatosis with polyangiitis (GPA), n = 5 (1.2%); and eosinophilic granulomatosis with polyangiitis (EGPA), n = 3 (0.7%). All subgroups experienced clinically meaningful reduction in postoperative 22-item Sino-Nasal Outcome Test (SNOT-22) scores. At median follow-up of 28 months (interquartile range [IQR], 10-47 months), 19 patients (4%) underwent revision ESS (CRSwNP, n = 6; CRSsNP, n = 13). Revision ESS rates were 3.5% and 5.1% for CRSwNP and CRSsNP, respectively. Revision ESS rate for subtypes were: AERD 2%; AFS 2%; immunodeficiency 14%; GPA 40%; EGPA 0%; and "all other CRS" 4% at median follow-up duration of 36, 28, 41, 37, 44, and 26 months, respectively. All CRS subtypes demonstrated clinically meaningful improvement in postoperative SNOT-22 scores following ESS. Our overall revision ESS rate was 4% (3.5% in CRSwNP). AFS, AERD, and EGPA groups demonstrated low revision rates, while immunodeficiency and GPA patients required more revision surgery. A contemporary understanding of CRSwNP subtypes facilitated surgical and medical strategies in improving outcomes for AERD, AFS, and EGPA patients. CRSsNP subtypes with immunodeficiency and GPA merit further investigation to optimize outcomes.

HBsAg-negative and anti-HBc-positive in eosinophilic granulomatosis with polyangiitis: a retrospective pilot study.

We examined whether resolved hepatitis B virus (HBV) infection was associated with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and affected AAV activity at diagnosis and prognosis during the follow-up. We reviewed the electronic medical records of 153 AAV patients, and included 91 hepatitis B surface antigen (HBsAg)-negative patients having results of both antibody to hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs). We collected clinical and laboratory data, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis and relapse rates during the follow-up. We divided patients into the two groups according to the presence of anti-HBc and compared variables between them in patients with AAV or those with each variant. The mean age and follow-up duration were 59.8 ± 15.2-year-old and 48.0 ± 47.5months. Fifty patients (54.9%) had anti-HBc, and 61 patients (67.0%) had anti-HBs. Only thirty-six (39.6%) patients had ever experienced relapse after remission. There were no remarkable differences between HBsAg-negative AAV patients with and without anti-HBc. However, in eosinophilic granulomatosis with polyangiitis (EGPA) patients, patients with HBs-negative/anti-HBc-positive (resolved HBV infection) showed the higher initial mean BVAS and FFS (2009) than those without. Patients having anti-HBc exhibited significantly increased risk of relapse of EGPA than those having not (RR 16.0). Also, EGPA patients with HBs-negative/anti-HBc-positive showed meaningfully lower cumulative relapse-free survival rates than those without during the follow-up duration (p = 0.043). In conclusion, resolved HBV infection may importantly influence vasculitis activity at diagnosis and subsequently relapse after remission in EGPA patients.

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.

ANCA associated vasculitis in patients from Saudi Arabia.

Objective:To explore clinical and laboratory features, therapy and outcome of antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) patients from our tertiary care center.Methods:This study of AAV patients seen in Rheumatology clinics at King Khalid University hospital (KKUH), King Saud University, Riyadh during the period 1990-2014 was carried out retrospectively. Demographic, clinical, haematological and immunological parameters along with therapy, complications and outcome were retrieved from patients' medical charts. Different characteristics were compared between the three groups of AAV; GPA (Granulomatosis with polyangiitis), MPA (Microscopic polyangiitis) and EGPA (Eosinophilic granulomatosis with polyangiitis).Results:We identified 34 AAV patients (21 males: 13 females; 31 Saudis: 3 non-Saudis) comprising of 23 GPA, 2 MPA and 9 EGPA cases. The mean age of onset was 42.1±17.6 years (range 11-75) and mean duration of disease was 8.7± 5.1 years (range 1-20). The most frequently affected system was pulmonary in all AAV (73.5%), GPA (65.2%) and EGPA (100%) while it was renal in MPA (100%) patients. Ophthalmological and upper airways involvement was higher in GPA. Neurological involvement was higher in EGPA (p<0.05). ANCA were detected in 79.4% of AAV patients, of them c-ANCA were 77.8% and p-ANCA 22.2%. ANCA was positive in 91.3% GPA, 100% MPA and 44.4% EGPA patients. In GPA c-ANCA were detected in 80.9% and p-ANCA in 17.4%, in MPA, c-ANCA were detected in 50% and p-ANCA in 50%, in EGPA, c-ANCA were observed in 75% and p-ANCA in 25%. GPA patients had PR3 specificity in 93.3%, and MPO in 6.7%, PR3 was present in all MPA patients (100%), while EGPA patients had MPO (100%). Therapy administered were corticosteroids (100%), intravenous cyclophosphamide (58.8%), azathioprine (50%) and rituximab (11.8%). Infections were noted in 29.4%.Conclusions:The 10-year survival in our AAV patients was 95%. ANCA pattern was similar to Caucasian AAV patients and different from Japanese and Chinese AAV patients.

Rheumatoid factor false positivity in patients with ANCA-associated vasculitis not having medical conditions producing rheumatoid factor.

We investigated the rate of rheumatoid factor (RF) false positivity at diagnosis and its influence on clinical and prognostic features and rheumatoid arthritis (RA) development during the follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients without RA or other medical conditions triggering RF false positivity. We reviewed the medical records of 128 AAV patients. We divided patients with AAV and each variant into two groups according to RF positivity and compared variables between the two groups. Odds ratio and cumulative relapse-free survival rate were obtained by multivariate logistic regression analysis and the Kaplan-Meier survival analysis, respectively. The mean age at diagnosis was 53.6years and 41 patients were male. Of 128 AAV patients, 69 patients (53.9%) were classified as microscopic polyangiitis (MPA), 29 (22.7%) as granulomatosis with polyangiitis (GPA) and 30 (23.4%) as eosinophilic GPA (EGPA). The rate of RF false positivity was 39.1% in AAV patients. On univariate analysis, general, cutaneous and mucous and ocular manifestations and myeloperoxidase (MPO)-ANCA (or perinuclear (P)-ANCA) positivity were associated with RF false positivity in patients with AAV. On multivariate analysis, cutaneous manifestation was the only independent predictor of RF false positivity in EGPA patients. RF false positivity had no influence on cumulative relapse-free survival rate of AAV or RA development during the follow-up. RF false positivity rate was 39.1% in AAV patients and it was associated with cutaneous manifestation in EGPA patients at diagnosis, but not relapses of AAV or RA development during the follow-up.

Echocardiographic features in patients with ANCA-associated vasculitis within 3months before and after diagnosis.

We investigated the all-inclusive echocardiographic features in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) within 3months before and after diagnosis. We reviewed the medical records of 89 AAV patients taking echocardiography and 35 age- and gender-matched controls. We collected clinical and laboratory data and echocardiographic results. We compared the variables between patients with AAV of each variant and controls and among those with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). The mean age and period from diagnosis to echocardiography were 54.5years (30 men) and 1.4months. The mean age of controls was 51.6years. AAV patients exhibited lower mean left ventricle ejection fraction (LVEF) (64.0 vs. 69.1%, P=0.002) and higher mean E/E' ratio (11.7 vs. 8.8, P=0.001) and right ventricle systolic pressure (RVSP) (30.2 vs. 23.2mmHg, P<0.001) than the controls. Each variant of AAV presented a different pattern of echocardiographic features in comparison with controls. MPA patients exhibited systolic and diastolic dysfunctions and pulmonary arterial hypertension more often than controls. Meanwhile, GPA patients exhibited only diastolic dysfunction, and EGPA patients had systolic dysfunction and pulmonary arterial hypertension more frequently than controls. No meaningful differences in echocardiographic features appeared among AAV variants. AAV patients exhibited reduced systolic function and advanced diastolic dysfunctions and pulmonary arterial hypertension near the time of diagnosis compared with controls. Each variant of AAV presented a different pattern in echocardiographic features.

O14-1 - A Case of Heart Failure Caused by Cardiac Involvement in Eosinophilic Granulomatosis with Polyangiitis

A 58-year-old woman presented with increasing shortness of breath and fatigue for three months. Her medical history revealed that she had started suffering from bronchial asthma and numbness in both legs about one year before admission. A chest x-ray showed pulmonary congestion and cardiomegaly. Transthoracic echocardiography demonstrated diffuse hypokinesis of the left ventricle with an ejection fraction of 38%. Intracardiac thrombi were detected in the left ventricular apex and left atrial appendage. Brain magnetic resonance imaging showed multiple cerebellar infarctions, but fortunately the lesions were asymptomatic. Laboratory examination revealed that B-type natriuretic peptide was elevated to 2700 pg/dL and eosinophils was elevated to 59.4%. Based on these findings, we diagnosed heart failure due to cardiac involvement of eosinophilic granulomatosis with polyangiitis (EGPA). In addition to standard heart failure therapy, oral prednisolone was introduced at a dose of 30 mg daily. Right ventricular myocardial biopsy was performed 7 days after steroid therapy. The pathological findings were compatible with post-myocarditic change, but without eosinophil infiltration. Although her heart failure symptoms were improved and left ventricular ejection fraction was increased to 51%, severe numbness and pain remained uncontrolled. Therefore, we decided to treat the patient with intravenous cyclophosphamide and high-dose intravenous immunoglobulin in addition to steroid therapy. We herewith report a case of heart failure associated with cardiac involvement in an EGPA patient.

Heart failure not responsive to standard immunosuppressive therapy is successfully treated with high dose intravenous immunoglobulin therapy in a patient with Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Glucocorticoids and immunosuppressive drugs represent the first-line treatment of eosinophilic granulomatosis with polyangiitis (EGPA, former Churg-Strauss syndrome), even though the combined therapy is not successful in achieving the disease remission in some patients with neurological or cardiac involvement. We describe a case of an EGPA male patient with impaired left ventricular function not responsive to glucocorticoid and immunosuppressive therapy. We observed that high-dose (2g/kg/4weeks) intravenous immunoglobulin (IVIG) therapy significantly improved cardiac function, which was deteriorated after reducing IVIG dose at 0.5g/kg/4weeks, and was restored increasing again IVIG dose to 2g/kg/4weeks. The finding highlights the relevance of IVIG as treatment of choice in EGPA patients with cardiac involvement not responsive to the standard glucocorticoid and immunosuppressive therapy. Moreover, at a follow-up of 24months, the continuance of high dose IVIG therapy was required to maintain a sustained remission of the heart failure.

The Presence of Anti-Lactoferrin Antibodies in a Subgroup of Eosinophilic Granulomatosis with Polyangiitis Patients and Their Possible Contribution to Enhancement of Neutrophil Extracellular Trap Formation.

Lactoferrin (Lf) is one of the antigens of antineutrophil cytoplasmic antibodies (ANCA) and functions as an endogenous suppressor of neutrophil extracellular trap (NET) formation. However, the prevalence and pathogenicity of anti-lactoferrin antibodies (aLf) in ANCA-associated vasculitis (AAV) remain unrevealed. This study aimed to examine the significance of aLf in AAV, initially. Sixty-five sera from AAV patients, including 41 microscopic polyangiitis, 5 granulomatosis with polyangiitis, and 19 eosinophilic granulomatosis with polyangiitis (EGPA) patients, were subjected to aLf detection using enzyme-linked immunosorbent assay. Clinical characteristics were compared between aLf-positive and aLf-negative patients. Neutrophils from healthy donors were exposed to suboptimal dose (10 nM) of phorbol myristate acetate (PMA) with aLf followed by evaluation of NET formation. Results demonstrated that 4 out of 65 AAV sera (6.2%) were positive for aLf. All of them were EGPA sera (4/19, 21.1%). In EGPA, the frequency of renal involvement, serum CRP levels, and Birmingham Vasculitis Activity Score (BVAS) in the aLf-positive patients was significantly higher than those in the aLf-negative patients, and the aLf titer correlated positively with the serum CRP level and BVAS. The NET formation was particularly enhanced by combined stimulation of 10 nM PMA and 1 µg/mL aLf. IgG isolated from sera of the aLf-positive EGPA patients (250 µg/mL) enhanced NET formation induced by 10 nM of PMA, and the effect was abolished completely by absorption of the aLf. This pilot study suggests that aLf enhance NET formation induced by PMA and are associated with disease activity of EGPA.

Comprehensive evaluation of cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA) with cardiac magnetic resonance

BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis characterized by hypereosinophilia. EGPA typically develops in three clinical phases, beginning with asthma, followed by tissue eosinophilia and finally systemic vasculitis. Cardiac involvement is the most important predictor of mortality; it occurs in approximately 15–60% of EGPA patients, a significant proportion of whom are asymptomatic and have normal electrocardiogram (ECG) and echocardiogram. Early detection and management of cardiac disease could positevely affect prognosis. Cardiovascular magnetic resonance (CMR) has emerged as the gold standard cardiac imaging technique in the evaluation of cardiomyopathies, due to its ability to reliably assess anatomy, function, and tissue characterization. AimPurpose of this study was to assess the role of CMR in detecting cardiac disease in patients with EGPA in clinical remission. MethodsA dedicated CMR protocol including functional analysis, and pre and post-contrast tissue characterization was performed in 11 patients with EGPA and the results were compared with 11 healthy subjects. ResultsEGPA patients had lower left ventricular ejection fraction compared to controls (56±19 vs 68.7±5.2, p value 0.02). Late gadolinium enhancement (LGE), representing replacement fibrosis, was positive in 9/11 (82%) patients, mainly with a non-ischemic pattern. In 3/11 (27%) patients a left ventricular thrombus was detected; in 3/11 (27%) patients myocardial edema was detected. CMR parameters of interstitial fibrosis were significantly more elevated in EGPA patients compared to controls. ConclusionsPatients with EGPA in clinical remission showed a high cardiovascular burden as demonstrated by lower EF, signs of active inflammation, presence of interstitial and replacement fibrosis and intraventricular thrombosis. Further studies on wider populations are warranted to better understand how these findings could impact on prognosis and eventually guide therapy.

Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients.

BackgroundThe clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied.MethodsFourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed.ResultsThe most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10–45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200–1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47–11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5–7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6–83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR.ConclusionsRenal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.

Otologic and Rhinologic Manifestations of Eosinophilic Granulomatosis with Polyangiitis

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disease that manifests as asthma, recurrent sinusitis and peripheral eosinophilia. In this study, we investigated the clinical features of the ear and nasal manifestations of EGPA in comparison with those of granulomatosis with polyangiitis (GPA). Materials and Methods: Twenty-one patients diagnosed with EGPA were studied. The frequency of otologic manifestations, the degree of hearing loss and the frequency of nasal symptoms were assessed. The onset of ear symptoms, sinusitis and asthma in patients with EGPA were also examined. Results: Eleven patients (52.4%) with EGPA demonstrated otologic symptoms. The EGPA patients commonly presented mild-to-moderate mixed or sensorineural hearing loss. The pattern of hearing loss was mainly flat, and all but 1 patient achieved complete remission from their hearing impairments. Eighteen patients (85.7%) with EGPA demonstrated nasal symptoms. Patients with EGPA showed a significantly higher incidence of nasal polyps than did those with GPA. The median Lund and Mackey scoring system score was 13.7 for patients with EGPA, and ethmoid sinus shadows were more severe than those of the maxillary sinus. Most ear symptoms associated with EGPA were observed after definitive diagnosis, although sinusitis and asthma tended to manifest themselves before diagnosis. There were significant differences between the onset of ear symptoms and those of asthma and sinusitis. Conclusion: As over 80% of patients with EGPA had nasal symptoms and over half had ear symptoms, otolaryngologists should be aware of this disease. Recognition of the characteristic ear and nasal symptoms are thought to be particularly important to obtain an early diagnosis of EGPA.

Th17 cells reflect colon submucosal pathologic changes in active eosinophilic granulomatosis with polyangiitis.

BackgroundChronic eosinophilic pneumonia (CEP) or eosinophilic gastroenteritis (EG), or both, with asthma precede the onset of eosinophilic granulomatosis with polyangiitis (EGPA) in half of all EGPA patients. It is not known what determines whether patients with CEP or with EG following asthma will develop EGPA.MethodsWe studied 17 EGPA patients and 12 patients with CEP but without EGPA. We assayed serum ICAM-1, VCAM-1, and VEGF, and the percentage of peripheral blood CD4+ T cells producing IL-17 (Th17 cells), at both onset and remission. We also examined the numbers of submucosal eosinophils and the basement membrane-to-crypt and crypt-to-crypt distance to evaluate edema in the colon submucosa at onset and remission in EGPA and at onset in CEP.ResultsNine of 12 (75.0 %) CEP patients had symptoms or endoscopic findings. Colonic submucosal eosinophil counts and edema in EGPA at onset were greater than at remission or in CEP at onset. Th17 cells (%) and serum ICAM-1 levels at onset were greater in EGPA than in CEP. In EGPA, peripheral blood Th17 cells (%) were significantly correlated with serum ICAM-1 level, colonic submucosal eosinophil count, and degree of edematous change; inversely correlated with serum VEGF level; but not correlated with VCAM-1 level.ConclusionsEosinophilia and colonic submucosal edematous change were greater in EGPA than in CEP. The mechanism of vasculitis in EGPA appears related to increases in serum Th17 cell numbers and ICAM-1 levels and decreases in VEGF levels.

Rituximab as induction therapy in relapsing eosinophilic granulomatosis with polyangiitis: A report of 6 cases

ObjectiveRecently few reports have suggested a potential benefit of rituximab in patients with eosinophilic granulomatosis with polyangiitis (EGPA). However, the current evidence is limited. We describe the efficacy and safety of rituximab in six patients with relapsing EGPA. MethodsCandidates for rituximab therapy were selected from a cohort of 118 patients with EGPA. The main indication for B-cells depletion was moderately severe or severe relapsing disease that was refractory to conventional immunosuppression. A primary end-point was a complete or partial remission within 3 to 6 months after rituximab administration. ResultsAll six patients (four ANCA-positive and two ANCA-negative) had active EGPA manifesting by severe lung disease and/or deteriorating peripheral neuropathy. The median duration of follow-up after the first rituximab dose administration was 10 months. All patients rapidly responded to rituximab treatment, e.g. disappearance of lung infiltrates, improvement of asthmatic symptoms, at least partial recovery of motor and sensory function. Within 3 to 6 months, complete (4/6) or partial (2/6) remission was achieved in all patients. After switching to rituximab all patients except one discontinued cyclophosphamide or other immunomodulators. Four patients continued maintenance treatment with rituximab. One patient developed severe bronchospasm during infusion and two patients presented with moderately severe purulent bronchitis that was successfully treated with intravenous antibiotics. ConclusionOur retrospective case series suggest that rituximab may be effective for induction of remission in selected EGPA patients. These data warrant further studies to evaluate safety and efficacy of rituximab in EGPA.

Omalizumab in patients with eosinophilic granulomatosis with polyangiitis: a 36-month follow-up study

Objective: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis characterized by asthma and blood eosinophilia, with the lung being the organ most frequently affected. Oral glucocorticoids and/or immunosuppressive drugs are the mainstay therapy of EGPA. Occasional reports suggest that EGPA patients can be treated with omalizumab in addition to conventional therapy to achieve asthma control. To investigate the long-term effects of omalizumab in patients with EGPA and asthma (2 females, 3 males, age 41–64 years), we carried out a 36-month follow-up observational study. At the time of enrollment, the patients were on maintenance therapy and had moderate to severe allergic asthma, eosinophilia and rhinosinusitis. Mononeuropathy/polyneuropathy and/or histological evidence of tissue eosinophilic infiltration were also present. Methods: Patients were treated with omalizumab (300–600 mg s.c. every 2–4 weeks) as add-on therapy to prednisone, inhaled steroids and bronchodilators. During omalizumab treatment, spirometry, the asthma control test (ACT) score and eosinophilia were evaluated, and prednisone dosage was recorded. Results: During the 36 months of omalizumab treatment asthma progressively improved as indicated by spirometry and the ACT score. Eosinophilia progressively decreased. The oral prednisone dose was reduced or withdrawn during treatment. No adverse events were recorded. Conclusions: In patients with EGPA and moderate to severe allergic asthma, omalizumab can be beneficial and safe. It enables corticosteroid tapering while decreasing eosinophilia and improving asthma symptoms over 36 months.

Manifestation of eosinophilic granulomatosis with polyangiitis in head and neck.

Besides an obvious clinical involvement of the ear, nose and throat (ENT)-region in Eosinophilic Granulomatosis with Polyangiitis (EGPA), systematic data is sparse. Only a few case series and case reports are available that particularly describe rhinological, otological or other manifestations of EGPA in the ENT-region. Therefore, the objective of this study is to systematically describe data on ENT-region involvement in a large series of EGPA patients. EGPA patients examined in the Department of Otorhinolaryngology of the Christian-Albrechts-University of Kiel between 1990 and 2010 were included in the study. Criteria for ENT-manifestation were assigned to five subgroups (history, ENT examination, audiological and rhinological diagnostic findings and cranial MRI) and documented cumulatively. EGPA patients were examined in a standardized way based on the validated Ear Nose and Throat Activity Score (ENTAS) or its precursor, including audiological and rhinological diagnostic findings. MRI scans were analysed to further evaluate ENT involvement. A total of 95 EGPA patients were included in the study. In approximately 80% of them, ENT-involvement was documented and the assumption of a frequent rhinological manifestation in patients with EGPA was confirmed. Moreover, the data reveals remarkable evidence for an otological manifestation. A missing correlation between the rhinological and the otological manifestation indicates an independent autoimmune-inflammatory process for this manifestation. The data of the largest monocentric study presented here confirms the hypothesis of a frequent ENT involvement in EGPA patients, in whom rhinological and otological manifestations are most common. Therefore, treatment should include long term follow-up and should be managed interdisciplinary.

Cardiac involvement in Churg-Strauss syndrome

Churg-Strauss syndrome, recently renamed eosinophilic granulomatosis with polyangiitis (EGPA), is a rare form of systemic vasculitis, characterized by disseminated necrotizing vasculitis with extravascular granulomas occurring among patients with asthma and tissue eosinophilia. EGPA is classified as a small and medium-sized vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) and the hypereosinophilic syndrome. Typical clinical features include asthma, sinusitis, transient pulmonary infiltrates and neuropathy. Blood eosinophils are often >1500/µl or more than 10% on the differential leukocyte count. Blood eosinophils should always be tested in unexplained cardiac disorders, and may normalize even after low doses of corticosteroids. ANCA are positive in 40-60% of cases, mainly anti-myeloperoxidase. Heart involvement occurs in approximately 15-60% of EGPA patients, especially those who are ANCA negative. Any cardiac structure can be involved, and patients present with myocarditis, heart failure, pericarditis, arrhythmia, coronary arteritis, valvulopathy, intracavitary cardiac thrombosis. Although cardiovascular involvement is usually an early manifestation, it can also occur later in the course of the disease. A significant proportion of patients with cardiac involvement is asymptomatic. In the absence of symptoms and major ECG abnormalities, cardiac involvement may be detected in nearly 40% of the patients. All patients with EGPA should be studied not only with a detailed history of cardiac symptoms and ECG, but also with echocardiography; if abnormalities are detected, a cardiac magnetic resonance study should be performed. Coronary angiography and endomyocardial biopsy should be reserved to selected cases. Heart involvement carries a poor prognosis and causes 50% of the deaths of these patients. It is often insidious and underestimated. Optimal therapy is therefore important and based on high-dose corticosteroids plus immunosuppressive agents, particularly cyclophosphamide in case of myocardial inflammation. Thus, early diagnosis of cardiac involvement and subsequent therapy may prevent progression of cardiac disease. At present, the role of troponin and brain natriuretic peptide in monitoring and therapy remains unclear. Orthotopic heart transplantation is feasible in case of severe disease, even if the experience is limited in -EGPA, and optimal post-transplantation immunosuppressive strategy has yet to be defined.