Patrick Nachman - Academia.edu (original) (raw)

Papers by Patrick Nachman

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015

Background. Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis ... more Background. Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. Methods. Biopsy-proven AAV patients (diagnosed 1/1991-6/ 2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. Results. A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, ≥3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0-8.7; P = 0.001). Conclusions. More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

Objectives-Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA-SVV) is an autoimmun... more Objectives-Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA-SVV) is an autoimmune systemic process increasingly recognised since the advent of antibody testing for the disease. Prompt diagnosis and institution of immunosuppressive therapy has been shown to improve patient outcome. The goal of this study was to better understand how patients navigate the health care system from symptom presentation to biopsy diagnosis, and to study the effects of prompt versus delayed diagnosis. Methods-Disease symptoms and number of physicians seen prior to renal biopsy were assessed for 127 ANCA-SVV patients. Direct, delayed, and quest pathways to diagnosis and treatment of vasculitis were defined for both patients and providers. Kruskal-Wallis and Fisher exact tests were used to evaluate continual measures and compare categorical variables across pathways. Results-Among patients who sought direct care, physician delay in referral to a nephrologist was common (49/127, 71%, p=0.0023). Patients who delayed seeking care also experienced a delayed diagnosis 57% of the time (p=0.0023). Patients presenting with prodromal flu or upper respiratory involvement were more likely to have a delay/quest patient pathway (56% and 55%, respectively) than a direct patient pathway (44%, p=0.033 and 45%, p=0.019, respectively). There was a trend for patients with more severe loss of renal function to have a more direct referral to a nephrologist. Conclusion-Delay in diagnosis of ANCA SVV may be due to lack of or non-specific symptoms, especially in patients who present with non-renal manifestations of disease. Better algorithms are needed to identify extra-renal manifestations, expedite diagnosis and improve patient outcomes.

Annals of the Rheumatic Diseases, 2020

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relaps... more ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activi...

Journal of the American Society of Nephrology, 1996

In this study, the rate of remission, relapse, and treatment resistance in 107 patients with micr... more In this study, the rate of remission, relapse, and treatment resistance in 107 patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies were assessed. Patients with Wegener's granulomatosis were excluded. Prospective criteria were identified to assess remission, relapse, and resistant disease. Ninety-seven of the 107 patients received treatment with corticosteroids (N = 25) or with cyclophosphamide and corticosteroids (N = 72). Of these patients, 75 (77.3%) went into remission (complete remission, N = 61; remission on therapy, N = 14). Of the 75 responders, 32 patients (43%) remained in long-term remission, for a mean follow-up of 44 +/- 29 months; 15 patients (20%) progressed to ESRD without signs of relapse, for a mean of 21.4 +/- 22.8 months after the end of treatment; 6 patients died. Twenty-two of the 75 patients who initially responded to treatment (29%) suffered a relapse that occurr...

PLOS ONE, 2019

Background Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MP... more 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 affinitypurified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis. We used lectin binding assays, liquid chromatography, and mass spectrometrybased 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.

Kidney International, 2019

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a dive... more In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complementmediated kidney diseases, and monoclonal gammopathies of renal significance.

Glomerulonephritis, 2017

Childhood-onset systemic lupus erythematosus (cSLE) has been defined as a subset of SLE with onse... more Childhood-onset systemic lupus erythematosus (cSLE) has been defined as a subset of SLE with onset prior to 18 years of age. Around 15% of SLE patients present with nephritis before this age, and debatably these patients have a greater genetic component to their disease etiology, a more systemic involvement, and a more severe disease course. Patients develop their loss of tolerance to self at an earlier time than patients with adult-onset SLE, or at least their loss of tolerance progresses sooner to immune complex deposition and tissue injury. In this chapter, we review the joint approach of pediatric nephrologists and rheumatologists towards patients with cSLE and nephritis. We address the areas where evidence exists and the areas wherewemust rely on expert opinion or evidence based on primarily adult studies. Fortunately, 5and 10-year mortality is lower than in adult-onset lupus nephritis, and patient and renal survival has improved over the years. However, relapses during the transition from adolescence to adulthood are common and cardiovascular and infectious complications are frequent in long-term survivors.

Autoimmunity Reviews, 2017

Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that pri... more Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that primarily affect small blood vessels of the airway and kidneys. Lung involvement, one of the hallmarks of microscopic polyangiitis and granulomatosis with polyangiitis, is associated with increased mortality and morbidity. In recent years, several retrospective series and case reports have described the association of interstitial lung disease (ILD) and ANCA vasculitis, particularly those positive for ANCA specific for myeloperoxidase. In the majority of these patients pulmonary fibrosis occurs concurrently or predates the diagnosis of ANCA vasculitis. More importantly, these studies have shown that ILD has an adverse impact on the long-term prognosis of ANCA vasculitis. This review focuses on the main clinical and radiologic features of pulmonary fibrosis associated with anti-neutrophil cytoplasmic antibodies. Major histopathology features, prognosis and therapeutic options are summarized.

Current Treatment Options in Rheumatology, 2016

This article is part of the Topical Collection on Vasculitis Keywords Vasculitis I Glomerulonephr... more This article is part of the Topical Collection on Vasculitis Keywords Vasculitis I Glomerulonephritis I ANCA-associated vasculitis I IgA vasculitis I Cryoglobulinemic vasculitis Opinion statement Small-vessel vasculitides (SVV) are a group of complex and chronic systemic autoimmune disorders associated with significant morbidity. Renal involvement is a major determinant of long-term outcome in all SVV. Depending on the disorder, SVV can be associated with frequent, and often life-threatening, relapses and increased burden from long-term exposure to toxic therapies and accumulating, irreversible organ damage. Prompt diagnosis or determination of active disease and quick initiation of appropriate treatment are therefore paramount in the management of SVV. For rapidly progressive glomerulonephritis or other severe, life-threatening manifestations in either anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) or cryoglobulinemic vasculitis (CV), we recommend intravenous pulse methylprednisolone, plasmapheresis, and intravenous monthly cyclophosphamide. Hemodialysis is also used when indicated. Dose adjustments are made based on the patient's weight, degree of renal impairment, and tolerability. Corticosteroids and plasmapheresis are tapered according to the patient's response. Although a clearer role for rituximab in the treatment of AAV and CV is emerging, we reserve rituximab for disease relapse or disease refractory to the aforementioned treatments. We also use rituximab in less severe disease and for maintenance of remission in AAV and CV when indicated. Corticosteroids are a mainstay of therapy in IgA nephropathy (IgAN) and vasculitis (IgAV). In rapidly progressive glomerulonephritis due to IgAN or IgAV, we recommend intravenous cyclophosphamide. Again, dose adjustments are made based on the patient's weight, degree of renal impairment, and tolerability.

Annals of the rheumatic diseases, Jan 30, 2015

B cell depletion is an effective remission induction and maintenance therapy in patients with ant... more B cell depletion is an effective remission induction and maintenance therapy in patients with antineutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitis (AAV). 1-6 Rituximab targets both pathogenic effector B cells and protective regulatory B cells. To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies following B cell depletion. We reported that CD5 + B cells, as a surrogate marker of B regulatory cells, are decreased in patients with active AAV and normalise during disease remission. 7 After B cell depletion, patients who repopulated with a low or decreasing percentage of CD5 + B cells and were on low maintenance immunosuppression had a shorter time to relapse than patients on similar levels of immunosuppression with normalised CD5 + B cells or patients with similarly low CD5 + B cells but higher immunosuppression. The CD5 + CD24 hi CD38 hi B cell subpopulation correlates inversely with active disease but parallels both interleukin (IL)-10 production and suppression of ANCA. 8 CD5 may identify B cells enriched in IL-10

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with i... more Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Sta...

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)... more Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort. Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (≤2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests. Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9-29). Time to remission and relapse were similar between rituximab inf...

Seminars in Respiratory and Critical Care Medicine, 2011

Vasculitides that affect the lung represent a diverse group of diseases with various systemic cli... more Vasculitides that affect the lung represent a diverse group of diseases with various systemic clinical manifestations, and include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Churg-Strauss syndrome (CSS), and anti-glomerular basement membrane (anti-GBM) disease (Goodpasture syndrome). The etiologies of these diseases remain largely unknown. Although the pathogenic mechanisms of each differ, these diseases overlap by the presence of anti-neutrophil cytoplasmic autoantibodies in the vast majority of patients with MPA and GPA, and a substantial minority of patients with CSS and anti-GBM disease. This article reviews the current understanding of the pathogenesis of these four disease entities.

The New England journal of medicine, Jan 6, 2014

The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with ... more The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission. Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both). The 115 enrolled patients ...

Nephrology Dialysis Transplantation, 2005

Background. The treatment approaches to antineutrophil cytoplasmic autoantibody (ANCA) small vess... more Background. The treatment approaches to antineutrophil cytoplasmic autoantibody (ANCA) small vessel vasculitis expose patients to the risks associated with long-term use of corticosteroids and cytotoxic agents. In an effort to explore approaches to minimize risks, we conducted a pilot efficacy and safety study of mycophenolate mofetil (MMF) in the treatment of subjects with nonlife-threatening recurrent or cyclophosphamide-resistant ANCA-vasculitis. Methods. MMF was initiated at 500 mg orally twice daily and gradually increased to a target dose of 1000 mg twice daily for a duration of 24 weeks. Concomitant therapy with corticosteroids was allowed. The Birmingham Vasculitis Activity Score (BVAS) was used to assess disease activity and treatment efficacy. ANCA titres, serum creatinine and adverse events were secondary measures of efficacy and/or toxicity. Results. Twelve subjects were enrolled in the study. Treatment with MMF led to an improvement in disease activity as measured by the BVAS at 24 weeks (P ¼ 0.0013) and 52 weeks (P ¼ 0.0044) as compared to baseline. The BVAS decreased from an average of 9.1±3.5 at baseline (range, 3-17) to an average of 2.8±1.9 (range, 1-6) at 24 weeks and to 2.8±4.3 (range, 0-13) at 52 weeks. Early and sustained reductions in BVAS occurred in subjects initially classified as disease relapses vs those with treatment resistance. Side effect profile was consistent with the mechanism of action and pharmacokinetic disposition of MMF. Conclusions. MMF is a reasonable option in the treatment of non-life-threatening recurrent or resistant vasculitis and may obviate the immediate need for recurrent use of cytotoxic agents.

Nephrology Dialysis Transplantation, 2007

Background. Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)as... more 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.

Kidney International, 2006

Myeloperoxidase (MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantib... more Myeloperoxidase (MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantibodies (ANCA) found in patients with small-vessel vasculitis and pauci-immune necrotizing glomerulonephritis. To date, the target epitopes of MPO-ANCA remain poorly defined. Human MPO-ANCA do not typically bind mouse MPO. We utilized the differences between human and mouse MPO to identify the target regions of MPO-ANCA. We generated five chimeric MPO molecules in which we replaced different segments of the human or mouse molecules with their homologous counterpart from the other species. Of serum samples from 28 patients screened for this study, 43 samples from 14 patients with MPO-ANCA-associated vasculitis were tested against recombinant human and mouse MPO and the panel of chimeric molecules. Sera from 64 and 71% of patients bound to the carboxy-terminus of the heavy chain, in the regions of amino acids 517-667 or 668-745, respectively. No patient serum bound the MPO light chain or the aminoterminus of the heavy chain. All sera bound to only one or two regions of MPO. Although the pattern of MPO-ANCA binding changed over time (4-27 months) in 6 of 10 patients with several serum samples, such changes were infrequent. Other target regions of MPO-ANCA may not have been detected due to conformational differences between the native and recombinant forms of MPO. MPO-ANCA do not target a single epitope, but rather a small number of regions of MPO, primarily in the carboxy-terminus of the heavy chain.

Kidney International, 2009

The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the easter... more The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the eastern part of the Netherlands. As part of the overall study, we provide reference values of estimated glomerular filtration rate (GFR) for this Caucasian population without expressed risk. Age-stratified, randomly selected inhabitants received a postal questionnaire on lifestyle and medical history. In a large subset of the responders, serum creatinine was measured. The GFR was then measured using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. To limit possible bias, serum creatinine was calibrated against measurements performed in the original MDRD laboratory. The study cohort included 2823 male and 3274 female Caucasian persons aged 18-90 years. A reference population of apparently healthy subjects was selected by excluding persons with known hypertension, diabetes, cardiovascular-or renal diseases. This healthy study cohort included 1660 male subjects and 2072 female subjects, of which 869 of both genders were 65 years or older. The median GFR was 85 ml/min/1.73 m 2 in 30-to 34-year-old men and 83 ml/min/1.73 m 2 in similar aged women. In these healthy persons, GFR declined approximately 0.4 ml/min/year. Our study provides age-and gender-specific reference values of GFR in a population of Caucasian persons without identifiable risk.

Kidney International, 1999

Recurrent ANCA-associated small vessel vasculitis after transsmall vessel vasculitis (ANCA-SVV) a... more Recurrent ANCA-associated small vessel vasculitis after transsmall vessel vasculitis (ANCA-SVV) and glomeruloneplantation: A pooled analysis. phritis, this group of diseases continues to cause end-Background. Recurrent antineutrophil cytoplasmic antistage renal disease in a substantial proportion of patients. body (ANCA)-associated small vessel vasculitis (ANCA-SVV) As a result, one would anticipate that the number of after renal transplantation has been described in case series. patients with ANCA-SVV and end-stage renal disease However, general information regarding the frequency, character, and predictors of recurrent disease after transplantation is will increase, bringing to the forefront issues pertaining currently lacking. We considered the rate of relapse, whether to renal transplantation in this patient population. a positive ANCA at the time of transplantation predicted re-Successful renal transplantation in patients with ANCAlapse, and whether cyclosporine A prevented recurrent disease. SVV has been reported in multiple case reports [1-3]. Methods. We performed a pooled analysis of published data, These include patients who were in full remission and added to the experience at the Universities of North Carolina (14 patients) and Lund, Sweden (11 patients). To avoid rewith negative ANCA tests, but also patients in remission porting bias, only case series were included for analysis. Subwith positive ANCA tests at the time of transplantation group analysis was performed by disease category (Wegener's

Journal of the American Society of Nephrology, 2004

Granulopoiesis-related genes are distinctively upregulated in peripheral leukocytes of patients w... more Granulopoiesis-related genes are distinctively upregulated in peripheral leukocytes of patients with antineutrophil cytoplasmic autoantibodies (ANCA)-associated glomerulonephritis. Affymetrix microarrays identified the upregulation of nine neutrophilic primary granule genes, including myeloperoxidase (MPO) and proteinase 3 (PR3), plus five secondary granule genes. Coordinate expression of granulocyte maturation marker CD35, measured by TaqMan PCR, and positive in situ staining for PR3 transcripts in polymorphic neutrophils and monocytes indicate that these genes are expressed in "mature" cells. Increased transcripts correlated with disease activity and absolute neutrophil values but not with "left shift," drug regimen, cytokine levels, hematuria, proteinuria, ANCA titer, serum creatinine, gender, or age. Upregulation of PR3 and MPO transcripts was specifically associated with ANCA disease (n ϭ 56) as these changes were not detected in patients with ESRD (n ϭ 25) or systemic lupus erythematosus (n ϭ 17), as determined by TaqMan PCR. This is the first report of this phenomenon in nonneoplastic cells. The data raise the hypothesis that, in addition to the presence of anti-MPO or anti-PR3 autoantibodies, a second critical component in the cause of this disease is the reactivation of once-silenced genes leading to increased antigen availability.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2015

Background. Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis ... more Background. Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. Methods. Biopsy-proven AAV patients (diagnosed 1/1991-6/ 2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. Results. A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, ≥3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0-8.7; P = 0.001). Conclusions. More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity.

Carolina Digital Repository (University of North Carolina at Chapel Hill), 2013

Objectives-Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA-SVV) is an autoimmun... more Objectives-Antineutrophil cytoplasmic antibody small-vessel vasculitis (ANCA-SVV) is an autoimmune systemic process increasingly recognised since the advent of antibody testing for the disease. Prompt diagnosis and institution of immunosuppressive therapy has been shown to improve patient outcome. The goal of this study was to better understand how patients navigate the health care system from symptom presentation to biopsy diagnosis, and to study the effects of prompt versus delayed diagnosis. Methods-Disease symptoms and number of physicians seen prior to renal biopsy were assessed for 127 ANCA-SVV patients. Direct, delayed, and quest pathways to diagnosis and treatment of vasculitis were defined for both patients and providers. Kruskal-Wallis and Fisher exact tests were used to evaluate continual measures and compare categorical variables across pathways. Results-Among patients who sought direct care, physician delay in referral to a nephrologist was common (49/127, 71%, p=0.0023). Patients who delayed seeking care also experienced a delayed diagnosis 57% of the time (p=0.0023). Patients presenting with prodromal flu or upper respiratory involvement were more likely to have a delay/quest patient pathway (56% and 55%, respectively) than a direct patient pathway (44%, p=0.033 and 45%, p=0.019, respectively). There was a trend for patients with more severe loss of renal function to have a more direct referral to a nephrologist. Conclusion-Delay in diagnosis of ANCA SVV may be due to lack of or non-specific symptoms, especially in patients who present with non-renal manifestations of disease. Better algorithms are needed to identify extra-renal manifestations, expedite diagnosis and improve patient outcomes.

Annals of the Rheumatic Diseases, 2020

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relaps... more ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activi...

Journal of the American Society of Nephrology, 1996

In this study, the rate of remission, relapse, and treatment resistance in 107 patients with micr... more In this study, the rate of remission, relapse, and treatment resistance in 107 patients with microscopic polyangiitis and necrotizing and crescentic glomerulonephritis associated with antineutrophil cytoplasmic autoantibodies were assessed. Patients with Wegener's granulomatosis were excluded. Prospective criteria were identified to assess remission, relapse, and resistant disease. Ninety-seven of the 107 patients received treatment with corticosteroids (N = 25) or with cyclophosphamide and corticosteroids (N = 72). Of these patients, 75 (77.3%) went into remission (complete remission, N = 61; remission on therapy, N = 14). Of the 75 responders, 32 patients (43%) remained in long-term remission, for a mean follow-up of 44 +/- 29 months; 15 patients (20%) progressed to ESRD without signs of relapse, for a mean of 21.4 +/- 22.8 months after the end of treatment; 6 patients died. Twenty-two of the 75 patients who initially responded to treatment (29%) suffered a relapse that occurr...

PLOS ONE, 2019

Background Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MP... more 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 affinitypurified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis. We used lectin binding assays, liquid chromatography, and mass spectrometrybased 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.

Kidney International, 2019

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a dive... more In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complementmediated kidney diseases, and monoclonal gammopathies of renal significance.

Glomerulonephritis, 2017

Childhood-onset systemic lupus erythematosus (cSLE) has been defined as a subset of SLE with onse... more Childhood-onset systemic lupus erythematosus (cSLE) has been defined as a subset of SLE with onset prior to 18 years of age. Around 15% of SLE patients present with nephritis before this age, and debatably these patients have a greater genetic component to their disease etiology, a more systemic involvement, and a more severe disease course. Patients develop their loss of tolerance to self at an earlier time than patients with adult-onset SLE, or at least their loss of tolerance progresses sooner to immune complex deposition and tissue injury. In this chapter, we review the joint approach of pediatric nephrologists and rheumatologists towards patients with cSLE and nephritis. We address the areas where evidence exists and the areas wherewemust rely on expert opinion or evidence based on primarily adult studies. Fortunately, 5and 10-year mortality is lower than in adult-onset lupus nephritis, and patient and renal survival has improved over the years. However, relapses during the transition from adolescence to adulthood are common and cardiovascular and infectious complications are frequent in long-term survivors.

Autoimmunity Reviews, 2017

Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that pri... more Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that primarily affect small blood vessels of the airway and kidneys. Lung involvement, one of the hallmarks of microscopic polyangiitis and granulomatosis with polyangiitis, is associated with increased mortality and morbidity. In recent years, several retrospective series and case reports have described the association of interstitial lung disease (ILD) and ANCA vasculitis, particularly those positive for ANCA specific for myeloperoxidase. In the majority of these patients pulmonary fibrosis occurs concurrently or predates the diagnosis of ANCA vasculitis. More importantly, these studies have shown that ILD has an adverse impact on the long-term prognosis of ANCA vasculitis. This review focuses on the main clinical and radiologic features of pulmonary fibrosis associated with anti-neutrophil cytoplasmic antibodies. Major histopathology features, prognosis and therapeutic options are summarized.

Current Treatment Options in Rheumatology, 2016

This article is part of the Topical Collection on Vasculitis Keywords Vasculitis I Glomerulonephr... more This article is part of the Topical Collection on Vasculitis Keywords Vasculitis I Glomerulonephritis I ANCA-associated vasculitis I IgA vasculitis I Cryoglobulinemic vasculitis Opinion statement Small-vessel vasculitides (SVV) are a group of complex and chronic systemic autoimmune disorders associated with significant morbidity. Renal involvement is a major determinant of long-term outcome in all SVV. Depending on the disorder, SVV can be associated with frequent, and often life-threatening, relapses and increased burden from long-term exposure to toxic therapies and accumulating, irreversible organ damage. Prompt diagnosis or determination of active disease and quick initiation of appropriate treatment are therefore paramount in the management of SVV. For rapidly progressive glomerulonephritis or other severe, life-threatening manifestations in either anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) or cryoglobulinemic vasculitis (CV), we recommend intravenous pulse methylprednisolone, plasmapheresis, and intravenous monthly cyclophosphamide. Hemodialysis is also used when indicated. Dose adjustments are made based on the patient's weight, degree of renal impairment, and tolerability. Corticosteroids and plasmapheresis are tapered according to the patient's response. Although a clearer role for rituximab in the treatment of AAV and CV is emerging, we reserve rituximab for disease relapse or disease refractory to the aforementioned treatments. We also use rituximab in less severe disease and for maintenance of remission in AAV and CV when indicated. Corticosteroids are a mainstay of therapy in IgA nephropathy (IgAN) and vasculitis (IgAV). In rapidly progressive glomerulonephritis due to IgAN or IgAV, we recommend intravenous cyclophosphamide. Again, dose adjustments are made based on the patient's weight, degree of renal impairment, and tolerability.

Annals of the rheumatic diseases, Jan 30, 2015

B cell depletion is an effective remission induction and maintenance therapy in patients with ant... more B cell depletion is an effective remission induction and maintenance therapy in patients with antineutrophil cytoplasmic auto-antibody (ANCA)-associated vasculitis (AAV). 1-6 Rituximab targets both pathogenic effector B cells and protective regulatory B cells. To avoid infections and adverse events from therapy, clinicians require improved markers of disease activity and impending relapse to guide immunosuppression strategies following B cell depletion. We reported that CD5 + B cells, as a surrogate marker of B regulatory cells, are decreased in patients with active AAV and normalise during disease remission. 7 After B cell depletion, patients who repopulated with a low or decreasing percentage of CD5 + B cells and were on low maintenance immunosuppression had a shorter time to relapse than patients on similar levels of immunosuppression with normalised CD5 + B cells or patients with similarly low CD5 + B cells but higher immunosuppression. The CD5 + CD24 hi CD38 hi B cell subpopulation correlates inversely with active disease but parallels both interleukin (IL)-10 production and suppression of ANCA. 8 CD5 may identify B cells enriched in IL-10

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with i... more Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV. Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals. A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Sta...

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2015

Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)... more Rituximab has been used in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) since 2003. Our objective was to describe outcomes and adverse events following rituximab since that time in an inception cohort. Patients with AAV (diagnosed 1991-2012) who received rituximab (n = 120) were evaluated and incidence per person-year (PPY) with 95% confidence interval was calculated for relapse and infections. Time to remission and relapse by number of rituximab infusions given per treatment course (≤2 versus >2) and by ever having been exposed to cyclophosphamide were compared using Kaplan-Meier curves. Rituximab-treated patients were characterized in comparison with AAV patients treated with cyclophosphamide but not exposed to rituximab (n = 351) using Fisher's exact or rank tests. Rituximab resulted in 86% achieving remission and 41% having a subsequent relapse in a median of 19 months (range 9-29). Time to remission and relapse were similar between rituximab inf...

Seminars in Respiratory and Critical Care Medicine, 2011

Vasculitides that affect the lung represent a diverse group of diseases with various systemic cli... more Vasculitides that affect the lung represent a diverse group of diseases with various systemic clinical manifestations, and include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Churg-Strauss syndrome (CSS), and anti-glomerular basement membrane (anti-GBM) disease (Goodpasture syndrome). The etiologies of these diseases remain largely unknown. Although the pathogenic mechanisms of each differ, these diseases overlap by the presence of anti-neutrophil cytoplasmic autoantibodies in the vast majority of patients with MPA and GPA, and a substantial minority of patients with CSS and anti-GBM disease. This article reviews the current understanding of the pathogenesis of these four disease entities.

The New England journal of medicine, Jan 6, 2014

The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with ... more The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission. Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both). The 115 enrolled patients ...

Nephrology Dialysis Transplantation, 2005

Background. The treatment approaches to antineutrophil cytoplasmic autoantibody (ANCA) small vess... more Background. The treatment approaches to antineutrophil cytoplasmic autoantibody (ANCA) small vessel vasculitis expose patients to the risks associated with long-term use of corticosteroids and cytotoxic agents. In an effort to explore approaches to minimize risks, we conducted a pilot efficacy and safety study of mycophenolate mofetil (MMF) in the treatment of subjects with nonlife-threatening recurrent or cyclophosphamide-resistant ANCA-vasculitis. Methods. MMF was initiated at 500 mg orally twice daily and gradually increased to a target dose of 1000 mg twice daily for a duration of 24 weeks. Concomitant therapy with corticosteroids was allowed. The Birmingham Vasculitis Activity Score (BVAS) was used to assess disease activity and treatment efficacy. ANCA titres, serum creatinine and adverse events were secondary measures of efficacy and/or toxicity. Results. Twelve subjects were enrolled in the study. Treatment with MMF led to an improvement in disease activity as measured by the BVAS at 24 weeks (P ¼ 0.0013) and 52 weeks (P ¼ 0.0044) as compared to baseline. The BVAS decreased from an average of 9.1±3.5 at baseline (range, 3-17) to an average of 2.8±1.9 (range, 1-6) at 24 weeks and to 2.8±4.3 (range, 0-13) at 52 weeks. Early and sustained reductions in BVAS occurred in subjects initially classified as disease relapses vs those with treatment resistance. Side effect profile was consistent with the mechanism of action and pharmacokinetic disposition of MMF. Conclusions. MMF is a reasonable option in the treatment of non-life-threatening recurrent or resistant vasculitis and may obviate the immediate need for recurrent use of cytotoxic agents.

Nephrology Dialysis Transplantation, 2007

Background. Case reports have described the onset of antineutrophil cytoplasmic antibody (ANCA)as... more 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.

Kidney International, 2006

Myeloperoxidase (MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantib... more Myeloperoxidase (MPO) is one of the major target antigens of antineutrophil cytoplasmic autoantibodies (ANCA) found in patients with small-vessel vasculitis and pauci-immune necrotizing glomerulonephritis. To date, the target epitopes of MPO-ANCA remain poorly defined. Human MPO-ANCA do not typically bind mouse MPO. We utilized the differences between human and mouse MPO to identify the target regions of MPO-ANCA. We generated five chimeric MPO molecules in which we replaced different segments of the human or mouse molecules with their homologous counterpart from the other species. Of serum samples from 28 patients screened for this study, 43 samples from 14 patients with MPO-ANCA-associated vasculitis were tested against recombinant human and mouse MPO and the panel of chimeric molecules. Sera from 64 and 71% of patients bound to the carboxy-terminus of the heavy chain, in the regions of amino acids 517-667 or 668-745, respectively. No patient serum bound the MPO light chain or the aminoterminus of the heavy chain. All sera bound to only one or two regions of MPO. Although the pattern of MPO-ANCA binding changed over time (4-27 months) in 6 of 10 patients with several serum samples, such changes were infrequent. Other target regions of MPO-ANCA may not have been detected due to conformational differences between the native and recombinant forms of MPO. MPO-ANCA do not target a single epitope, but rather a small number of regions of MPO, primarily in the carboxy-terminus of the heavy chain.

Kidney International, 2009

The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the easter... more The Nijmegen Biomedical Study is a population-based cross-sectional study conducted in the eastern part of the Netherlands. As part of the overall study, we provide reference values of estimated glomerular filtration rate (GFR) for this Caucasian population without expressed risk. Age-stratified, randomly selected inhabitants received a postal questionnaire on lifestyle and medical history. In a large subset of the responders, serum creatinine was measured. The GFR was then measured using the abbreviated Modification of Diet in Renal Disease (MDRD) formula. To limit possible bias, serum creatinine was calibrated against measurements performed in the original MDRD laboratory. The study cohort included 2823 male and 3274 female Caucasian persons aged 18-90 years. A reference population of apparently healthy subjects was selected by excluding persons with known hypertension, diabetes, cardiovascular-or renal diseases. This healthy study cohort included 1660 male subjects and 2072 female subjects, of which 869 of both genders were 65 years or older. The median GFR was 85 ml/min/1.73 m 2 in 30-to 34-year-old men and 83 ml/min/1.73 m 2 in similar aged women. In these healthy persons, GFR declined approximately 0.4 ml/min/year. Our study provides age-and gender-specific reference values of GFR in a population of Caucasian persons without identifiable risk.

Kidney International, 1999

Recurrent ANCA-associated small vessel vasculitis after transsmall vessel vasculitis (ANCA-SVV) a... more Recurrent ANCA-associated small vessel vasculitis after transsmall vessel vasculitis (ANCA-SVV) and glomeruloneplantation: A pooled analysis. phritis, this group of diseases continues to cause end-Background. Recurrent antineutrophil cytoplasmic antistage renal disease in a substantial proportion of patients. body (ANCA)-associated small vessel vasculitis (ANCA-SVV) As a result, one would anticipate that the number of after renal transplantation has been described in case series. patients with ANCA-SVV and end-stage renal disease However, general information regarding the frequency, character, and predictors of recurrent disease after transplantation is will increase, bringing to the forefront issues pertaining currently lacking. We considered the rate of relapse, whether to renal transplantation in this patient population. a positive ANCA at the time of transplantation predicted re-Successful renal transplantation in patients with ANCAlapse, and whether cyclosporine A prevented recurrent disease. SVV has been reported in multiple case reports [1-3]. Methods. We performed a pooled analysis of published data, These include patients who were in full remission and added to the experience at the Universities of North Carolina (14 patients) and Lund, Sweden (11 patients). To avoid rewith negative ANCA tests, but also patients in remission porting bias, only case series were included for analysis. Subwith positive ANCA tests at the time of transplantation group analysis was performed by disease category (Wegener's

Journal of the American Society of Nephrology, 2004

Granulopoiesis-related genes are distinctively upregulated in peripheral leukocytes of patients w... more Granulopoiesis-related genes are distinctively upregulated in peripheral leukocytes of patients with antineutrophil cytoplasmic autoantibodies (ANCA)-associated glomerulonephritis. Affymetrix microarrays identified the upregulation of nine neutrophilic primary granule genes, including myeloperoxidase (MPO) and proteinase 3 (PR3), plus five secondary granule genes. Coordinate expression of granulocyte maturation marker CD35, measured by TaqMan PCR, and positive in situ staining for PR3 transcripts in polymorphic neutrophils and monocytes indicate that these genes are expressed in "mature" cells. Increased transcripts correlated with disease activity and absolute neutrophil values but not with "left shift," drug regimen, cytokine levels, hematuria, proteinuria, ANCA titer, serum creatinine, gender, or age. Upregulation of PR3 and MPO transcripts was specifically associated with ANCA disease (n ϭ 56) as these changes were not detected in patients with ESRD (n ϭ 25) or systemic lupus erythematosus (n ϭ 17), as determined by TaqMan PCR. This is the first report of this phenomenon in nonneoplastic cells. The data raise the hypothesis that, in addition to the presence of anti-MPO or anti-PR3 autoantibodies, a second critical component in the cause of this disease is the reactivation of once-silenced genes leading to increased antigen availability.