Vascular endothelial growth factor (VEGF)-A and VEGF-A165b are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

BACKGROUND: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. METHODS: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). RESULTS: Results revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

Immunopathogenesis of ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Serum Mannose-Binding Lectin Levels Are Correlated with the Disease Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center Study.

Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.

Subtypes in eosinophilic granulomatosis with polyangiitis classified according to rheumatoid factor.

To investigate the relevance of RF in patients with EGPA, we reviewed consecutive patients who were newly diagnosed with EGPA from August 1998 to February 2019 in Keio University Hospital with RF titer at diagnosis available. We divided the patients according to the median level of RF titer of 75 IU/mL and compared clinical features between the two groups. Among 16 patients identified, 8 patients were in the RF high group and the other 8 patients were in the RF low group. All patients in the high RF group were negative for MPO-ANCA, whereas all in the low RF group was positive for MPO-ANCA with a mean titer of 103 IU/mL. The eosinophil count at diagnosis was significantly higher in the RF high group than the RF low group (20001/µL vs 5144/µL, p < 0.01). Gastrointestinal lesion was significantly more frequent in the RF high group, and parenchymal organ lesions, such as heart and renal organ involvement, were frequent in the RF low group. With principal component analysis, RF high and low groups were clearly divided by the combination of eosinophil count, MPO-ANCA titer, gastrointestinal lesions, musculoskeletal symptoms, and disease activity score. Those results suggest EGPA can be divided into two groups in association with RF.Key Points• Our study showed that patients with EGPA can be separated into two groups according to RF titer.• The two subtypes reflect different underlying pathogenesis in EGPA, and the optimal treatment for them may be different.

A challenging diagnosis of MPO-C-ANCA EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic small-vessel vasculitic disease that can present with positive MPO-P-ANCA (myeloperoxidase-perinuclear-anti-neutrophil cytoplasmic antibody). It is a rare condition that is difficult to diagnose. We present the case of a 64-year-old man with late-onset adult asthma and treated nasopharyngeal carcinoma who initially presented to us with proximal myopathy. Thereafter, he developed a constellation of fleeting symptoms which included rhinosinusitis, mononeuritis multiplex, skin vasculitis and arthritis. Blood investigations showed that he had eosinophilia, and skin biopsy demonstrated dermal vasculitis with eosinophils. He was found to be MPO-C-ANCA positive, and although initially thought to have granulomatosis with polyangiitis, the diagnosis was later revised to EGPA. This case highlights the diagnostic challenges with atypical presentations of EGPA and also presents a rare case of positive MPO-C-ANCA that has never been described in EGPA before.

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.

Histopathological Findings and Increased D-Dimer Are Predictive Factors of Systemic Thromboses in Eosinophilic Granulomatosis With Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA; ie, Churg-Strauss syndrome) is one of the antineutrophil cytoplasmic antibody-associated vasculitis syndromes. Although extravascular granulomatoses are a well-known histopathological feature, the diverse histopathologic spectrum of cutaneous lesions has not been described in detail. Thus, this study sought to investigate the possible correlation between the clinical features and histopathology of cutaneous lesions in EGPA cases, focusing on systemic thrombogenic conditions, such as visceral infarction and deep vein thrombosis. Fourteen cases of EGPA diagnosed at the Department of Dermatology in Asahikawa Medical University from 1977 to 2017 were clinically and histopathologically reviewed. In 6 (43%) cases, skin lesions were the initial manifestation of EGPA. Among the cutaneous lesions, purpura and erythema were the most common. Persistent proteinuria and macrohematuria were observed in only 2 myeloperoxidase-antineutrophil cytoplasmic antibody-positive cases. Systemic thrombotic symptoms, such as cerebral infarction and deep vein thrombosis, were detected in 5 (36%) cases, and, in 3 of those cases, thromboses in dermal or subcutaneous vessels were observed histopathologically. Elevation of plasma D-dimer level (>2.5 µg/mL) was significantly correlated with concomitant systemic thrombotic symptoms (P = 0.0152, Fischer exact test). The histopathological finding of thrombotic features and increased plasma D-dimer were predictive factors of EGPA accompanied with systemic thromboses, such as deep vein thromboses and cerebral infarction.

Perinuclear antineutrophil cytoplasmic antibody-associated pulmonary vasculitis masquerading as lung metastasis.

Churg-Strauss syndrome (CSS) is an uncommon systemic disorder leading to inflammation of small and medium vessels by an immunological mechanism. Lungs are the most frequent organ affected. It is an allergic granulomatosis with polyangiitis associated with the presence of perinuclear antineutrophil cytoplasmic antibody. We describe a rare presentation of CSS as bilateral multiple cavitating nodules in a 50-year-old man with diabetes.

Five factor score of more than 1 is associated with relapse during the first 2 year-follow up in patients with eosinophilic granulomatosis with polyangiitis.

AIM: We investigated what variables at diagnosis might be associated with the relapse of eosinophilic granulomatosis with polyangiitis (EGPA) and whether five factor score (FFS) at diagnosis might predict it. METHODS: We reviewed the medical records of 30 patients with EGPA having results of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA) and proteinase 3 (PR3)-ANCA and having achieved remission during the first therapeutic regimen administration within follow-up duration for at least more than 2 years. Clinical manifestations, the presence of relapse and items for FFS at diagnosis were collected and compared among groups. RESULTS: The mean age of patients (18 women) was 50.3 years and the mean follow-up duration was 2175 days. EGPA patients having MPO-ANCA had shown higher frequency of skin involvement and proteinuria over 1 g/day than those having PR3-ANCA and no ANCA. EGPA patients with relapse had more frequent baseline MPO-ANCA and kidney involvement,including proteinuria over 1 g/day and renal insufficiency and higher FFS at diagnosis than those without. However, only FFS showed the predictive significance for relapse (Exp(B) 2.624, P = 0.014) on Cox Hazard model analysis. When the cutoff of FFS for the relapse was set as 1, relapse was identified more frequently in patients with FFS ≥ 1 than those with FFS <1 (68.8% vs. 7.1%, P = 0.001; relative risk 28.6). CONCLUSION: In this study, FFS at diagnosis was associated with relapse and FFS ≥ 1 was the independent predictor of relapse during follow-up for more than 2 years.

Clinical and prognostic features of Korean patients with MPO-ANCA, PR3-ANCA and ANCA-negative vasculitis.

OBJECTIVES: We reclassified Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) into 3 categories of AAV including MPO-ANCA, PR3-ANCA and ANCA-negative vasculitis, and investigated clinical and prognostic features. METHODS: We reviewed the medical records of 133 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), who had either myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA or no ANCA, and who had ever achieved the first remission. We compared clinical manifestations, initial Birmingham vasculitis activity score (BVAS) and five factor score (FFS), and relapse rates. RESULTS: Patients with ANCA-negative vasculitis had the youngest mean age at diagnosis (50.0 years old) among AAV categories. General, cutaneous and renal manifestations were commonly observed in MPO-ANCA vasculitis, while mucous membrane, eye, ear nose throat (ENT) and renal manifestations were often documented in PR3-ANCA vasculitis. ENT manifestation was also frequently observed in ANCA-negative vasculitis. However, there were no significant differences in pulmonary and nervous system manifestations among 3 AAV categories. There were no significant differences in cumulative relapse free survival according to the presence of MPO-ANCA or PR3-ANCA or no ANCA. Meanwhile, initial BVAS or BVAS for GPA ≥13.5 in MPO-ANCA vasculitis and initial FFS (1996) ≥1 in MPO-ANCA and ANCA-negative vasculitis were significant predictors of relapse of each AAV category. CONCLUSIONS: Clinical manifestations varied AAV categories, and neither MPO-ANCA nor PR3-ANCA significantly affected relapse of AAV. Initial BVAS or BVAS for GPA and FFS (1996) helped to predict relapse of specified AAV categories.

IgA antibodies to myeloperoxidase in patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

OBJECTIVES: To determine the prevalence of anti-myeloperoxidase (MPO) antibodies of IgA (IgA anti-MPO) isotype in patients with eosinophilic granulomatosis with polyangiitis (EGPA), and the association of the IgA antibodies with IgG anti-MPO and with disease activity. METHODS: Serum samples from patients with EGPA followed in a multicenter longitudinal cohort were tested by ELISA for the presence of IgA anti-MPO and IgG anti-MPO antibodies. Sera from 87 healthy controls were used to define a positive test. Sera from 168 patients with EGPA (298 samples) were tested. Frequencies of positive testing for IgA anti-MPO were compared between patients with active EGPA, patients in remission, and controls. RESULTS: IgA anti-MPO was detected in 10 of 168 (6%) patients with EGPA (11 of 298 serum samples) compared to 1 of 87 (1%) healthy controls (p=0.10). All 11 samples testing positive for IgA anti-MPO also tested positive for IgG anti-MPO. Ninety samples tested positive for IgG anti-MPO but negative for IgA. Samples taken during active EGPA were positive for IgA anti-MPO in 6/72 cases (8%), compared to 5/226 (2%) during remission (p=0.03). Among samples taken during moderate or high disease activity, 5/41 were positive (12%, p=0.01 compared to remission). CONCLUSIONS: Although IgA anti-MPO antibodies are detectable in some patients with EGPA and may be detectable more frequently during active disease, their presence seems unlikely to provide information beyond what is obtained from conventional IgG anti-MPO.

Neutrophil extracellular traps formation in patients with eosinophilic granulomatosis with polyangiitis: association with eosinophilic inflammation.

OBJECTIVES: Eosinophilic granulomatosis with polyangiitis (EGPA) is associated with an inflammation and the presence of antineutrophil cytoplasmic antibodies (ANCA). Thus, we investigated the impact of ANCAs and eosinophilic inflammation on neutrophil activation and extracellular traps (NETs) formation. METHODS: We recruited 29 patients in the remission of EGPA (17 ANCA-negative and 12 ANCA-positive, including 7 p-ANCA-positive and 5 c-ANCA-positive patients). Healthy donors' neutrophils were stimulated with EGPA patients' serum. NETs formation was assessed by immunofluorescence and scanning electron microscopy. RESULTS: EGPA patients presented enhanced ability to generate NETs compared to healthy subjects (20.3±8.2% vs. 2.7±1.5%, p=0.0036). However, there were no differences in NETs formation between ANCA-positive and ANCA-negative patients (23±11.2% vs. 17±6.1%, p=0.15). There was also no correlation between NETs generation and the amount of circulating DNA in EGPA patients. Among ANCA-positive patients, p-ANCA-positives showed the highest percentage of NETs as compared to cANCA-positive and ANCA-negative patients (27.3±10.3% vs. 17.8±10.5% and vs. 17±6.1%, both p<0.01, respectively). Eosinophils number correlated with the percentage of NETs in the whole EGPA group (r=0.53, p=0.039), but we failed to observe the correlation with an eosinophil cationic protein (r=0.49, p=0.058). CONCLUSIONS: EGPA patients' serum has the ability to induce NETosis with no regard to the ANCA status in contrast to other vasculitides, where p-ANCA were considered as the main factor. Interestingly, NETs formation in EGPA patients connected with the number of eosinophils might be of major relevance. Further studies are required to assess which eosinophil-derived factors might be responsible for the neutrophils activation in EGPA patients.

ANCA-negative eosinophilic granulomatosis with polyangitis (EGPA) manifesting as a large intracardiac thrombus and glomerulonephritis with angionecrosis.

A 59-year-old woman with a history of bronchial asthma presented with a prolonged fever and eosinophilia. There was transient proteinuria and troponin level was elevated. Antineutrophil cytoplasmic antibody was negative and she did not fulfil criteria for eosinophilic granulomatosis with polyangitis (EGPA). Echocardiography showed a large apical mass in the left ventricle, but there was no systolic dysfunction, local asynergy or ventricular remodelling. On MRI, apical mass was compatible with a thrombus and endocardial region was diffusely damaged. Loeffler endocarditis-like cardiac manifestation led to meticulous examination, which found no aetiology for eosinophilia. Finally, renal biopsy revealed eosinophil infiltration and glomerular angionecrosis, confirming as EGPA. This case highlights the isolated large cardiac thrombus as a rare presenting sign for EGPA and underscores current complicated strategy to diagnose EGPA. Of note, this clinical challenge was mostly caused by inchoate comprehension of hypereosinophilia-related disorders.

Churg-Strauss syndrome associated with antiphospholipid antibodies in a patient with retinal vasculitis. / Síndrome de Churg-Strauss asociado con anticuerpos antifosfolipídicos en un paciente con vasculitis retiniana.

CASE REPORT: We present the case of a 69-year-old woman with unilateral retinal vasculitis. Investigations showed asthma, rhinosinusitis, nasal polyposis, peripheral blood eosinophilia, increased sedimentation rate, proteinuria, and antiphospholipid antibodies. Anti-neutrophil cytoplasmic antibodies (ANCA) were negative. DISCUSSION: Although her anti-neutrophil cytoplasmatic antibody (ANCA) status was negative, taking into account the other clinical and laboratory features, retinal vasculitis was thought to be an ocular manifestation of Churg-Strauss syndrome. Treatment was started with high-dose corticosteroids and anticoagulant therapy.

Gynecological involvement in eosinophilic granulomatosis with polyangiitis.

Gynceological involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides is rare. We describe a case of ANCA-associated vasculitis in an elderly woman presenting with fevers, cough and a rash. Further investigations revealed vasculitic involvement of the ovaries, fallopian tubes, uterus and omentum with an eosinophil-rich infiltrate.

Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Long-Term Followup of a Multicenter Cohort of 101 Patients With Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss).

OBJECTIVE: To assess the long-term outcome in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA). METHODS: A total of 101 patients fulfilling the American College of Rheumatology criteria for EGPA were included between 1990 and 2011. Clinical features, antineutrophil cytoplasm autoantibodies (ANCAs), and Five-Factors Score (FFS) were assessed at diagnosis. Overall and cumulative survival rates, relapse-free survival, and sequelae were studied based on ANCA status and FFS. RESULTS: The rate of cardiomyopathy did not differ according to ANCA status. A total of 79.6% of patients achieved first remission, but 81.1% relapsed. ANCA-positive patients did not relapse more frequently but exhibited more severe disease with mononeuritis (P = 0.0004) and renal involvement (P = 0.02). Being Italian was the only prognostic factor associated with a higher relapse-free survival (P = 0.01), thanks to a longer maintenance of immunosuppressive drugs, suggesting the need for prolonged low-dose corticosteroids. Overall, survival reached 93.1% after a median followup of 6 years. No factor was associated with mortality, but patients over age 65 years with cardiomyopathy or ANCA positivity had more serious outcomes. Sequelae affected 83.2% of patients. Ear, nose, and throat (ENT) involvement was a protective factor for renal (P = 0.04) and cardiac (P = 0.03) morbidity. ANCA positivity was correlated with chronic kidney disease (P = 0.03) and chronic neurologic disability (P = 0.02). CONCLUSION: The actual challenges of EGPA management concern morbidity prevention and quality of life improvement. Long-term corticosteroid treatment appears to reduce relapse risk. ENT involvement is associated with less renal and cardiac morbidity. ANCA positivity predicts renal and neurologic damage.