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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies., Competing Interests: Declaration of interests AK reports being a site investigator in the ADVOCATE trial funded by ChemoCentryx (NCT02994927); received research support and consultancy fees from Otsuka and CSL Vifor; and received consultancy fees from Catalyst Biosciences, Walden Biosciences, GlaxoSmithKline, and Delta4. IMB consulted for Boehringer-Ingelheim, Novartis, Catalyst Biosciences, Toleranzia, Vera, and Hansa Biopharma; received educatonal grants from CSL Vifor; is the owner of BiPath; and is on the Board of Directors of the Renal Pathology Society. AB reports being a national principal investigator in the ADVOCATE trial funded by ChemoCentryx; and reports consultation fees and honoraria from AstraZeneca, Bayer, ChemoCentryx, Fresenius, MSD/Merck, and CSL Vifor. JHS reports being the co-principal investigator in the RAVE trial, an investigation of rituximab in ANCA-associated vasculitis funded by both the National Institute of Allergy and Infectious Diseases (NIAID) and Genentech; received funding from the National Institutes of Health (NIH)/NIAID (grant UM1AI144295) for an Autoimmunity Center of Excellence; reports consulting fees, payments, or honoraria from AbbVie, Amgen, Argenx, Bristol-Myers Squibb, Chemocentryx, Horizon Therapeutics, Kyverna Therapeutics, Novartis, PPD, Q32 Bio, Roche, Sana, Sanofi, Spruce Biosciences, Steritas, and Zenas BioPharma; chairs the scientific advisory board for Steritas (which licenses the Glucocorticoid Toxicity Index) but has no fiduciary role at the company; reports royalties from UpToDate; and JHS's hospital, the Massachusetts General Hospital, owns the intellectual property of the Glucocorticoid Toxicity Index. GMK reports no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3-targeting ANCAs (PR3-ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity., Methods: The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen for differential PR3-ANCA binding. A patient-derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation-free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments., Results: Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared to iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518., Conclusion: The preferential binding of PR3-ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches., (© 2022 American College of Rheumatology.)

BACKGROUNDBaseline expression of FCRL5, a marker of naive and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).METHODSA previously validated quantitative PCR-based (qPCR-based) platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299).RESULTSBaseline FCRL5 expression was significantly higher in patients achieving complete remission (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not cyclophosphamide-azathioprine (CYC/AZA). Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared with FCRL5lo subjects (84% versus 57% [P = 0.016], 68% versus 40% [P = 0.02], and 68% versus 29% [P = 0.0009], respectively).CONCLUSIONOur data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.FUNDINGThe analysis for this study was funded by Genentech Inc.

Objective: To examine the association between macrophage migration inhibitory factor (MIF) promoter polymorphisms and granulomatosis with polyangiitis (GPA) in human subjects, and to assess the role of MIF in a murine model of granulomatous vasculitis., Methods: The human study involved 1,077 patients with GPA and healthy controls whose serum was genotyped by capillary electrophoresis for the MIF -794 CATT 5-8 promoter microsatellite (rs5844572). MIF promoter, CATT-length-dependent gene expression in response to β-glucan was assessed by gene reporter assays. In mouse studies, granulomatous disease was induced by injection of Candida albicans β-glucan into wild-type (WT) or Mif-knockout (Mif-KO) C57BL/6 mice and C57BL/6 mice transgenically overexpressing Mif in lung epithelium (Mif lung-Tg2.1). Mice were treated with a neutralizing anti-MIF antibody and analyzed for the density of pulmonary granulomas, expression of inflammatory chemokines, and frequency of mortality., Results: The percentage of human subjects carrying >5 CATT repeats in each MIF allele (high genotypic MIF expressers) was 60.2% among patients with GPA and 53.9% among healthy controls (adjusted P = 0.049). In response to granulomatous stimulation, human MIF gene expression increased proportionally with CATT length. Mif lung-Tg2.1 mice exhibited more pulmonary granulomas than WT mice, which in turn showed more granulomas than Mif-KO mice. A significantly higher percentage of Mif lung-Tg2.1 mice, compared to Mif-KO or WT mice, died when injected with Candida albicans β-glucan, and treatment of these mice with an anti-MIF monoclonal antibody protected against a lethal outcome. Levels of MIF-dependent neutrophil/macrophage chemokines were elevated in the bronchoalveolar lavage fluid or plasma of Mif lung-Tg2.1 mice., Conclusion: Patients with GPA have an increased frequency of high MIF expression CATT alleles. Higher Mif expression increases the incidence of mortality and pulmonary granulomas in Mif lung-Tg2.1 mice, while anti-MIF treatment protects these mice against death. Blockade of MIF in high genotypic MIF expressers may therefore offer a selective pharmacologic therapy for GPA., (© 2018, American College of Rheumatology.)

Objective: To examine temporal trends in mortality rates in a large nationwide cohort of patients with end-stage renal disease (ESRD) due to granulomatosis with polyangiitis (Wegener's) (GPA-ESRD)., Methods: We identified cases of GPA-ESRD reported in the US Renal Data System between 1995 and 2014, using coding by nephrologists for the cause of ESRD. The cohort was divided into four 5-year subcohorts based on the year of onset of ESRD (1995-1999, 2000-2004, 2005-2009, and 2010-2014) to assess trends in mortality rates and hazard ratios (HRs) for overall death and cause-specific death, adjusting for potential confounders., Results: Between 1995 and 2014, there were 5,929 incident cases of GPA-ESRD. The mortality rate (incidence per 100 patient-years) declined from 19.0 in 1995-1999 to 15.3 in 2010-2014 (P for trend = 0.01). The multivariable-adjusted HR for mortality in the 2010-2014 cohort was 0.77 (95% confidence interval [95% CI] 0.66-0.90) (P for trend < 0.001 versus the 1995-1999 cohort). The corresponding cause-specific HRs for mortality, after accounting for competing risk, were 0.61 (95% CI 0.47-0.80) for CVD-related death and 0.42 (95% CI 0.28-0.63) for death due to infection (P for trend < 0.001)., Conclusion: In this study of nearly all patients in whom GPA-ESRD developed in the US over 2 decades, we observed significant improvements in mortality among GPA-ESRD patients. The number of cause-specific deaths due to CVD and the number due to infections declined significantly during the study period. These findings are encouraging and likely reflect improved management of both GPA and ESRD., (© 2018, American College of Rheumatology.)

Background: Renal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to granulomatosis with polyangiitis (GPA) is unknown., Methods: We identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure., Results: During the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06-0.16)., Discussion: Renal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population., Competing Interests: Competing interests: ZSW has received funding from a Scientist Development Award from the Rheumatology Research Foundation, a Fund for Medical Discovery Award from the Executive Committee on Research at Massachusetts General Hospital, and an NIH Loan Repayment Award., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity., Methods: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio., Results: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD., Conclusions: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Objective: Granulomatosis with polyangiitis (Wegener's) (GPA) is a type of antineutrophil cytoplasmic antibody-associated vasculitis that often entails severe end-organ damage and treatment-related complications that frequently lead to hospitalization and death. Nationwide trends in hospitalizations and in-hospital mortality over the past 2 decades are unknown and were evaluated in this study., Methods: Using the National Inpatient Sample, the largest all-payer inpatient database in the US, trends in hospitalizations with a discharge diagnosis of GPA (formerly Wegener's granulomatosis; International Classification of Disease, Ninth Revision, Clinical Modification code 446.4) between 1993 and 2011 were studied. Analyses were performed using hospital-level sampling weights to obtain US national estimates., Results: From 1993 to 2011, the annual hospitalization rate for patients with a principal diagnosis of GPA increased by 24%, from 5.1 to 6.3 per 1 million US persons (P < 0.0001 for trend); however, in-hospital deaths in this group declined by 73%, from 9.1% to 2.5% (P < 0.0001 for trend), resulting in a 66% net reduction in the annual in-hospital mortality rate. The median length of stay declined by 20%, from 6.9 days in 1993 to 5.5 days in 2011 (P = 0.0002 for trend). Infection was the most common principal discharge diagnosis when GPA was a secondary diagnosis, including among those who died during hospitalization., Conclusion: The findings from these nationally representative, contemporary inpatient data indicate that the in-hospital mortality of GPA has declined substantially over the past 2 decades, while the overall hospitalization rate for GPA increased slightly. Infection remains a common principal hospitalization diagnosis among GPA patients, including hospitalizations resulting in mortality., (© 2016, American College of Rheumatology.)

Objective: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function., Results: Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%., Conclusion: This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

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: anti-myeloperoxidase (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. 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., (© 2016, American College of Rheumatology.)

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patient's serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients., Case Summary: A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV., Conclusion: The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD.

Background: Granulomatosis with polyangiitis (GPA) is associated with an increased risk of mortality; however, recent mortality trends in GPA are unknown. We evaluated this issue in a general population context., Methods: Using data collected between 1992 and 2013 by The Health Improvement Network in the United Kingdom, we identified individuals diagnosed as incident cases of GPA and up to 10 non-GPA controls matched on sex, age, year of birth, and year of GPA diagnosis. The cohort was divided into two based on the year of diagnosis (i.e., 1992-2002 and 2003-2013) to evaluate changes in mortality. We calculated hazard ratios for death using a Cox-proportional hazards model and the rate differences using an additive hazard model, while adjusting for potential confounders., Results: We identified 465 cases of GPA (mean age: 60 years, 52% male). The early cohort (1992-2002) GPA patients had considerably higher mortality rates than the late cohort (2003-2013) (i.e., 72.0 vs. 35.7 cases per 1000 person-years), as compared with a moderate improvement in the comparison cohorts between the two periods (19.8 vs. 17.0 cases per 1000 person-years). The corresponding absolute mortality rate difference was 52.2 (95% CI: 25.1-79.2) cases and 18.7 (95% CI: 8.3-29.1) cases per 1000 person-years (p for interaction = 0.025). The resulting HRs for mortality were 4.34 (95% CI: 2.72-6.92) and 2.41 (95% CI: 1.74-3.34), respectively (p for interaction = 0.043)., Conclusion: This population-based study suggests that survival of GPA patients has improved considerably over the past 2 decades, affirming the benefits of recent trends in the management of GPA and its complications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Despite improvements in outcomes, recurrence of disease and drug-related toxicity continue to produce significant morbidity and mortality. Better understanding of the pathogenesis of AAV and the mechanism of action of cyclophosphamide has led to investigation of therapies that target B cells. Two randomized controlled trials have shown that rituximab is not inferior to cyclophosphamide for induction of remission in severe AAV, with no significant difference in the incidence of overall adverse events in rituximab- versus cyclophosphamide-treated patients. Data from ongoing clinical trials will determine the role of rituximab in the maintenance of remission.

Objective: To 1) describe the distribution of patient global assessment (PtGA) scores of disease activity in patients with granulomatosis with polyangiitis (GPA; Wegener's), 2) explore the discordance between PtGA scores and physician global assessment (PhGA) scores of disease activity, and 3) explore whether PtGA scores during disease remission are associated with future disease relapse., Methods: Data from the Wegener's Granulomatosis Etanercept Trial (WGET) were used. PtGA and PhGA scores were assessed on 100-mm visual analog scales (VAS). Presence of active disease was determined using the Birmingham Vasculitis Activity Score for WG (BVAS/WG), and remission was defined as a BVAS/WG score of 0. Disease relapse was defined as a BVAS/WG score of >0 after remission had been achieved. Discordance between PtGA and PhGA scores was defined as a difference of ≥20 points between the two measures. Mixed linear models were used in longitudinal analysis of PtGA scores., Results: Data were obtained from 180 patients in the WGET cohort, seen at a total of 1,719 study visits. The mean ± SD PtGA and PhGA disease activity scores (on 100-mm VAS) at baseline were 64.2 ± 27.4 and 55.5 ± 23.4, respectively. PtGA-PhGA discordance occurred in 53% of patients at baseline, and this was inversely associated with newly diagnosed disease (as opposed to relapsing disease) at baseline (odds ratio 0.37, 95% confidence interval [95% CI] 0.20-0.68) but not with age, sex, or presence of renal or pulmonary disease. Patients were in disease remission during 62% of the study visits. The mean PtGA score during visits immediately prior to relapse was 4.52 points higher (95% CI 0.66-8.4) than that at other remission visits (P = 0.03)., Conclusion: PtGA-PhGA discordance is common in GPA. A rise in the PtGA disease activity score during times defined by physicians as periods of remission is associated with subsequent occurrence of disease relapse. These findings support the addition of PtGA as an outcome measure for GPA., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA)., Methods: We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls., Results: Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10(-50) and 2.18 × 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10(-8) )., Conclusion: We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA., (Copyright © 2013 by the American College of Rheumatology.)

Objective: To examine the association of previously identified autoimmune disease susceptibility loci with granulomatosis with polyangiitis (Wegener's) (GPA), and to determine whether the genetic susceptibility profiles of other autoimmune diseases are associated with those of GPA., Methods: Genetic data from 2 cohorts were meta-analyzed. Genotypes for 168 previously identified single-nucleotide polymorphisms (SNPs) associated with susceptibility to different autoimmune diseases were ascertained in a total of 880 patients with GPA and 1,969 control subjects of European descent. Single-marker associations were identified using additive logistic regression models. Associations of multiple SNPs with GPA were assessed using genetic risk scores based on susceptibility loci for Crohn's disease, type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis (RA), celiac disease, and ulcerative colitis. Adjustment for population substructure was performed in all analyses, using ancestry-informative markers and principal components analysis., Results: Genetic polymorphisms in CTLA4 were significantly associated with GPA in the single-marker meta-analysis (odds ratio [OR] 0.79, 95% confidence interval [95% CI] 0.70-0.89, P = 9.8 × 10(-5) ). The genetic risk score for RA susceptibility markers was significantly associated with GPA (OR 1.05 per 1-unit increase in genetic risk score, 95% CI 1.02-1.08, P = 5.1 × 10(-5) )., Conclusion: RA and GPA may arise from a similar genetic predisposition. Aside from CTLA4, other loci previously found to be associated with common autoimmune diseases were not statistically significantly associated with GPA in this study., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's) (GPA)., Methods: Subjects were participants in the Wegener's Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 (SF-36) health survey that includes physical and mental component summary scores (PCS and MCS, respectively). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG)., Results: The data from 180 subjects in the WGET (median followup 2.3 years, mean number of visits 10) and 237 subjects in the VCRC-LS (median followup 2.0 years, mean number of visits 8) were analyzed. A 1 unit increase in the BVAS/WG corresponded to a 1.15 unit (95% confidence interval [95% CI] 1.02, 1.29) decrease for the PCS and a 0.93 (95% CI 0.78, 1.07) decrease for the MCS in the WGET, and to a 1.16 unit decrease for the PCS (95% CI 0.94, 1.39) and a 0.79 unit decrease for the MCS (95% CI 0.51, 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per 3 months), but worsened slightly (0.03 decrease in PCS every 3 months) among patients not achieving sustained remission (P = 0.005)., Conclusion: HRQOL, as measured by the SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA., (Copyright © 2012 by the American College of Rheumatology.)

Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).

Objective: Standard treatment for severe granulomatosis with polyangiitis (Wegener's) (GPA) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study, we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX)., Methods: Patients in the Wegener's Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women ages <50 years, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle-stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as an AMH level of <1.0 ng/ml., Results: Of 42 women in this analysis (mean age 35 years), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6 of 8 who received CYC during the trial developed diminished ovarian reserve, compared to 0 of 4 who did not receive CYC (P < 0.05). Changes in AMH correlated inversely with cumulative CYC dose (P < 0.01), with a 0.74 ng/ml decline in AMH level for each 10 gm of CYC., Conclusion: Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age., (Copyright © 2011 by the American College of Rheumatology.)

Objective: An association between therapeutic inhibition of tumor necrosis factor (TNF) and solid malignancies was observed during the Wegener's Granulomatosis Etanercept Trial (WGET), which included 180 patients with granulomatosis with polyangiitis (Wegener's) (GPA). The present study was conducted to determine the malignancy risk beyond the time of exposure to study therapy., Methods: The occurrence and type of solid malignancies were ascertained using a standardized data form. Data collected included vital status, histologic findings, and therapeutic interventions. The Surveillance, Epidemiology, and End-Results database was used to estimate a standardized incidence rate (SIR) for solid malignancies., Results: Post-trial followup data were available for 153 patients (85% of the original cohort), with a median followup time of 43 months. Fifty percent of these patients had received etanercept. There were no differences in demographic characteristics between the etanercept and placebo groups. Thirteen new solid malignancies were detected, 8 in the etanercept group and 5 in the placebo group. Compared to the general population, the risk of solid malignancies in the etanercept group was increased (SIR 3.92 [95% confidence interval 1.69-7.72]), but was not different from the risk in the placebo group compared to the general population (SIR 2.89 [95% confidence interval 0.94-6.73]). All solid malignancies occurred in patients who had been exposed to cyclophosphamide. The overall duration of disease and a history of malignancy before trial enrollment were associated with the development of malignancy during post-trial followup., Conclusion: The incidence of solid malignancy remained increased during long-term followup of the WGET cohort. However, this could not be attributed solely to etanercept exposure during the trial. Anti-TNF therapy with etanercept appears to further increase the risk of malignancy observed in patients with GPA treated with cytotoxic agents and should be avoided in these patients., (Copyright © 2011 by the American College of Rheumatology.)

Objective: There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener's granulomatosis (WG)., Methods: Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression., Results: Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47-9.03), P-selectin (OR 6.26, 95% CI 2.78-14.10), PR3-ANCA (OR 9.41, 4.03-21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22-0.57). BVAS/WG increased by 0.80 (95% CI 0.44-1.16), 0.83 (95% CI 0.42-1.25), and 0.81 (95% CI 0.48-1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96-2.12) per unit-increase in MCP-1., Conclusion: Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG.

Objective: To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease., Methods: We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort., Results: Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11-1.90), diastolic hypertension (OR 1.97, 95% CI 0.98-3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20-0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80)., Conclusion: Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Deficiency of α(1) -antitrypsin (α(1) AT) may be a determinant of susceptibility to Wegener's granulomatosis (WG). Several previous, mainly small, case-control studies have shown that 5-27% of patients with WG carried the α(1) AT deficiency Z allele. It is not clear whether the S allele, the other major α(1) AT deficiency variant, is associated with WG. This study investigated the relationship of the α(1) AT deficiency Z and S alleles with the risk of developing WG in a large cohort., Methods: We studied the distribution of the α(1) AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods., Results: Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98-2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33-∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele., Conclusion: Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α(1) AT deficiency and susceptibility to WG., (Copyright © 2010 by the American College of Rheumatology.)

Background: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen., Methods: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months., Results: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events., Conclusions: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.), (2010 Massachusetts Medical Society)

Objective: To assess the Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) with respect to its selection and weighting of items., Methods: This study used the BVAS/WG data from the Wegener's Granulomatosis Etanercept Trial. The scoring frequencies of the 34 predefined items and any "other" items added by clinicians were calculated. Using linear regression with generalized estimating equations in which the physician global assessment (PGA) of disease activity was the dependent variable, we computed weights for all predefined items. We also created variables for clinical manifestations frequently added as other items, and computed weights for these as well. We searched for the model that included the items and their generated weights yielding an activity score with the highest R(2) to predict the PGA., Results: We analyzed 2,044 BVAS/WG assessments from 180 patients; 734 assessments were scored during active disease. The highest R(2) with the PGA was obtained by scoring WG activity based on the following items: the 25 predefined items rated on >or=5 visits, the 2 newly created fatigue and weight loss variables, the remaining minor other and major other items, and a variable that signified whether new or worse items were present at a specific visit. The weights assigned to the items ranged from 1 to 21. Compared with the original BVAS/WG, this modified score correlated significantly more strongly with the PGA., Conclusion: This study suggests possibilities to enhance the item selection and weighting of the BVAS/WG. These changes may increase this instrument's ability to capture the continuum of disease activity in WG.

Objective: Weight gain is a side effect of glucocorticoid (GC) use, but the natural history and health implications of changes in weight that occur during the treatment of inflammatory disease are not understood., Methods: We evaluated data from the Wegener's Granulomatosis Etanercept Trial. Patients were categorized according to clinical outcome at 1 year: remission (no disease flares), single flare, or multiple flares. Risk factors for gaining > or =10 kg were examined in multivariate models., Results: Weights at baseline and 1 year were available for 157 (93%) of the 168 patients analyzed. During year 1, the mean cumulative prednisone dosage in the multiple flares subgroup was 7.9 gm, compared with 6.0 gm and 3.9 gm in the single flare and remission subgroups, respectively (P < 0.001). Patients in these subgroups gained an average of 2.6 kg, 4.1 kg, and 5.8 kg, respectively (P = 0.005). Weight gain did not correlate with cumulative GC dose (R = 0.10, P = 0.25). Thirty-five patients (22.3%) gained and maintained > or =10 kg in the first year. New diagnosis of Wegener's granulomatosis at baseline was an independent predictor of gaining > or =10 kg at 1 year (odds ratio 19.7, 95% confidence interval 2.4-162.6, P = 0.006). Among the 78 patients in the remission subgroup, 40 sustained remissions through the 2-year time point. For these 40 patients, the mean weight gained at year 1 did not regress by the end of year 2, despite the absence of continued GC use., Conclusion: Disease control was associated with lower cumulative GC doses but greater weight gain. More than one-fifth of patients gained >10 kg in the first year of treatment. The quantity of weight gained by patients during treatment has potential future health implications.

Objective: Venous thrombotic events (VTE), including both deep venous thrombosis and pulmonary emboli, are now recognized as an important complication of Wegener's granulomatosis (WG), but the mechanism(s) of this occurrence is unclear. The frequency of anticardiolipin antibodies (aCL), anti-beta2-glycoprotein antibodies (anti-beta2-GP), and several genetic hypercoagulable factors were examined in a large cohort of patients with WG., Methods: One hundred eighty patients with active WG had serum and DNA samples collected upon entry into a clinical trial. Of the 180 patients, 29 patients had VTE -- 13 before trial entry, 16 during trial. aCL (IgG, IgM, and IgA) and anti-beta2-GP (IgG and IgM) were evaluated in 176 patients. Factor V Leiden (FVL), the prothrombin gene mutation (G20210A, PGM), and methylenetetrahydrofolate reductase (MTHFR) gene mutation were tested in the 29 patients with thrombotic events, and 36 patients without., Results: aCL occurred with increased frequencies in patients with WG when compared to the general population (1%-5%): 12% had aCL and 3% had anti-beta2-GP. There was no difference in the prevalences of aCL or anti-beta2-GP based on clotting status. The prevalence of the genetic hypercoagulable factors examined in patients with WG was comparable to the reported rates in the general population., Conclusion: Although the incidence of clinically significant VTE is increased in patients with WG, this increased risk is not explained by increased prevalences of aCL, anti-beta2-GP, FVL, or mutations in PGM or MTHFR. These observations suggest a need to search for new genetic or acquired prothrombotic abnormalities to account for the increased thrombotic event rate in patients with active WG.

Background: The utility of antineutrophil cytoplasmic antibody (ANCA) levels to guide the management of patients with Wegener granulomatosis remains controversial., Objective: To determine whether pro-proteinase 3 (PR3)-ANCA levels are a better measure of disease activity than mature-PR3-ANCA levels, whether decreases in either level are associated with shorter time to remission, and whether increases are followed by relapse., Design: Prospective, observational cohort study., Setting: 8 United States medical centers that participated in a treatment trial for Wegener granulomatosis., Patients: 156 patients with Wegener granulomatosis enrolled during periods of active disease., Measurements: PR3-ANCA levels (by capture enzyme-linked immunosorbent assay) and disease activity (by the Birmingham Vasculitis Activity Score for Wegener granulomatosis)., Results: The ANCA levels were only weakly associated with disease activity across patients. The longitudinal association within patients was stronger, but changes in ANCA levels explained less than 10% of the variation in disease activity. Decreases in mature- and pro-PR3-ANCA levels were not statistically significantly associated with shorter time to remission, and increases in mature-PR3-ANCA levels (adjusted hazard ratio, 0.8 [95% CI, 0.4 to 1.9]; P = 0.67) and pro-PR3-ANCA levels (adjusted hazard ratio, 1.0 [CI, 0.5 to 2.1]; P = 0.99) were not associated with relapse. The proportion of patients who had relapse within 1 year of an increase in PR3-ANCA levels was 40% for mature-PR3 (CI, 18% to 56%) and 43% for pro-PR3 (CI, 22% to 58%)., Limitations: Samples were collected approximately every 3 months. Sensitivity and specificity of ANCA levels for detecting remission and relapse could not be calculated because each patient had different follow-up times., Conclusion: Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener granulomatosis activity. Decreases in PR3-ANCA levels are not associated with shorter time to remission, and increases are not associated with relapse. These findings suggest that ANCA levels cannot be used to guide immunosuppressive therapy.

Background: The pathogenic significance of antineutrophilic cytoplasmic antibodies (ANCA) in Wegener's granulomatosis is controversial. Their presence is influenced by the extent, severity, and activity of the disease at the time of sampling. The objective of this study was to determine the frequency of ANCA in patients with active Wegener's granulomatosis and to assess the influence of disease severity on test results., Methods: Baseline serum samples from the 180 participants in a multicentric prospective trial were tested for ANCA by indirect immunofluorescence, direct enzyme-linked immunosorbent assay (ELISA), and capture ELISA. Disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener's granulomatosis. All patients had active disease at enrollment. Patients were categorized as having severe (n=128) or limited (n=52) Wegener's granulomatosis., Results: When all ANCA detection methods were combined, 166 patients (92%) were ANCA positive, including 96% with severe disease and 83% with limited disease., Conclusion: ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis, but approximately 1 of 5 patients with active limited disease are ANCA negative. Immunofluorescence and both direct and capture ELISAs are required for optimal detection, suggesting that ANCA are not recognized equally well by all testing methods.

Objective: Previous studies in small cohorts of patients with Wegener's granulomatosis (WG) or antineutrophil cytoplasmic antibody (ANCA) associated vasculitis have yielded conflicting data regarding the prevalence of antiendothelial cell antibodies (AECA), ranging from 8% to 100%, and the use of AECA as a measure of disease activity. We examined a large, well-characterized cohort of patients with WG and active disease for the presence of AECA., Methods: Serum from subjects with WG who participated in a clinical therapeutic trial was collected at baseline, when all subjects had active disease. Clinical manifestations and disease activity were documented using the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Serum AECA (IgG) was measured by cyto-ELISA using unfixed human umbilical vein endothelial cells (HUVEC). The AECA positivity cutoff was determined using 71 healthy control samples. Statistical analyses utilized Student's t test, chi-square and Fisher's exact tests, and linear regression., Results: AECA were detected in 34 of 173 (20%) evaluated serum samples. Mean BVAS/WG did not differ between patients with (7.3 +/- 3.2) or without AECA (7.0 +/- 3.3) (p = 0.58). Among the 34 patients positive for AECA, the antibody titer did not correlate with disease activity (BVAS/WG; r = 0.09, p = 0.60). There were no statistically significant differences in the frequency of major clinical manifestations between patients with or without AECA., Conclusion: AECA, as measured using HUVEC, are not highly prevalent among patients with active WG, are not associated with specific clinical manifestations, and do not correlate with level of disease activity.

Objective: Etanercept is a soluble fusion protein designed to inhibit tumor necrosis factor (TNF). During the Wegener's Granulomatosis Etanercept Trial (WGET), a placebo-controlled trial of etanercept given in addition to standard therapy for remission induction and maintenance, more solid malignancies were observed in the etanercept group than in the group treated with standard therapy alone. This study was undertaken to further explore the potential association between anti-TNF therapy and the development of malignancy in these patients., Methods: One hundred eighty patients with active WG were enrolled and followed up for a median of 27 months. At enrollment, disease characteristics, treatment history, specific medical history items, and information about previous WG treatments and risk factors for malignancy were recorded. During the trial, the occurrence of malignancies and other adverse events was recorded prospectively., Results: All 6 solid malignancies observed during the WGET occurred in the etanercept group (P = 0.01 versus placebo group); based on a comparison of age- and sex-specific incidence rates, 1.92 solid malignancies would have been expected in this group. The solid malignancies included 2 cases of mucinous adenocarcinoma of the colon, 1 each of metastatic cholangiocarcinoma, renal cell carcinoma, and breast carcinoma, and 1 recurrent liposarcoma. There were no differences between the 2 treatment groups in sex distribution, disease severity, personal or family history of cancer, or tobacco and alcohol use. The etanercept group was older at baseline and less likely to be newly diagnosed with WG at the time of randomization. Patients who developed solid tumors were older than patients who did not. All etanercept-treated patients who developed solid tumors were also treated with cyclophosphamide during the trial. However, there were no differences between the groups in the amount of cyclophosphamide received during the trial or the percentage who had received cyclophosphamide before enrollment. There were also no differences in the mean duration of daily cyclophosphamide therapy or the maximum daily cyclophosphamide dosage before enrollment., Conclusion: Data from the WGET, the first substantial reported experience of the combined use of etanercept and cyclophosphamide in the treatment of WG, indicate that the combination of TNF inhibition and cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.

The treatment of Wegener's granulomatosis, one of the most common forms of systemic vasculitis, has changed substantially over the past two decades. The principal aims of therapy are to control the disease swiftly, to limit the extent and severity of permanent organ damage, and to minimize the short-term and long-term morbidities that often result from therapy. This review provides an overview of the treatment regimens that are currently available for inducing and maintaining remission in patients with Wegener's granulomatosis, and also discusses newer agents that might have a role in the management of this disease in the future. Severe toxicity associated with the available agents and, therefore, there is keen interest in the development of alternative treatment strategies for this disease.

The complexity of assessing disease activity, disease status, and damage in the vasculitides reflects the multisystemic pathologic manifestations of these often chronic illnesses. Major progress has been made in the past decade in the development of validated and widely accepted outcome measures for use in clinical trials. Over time, these tools have been regularly revised, expanded, and supplemented with new measures of disease prognosis and damage. As a result clinical research in this area has become increasingly complex. This article critically reviews the current status of tools for assessing disease activity and damage in "ANCA-associated" vasculitides (Wegener's granulomatosis and microscopic polyangiitis), summarizes the current level of validation of each measure, addresses central problems and controversies to be considered during development of new vasculitis assessment tools, and proposes a series of research agendas for consideration by the vasculitis research community.

Purpose: To evaluate the risk factors for herpes zoster as well as the incidence and timing of this complication in patients who were treated with immunosuppression because of active Wegener's granulomatosis., Subjects and Methods: We studied the 180 Wegener's granulomatosis patients in the Wegener's Granulomatosis Etanercept Trial (WGET). Herpes zoster events during WGET were documented prospectively. Follow-up questionnaires were employed to describe the location, treatment, and complication(s) of herpes zoster and its therapy. Univariate and multivariate analyses were performed to evaluate risk factors, including history of herpes zoster, for the occurrence of herpes zoster during the trial. All analyses were based on the time to first occurrence of herpes zoster., Results: Eighteen patients (10% of the WGET cohort) suffered a total of 19 herpes zoster episodes over a mean follow-up period of 27 months. The annual incidence of herpes zoster in the WGET cohort was 45 cases/1000 patient-years (95% confidence interval [CI]: 27, 70). The median time from enrollment to the occurrence of herpes zoster in the subgroup of patients with that complication was 16.5 months (+/- 9.4). Fifteen of the 19 herpes zoster events (79%) occurred between months 6 and 36, many months after the period of most intensive immunosuppression. In univariate analyses, history of serum creatinine > or =1.5 mg/dL before enrollment was associated with a relative risk (RR) of 3.0 (95% CI: 1.1, 7.8) for herpes zoster during WGET (P=.03). In multivariate analyses, serum creatinine > or =1.5 mg/dL was associated with an RR of 6.3 (95% CI: 2.0, 19.8; P=.002), and female sex with an RR of 4.6 (95% CI: 1.6, 13.2; P=.004)., Conclusion: Renal dysfunction and female sex were consistently strong risk factors for herpes zoster events in this population. Contrary to expectation, most herpes zoster events did not occur during periods of most intensive immunosuppression. These data may inform studies of interventions designed to prevent herpes zoster in patients on treatment for immune-mediated diseases.

Objective: To analyze damage occurring in patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET) and to correlate that damage with disease activity, adverse events, and quality of life., Methods: The Vasculitis Damage Index (VDI) was applied to all 180 patients at trial entry and every 6 months throughout the trial. Items of damage were analyzed by presumed etiology (i.e., secondary to WG, to therapy, or both) and time of occurrence. Spearman's rank correlation coefficients were calculated between VDI scores and the Birmingham Vasculitis Activity Score for WG (BVAS/WG), frequency of flares, number of adverse events, and the patients' quality-of-life assessments., Results: The mean VDI score was 1.3 at the study enrollment and 1.8 at the end of the trial. This increase was due to damage that occurred despite (or because of) therapy, including visual impairment, hearing loss, nasal blockade, pulmonary fibrosis, hypertension, renal insufficiency, peripheral neuropathy, gonadal failure, and diabetes mellitus. Only 11% of the enrolled patients had not sustained a single VDI item after 1 year of enrollment. When adjusted for baseline VDI, the baseline BVAS/WG correlated moderately well with the VDI score at 1 year (r = 0.20, P = 0.015). Increases in adjusted VDI scores also correlated with the number of adverse events, particularly among patients with limited WG (P = 0.06)., Conclusion: Damage from both active disease and its treatment remain important problems for patients with WG. Despite the dramatic improvements in patient survival achieved over the last several decades, only a few patients with WG emerge from a period of active disease without sustaining some damage from the disease itself, its treatment, or both. An important measure of future therapeutic approaches will be their ability to reduce the damage accrued over time.

Purpose of Review: To review three major randomized clinical trials in forms of vasculitis associated with anti-neutrophil cytoplasmic antibodies., Recent Findings: The design features, results, and context of the Cyclophosphamide versus Azathioprine for the Remission Phase of Vasculitis, Non-renal AAV alternatively treated with Methotrexate, and Wegener Granulomatosis Etanercept Trial are reviewed., Summary: Until recently, therapies for Wegener granulomatosis and microscopic polyangiitis have been based primarily on a relatively small number of nonrandomized studies. During the past 18 months, three randomized, controlled trials (one double-blinded) have been performed in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Careful comparisons of the results of these trials yield insights into new standards of care for vasculitis associated with anti-neutrophil cytoplasmic antibodies. This paper summarizes the designs of these three trials; highlights their principal conclusions, strengths, and shortcomings; and distills from their results several recommendations on major questions related to the therapy of vasculitis associated with anti-neutrophil cytoplasmic antibodies.

Background: Venous thrombotic events (VTEs) have been observed in Wegener granulomatosis, but the incidence rate is not known., Objective: To measure the incidence of VTEs in patients with Wegener granulomatosis., Design: Prospective, observational cohort study., Setting: A multicenter, randomized, double-blind, placebo-controlled treatment trial for Wegener granulomatosis., Patients: 180 patients with Wegener granulomatosis enrolled during periods of active disease., Measurements: Venous thrombotic events (deep venous thromboses or pulmonary emboli) were documented and confirmed prospectively. Incidence rates were calculated on the basis of time to first VTE., Results: Thirteen patients had VTEs before enrollment. During 228 person-years of prospective follow-up, 16 VTEs occurred in 167 patients with no history of VTE. Median time from enrollment to VTE for patients with an event was 2.1 months. The incidence of VTE among patients with Wegener granulomatosis was 7.0 per 100 person-years (95% CI, 4.0 to 11.4)., Limitations: Although prospectively recorded, screening for VTEs did not occur., Conclusions: The incidence rate of VTEs in Wegener granulomatosis is high when compared with available rates in the general population, patients with lupus, and patients with rheumatoid arthritis. These results have important implications for clinical care of patients with Wegener granulomatosis.

Objective: To identify serum ion patterns that distinguish remission from active disease in patients with Wegener's granulomatosis (WG)., Methods: Using sera collected in the WG Etanercept Trial, we selected samples from patients who either were undergoing a period of extended disease remission or had recent flares of active WG. Unfractionated samples were randomized into sets for training and testing, such that remission sera and active disease sera could be analyzed without batch bias. Molecular species within the sera were ionized by high-resolution, matrix-assisted laser desorption ionization time-of-flight mass spectrometry. We then used a bioinformatics pattern-recognition tool to identify optimal combinations of ions. During the training stage, the clinical data (remission versus active disease) were provided in association with the spectral data from each sample. In the testing stage, we performed blinded testing on a previously unexamined set of samples., Results: The most robust model, trained on a total of 82 samples (42 remission, 40 active disease), included 7 key ions with mass:charge ratios of 803.239, 2,171.672, 2,790.574, 3,085.237, 5,051.726, 5,833.989, and 6,630.465. The combined relative amplitudes of these 7 ions identified 5 distinct clusters of either remission or active disease samples during the training stage. In the testing stage, this model segregated 72 samples into the same 5 clusters, including 1 large remission cluster (n = 28) and another large active disease cluster (n = 32). Three smaller clusters of active disease or remission samples were also identified, with remission clusters populated by 2 samples in one cluster and 8 in another, and an active disease cluster populated by 2 samples. The model categorized 35 of 37 remission samples correctly (sensitivity 95%, 95% confidence interval [95% CI] 82.1-99.4) and 32 of 35 active disease samples correctly (specificity 91%, 95% CI 78.1-98.1)., Conclusion: This serum proteomic profiling approach appears to be useful in distinguishing between states of stable clinical remission and active disease. Further validation and refinement of this strategy may help clinicians apply immunosuppressive therapies more judiciously among their patients, thereby avoiding morbidity and mortality from excessive treatment. Identification of the most robust and clinically useful combinations of ions will permit the rational selection of molecules for sequencing and analysis.

Objective: To determine the computed tomography (CT) evolution of various pulmonary manifestations of Wegener's Granulomatosis (WG) following appropriate pharmacologic treatment of the disease., Methods: Eleven patients with WG were identified, each of whom had had at least two CT examinations. CTs were reviewed retrospectively to identify pulmonary lesions of WG. Lesions were categorized as nodules, cavities, lobar atelectasis, pulmonary bands, or infiltrates. To determine the evolution of each individual lesion following pharmacologic treatment, the authors compared the lesions at presentation to their appearances on follow-up CT examinations., Results: A total of 112 lesions were identified (nodules = 70, cavities = 25, lobar atelectasis = 7, pulmonary bands = 6, infiltrates = 4). The mean time interval between CT examinations was 34 weeks (range: 3-248 weeks). Treated nodules tended to become smaller (33/70, 47%), to resolve (14/70, 20%), or to remain unchanged (8/70, 11%). However, the nodules became larger or cavitated in a substantial minority of cases (13/70, 19% and 2/70, 3%, respectively). Although more than half of the treated cavities became smaller (13/25, 52%) or resolved (1/25, 4%), many evolved into nodules (6/25, 24%) or enlarged (5/25, 20%). All cases of lobar atelectasis (14/14, 100%) and transpulmonary bands (6/6, 100%) were unchanged at follow-up. All infiltrates were either resolved (3/4, 75%) or substantially improved (1/4, 25%)., Conclusion: WG has a wide spectrum of pulmonary manifestations. Nodules, cavities, and infiltrates are among the most common lesions seen on CT. Although these findings tend to improve with treatment, mixed responses are not uncommon. Lobar atelectasis and transpulmonary bands tend not to improve, even with the occurrence of clinical disease remission.

Objective: To report baseline data on 180 patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET), and to examine demographic and clinical differences between patients with limited disease and those with severe disease., Methods: Definitions of limited and severe disease were agreed upon by consensus of the investigators at a pretrial meeting and were incorporated into the protocol as a stratification criterion. These data were applied prospectively to the WGET patient cohort, based on clinical features and the intention to treat patients according to disease activity. Data related to disease onset, date of diagnosis, clinical features, antineutrophil cytoplasmic antibody assays, tissue biopsy findings, and other medical history were collected on a baseline medical history form. Physician-investigators from each center participated in the development of this form, and all were certified in its use prior to the start of the trial. Selected data on patients who were screened for the trial but were not enrolled were also collected., Results: Several significant differences between the limited and severe disease subsets were observed. Patients with limited disease were nearly a decade younger at disease onset compared with patients with severe disease. Thirty-three percent of patients with severe disease were women, compared with 58% of those with limited disease. Despite their younger age at symptom onset, patients with limited disease tended to have longer disease duration, a greater likelihood of experiencing exacerbation of previous disease following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders at the time of enrollment (e.g., saddle-nose deformity). Patients with limited WG were less likely than those with severe disease to have antibodies to either proteinase 3 or myeloperoxidase. Patients with severe disease had a higher likelihood of previous thyroid disease, particularly either Graves' disease or Hashimoto thyroiditis, suggesting the possibility of different pathogenetic factors within these disease subsets. Other observed differences between these subsets, such as the greater frequency of alveolar hemorrhage in the severe disease group, were related to the a priori definitions of limited and severe disease., Conclusion: There are significant differences between patients with limited WG and those with severe WG with regard to sex, age, the likelihood of recurrent disease, the risk of damage in certain organ systems, and, possibly, etiologic factors. These differences (and perhaps other differences that are currently unrecognized) in patient subsets may have implications for mechanisms of pathogenesis, prognosis, response to treatment, and the design of future clinical investigations.

Background/aims: We examined the correlations between renal biopsy findings in Wegener's granulomatosis and renal function at baseline and 1 year in 22 patients who presented between 1988 and 1999., Methods: Renal histology was independently reviewed by 2 pathologists who were masked to the clinical data. The primary outcome was the relationship of the percentage of normal glomeruli to reciprocal serum creatinine at baseline and 1 year. Other histologic data were collected using a series of ordinal rating scales. Acute and chronic sum scores were calculated., Results: The median serum creatinine (SCr) at baseline was 3.9 mg/dl (0.8-14 mg/dl). Seven patients initially required hemodialysis, of whom 4 subsequently regained independent renal function. By 1 year of follow-up, the median (SCr) for patients with independent renal function was 1.9 mg/dl (0.9-6.8 mg/dl). Reciprocal SCr at baseline correlated with the percentage of normal glomeruli (r = 0.584, p = 0.005), crescent score (r = -0.595, p = 0.003), interstitial fibrosis as a percentage of cortical surface area (r = -0.669, p = 0.002), interstitial inflammation (r = -0.439, p = 0.041), eosinophil (r = -0.495, p = 0.019), neutrophil score (r = -0.557, p = 0.005), and acute sum score (r = -0.499, p = 0.018). However, only the percentage of normal glomeruli (r = 0.493, p = 0.023), the crescent score (r = -0.452, p = 0.035), and interstitial fibrosis as a percentage of cortical surface area (r = -0.466, p = 0.052) correlated with reciprocal SCr at 1 year of follow-up., Conclusion: In this relatively small data set, the percentage of normal glomeruli, the crescent score, and interstitial fibrosis as a percentage of cortical surface area correlated with renal function at both baseline and 1 year of follow-up., (Copyright 2002 S. Karger AG, Basel)

Objective: To evaluate the effect of achieving a negative postinduction antineutrophil cytoplasmic antibody ANCA) assay on the risk of relapse, end-stage renal disease (ESRD) and death in ANCA-associated vasculitis (AAV).Methods: We emulated a target trial using observational data from the Mass General Brigham AAV cohort comparing patients who achieved versus did not achieve serological remission (negative ANCA assay) within 180 days of induction. Outcomes were relapse, ESRD or death within 5 years, obtained from medical records, the US Renal Data System and the National Death Index. We placed a 'clone' of each patient in both trial arms, censored those deviating from their assigned protocol and weighted each by the inverse probability of censoring. Outcomes were assessed by pooled logistic regression.Results: The study included 506 patients with AAV. The mean age was 61 years (SD 18) and the majority were women (58%), white (87%), myeloperoxidase-ANCA+ (72%) and had renal involvement (68%). Rituximab (59%) or cyclophosphamide (33%) was most often used for induction treatment. Within 5 years, 81 (16%) died, 51 (10%) had ESRD and 64 (13%) had relapse. Patients treated to a negative ANCA assay within 180 days had HR 0.55 (95% CI 0.38 to 0.81) for relapse and HR 0.87 (95% CI 0.61 to 1.25) for the composite of ESRD or death within 5 years.Conclusions: In this emulated target trial from a large AAV cohort, achieving serological remission within 180 days of induction was associated with lower risk of relapse, but no statistically significant difference in ESRD or mortality outcomes. [ABSTRACT FROM AUTHOR]

The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) comprise a major subset of diseases that cause destructive inflammation of small and medium‐sized blood vessels. Although these conditions have a predilection for pulmonary and renal involvement, they are in fact protean diseases that can involve essentially any organ system. AAV is among the most difficult rheumatic diseases to diagnose and treat. Therapy for AAV has evolved over the past two decades. Rituximab, an anti‐CD20 monoclonal antibody, is now the preferred agent for remission induction in conjunction with a reduced‐dose glucocorticoid taper. Rituximab is also often a key therapy for remission maintenance. Glucocorticoid toxicity reduction has become a major priority for treatment regimens. Avacopan, an important new adjunct to remission induction therapy, may reduce glucocorticoid use and its resulting toxicity. The role of avacopan as a remission maintenance agent requires further study. The duration of immunosuppression following remission is guided by a number of factors, including the patient's overall clinical state, the degree of damage from previous disease activity, the tolerability of remission maintenance medications, and SARS–CoV‐2 vaccination and immunity status. Certain features, including history of previous relapse, the presence of ANCA directed against proteinase 3, and a diagnosis of granulomatosis with polyangiitis, favor prolonged remission maintenance therapy. The interval between rituximab doses can usually be lengthened over time during the maintenance phase. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to validate the diagnosis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) as the primary cause of end‐stage renal disease (ESRD) in the US Renal Data System (USRDS). Methods: We identified patients with ESRD in the Mass General Brigham (MGB) health care system who were enrolled in the USRDS. The health records of those with AAV listed as the primary cause of ESRD in the USRDS were reviewed to confirm the diagnosis and estimate positive predictive value (PPV). Sensitivity was estimated by evaluating the primary cause of ESRD listed in the USRDS for patients with ESRD due to AAV in the MGB AAV cohort. Results: We identified 89 MGB patients with ESRD due to AAV in the USRDS. Of these, 85 cases were confirmed to be true cases of AAV (PPV = 94%). Among the patients classified as having AAV, 84 (99%) had an ANCA test, which was predominantly myeloperoxidase/P‐ANCA (47 [55%]); 36 (42%) had a renal biopsy, and all biopsies were supportive of the diagnosis. The majority (81 [90%]) was identified as AAV by International Classification of Diseases Ninth Revision or International Classification of Diseases 10th Revision codes for granulomatosis with polyangiitis (446.4 or M313.1). Of the 77 MGB AAV cohort patients with ESRD who were linked to the USRDS, 41 (53%) had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to nonspecific nephritis. Conclusion: The diagnosis of AAV as the cause of ESRD in the USRDS has a high PPV; sensitivity was moderate. These findings support the continued use of the USRDS to study ESRD due to AAV. [ABSTRACT FROM AUTHOR]

Objective: To provide evidence‐based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody–associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel. Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low‐quality evidence supporting the recommendations. Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases. [ABSTRACT FROM AUTHOR]