Mass Balance and Metabolic Profiling of Avacopan, a Selective C5a Receptor 1 Antagonist, in Healthy Humans.

With Complements from ANCA Mice

47-Year-Old Woman With Bilateral Flank Pain

BackgroundIn 2022 the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) presented new classification criteria for the three subsets of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis...

BackgroundAnti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life- or organ-threatening condition in which patients experience severe inflammation of small- to medium-sized blood vessels. Clinical relapses are common in ANCA-associated vasculitis...

Comparative proteomic analysis of neutrophils from patients with microscopic polyangiitis and granulomatosis with polyangiitis

Background/Purpose:Comparisons of pediatric ANCA‐associated vasculitis subtypes (AAV) are limited by the paucity of reported cases, standardized definitions, and overlapping classification criteria. Published work from ARChiVe (A Registry for Childhood Vasculitis) demonstrated modifications of validated classification algorithms applied to pediatric patients with AAV can classify each patient to mutually exclusive diagnostic categories. We compared presenting features of children with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) classified according to this methodology.Methods:A pediatric modification of the European Medicines Agency (EMA) algorithm for classifying AAV and polyarteritis nodosa (incorporating the EULAR/PRINTO/PRES pediatric classification criteria for GPA) was applied to patients in ARChiVe censored to April 2012. We compared characteristics of patients classified as having MPA and GPA. STATA (Statcorp, 2013) was used to calculate frequencies, percentages, and chi‐squared with fisher's exact for categorical variables and means, standard deviations, and t‐tests for continuous variables.Results:One hundred fifty‐two of 227 children in ARChiVe met criteria for diagnosis of MPA (n = 22) or GPA (n = 130). Characteristics and presenting features are shown in Table . Children with MPA were younger at diagnosis (mean diff. 2.7y, p = <0.01). Renal involvement was predominant in both groups. Renal biopsies in 40% of both groups were consistent with pauci‐immune, necrotizing glomerulonephritis. Children with MPA had higher rates of nephrosis, renal failure requiring dialysis, and abnormal creatinine clearance (Table ). Upper and lower airway involvement was more prevalent among those with GPA largely in accordance with surrogate GPA features used to differentiate GPA and MPA in the EMA algorithm. The majority of patients presented with constitutional symptoms, however, other organ systems were less frequently involved. Most patients received combination therapy corticosteroids and cytoxan (64% MPA, 81% GPA) with additional plasmapheresis (29% MPA, 21% GPA), rituximab (14% MPA, 3% GPA) or methotrexate (7% MPA, 1% GPA). The remainder of children received combination corticosteroids and methotrexate or rituximab, without cytoxan (12% MPA, 11% GPA). A larger proportion of patients with MPA received antihypertensive agents and/or ACE inhibitors (64% vs 35%, p = 0.01). Characteristics & Presenting Clinical Features of children with microscopic polyangiitis or granulomatosis with polyangiitis in the ARChiVe cohort (n = 152) Algorithm‐derived diagnosis Characteristic/Feature MPA (n = 22) GPA (n = 130) p‐value Female, n(%) 15 (68) 83 (64) 0.81 Caucasian, n (%) 11 (50) 85 (66) 0.231 Age at diagnosis, yrs, mean (sd) 11.6 (5) 14.2 (3) <0.01* Median (range) 12.8 (9–15) 14.9 (4–19) Symptom duration prior to diagnosis, mos, mean (sd) 4.4 (9) 5.2 (10) 0.72 Median (range) 3.4 (0–35.8) 4.8 (0–66.8) MD‐assigned diagnosis (clinical diagnosis) MPA or isolated MPA 8 (36) 18 (14) 0.027* WG or limited WG 7 (32) 107 (82) <0.01* ANCA 3 (14) 1 (1) 0.01* Unclassified 4 (18) 4 (3) 0.02* General Features Fatigue 19 (86) 113 (87) 1.00 Fever 10 (46) 71 (55) 0.49 Weight loss 10 (46) 60 (46) 1.00 Renal 18 (82) 103 (79) 1.00 Hypertension 8 (36) 28 (22) 0.17 Hematuria and proteinuria with red blood cell casts 16 (73) 97 (75) 0.80 Nephrotic range proteinuria with edema 6 (27) 14 (11) 0.04* Renal failure requiring dialysis 7 (32) 17 (13) 0.05* Creatinine clearance >25% lower limit of normal 8 (89) 18 (36) <0.01* Biopsy‐proven glomerulonephritis 6 (27) 28 (22) 0.58 Pulmonary 9 (41) 105 (81) <0.01* Chronic cough 6 (27) 79 (61) <0.01* Shortness of breath 4 (18) 63 (49) 0.01* Hemoptysis/alveolar hemorrhage 3 (14) 54 (42) 0.02* Fixed pulmonary infiltrates ± cavitations, nodules 4 (18) 99 (76) <0.01* Head, Ear, Nose, & Throat 4 (18) 97 (75) <0.01* Bloody nasal discharge ± crusting 0 (0) 68 (52) <0.01* Chronic sinusitis, otitis, or mastoiditis 0 (0) 63 (48) <0.01* Subglottic involvement 0 (0) 16 (12) 0.13 Cranial bone ± cartilage destruction 0 (0) 10 (8) 0.36 Acute hearing loss 0 (0) 15 (12) 0.13 Red ± painful eye conditions 2 (9) 34 (26) Gastrointestinal/Abdominal 15 (68) 51 (39) 0.01* Chronic nausea 9 (41) 17 (13) <0.01* Skin 10 (45) 71 (55) 0.49 Musculoskeletal 80 (62) 14 (64) 1.00 Nervous System 35 (27) 6 (27) 1.00 Cardiovascular 9 (7) 1 (5) 1.00 ANCA Serology pANCA or anti‐MPO 14 (70) 35 (29) <0.01 cANCA or anti‐PR3 6 (30) 86 (71) <0.01Conclusion:Children with AAV had predominantly renal and constitutional manifestations. Younger age and a more severe renal disease phenotype may characterize MPA with patients requiring additional treatment for the consequences of kidney disease. The wide variations in time to diagnosis continue to suggest that pediatric AAV is poorly recognized. Ongoing biomarker‐driven studies may complement systems for subclassifying patients with AAV.

ANCA-associated renal vasculitis

Background:Classification of ANCA-associated vasculitis (AAV) has emerged in order to identify more homogenous subgroups of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). However, the exact value of classifying patients according to antibody specificity (proteinase 3 [PR3] or myeloperoxidase [MPO]) is still unclear.Objectives:To assess demographic, clinical and prognostic differences among subgroups of AAV patients, according to clinicopathological classification (GPAvs. MPA) and antibody specificity (PR3vs. MPO) in a single-centre cohort.Methods:A clinical retrospective (1990-2019) observational analysis was performed. Among all patients with ANCA positivity, we analysed patients with GPA and MPA diagnosed according to 2018 Draft Classification Criteria for AAV1, who were homogeneously treated and followed by the authors. Demographic, clinical and laboratory data, as well as disease outcomes, particularly BVAS, disease relapses and survival, were reviewed.Results:Among a total 140 patients with any form of AAV, 32 were excluded for a diagnosis of isolated interstitial lung disease (n=10), cocaine-induced AAV (n=3), ANCA negative or undetermined disease (n=16), atypical ANCA or double PR3/MPO positivity (n=3). Finally, 108 patients with MPA (n=66) or GPA (n=42) were included (83 MPO, 25 PR3). GPA was associated with PR3 in 55% and MPO 45% of patients. MPA was associated with MPO in 97% and PR3 in 3% of patients. GPA patients with PR3 or MPO presented with similar clinical features, disease extent and BVAS. However, compared with GPA/PR3, GPA/MPO were more frequently women (p=0.002). MPA patients presented more frequent with renal involvement (p=0.008) and GPA patients with ENT/ocular involvement (p<0.001). Patients with MPO were older (p=0.028) and more frequently women (p=0.001) than PR3 patients. When antibody specificity was compared, differences on organ-specific manifestations were less clear than between clinical phenotypes (GPA vs. MPA), and were only seen in ENT/ocular involvement (more frequent in PR3 than in MPO patients) and in muscle biopsies disclosing vasculitis (more frequent in MPO than in PR3 patients). GPA and PR3 patients presented more frequent relapsing disease than MPA and MPO patients, respectively (GPA 60% vs. MPA 36%; p=0.018 / PR3 60% vs. MPO 41%; p=0.094). While GPA tended to have a better survival rate than MPA patients (p=0.066) (Graph1), the MPO-associated disease (GPA or MPA) had clearly worse survival prognosis than PR3-AAV (p=0.008) (Graph2), similarly to what occurred in GPA-MPO (compared with GPA-PR3).Conclusion:A high proportion of GPA patients with MPO-ANCA (45%) is observed in our series. GPA is associated with a more frequent relapsing disease than MPA. MPA and presence of MPO were more frequent in females and older patients. Clinical features were similar in GPA patients with PR3 or MPO. The presence of MPO (in GPA or MPA) seems to be the main factor associated with mortality in AAV.Table 1.Symptomatology and ultrasound findings in the patients examined. PMR: Polymyalgia RheumaticaUltrasoundSymptomsCranial(n=17)PMR only(n=17)Non-specific symptoms (n=18)PMR (+) (n=7)PMR (-) (n=10)Temporal (+)7301Facial (+)2100Axilliary (+)0031

Clinical trials and observational studies have established cyclophosphamide (CY) or rituximab plus glucocorticoid (GC) as standard remission induction therapies in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, because these regimens are associated with serious adverse drug reactions, the development of drugs with novel mechanisms of actions are needed. Progress in basic and clinical research has identified novel candidate targeting molecules, including B-cell activating factor (BAF), C5a receptor, and interleukin-6. The combination of rituximab and BAF blockade in patients with MPA and GPA is under investigation in an effort to strike a better benefit-risk balance. Phase II clinical trials of avacopan (CCX168), an orally administered C5a receptor antagonist, have suggested a reduction in the dosage of concomitant GC or the replacement of GC in patients with MPA and GPA. The results from a currently ongoing phase III trial are awaited. Anecdotal case reports and an open-label pilot study have indicated the effectiveness of tocilizumab in patients with MPA and GPA. A randomized clinical trial comparing tocilizumab and intravenous CY in combination with GC is currently in progress. Molecular targeted therapy is expected to transform the treatment strategy for MPA and GPA to allow GC-free or at least less GC-dependent forms of therapy.

Background:In spite of significantly improved therapy during the last years, long-term morbidity and mortality has remained high in ANCA-associated vasculitis (AAV). The main causes of death within the first year...

BackgroundBoth microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils are thought to be involved in their pathology. Clinically, it is often difficult...

BackgroundAnti-B-cell therapy with rituximab (RTX) plays an important role in the induction and maintenance therapy of ANCA- associated vasculitis (AAV). Late-onset neutropenia (LON) has been reported following RTX therapy.ObjectivesBased on...

BackgroundThe epidemiological findings of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) differ geographically. Until now, there has been no study about the prevalence of AAV in Turkey.ObjectivesIn our study, we aimed to...

Background:In the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), neutrophils play a crucial role, serving as both the target cells attacked by ANCA and the main participating cells in...

BackgroundIn antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitis (AAV), involvement of complements, especially alternative pathway of complement, has been reported in researches using mouse models. In human, while some studies have identified...