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Gary S Hoffman - One of the best experts on this subject based on the ideXlab platform.

  • immunoglobulin ig m antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis
    Clinical and Experimental Immunology, 2017
    Co-Authors: Jeremy Clain, Gary S Hoffman, Carol A Langford, Cees G M Kallenberg, P Merkel, John H Stone, Amber M Hummel, Fernando C Fervenza, W J Mccune, Paul A Monach
    Abstract:

    Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

  • myeloperoxidase antineutrophil cytoplasmic antibody anca positive and anca negative patients with granulomatosis with polyangiitis wegener s distinct patient subsets
    Arthritis & Rheumatism, 2016
    Co-Authors: Eli M Miloslavsky, Gary S Hoffman, Hyon K Choi, Peter A Merkel, Na Lu, Sebastian Unizony, Robert Spiera, Carol A Langford, Cees G M Kallenberg, William E St Clair
    Abstract:

    Objective. To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: antimyeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Results. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P <0.01), primarily because of a lower prevalence of renal involvement. Conclusion. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA.

  • myeloperoxidase anca positive and anca negative patients with granulomatosis with polyangiitis distinct patient subsets
    Arthritis & Rheumatism, 2016
    Co-Authors: Eli M Miloslavsky, Gary S Hoffman, Hyon K Choi, Sebastian Unizony, Robert Spiera, Carol A Langford, Cees G M Kallenberg, P Merkel, P Seo, E W St Clair
    Abstract:

    Objective To examine the impact of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis on demographic features, disease manifestations, and clinical outcomes. We focused on patients that account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO) ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (GPA). Methods Pooled analysis of the Wegener's Granlomatosis Etanercept Trial (WGET) and the Rituximab in AAV (RAVE) trial comparing MPO-ANCA+ GPA and ANCA-negative GPA patients to proteinase 3 (PR3) ANCA+ GPA and MPO-ANCA+ microscopic polyangiitis (MPA) patients. Results Of the 365 patients analyzed, 273 (75%) had PR3-ANCA+ GPA, 33 (9%) had MPO-ANCA+ GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA+ MPA. MPO-ANCA+ GPA patients were younger at diagnosis compared to MPO-ANCA+ MPA patients (53 versus 61 years, P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA+ GPA patients. Relapse was more frequent in MPO-ANCA+ GPA patients than in patients with MPO-ANCA+ MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower BVAS/WG scores at trial entry than PR3-ANCA+ patients with GPA (4.5 versus 7.7, P<0.01), primarily because of a lower prevalence of renal involvement. Conclusion We were unable to demonstrate important clinical differences between MPO-ANCA+ and PR3-ANCA+ patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV. This article is protected by copyright. All rights reserved.

  • sat0370 antineutrophil cytoplasmic antibody anca type and body mass index in anca associated vasculitis
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Zachary S Wallace, Gary S Hoffman, Paul A Monach, Robert Spiera, Carol A Langford, P Merkel, P Seo, Ulrich Specks, Cgm Kallenberg, B St Clair
    Abstract:

    Background Recent studies have highlighted important phenotypic, genetic, and treatment differences between PR3- and MPO-ANCA+ ANCA-associated vasculitis (AAV) patients 1,2 . No study has evaluated differences in body mass index (BMI) between the PR3- and MPO-ANCA+ AAV subtypes. Objectives We sought to evaluate whether differences in BMI exist between patients with active PR3-ANCA+ and MPO-ANCA+ AAV using data from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial 3 . Methods We analyzed AAV patients who were either anti-proteinase 3 (PR3) antibody+ or anti-myeloperoxidase (MPO) antibody+ from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial. In univariate analyses, we compared the BMI/weight of PR3- and MPO-ANCA+ AAV patients at enrollment, using linear regression to adjust for age, gender, glucocorticoids prior to enrollment, relapsing disease at baseline, and baseline disease activity. We used an analysis of response profile to evaluate trends in BMI and weight by ANCA type, adjusted for the above confounders as well as cumulative steroid dosing during the trial and flares during the trial. Results Three fourths of the patients were PR3+ (147, 75%). PR3-ANCA+ patients had a higher BMI at baseline compared to MPO-ANCA+ patients (29.6±6.6 vs. 27.2 ± 5.3; P=0.01); the same was true for weight differences (89.3 ±22kg vs. 77.2 ± 16.0kg, respectively, P 2 (±1.1) higher than MPO-ANCA+ patients) remained significant (P=0.047 for BMI and 0.04 for weight, respectively) after accounting for confounders. The difference in weight between PR3-ANCA+ and MPO-ANCA+ patients remained stable during the study (P=0.3). Conclusions PR3-ANCA+ patients have a significantly higher BMI than MPO-ANCA+ patients, even after adjustment for important potential confounders. Our findings may have important implications for our understanding of AAV pathogenesis, its relationship to metabolic pathways, and the management of AAV. References Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: A meta-analysis. Ann Rheum Dis. 2015. doi: 10.1136/annrheumdis-2015-207601. Hilhorst M, van Paassen P, Tervaert JW, Limburg Renal Registry. Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am Soc Nephrol. 2015;26(10):2314–2327. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232. Disclosure of Interest None declared

  • allosteric modulation of proteinase 3 activity by anti neutrophil cytoplasmic antibodies in granulomatosis with polyangiitis
    Journal of Autoimmunity, 2015
    Co-Authors: Lisa C Hinkofer, Gary S Hoffman, P Merkel, John H Stone, Amber M Hummel, Robert E F Spiera, William St Clair, Joseph W Mccune, John C Davis
    Abstract:

    Anti-neutrophil cytoplasmic antibodies (ANCA) with proteinase 3 (PR3) specificity are a useful laboratory biomarker for the diagnosis of Granulomatosis with Polyangiitis (GPA) and are believed to be implicated in the pathogenesis. It has been repeatedly suggested that disease activity of GPA is more closely related to the appearance and rise of PR3-inhibiting ANCA than to an increase of total ANCA. Previous studies on a limited number of patient samples, however, have yielded inconclusive results. To overcome the previous methodological limitations, we established a new ultrasensitive method to quantify the inhibitory capacity of PR3-ANCA using small volumes of plasma from patients with GPA. A large collection of longitudinally-collected samples from the Wegener Granulomatosis Etanercept Trial (WGET) became available to us to determine the functional effects of ANCA on PR3 in comparison to clinical disease manifestations. In these patient samples we not only detected PR3-ANCA with inhibitory capacity, but also PR3-ANCA with enhancing effects on PR3 activity. However no correlation of these activity-modulating PR3-ANCA with disease activity at either the time of enrollment or over the course of disease was found. Only patients with pulmonary involvement, especially patients with nodule formation in the respiratory tract, showed a slight, but not significant, decrease of inhibitory capacity. Epitope mapping of the activity-modulating PR3-ANCA revealed a binding on the active site surface of PR3. Yet these ANCA were able to bind to PR3 with an occupied active site cleft, indicating an allosteric mechanism of inhibition. The recently described signal ratio between the MCPR3-3 and MCPR3-2 capture ELISA was consistent with the binding of activity-modulating ANCA to the active site surface. Evidence for a shared epitope between activity-modulating PR3-ANCA and MCPR3-7, however, was very limited, suggesting that a majority of PR3-ANCA species do not inhibit PR3 by the same mechanism as previously reported for MCPR3-7.

Ronald J Falk - One of the best experts on this subject based on the ideXlab platform.

  • immunoglobulins g from patients with anca associated vasculitis are atypically glycosylated in both the fc and fab regions and the relation to disease activity
    PLOS ONE, 2019
    Co-Authors: Jacob J Hess, Candace D Henderson, Patrick H Nachman, Olivier M Lardinois, Caroline J Poulton, Charles J Jennette, Leesa J. Deterding, Ronald J Falk
    Abstract:

    Background Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (PR3) are pathogenic in ANCA-associated vasculitis (AAV). The respective role of IgG Fc and Fab glycosylation in mediating ANCA pathogenicity is incompletely understood. Herein we investigate in detail the changes in Fc and Fab glycosylation in MPO-ANCA and Pr3-ANCA and examine the association of glycosylation aberrancies with disease activity. Methodology Total IgG was isolated from serum or plasma of a cohort of 30 patients with AAV (14 MPO-ANCA; 16 PR3-ANCA), and 19 healthy control subjects. Anti-MPO specific IgG was affinity-purified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis. We used lectin binding assays, liquid chromatography, and mass spectrometry-based methods to analyze Fc and Fab glycosylation, the degree of sialylation of Fc and Fab fragments and to determine the exact localization of N-glycans on Fc and Fab fragments. Principal findings IgG1 Fc glycosylation of total IgG was significantly reduced in patients with active AAV compared to controls. Clinical remission was associated with complete glycan normalization for PR3-ANCA patients but not for MPO-ANCA patients. Fc-glycosylation of anti-MPO specific IgG was similar to total IgG purified from plasma. A major fraction of anti-MPO specific IgG harbor extensive glycosylation within the variable domain on the Fab portion. Conclusions/Significance Significant differences exist between MPO and PR3-ANCA regarding the changes in amounts and types of glycans on Fc fragment and the association with disease activity. These differences may contribute to significant clinical difference in the disease course observed between the two diseases.

  • classification of antineutrophil cytoplasmic autoantibody vasculitides the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis
    Arthritis & Rheumatism, 2012
    Co-Authors: Sofia Lionaki, Patrick H Nachman, Charles J Jennette, Susan L Hogan, Charles J Jennette, Elizabeth R Blyth, Brent J A, Ronald J Falk
    Abstract:

    The name of a disease should be informative about clinical and pathologic phenotypes, etiology and pathogenesis (when known), natural history and response to therapy. It should permit the differentiation of similar diseases that have different outcomes. Optimally, the name of a disease should reflect its underlying etiology. In 1994, the Chapel Hill Consensus Conference (CHCC) aimed to standardize nomenclature and definitions for vasculitis, including microscopic polyangiitis, Wegener’s granulomatosis, Churg Strauss syndrome, and polyarteritis nodosa.1 In 2007, the European Medicines Agency (EMA) classification system2 proposed the same disease names but different definitions that refined and expanded the 1990 American College of Rheumatology classification system.3 Since that time, granulomatosis with polyangiitis (GPA) has been proposed as an alternative term for Wegener’s granulomatosis, and will be used in place of Wegener’s granulomatosis for the remainder of this article.4 The Chapel Hill nomenclature was meant to provide disease definitions. Neither the CHCC nor EMA classification system provides diagnostic criteria for practicing physicians to discriminate microscopic polyangiitis (MPA) from GPA. The advent of widespread anti-neutrophil cytoplasmic antibody (ANCA) testing and accumulating evidence that ANCA may participate in the cause of small vessel vasculitis5 have spawned the terms ANCA associated vasculitis, ANCA vasculitis or ANCA disease as overarching terms for MPA, GPA and Kidney Limited Disease (KLD) that aid patients and clinicians in therapeutic decision-making. This approach has substantial value, yet may mask real differences in disease phenotype and prognosis unless the ANCA specificity is included in the diagnosis. We sought to evaluate the utility of three classification systems in predicting the outcomes of treatment resistance, disease relapse, end stage kidney disease (ESKD) and death in a cohort of ANCA vasculitis patients. The classification systems compared for this project were a system based on the Chapel Hill Consensus Conference (CHCC) definitions,1 the European Medicines Agency (EMA) classification system,2 and classification based on ANCA serologic specificity. We hypothesized that ANCA specificity that is anti-proteinase 3 (PR3) antibodies (PR3-ANCA) versus anti-myeloperoxidase (MPO) antibodies (MPO-ANCA), would provide a more useful classification system in distinguishing both clinical phenotype and prognosis in ANCA vasculitis than the CHCC or EMA systems alone. We also studied the added value of appending the ANCA specificity to the CHCC categories.

  • anti myeloperoxidase autoantibodies react with native but not denatured myeloperoxidase
    Clinical and Experimental Immunology, 2008
    Co-Authors: Ronald J Falk, Regina S Terrell, M Becker, J. Charles Jennette
    Abstract:

    We wondered whether anti-myeloperoxidase (MPO) autoantibodies (MPO-ANCA) found in patients with systemic vasculitis react with a conformational epitope or epitopes on the MPO molecule. Sera from 15 human MPO-ANCA, and a polyclonal and a monoclonal anti-MPO antibodies were reacted with MPO in native and denatured states. Human MPO-ANCA and mouse monoclonal anti-MPO reacted with native MPO, and a 120-kD band representing the MPO hologenzyme, but not with denatured MPO fragments; however, MPO-ANCA and mouse anti-MPO did not demonstrate competitive inhibition of binding to MPO. Polyclonal rabbit anti-MPO reacted with both native and denatured MPO. All MPO-ANCA tested showed the same patterns of reactivity with native and denatured MPO in dot blot and Western blot analyses. Both polyclonal and monoclonal anti-MPO antibodies inhibited MPO's protein iodination by over 90%, whereas MPO-ANCA IgGs, normal IgGs and disease control IgGs did not. These data suggest that (i) MPO-ANCA interact with a conformational epitope on the MPO molecule; and (ii) MPO-ANCA from different patients have similar reactivity with native versus denatured MPO.

  • association between thyroid disease and its treatment with anca small vessel vasculitis a case control study
    Nephrology Dialysis Transplantation, 2007
    Co-Authors: Sofia Lionaki, Charles J Jennette, Ronald J Falk, Susan L Hogan, Melanie S Joy, Hyunsook Chin, Patrick H Nachman
    Abstract:

    Background. Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)associated small-vessel vasculitis (ANCA SVV) with use of anti-thyroid agents, but an association with thyroid disease in general has not been described. This association was evaluated in a southeastern US population-based case–control study. Methods. Cases (n ¼ 158) had ANCA SVV with biopsy-proven glomerular involvement. Controls (n ¼ 99) were frequency matched by age, gender and state. Use of drugs and comorbidities prior to diagnosis of ANCA SVV were assessed by telephone interview. Information on medications used for thyroid conditions was available in a subset of cases (n ¼ 129). Logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Estimates among females were also of interest. Results. History of thyroid disease was reported in 31 cases (20%) and 7 controls (7%) (OR ¼ 3.7; 95% CI 1.5–9.2; P ¼ 0.005); among females 25/65 (38%) cases and 5/53 (9%) controls (OR ¼ 5.6; 95% CI 1.9–16.8; P ¼ 0.002). Use of anti-thyroid agents was reported in 2 cases and 0 controls (OR not calculable). Among cases, myeloperoxidase (MPO)-ANCA was more common (86%) than proteinase 3 (PR3)-ANCA in those with a history of thyroid disease than those without (53%) (P ¼ 0.007). Conclusions. Thyroid disease was associated with ANCA SVV, especially among women, and was most frequently associated with MPO-ANCA. The specific diagnosis and detailed clinical history of thyroid disease were not known; a limitation of the study. Use of anti-thyroid agents was uncommon. The association of thyroid disease with ANCA SVV may reflect a propensity for autoimmune disease.

  • alternative complement pathway in the pathogenesis of disease mediated by anti neutrophil cytoplasmic autoantibodies
    American Journal of Pathology, 2007
    Co-Authors: Hong Xiao, Ronald J Falk, Adrian Schreiber, Peter Heeringa, Charles J Jennette
    Abstract:

    Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.

P Merkel - One of the best experts on this subject based on the ideXlab platform.

  • clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3 in anca associated vasculitis
    Frontiers in Immunology, 2020
    Co-Authors: Carol A Langford, P Merkel, Gwen Thompson, Lynn Fussner, Amber M Hummel, Darrell R Schroeder, Francisco Silva, Melissa R Snyder, Paul A Monach
    Abstract:

    Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.

  • anca associated vasculitis
    Nature Reviews Disease Primers, 2020
    Co-Authors: Richard A Kitching, David Jayne, Paul A Lyons, P Merkel, Hansjoachim Anders, Neil Basu, Elisabeth Brouwer, Jennifer Gordon, Joyce Kullman, Caroline O S Savage
    Abstract:

    The majority of patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) have antineu-trophil cytoplasmic antibodies (ANCA) in their serum. This is particularly true of patients with “disseminated” disease, the great majority of whom are ANCA positive. WG and MPA are often termed “ANCA-associated vasculitides” (AAV), even though not all patients with these conditions have ANCA. The Churg—Strauss syndrome, another disorder classified as an AAV, is discussed in Chap. 23. Multiple antibodies may lead to positive immunofluores-cence testing for ANCA in either perinuclear (P-ANCA) or cytoplasmic (C-ANCA) patterns. However, only antibodies to myeloperoxidase (MPO) and proteinase-3 (PR3) are associated with the A AV. Antibodies directed against PR3 and MPO are termed PR3-ANCA and MPO-ANCA, respectively. WG may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. A host of ocular lesions may occur in the A AV, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor. Most of these lesions are more common in WG than in MPA. Lung disease in the AAV ranges from nodular lesions with a tendency to cavitate (in WG), to interstitial lung disease (MPA), and to alveolar hemorrhage (both WG and MPA). Segmental, necrotizing glomerulonephritis commonly accompanies the AAV. Because of the paucity of immunoreactants such as immunoglobulins and complement components in kidney biopsies relative to the biopsies from patients with immune complex-mediated glomerulonephritis, the glomerulonephritis of the A AV is termed “pauci-immune.”

  • immunoglobulin ig m antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis
    Clinical and Experimental Immunology, 2017
    Co-Authors: Jeremy Clain, Gary S Hoffman, Carol A Langford, Cees G M Kallenberg, P Merkel, John H Stone, Amber M Hummel, Fernando C Fervenza, W J Mccune, Paul A Monach
    Abstract:

    Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

  • myeloperoxidase anca positive and anca negative patients with granulomatosis with polyangiitis distinct patient subsets
    Arthritis & Rheumatism, 2016
    Co-Authors: Eli M Miloslavsky, Gary S Hoffman, Hyon K Choi, Sebastian Unizony, Robert Spiera, Carol A Langford, Cees G M Kallenberg, P Merkel, P Seo, E W St Clair
    Abstract:

    Objective To examine the impact of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis on demographic features, disease manifestations, and clinical outcomes. We focused on patients that account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO) ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (GPA). Methods Pooled analysis of the Wegener's Granlomatosis Etanercept Trial (WGET) and the Rituximab in AAV (RAVE) trial comparing MPO-ANCA+ GPA and ANCA-negative GPA patients to proteinase 3 (PR3) ANCA+ GPA and MPO-ANCA+ microscopic polyangiitis (MPA) patients. Results Of the 365 patients analyzed, 273 (75%) had PR3-ANCA+ GPA, 33 (9%) had MPO-ANCA+ GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA+ MPA. MPO-ANCA+ GPA patients were younger at diagnosis compared to MPO-ANCA+ MPA patients (53 versus 61 years, P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA+ GPA patients. Relapse was more frequent in MPO-ANCA+ GPA patients than in patients with MPO-ANCA+ MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower BVAS/WG scores at trial entry than PR3-ANCA+ patients with GPA (4.5 versus 7.7, P<0.01), primarily because of a lower prevalence of renal involvement. Conclusion We were unable to demonstrate important clinical differences between MPO-ANCA+ and PR3-ANCA+ patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV. This article is protected by copyright. All rights reserved.

  • sat0370 antineutrophil cytoplasmic antibody anca type and body mass index in anca associated vasculitis
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Zachary S Wallace, Gary S Hoffman, Paul A Monach, Robert Spiera, Carol A Langford, P Merkel, P Seo, Ulrich Specks, Cgm Kallenberg, B St Clair
    Abstract:

    Background Recent studies have highlighted important phenotypic, genetic, and treatment differences between PR3- and MPO-ANCA+ ANCA-associated vasculitis (AAV) patients 1,2 . No study has evaluated differences in body mass index (BMI) between the PR3- and MPO-ANCA+ AAV subtypes. Objectives We sought to evaluate whether differences in BMI exist between patients with active PR3-ANCA+ and MPO-ANCA+ AAV using data from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial 3 . Methods We analyzed AAV patients who were either anti-proteinase 3 (PR3) antibody+ or anti-myeloperoxidase (MPO) antibody+ from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial. In univariate analyses, we compared the BMI/weight of PR3- and MPO-ANCA+ AAV patients at enrollment, using linear regression to adjust for age, gender, glucocorticoids prior to enrollment, relapsing disease at baseline, and baseline disease activity. We used an analysis of response profile to evaluate trends in BMI and weight by ANCA type, adjusted for the above confounders as well as cumulative steroid dosing during the trial and flares during the trial. Results Three fourths of the patients were PR3+ (147, 75%). PR3-ANCA+ patients had a higher BMI at baseline compared to MPO-ANCA+ patients (29.6±6.6 vs. 27.2 ± 5.3; P=0.01); the same was true for weight differences (89.3 ±22kg vs. 77.2 ± 16.0kg, respectively, P 2 (±1.1) higher than MPO-ANCA+ patients) remained significant (P=0.047 for BMI and 0.04 for weight, respectively) after accounting for confounders. The difference in weight between PR3-ANCA+ and MPO-ANCA+ patients remained stable during the study (P=0.3). Conclusions PR3-ANCA+ patients have a significantly higher BMI than MPO-ANCA+ patients, even after adjustment for important potential confounders. Our findings may have important implications for our understanding of AAV pathogenesis, its relationship to metabolic pathways, and the management of AAV. References Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: A meta-analysis. Ann Rheum Dis. 2015. doi: 10.1136/annrheumdis-2015-207601. Hilhorst M, van Paassen P, Tervaert JW, Limburg Renal Registry. Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am Soc Nephrol. 2015;26(10):2314–2327. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232. Disclosure of Interest None declared

Charles J Jennette - One of the best experts on this subject based on the ideXlab platform.

  • anca glomerulonephritis and vasculitis
    Clinical Journal of The American Society of Nephrology, 2017
    Co-Authors: Charles J Jennette, Patrick H Nachman
    Abstract:

    ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg–Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. There is clinical, in vitro, and animal model evidence that ANCAs cause disease by activating neutrophils to attack small vessels. Immunomodulatory and immunosuppressive therapies are used to induce remission, maintain remission, and treat relapses. Over recent years, there have been major advances in optimizing treatment by minimizing toxic therapy and utilizing more targeted therapy.

  • classification of antineutrophil cytoplasmic autoantibody vasculitides the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis
    Arthritis & Rheumatism, 2012
    Co-Authors: Sofia Lionaki, Patrick H Nachman, Charles J Jennette, Susan L Hogan, Charles J Jennette, Elizabeth R Blyth, Brent J A, Ronald J Falk
    Abstract:

    The name of a disease should be informative about clinical and pathologic phenotypes, etiology and pathogenesis (when known), natural history and response to therapy. It should permit the differentiation of similar diseases that have different outcomes. Optimally, the name of a disease should reflect its underlying etiology. In 1994, the Chapel Hill Consensus Conference (CHCC) aimed to standardize nomenclature and definitions for vasculitis, including microscopic polyangiitis, Wegener’s granulomatosis, Churg Strauss syndrome, and polyarteritis nodosa.1 In 2007, the European Medicines Agency (EMA) classification system2 proposed the same disease names but different definitions that refined and expanded the 1990 American College of Rheumatology classification system.3 Since that time, granulomatosis with polyangiitis (GPA) has been proposed as an alternative term for Wegener’s granulomatosis, and will be used in place of Wegener’s granulomatosis for the remainder of this article.4 The Chapel Hill nomenclature was meant to provide disease definitions. Neither the CHCC nor EMA classification system provides diagnostic criteria for practicing physicians to discriminate microscopic polyangiitis (MPA) from GPA. The advent of widespread anti-neutrophil cytoplasmic antibody (ANCA) testing and accumulating evidence that ANCA may participate in the cause of small vessel vasculitis5 have spawned the terms ANCA associated vasculitis, ANCA vasculitis or ANCA disease as overarching terms for MPA, GPA and Kidney Limited Disease (KLD) that aid patients and clinicians in therapeutic decision-making. This approach has substantial value, yet may mask real differences in disease phenotype and prognosis unless the ANCA specificity is included in the diagnosis. We sought to evaluate the utility of three classification systems in predicting the outcomes of treatment resistance, disease relapse, end stage kidney disease (ESKD) and death in a cohort of ANCA vasculitis patients. The classification systems compared for this project were a system based on the Chapel Hill Consensus Conference (CHCC) definitions,1 the European Medicines Agency (EMA) classification system,2 and classification based on ANCA serologic specificity. We hypothesized that ANCA specificity that is anti-proteinase 3 (PR3) antibodies (PR3-ANCA) versus anti-myeloperoxidase (MPO) antibodies (MPO-ANCA), would provide a more useful classification system in distinguishing both clinical phenotype and prognosis in ANCA vasculitis than the CHCC or EMA systems alone. We also studied the added value of appending the ANCA specificity to the CHCC categories.

  • alternative complement pathway in the pathogenesis of disease mediated by anti neutrophil cytoplasmic autoantibodies
    American Journal of Pathology, 2007
    Co-Authors: Hong Xiao, Ronald J Falk, Adrian Schreiber, Peter Heeringa, Charles J Jennette
    Abstract:

    Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.

  • addendum to the international consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies quality control guidelines comments and recommendations for testing in other autoimmune diseases
    American Journal of Clinical Pathology, 2003
    Co-Authors: Judy Savige, Charles D Pusey, Charles J Jennette, Wendy Pollock, Wayne Dimech, Marvin J Fritzler, James A Goeken, Chris E Hagen, Rob Mcevoy, Michelle Trevisin
    Abstract:

    Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in Wegener granulomatosis, microscopic polyangiitis and its renal-limited variant (pauci-immune crescentic glomerulonephritis), and Churg-Strauss syndrome. The International Consensus Statement on testing and reporting of ANCA states that ANCA are demonstrated most readily in these conditions by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 or myeloperoxidase. The group that produced the International Consensus Statement has developed guidelines for the corresponding quality control activities, examples of comments for various IIF patterns and ELISA results, and recommendations for ANCA testing when inflammatory bowel disease and other nonvasculitic ANCA-associated autoimmune diseases are suspected.

Carol A Langford - One of the best experts on this subject based on the ideXlab platform.

  • clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3 in anca associated vasculitis
    Frontiers in Immunology, 2020
    Co-Authors: Carol A Langford, P Merkel, Gwen Thompson, Lynn Fussner, Amber M Hummel, Darrell R Schroeder, Francisco Silva, Melissa R Snyder, Paul A Monach
    Abstract:

    Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.

  • immunoglobulin ig m antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis
    Clinical and Experimental Immunology, 2017
    Co-Authors: Jeremy Clain, Gary S Hoffman, Carol A Langford, Cees G M Kallenberg, P Merkel, John H Stone, Amber M Hummel, Fernando C Fervenza, W J Mccune, Paul A Monach
    Abstract:

    Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3–ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

  • myeloperoxidase antineutrophil cytoplasmic antibody anca positive and anca negative patients with granulomatosis with polyangiitis wegener s distinct patient subsets
    Arthritis & Rheumatism, 2016
    Co-Authors: Eli M Miloslavsky, Gary S Hoffman, Hyon K Choi, Peter A Merkel, Na Lu, Sebastian Unizony, Robert Spiera, Carol A Langford, Cees G M Kallenberg, William E St Clair
    Abstract:

    Objective. To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: antimyeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). Methods. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Results. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P <0.01), primarily because of a lower prevalence of renal involvement. Conclusion. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA.

  • myeloperoxidase anca positive and anca negative patients with granulomatosis with polyangiitis distinct patient subsets
    Arthritis & Rheumatism, 2016
    Co-Authors: Eli M Miloslavsky, Gary S Hoffman, Hyon K Choi, Sebastian Unizony, Robert Spiera, Carol A Langford, Cees G M Kallenberg, P Merkel, P Seo, E W St Clair
    Abstract:

    Objective To examine the impact of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis on demographic features, disease manifestations, and clinical outcomes. We focused on patients that account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO) ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (GPA). Methods Pooled analysis of the Wegener's Granlomatosis Etanercept Trial (WGET) and the Rituximab in AAV (RAVE) trial comparing MPO-ANCA+ GPA and ANCA-negative GPA patients to proteinase 3 (PR3) ANCA+ GPA and MPO-ANCA+ microscopic polyangiitis (MPA) patients. Results Of the 365 patients analyzed, 273 (75%) had PR3-ANCA+ GPA, 33 (9%) had MPO-ANCA+ GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA+ MPA. MPO-ANCA+ GPA patients were younger at diagnosis compared to MPO-ANCA+ MPA patients (53 versus 61 years, P=0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA+ GPA patients. Relapse was more frequent in MPO-ANCA+ GPA patients than in patients with MPO-ANCA+ MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower BVAS/WG scores at trial entry than PR3-ANCA+ patients with GPA (4.5 versus 7.7, P<0.01), primarily because of a lower prevalence of renal involvement. Conclusion We were unable to demonstrate important clinical differences between MPO-ANCA+ and PR3-ANCA+ patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV. This article is protected by copyright. All rights reserved.

  • sat0370 antineutrophil cytoplasmic antibody anca type and body mass index in anca associated vasculitis
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Zachary S Wallace, Gary S Hoffman, Paul A Monach, Robert Spiera, Carol A Langford, P Merkel, P Seo, Ulrich Specks, Cgm Kallenberg, B St Clair
    Abstract:

    Background Recent studies have highlighted important phenotypic, genetic, and treatment differences between PR3- and MPO-ANCA+ ANCA-associated vasculitis (AAV) patients 1,2 . No study has evaluated differences in body mass index (BMI) between the PR3- and MPO-ANCA+ AAV subtypes. Objectives We sought to evaluate whether differences in BMI exist between patients with active PR3-ANCA+ and MPO-ANCA+ AAV using data from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial 3 . Methods We analyzed AAV patients who were either anti-proteinase 3 (PR3) antibody+ or anti-myeloperoxidase (MPO) antibody+ from the Rituximab in ANCA-Associated Vasculitis (RAVE) trial. In univariate analyses, we compared the BMI/weight of PR3- and MPO-ANCA+ AAV patients at enrollment, using linear regression to adjust for age, gender, glucocorticoids prior to enrollment, relapsing disease at baseline, and baseline disease activity. We used an analysis of response profile to evaluate trends in BMI and weight by ANCA type, adjusted for the above confounders as well as cumulative steroid dosing during the trial and flares during the trial. Results Three fourths of the patients were PR3+ (147, 75%). PR3-ANCA+ patients had a higher BMI at baseline compared to MPO-ANCA+ patients (29.6±6.6 vs. 27.2 ± 5.3; P=0.01); the same was true for weight differences (89.3 ±22kg vs. 77.2 ± 16.0kg, respectively, P 2 (±1.1) higher than MPO-ANCA+ patients) remained significant (P=0.047 for BMI and 0.04 for weight, respectively) after accounting for confounders. The difference in weight between PR3-ANCA+ and MPO-ANCA+ patients remained stable during the study (P=0.3). Conclusions PR3-ANCA+ patients have a significantly higher BMI than MPO-ANCA+ patients, even after adjustment for important potential confounders. Our findings may have important implications for our understanding of AAV pathogenesis, its relationship to metabolic pathways, and the management of AAV. References Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: A meta-analysis. Ann Rheum Dis. 2015. doi: 10.1136/annrheumdis-2015-207601. Hilhorst M, van Paassen P, Tervaert JW, Limburg Renal Registry. Proteinase 3-ANCA vasculitis versus myeloperoxidase-ANCA vasculitis. J Am Soc Nephrol. 2015;26(10):2314–2327. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232. Disclosure of Interest None declared