Antibody-associated Vasculitis Research Articles

#4709 PERSONALISED INDUCTION THERAPY IN ANCA GLOMERULONEPHRITIS

Abstract Background and Aims Patient and kidney outcome in ANCA glomerulonephritis (GN) remains unsatisfactory. Rituximab use failed to reduce the rate of infectious complications and demonstrates a significant rate of hypogammaglobulinaemia in ANCA vasculitis. Adjusting the rituximab dosage to the individual patient's need promises a reduction in treatment toxicity. Method Retrospective analysis of a single centre cohort of ANCA GN patients with disease flares between 2019 – 2022 using a stratified induction immunosuppression with rituximab and cyclophosphamide. Treatment intensity was adjusted to resolution of systemic inflammation and microscopic haematuria, peripheral CD19 cell count depletion and immunoglobulin G (IgG) levels. Results 45 patients (median age 57 years, 55.7% female, median eGFR 27 mls/min) were treated with a median dose of 1.5 grams Rituximab during induction (interquartile range, IQR 1 – 2 grams). 18 patients received concomitant intravenous cyclophosphamide pulses to control the acute inflammation (median cumulative dose of 2 grams, IQR 1.65 – 3 grams). Peripheral B cell depletion was 91.4% at 3 months and 90.3% at 6 months (<3 CD19 cells/ul). During the initial 12 months treatment, IgG level fell below 7g/l in 20 patients, below 5g/l in nine patients and below 3g/l in one patient. Seven patients required renal replacement therapy at diagnosis (15.6%). Five patients recovered kidney function and three patients developed end stage kidney disease (6.7%). Twelve infections were reported requiring antibiotic treatment (26.7%), seven severe infections were documented requiring hospitalisation (13.3%) and one patient died (2.2%). Conclusion An early assessment of treatment response assists adjusting vasculitis therapy. Adjusting management to the patient's individual immunological and treatment response may result in better outcome with less treatment toxicity.

#4201 DYNAMICS OF INFLAMMATION EARLY AND LATE AFTER RENAL TRANSPLANTATION: CHARACTERIZATION OF THE IMMUNOLOGICAL PROCESSES IN A RAT RENAL TRANSPLANT MODEL

Abstract Background and Aims The pathophysiology of rejection after renal transplantation (RTx) has not been unraveled completely. In previous studies, Th17 cells were shown to be involved in several autoimmune diseases affecting the kidney, e.g. lupus nephritis, glomerulonephritis and ANCA vasculitis. The aim of this study was to decipher the dynamics of rejection after RTx with focus on the Th17 cells and IL17 cytokine family. Method For this purpose, the established Fischer to Lewis rat RTx model was used. In this model, renal rejection is elicited and develops over time. The donor renal grafts were harvested from Fischer rats and exposed to static cold storage using HTK or UW buffer. The Lewis recipients were treated for 10 days post-transplant with ciclosporin A and then immunosuppressive therapy stopped. Recipients were harvested early (2 hours, 30 days) and late after RTx (12 weeks, 28 weeks). To analyze the dynamics of inflammation, kidney sections were stained for CD3+ (T-cells) and MPO (neutrophils). RT-PCR was used to detect cytokine gene expression of several target genes within the renal grafts. IL17A Elispot was established to analyse circulating Th17 cells in the recipients. Results Generally, the cold ischemia time of the renal allograft was associated with the lifetime of the recipients. Furthermore, with increasing cold ischemia time of the graft, intra-renal CD3+ T-cell infiltration was enhanced. An increased CD3+ and a diminished number of MPO+ neutrophils were detected in the renal grafts late after RTx compared to early timepoints. Moreover, the intra-graft IL17C gene expression was enhanced late after renal transplantation while CXCL1 and CXCL2 were upregulated early after renal transplantation. IL17A gene expression reached higher levels than IFNg in later timepoints e.g. 30 days, while in early stages IL17A was below IFNg. The impact of cold storage buffer on the immunogenicity of the renal transplant was investigated, too. The use of UW led to a higher intra-renal CD3+ T-cell infiltration at later timepoints compared with HTK. In early stages after transplantation, higher levels of intra-renal MPO+ neutrophils were found upon cold storage using UW compared to cold storage using HTK. Conclusion The inflammatory process during chronic kidney rejection is T-cell driven and may involve the IL17C cascade. The early phase is dominated by neutrophils with enhanced intra-renal expression of CXCL1 and CXCL2. Furthermore, the polarization of the T-cell driven immune response may change depending on the time point after transplantation.

#2663 KIDNEY INVOLVEMENT IN MYELODYSPLASTIC SYNDROMES

Abstract Background and Aims Myelodysplastic syndromes (MDS) are hematologic disorders characterized by ineffective and dysplastic hematopoiesis that can be associated with systemic inflammatory and autoimmune diseases. The objective of this study was to describe kidney involvement in MDS patients, their treatments, and outcomes. Method We conducted a French and American multicenter retrospective observational study in nine centers, identifying MDS patients with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities. Results Seventeen patients (males n = 11, median age 76 [70-79]) developed a kidney disease 6 months [0-31] after the diagnosis of MDS. Median urinary protein to creatinine ratio was 1.9g/g [0.8-3.3], and median serum creatinine was 3.5mg/dL [1.5-4.7]. Twelve patients (70%) had AKI at presentation, and 14 (82%) extra-renal symptoms, which consisted mostly in cutaneous and pneumological manifestations. The renal diagnoses included antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) (n = 8, 47%), ANCA negative vasculitis (n = 4, 24%), C3 glomerulonephritis (n = 2), immune complex-mediated glomerulonephritis (n = 1), polyarteritis nodosa (n = 1), and IgA vasculitis (n = 1). Kidney biopsies were performed in 10 of the cases. All patients, except one, received a treatment following the MDS-associated kidney injury (n = 16, 94% with steroids). The effect of MDS treatment on kidney injury could be assessed in 8 patients treated with azacitidine, and renal function evolution was heterogenous. After a median follow-up of 9 months [4.1-14.2], 4 patients had CKD stage 3, 4 CKD stage 4, 5 an end stage kidney disease. Three patients evolved to an acute myeloid leukemia (AML), and 3 died. Compared to 84 MDS controls, patients who had a kidney involvement were younger (p = 0.03), had a higher number of dysplasia lineages (3 lineages, p = 0.001), and were more eligible to receive hypomethylating agents (p = 0.031), but no survival difference was seen between the two groups (p = 0.5227). Compared to 265 AAV without MDS, MDS-associated AAV were older (p = 0.019), ANCA serology was more frequently negative (p = 0.014), and more cutaneous lesions were seen (p = 0.003). Conclusion The spectrum of kidney injuries associated with MDS is mostly represented by vasculitis, and especially AAV. A diagnosis of ANCA vasculitis in an elderly patient, or with a cutaneous manifestation, or without ANCA positivity, should lead to the search for a possible MDS.

#5104 GLOMERULAR DISEASES ASSOCIATED WITH SARS-COV2 INFECTION AND VACCINATION: A MULTICENTRIC REGIONAL RETROSPECTIVE STUDY

Abstract Background and Aims The SARS-CoV2 caused a pandemic disease, leading to millions of cases and fatalities worldwide. Kidney involvement is frequent and glomerular diseases (GD) have been reported in association with infection. Podocytopathies, endothelial injury with thrombotic microangiopathy are the most common histological findings in literature. From January 2021 anti SARS-CoV2 vaccination became available. Several GD has also been associated with vaccination. IgA nephropathy (IgAN) and minimal change disease (MCD) are the most common GD reported in patients who received vaccination. Our aim was to assess the histological findings in patients who presented kidney involvement after SARS-CoV2 infection and/or vaccination and to compare the frequencies of GD in these patients to those in non-Covid19 population. Method We conducted a retrospective study of kidney pathology in patients undergoing native kidney biopsy within 90 days of SARS-CoV2 infection and/or vaccination, between February 2020 and August 2022 in Apulia Region of Italy. We considered separately patients without history of urinary abnormalities and/or kidney dysfunction prior to infection and/or vaccination in order to detect GD which were more likely to be related to infection and/or vaccination than to pre-existent pathologies. We used a database of kidney biopsies performed in a period of 5 years (from January 2015 to February 2020) prior to the Covid19 pandemic as a control comparison cohort to examine glomerular diseases frequencies. Results Among the 808 biopsies: 36 (4.4%) were carried out within 90 days of SARS-CoV2 infection (Group 1) and 142 (17.6%) within 90 days of vaccination (Group2). Among them, we identified 12 patients with renal symptoms raised after COVID19 infection (Group 3) and 26 patients after vaccination (Group 4). In the Group 1 the main histological diagnosed founded were: podocytopathies (25.1%), IgAN (16.7%) and ANCA-vasculitis (13.9%). In Group 2, the most common histological diagnosis were IgAN (18.3%), podocytopathies (17%) and membranous nephropathy (MN) (10.6%). In the Group 3 we found a predominance of podocytopathies (33.3%) followed by ANCA-vasculitis and IgAN (three patients each, 25%). In the Group 4, the most frequent GD were podocytopathies (36.6%) followed by ANCA-vasculitis (19.2%) and IgAN (15.4%). Between the 1380 kidney biopsies from the 5 years pre-Covid19 period, the most frequent histological diagnosis were IgAN (18.3%), podocytopathies (18%) and MN (10.9%). Comparing Group 1 and Group 2 data with the 5 years pre-Covid19 database we found a significant increased prevalence only of ANCA vasculitis in group 1 (13.9% of patients after Covid19 infection vs 5.6% of pre-covid database (p-value: 0.03)). Comparing data from patients who had developed renal signs after Covid19 infection (group 3) and/or vaccination (group 4) with those in the 5 years database a significant higher prevalence of ANCA-related crescentic glomerulonephritis was found in both group. The 25% of patients of the Group 3 and the 19.2% of the Group 4 had a histological diagnosis of vasculitis, while these were found only in the 5.7% of patients from the pre-Covid19 database (p-value: 0.004 for Group 3 and 0.003 for Group 4). Furthermore podocytopathies in group 4 were significantly higher than pre-covid19 (36.6%vs18.3%, p = 0.02). Conclusion We found a higher prevalence of ANCA vasculitis and podocytopathies in patients with symptoms developed after SARS CoV2 infection/immunization compared to diagnosis prevalence in a pre-Covid19 reference database.

#2754 EPIDEMIOLOGY OF PAUCI-IMMUNE ANCA-ASSOCIATED GLOMERULONEPHRITIS – REPORT FROM AN AUSTRALIAN POPULATION-BASED STUDY

Abstract Background and Aims ANCA-associated vasculitis is a group of autoimmune vasculitides of unknown aetiology that predominantly affect small blood vessels among different organ systems, with different phenotypic manifestations. Although vasculitides were reported to account for 12 percent of all renal biopsies in the state of Victoria [1] and crescentic glomerulonephritis was reported to account for 6 percent of all renal biopsies in the state of Queensland [2], the epidemiology data on renal predominant ANCA vasculitis, particularly renal biopsy confirmed ANCA associated glomerulonephritis (AAGN) is limited. Method This retrospective study was performed at the Royal Brisbane and Women's Hospital, a major tertiary hospital that service a population of 1,030,006 in North Brisbane, Australia. The 2012 Chapel Hill Consensus Conference definitions were used to identify renal predominant ANCA vasculitis. Patients with pauci-immune glomerulonephritis confirmed on kidney biopsy between 1st January 2005 to 1st October 2021 were selected. Clinical data was collected via electronic and paper medical records. Modified Monash Model classification was used to determine rurality of cases. Results 1433 kidney biopsy results were reviewed. 80 cases of biopsy-confirmed pauci-immune AAGNs were identified. There was no significant difference in gender (Male; 42/80 (53%), p = 0.87). There was a preponderance towards MPO-positive AAGN (53/80), as opposed to PR3-positive disease (21/80), 5/80 were ANCA negative and 1/80 did not have ANCA serology available. The mean age of diagnosis was similar between MPO and PR3 (63.7 vs 59.5 years, p = 0.34) and between males and females (63.3 vs 59.3, p = 0.42). There was no seasonal variation in AAGN diagnoses – 23/80 in spring, 20/80 in summer, 14/80 in autumn, 23/80 in winter ( χ2 = 1.48, p = 0.69). Fourteen (18%) patients died during the study period, 3 of which died prematurely before age 65. Within our cohort, 16% (13/80) of cases lived in regional/rural areas. Interestingly, all 3 premature deaths were from these areas. This may reflect poorer access to health care in regional/rural settings. Conclusion Pauci-immune ANCA-associated glomerulonephritis remains rare in North Brisbane, with estimated annual incidence of 4.6/million population, representing 5.6% of all kidney biopsies. The incidence is significantly lower than an American-based study that reported an incidence of 20 cases/million population [3] whilst a Swedish study reported an incidence of 13.2 cases/million population [4]. The reason behind the geoepidemiology variation is unclear, though there are evidence suggesting complex interaction of polygenic genetic susceptibility, epigenetic influences, and environmental associations such as rurality of living. Within our cohort, the incidence of MPO AAGN was 2.5 fold higher than PR3 AAGN, this is similar to other observed European and American data [5]. Our findings add to the current literature, particularly where epidemiological data on AAGN from the southern hemisphere is limited.

#4683 CHARACTERISTICS AND OUTCOMES OF MPO VERSUS PR3 ANCA ASSOCIATED GLOMERULONEPHRITIS: A REPORT FROM AN AUSTRALIAN POPULATION-BASED STUDY

Abstract Background and Aims ANCA-associated vasculitis is a group of autoimmune vasculitides of unknown aetiology that predominantly affect small blood vessels among different organ systems, with different phenotypic manifestations. Myeloperoxidase (MPO) and Proteinase 3 (PR3) have emerged as two main serological subtypes and growing evidence has shown there are differences between their disease characteristics [1,2]. We investigate into the difference in histological presentation, disease manifestation and progression, as well as mortality rate in patients with biopsy confirmed ANCA associated glomerulonephritis (AAGN). Method This retrospective study was performed at the Royal Brisbane and Women's Hospital, a major tertiary hospital that service a population of 1,030,006 in North Brisbane, Australia. The 2012 Chapel Hill Consensus Conference definitions was used to identify renal predominant ANCA vasculitis. Patients with pauci-immune glomerulonephritis confirmed on kidney biopsy between 1st January 2005 to 1st October 2021 were selected for review. Biopsies were categorised according to Berden's histopathologic classification. Clinical data were collected via medical records. Results Of 80 cases of AAGN identified during the study period, 53 cases were MPO/pANCA positive and 21 cases were PR3/cANCA positive, there were 5 ANCA negative cases and one indeterminate case due to unavailable serology results. There was no statistical significant difference between gender and ANCA subtype (Male MPO 53% and Male PR3 48%, p=0.57). Lung involvement was the most common extra-renal manifestation of AAGN. Similar rates were found between MPO and PR3 positive diseases, 30% (16/53) and 29% (6/21), respectively. PR3 AAGN were much more likely to have sinus involvement, 14% (3/21) vs 4% (2/53) (Relative Risk 3.8, p=0.13). Berden classification was used to classify renal biopsy results (Table 1). There were more cases of sclerotic AAGN within the MPO group whereas crescentic AAGN cases were more common in the PR3 group (Fisher Exact test, p=0.43) Estimated Glomerular Filtration Rate (eGFR) were measured at time of AAGN diagnosis compared to at 3 years. In the MPO group, 45% cases had recovery of eGFR by at least 5mls/min, compared to 62% in PR3 group (P = .30). In addition, 91% (40/44) had improvement of MPO titre following induction treatment, compared to 83% (15/18) in PR3 group had improvement in their titre (p=0.40). Eighteen percent (14/80) of AAGN cases died during the study period. The crude mortality rate for MPO, PR3 and ANCA negative cases were 21% (11/53), 10% (2/21) and 20% (1/5) respectively (p=0.33). Conclusion In our cohort, MPO AAGN was more prevalent (RR 2.5), more likely to have sclerotic class on biopsy (i.e. typically carries the worst prognosis), less likely to have eGFR recovery following treatment and had a higher mortality rate. This is despite the MPO group having a higher titre response rate. Both MPO and PR3 are associated with lung involvement but sinus involvement was significantly more common in PR3 disease. ANCA negative pauci-immune GN remains an uncommon, recognised subtype. Allowing for rarity of disease, larger longitudinal cohort studies are desirable to further define the disease characteristics between AAGN subtypes.

ANCA vasculitis expands the spectrum of autoimmune manifestations of activated PI3 kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a combined immunodeficiency with a broad clinical phenotype, including not only an increased propensity for sinopulmonary and herpesviruses infections but also immune dysregulation, such as benign lymphoproliferation, autoimmunity, and malignancy. Autoimmune complications are increasingly recognized as initial presenting features of immune dysregulation in inborn errors of immunity (IEIs), including APDS, so awareness of the spectrum of autoimmune features inherit within these disorders is critical. We present here a patient vignette to highlight cutaneous antineutrophil cytoplasmic antibody (ANCA) vasculitis as an underrecognized autoimmune manifestation of APDS. The genetic defects underlying APDS result in increased PI3Kδ signaling with aberrant downstream signaling pathways and loss of B- and/or T-cell immunologic tolerance mechanisms, which promote the development of autoimmunity. An understanding of the molecular pathways and mechanisms that lead to immune dysregulation in APDS has allowed for significant advancements in the development of precision-medicine therapeutics, such as leniolisib, to reduce the morbidity and mortality for these patients. Overall, this case and review highlight the need to maintain a high index of suspicion for IEIs, such as APDS, in those presenting with autoimmunity in combination with a dysregulated immune phenotype for prompt diagnosis and targeted intervention.

P200 The relationship between patient and physician global assessment in patients with anti-neutrophil cytoplasmic antibody associated vasculitis

Abstract Background/Aims Patients with anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) often have reduced health-related quality of life (HRQoL) as assessed by the SF-36 questionnaire. Global assessment provides a patient and physician’s view on the patient’s overall health and wellbeing. The aim of this project was to examine the level of agreement between the patient and physician global assessment (PtGA and PhGA) in patients with AAV. Methods Patients attending our dedicated tertiary vasculitis clinic were recruited into this prospective study. PtGA and PhGA scores, out of 100, were assessed via a visual analog scale, with higher scores representing better health. SF-36 assessed HRQoL. Discordance was defined as an absolute difference of ≥ 20 between PhGA and PtGA. Active disease was defined as a BVAS of ≥ 1. Results Ninety-seven patients (mean age 58 years, 46% male) participated. Forty-three (44%) patients had active disease. The majority (88%) were on immunosuppressive therapy with renal (79.4%), lung (42.3%) and sino-nasal (40.2%) being the most commonly involved systems. The mean (SD) PtGA and PhGA was 63.4 (22.2) and 60.8 (24.8) respectively (t = 2.63, p = 0.0049). Mean (SD) PtGA in active versus inactive disease was 59 (22.8) and 66 (21.5) respectively (t = 1.49, p = 0.07). PhGA scores were higher than PtGA in 44 patients with an overall mean difference of + 13.7 (95% confidence interval [CI] 9.97, 17.46, p < 0.001). PtGA scores were higher than PhGA in 48 patients (mean difference +17.9, 95% CI 22.6, 13.3, p < 0.001). Scores were discordant in 26 patients, with PhGA>PtGA (negatively discordant) in 10 (38%). Mean (SD) PhGA in discordant patients versus non-discordant patients was 47.5 (24.7) versus 65.7 (23.1) respectively (t = 1.71, p = 0.001). Mean (SD) age in positively discordant versus negatively discordant patients was 58.8 (17.3) versus 69.1 (8) respectively (t = 1.71, p = 0.026). The percentage of patients with active disease (n=number of patients) in positively discordant versus negatively discordant patients was 50% (n = 8) versus 30% (n = 3) respectively (p = 0.008). Bland-Altman plots showed no systematic bias as global scores increased. Conclusion Overall, physicians did not overestimate patients' global health when using the global assessment tool. Discordance rates were 26%, within which physicians were likelier to assess the patient's global health as lower than patients did themselves. Positively discordant patients (PhGA<PtGA) were likelier to have active disease and were younger on average. Disclosure A. Bhonsle: None. T. Coughlan: None. R. Graven: None. P. Bussa: None. M. Gingold: None. K. Polkinghorne: None. J. Ryan: None. A. Kitching: None.

Protein Profiling in Presymptomatic Individuals Separates Myeloperoxidase-Antineutrophil Cytoplasmic Antibody and Proteinase 3-Antineutrophil Cytoplasmic Antibody Vasculitides.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset. The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls. Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity. To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes.

Identification of new immune subtypes of renal injury associated with anti-neutrophil cytoplasmic antibody-associated vasculitis based on integrated bioinformatics analysis.

Background: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that may lead to end-stage renal disease. However, few specifific biomarkers are available for AAV-related renal injury. The aim of this study was to identify important biomarkers and explore new immune subtypes of AAV-related renal injury. Methods: In this study, messenger RNA expression profiles for antibody-associated vasculitis and AAV-associated kidney injury were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was performed to identify the most relevant module genes to AAV. Key module genes from WGCNA were then intersected with AAV- and nephropathy-related genes from the Genecards database to identify key genes for AAV-associated kidney injury. Subsequently, the expression of key genes was validated in independent datasets and the correlation of genes with clinical traits of kidney injury was verified by the Nephroseq database. Finally, non-negative matrix factorization (NMF) clustering was performed to identify the immune subtypes associated with the key genes. Results: Eight co-key genes (AGTR2, ANPTL2, BDKRB1, CSF2, FGA, IL1RAPL2, PCDH11Y, and PGR) were identifified, and validated the expression levels independent datasets. Receiver operating characteristic curve analysis revealed that these eight genes have major diagnostic value as potential biomarkers of AAV-related renal injury. Through our comprehensive gene enrichment analyses, we found that they are associated with immune-related pathways. NMF clustering of key genes identified two and three immune-related molecular subtypes in the glomerular and tubular data, respectively. A correlation analysis with prognostic data from the Nephroseq database indicated that the expression of co-key genes was positively co-related with the glomerular filtration rate. Discussion: Altogether, we identifified 8 valuable biomarkers that firmly correlate with the diagnosis and prognosis of AAV-related renal injury. These markers may help identify new immune subtypes for AAV-related renal injury.

142 A Case of Hydralazine Induced Severe Renal-Limited ANCA Vasculitis Leading to ESRD in a 63-Year-Old Man

142 A Case of Hydralazine Induced Severe Renal-Limited ANCA Vasculitis Leading to ESRD in a 63-Year-Old Man

Unusual Presentation of Anca Vasculitis with Otitis Media and CVA

A 42-year-old African female (Kenyan in origin), known to have hypertension that was diagnosed during gestation and persisted; presented with a history of dysphagia for four years. Before her admission, she had presented to the surgical clinic with ear fullness and ear pain with throbbing headaches, and she was diagnosed with bilateral oto-mastoditis. Her symptoms subsequently, progressed to a multisystemic disease involving the lungs, brain, kidneys, and peripheral nerves. ANCA vasculitis is a rare disease, the main target organs in granulomatous polyangiitis include the ear, nose throat, and upper respiratory tract, and glomerulonephritis of the kidney and the lungs. Localized disease manifestation can include the nose (rhinorrhea, nasal crusts, septal perforation) and ear (otitis media, hearing loss, sensorineural deficits). The diagnosis of vasculitis from localized disease manifestation can be difficult to diagnose.

Propylthiouracil-related ANCA vasculitis

Propylthiouracil-related ANCA vasculitis

PRTN3 variant correlates with increased autoantigen levels and relapse risk in PR3-ANCA versus MPO-ANCA disease.

A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.

Treatment of Recurrent Antineutrophil Cytoplasmic Antibody-Associated Vasculitis After Kidney Transplant With Rituximab: A Successful Case Report

Antineutrophil cytoplasm antibody-associated systemic vasculitis is a rare disease that frequently leads to end-stage renal disease. Kidney transplant should be delayed until patients are in complete clinical remission for at least 6 months, but the persistence of antineutrophil cytoplasmic antibody titers should not delay transplant. Recurrence of disease after kidney transplant is rare, with only a few cases described in the literature with heterogenous clinical manifestations, therapeutic approaches, and prognosis. We describe the case of a young male patient with recurrent antineutrophil cytoplasmic antibody vasculitis, 5 years after kidney transplant, successfully treated with methylprednisolone pulses plus rituximab. Rituximab presents a new valid option for the treatment of antineutrophil cytoplasmic antibody vasculitis relapse in kidney grafts.

332. Adding low dose cyclophosphamide to rituximab is associated with sustained remission in ANCA vasculitis patients

332. Adding low dose cyclophosphamide to rituximab is associated with sustained remission in ANCA vasculitis patients

Challenges of defining renal response in ANCA-associated vasculitis: call to action?

Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.

Pediatric ANCA vasculitis: clinical presentation, treatment, and outcomes in a French retrospective study.

Pediatric ANCA vasculitis is a rare group of diseases with a scarcity of data in children. Annual incidence appeared to increase in the last several years, placing higher interest in the clinical and therapeutical outcomes of the disorder. Also, the growing use of rituximab questions the latest outcomes in these diseases. We therefore conducted a retrospective study to better understand the current characteristics, management, and the latest outcomes of the disorder. We conducted a 9-year retrospective study of 46 children in 14 different centers across France to describe their clinical and laboratory presentations, therapeutic regimens, and kidney outcome. P-ANCA appeared to be a potential marker for higher relapse risk. Compared to adults, we found that ear-nose-throat presentations were frequent (45.7%) and more severe. Despite an evolution in the treatment management, kidney outcome remained poor with a substantial proportion of chronic kidney disease (54.8% at 1year). Mortality stays low with 3 patients (6.5%) deceased at the end of our study. Clinical presentation was as previously described and time to diagnosis remains long. P-ANCA is a statistically significant marker for increased relapse risk. We observed a modification in the treatment regimens over the past several years with a growing use of rituximab and a decreasing use of cyclophosphamide. Despite these changes, kidney outcome remains poor and prospective studies should be conducted to assess the most appropriate therapeutic modality for each patient. A higher resolution version of the Graphical abstract is available as Supplementary information.

Adding low dose cyclophosphamide to rituximab for remission-induction may prolong relapse-free survival in patients with ANCA vasculitis: A retrospective study

ObjectiveRituximab (RTX) and cyclophosphamide (CYC) are effective remission-induction therapies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, combining these therapies may favor prognosis in patients with a major disease presentation. We conducted a retrospective study to compare patients treated with a combination of RTX and low dose CYC (RTX-CYC) or with RTX only, both followed by tailored maintenance with RTX, with regard to long-term outcomes. MethodsPatients treated in the Maastricht University Medical Center between March 2007 and January 2019, were screened for eligibility. The primary outcome variable was major relapse rate after two and five years. Secondary outcome variables were clinical data and laboratory parameters. ResultsOf the 246 screened patients, 34 received RTX-CYC and 28 RTX only for remission-induction. All patients were followed for at least two years, with a median follow-up of 48 months (IQR 24–60). At baseline, renal involvement was more prevalent in the RTX-CYC patients (85% vs. 61%, P = 0.028). Major relapse rates within two years, but not after five years, were significantly lower in the RTX-CYC group (3% vs. 24%, P = 0.032). The rate of infections, hypogammaglobulinemia, end-stage renal disease, malignancies, and mortality did not differ after two and five years. ConclusionAdding low dose CYC to RTX is safe and may prevent major relapses in patients with severe AAV in the first two years after remission-induction. Randomized controlled trials that compare the efficacy and safety between RTX and a combination of RTX with CYC are needed.

355: RHINOVIRUS-ASSOCIATED ANCA VASCULITIS: A RARE ASSOCIATION

Introduction: The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV) are immune mediated diseases, associated with antigen exposure and host immune response. Approximately 52–80% of patients with AAV have pulmonary abnormalities on chest CT, mainly interstitial lung disease (ILD), granuloma, or alveolar hemorrhage. Myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) has been particularly associated with interstitial lung disease and the majority of patients present with pulmonary symptoms prior to the diagnosis of ANCA vasculitis. ILD is a relatively uncommon manifestation of MPO-ANCA, but signifies a poor prognosis. We present a patient with rhinovirus infection associated ANCA vasculitis. Description: A 42-year-old female with a past medical history of COPD, bipolar disorder, and intravenous drug use presented to the emergency department in acute respiratory distress. Computed tomography of the chest revealed bilateral diffuse, patchy ground glass opacities. Respiratory PCR testing was positive for rhinovirus. The patient was admitted to the ICU for acute hypoxic respiratory failure. Her respiratory status continued to decline during the ICU stay. Serum studies including DsDNA, SSA, SSB, anticentromere, myositis, aldolase and ANCA were obtained. The studies were positive for MPO-ANCA. The patient was treated with high dose methylprednisolone. Subsequently, the oxygen demand improved and the patient made a full recovery, with plan for outpatient biopsies. Discussion: MPO-ANCA is a marker which may be induced by various drugs, dust inhalation, smoking, heavy metal exposure, or silica exposure. The hypothesized mechanism involves cytokines produced by antigens to induce MPO expression within the neutrophil cell membrane. The ANCA component binds to MPO to induce neutrophil activation which then activates the inflammatory cascade. The overproduction of cytokines causes vascular endothelial cell damage and ultimately vasculitis. One proposed mechanism of MPO-ANCA involves the alteration in degradation of neutrophil extracellular traps (NETs) likely due to infections. This mechanism leads to an increase in MPO-ANCA binding. NETs have a proliferative effect on lung fibroblasts, and thus are seen alongside fibroblasts in patients with MPO-ANCA interstitial pneumonia.