ANCA-associated Vasculitis Disease Research Articles

Clinical associations with thyroid disease in ANCA-associated vasculitis.

To evaluate the frequency and the clinical relevance of thyroid disease in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. A total of 305 AAV patients admitted to the Second Affiliated Hospital of Chongqing Medical University between October 2010 and December 2023 were analyzed. Demographic, clinical, and laboratory data were compared between AAV patients with and without thyroid disease. Univariate and multivariate logistic regression analyses were conducted to identify factors associated with thyroid disease in AAV patients. Among the 305 AAV patients, 52 (17.0%) had concurrent thyroid disease. In univariate analysis, gender, coronary artery disease, renal involvement, anti-Ro/SSA antibodies, anti-Ro52 antibodies, anti-thyroglobulin antibodies (TgAb), and anti-thyroid peroxidase antibodies (TPOAb) exhibited significant differences between AAV patients with and without thyroid disease (P < 0.05). Multivariate analysis revealed that female gender (odds ratio (OR) = 2.423, 95% confidence interval (95% CI) 1.241, 4.729; P = 0.009), concurrent coronary artery disease (OR = 2.998, 95% CI 1.280, 7.019; P = 0.011), and positive anti-Ro/SSA antibodies (OR = 4.697, 95% CI 1.960, 11.257; P = 0.001) were associated with thyroid disease in AAV patients. AAV patients have a higher incidence of thyroid disease. Regular monitoring of thyroid function is advised for AAV patients, particularly for women, those with coronary artery disease, and those who are positive for anti-Ro/SSA antibodies. Key Points • AAV patients have a higher incidence of thyroid disease. • The potential clinical relevance of AAV patients with thyroid disease was explored. • Regular monitoring of thyroid function is advised for AAV patients.

Classification Criteria for ANCA Associated Vasculitis - Ready for Prime Time?

This review aims to summarize the evolution and recent developments in the classification of ANCA associated vasculitis (AAV) and to summarize evaluations of the 2022 ACR/EULAR classification criteria of AAV in several cohorts. The classification of AAV has been a field of controversy for some time. The parallel existence of classification criteria and disease definitions produced some overlap in classification, leading to challenges when comparing different cohorts. The 2022 ACR/EULAR classification criteria derived from the largest study ever conducted in vasculitis account for significant changes in vasculitis classification with the integration of ANCA and modern imaging. These criteria show good performance compared to previous ones but also raise questions as ANCA serotypes have substantial impact on classification. In addition, there are some discrepancies with earlier agreed histopathological features of AAV disease phenotypes. During the last 35years, several sets of classification criteria have evolved to facilitate epidemiologic studies and clinical trials in AAV. While some of these criteria have been in use for many years, they were criticized due to either not using ANCA or not integrating surrogate markers for vasculitis but also due to overlapping when used in parallel. The long-awaited new ACR/EULAR criteria for AAV were published in 2022 and are the result of a large international study, introducing for the first time ANCA and modern imaging in the classification of AAV. Though the criteria show good performance, they bring several other challenges with practical application.

Thyroid disease in ANCA-associated vasculitis: a clinical and epidemiological study

ObjectivesTo describe clinical and laboratory characteristics and outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and thyroid disease (TD). We also aimed to calculate incidence and identify predictors...

Clinical features and outcomes of small airway disease in ANCA-associated vasculitis.

To clarify the prevalence, features and outcomes of small airway disease (SAD) in a Chinese cohort with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) related pulmonary involvement. SAD was recorded when the manifestations of either centrilobular nodules or air trapping were observed according to CT scans, except for infection or other airway-related comorbidities. Baseline and follow-up data were collected retrospectively. Of the 359 newly diagnosed AAV patients with pulmonary involvement, 92 (25.6%) had SAD, including 79 (85.9%) cases of anti-MPO-ANCA positive, 9 (9.8%) cases of anti-PR3-ANCA positive and 2 (2.2%) cases of double positive. Patients with SAD were more likely to be younger, female, non-smokers, have more ear-nose-throat (ENT) involvement, and have higher baseline Birmingham Vasculitis Activity Score (BVAS) compared to patients without SAD. Several AAV-related SAD patients have improved lung function and CT scans after immunosuppressive therapy. Patients with SAD had a better prognosis compared to those without SAD. When dividing all patients into three groups: isolated SAD (only small airway involvements), SAD with other lower airway involvements, and non-SAD, patients in the SAD with other lower airway involvements group had the highest risk of infection, while patients in the non-SAD group had the worst long-term outcomes. Similar results were observed in anti-MPO-ANCA positive patients when performing subgroup analyses. SAD is a unique manifestation of AAV-related lung involvement and exhibits distinct clinical features. It is vital to focus on SAD because of its association with prognosis and infection in AAV patients, especially in anti-MPO-ANCA positive patients. Moreover, SAD might represent a better response to immunosuppressors.

Renal histopathological predictors of end-stage kidney disease in ANCA-associated vasculitis with glomerulonephritis: a single-centre study in Korea

This study investigated whether histopathological classification and histologic lesion scores could significantly and independently predict the progression to end-stage kidney disease (ESKD) in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis-glomerulonephritis (AAV-GN). This study included 113 patients with AAV-GN confirmed by kidney biopsy. The glomerular, tubulointerstitial, and vascular lesions were systematically assessed using a scoring system. The scoring system was adopted from the Banff scoring system but also the Oxford study and the revision of the ISN/RPS. For comparison, the scores were classified into two groups; the low, and the high, and the difference was investigated between ESKD and non-ESKD groups using Cox proportional analysis. At diagnosis, the median age was 59.0 years and 33.6% were males. Of 113 patients, 44.2% had ESKD progression during follow-up. There were significant differences in several kidney-, inflammation-, and AAV-pathogenesis-related variables between AAV-GN patients with ESKD and those without. The sclerotic class exhibited the worst renal prognosis among the four histopathological classes. Among histopathological features, high interstitial fibrosis, tubular atrophy and global glomerulitis scores were significantly associated with ESKD progression. Whereas multivariable Cox analysis revealed only a high global glomerulitis score which means global endocapillary hypercellularity in a larger number of glomeruli is an independent predictor of ESKD progression. Moreover, among clinical and histopathological features, a high global glomerulitis score could also predict ESKD progression in addition to serum blood urea nitrogen and creatinine. This study demonstrated the worst renal prognosis for the sclerotic class and first discovered that a high global glomerulitis score was an independent predictor of ESKD in patients with AAV-GN.

Low-Dose Intravenous Methylprednisolone in Remission Induction Therapy for ANCA-Associated Vasculitis.

Glucocorticoids (GC) remain integral to the management of ANCA associated vasculitis (AAV), but are associated with significant adverse effects. Recent studies have shown reduced oral GC dosing to be safe and effective, however data guiding the use of intravenous (IV) methylprednisolone (MTP) is limited. A single centre, retrospective cohort of patients with AAV were divided into two groups; low-dose GC (patients receiving 250mg IV MTP followed by a tapering course of 30mg prednisolone daily) versus high-dose GC (1.5g IV MTP followed by tapering course of 40-60mg prednisolone daily). Primary outcomes included; end stage kidney disease (ESKD) and mortality, secondary outcomes; glucocorticoid related toxicity, remission and relapse rates. This study was applied to patients with newly diagnosed AAV, including those with severe or life-threatening disease. Sixty-five patients were included in the final analysis, 34 in the high dose and 31 in the low-dose treatment group. At diagnosis, more advanced renal impairment and histological disease was present in the low-dose cohort. The rate of ESKD was similar between groups at 6 and 12 months (P=0.22, P=0.60 respectively). More deaths occurred in the high-dose group (26.5% vs 6.5%, P=0.05) although on multivariable analysis this was not significant (P=0.06). Remission rates were comparable and there was no significant difference in relapses. Adverse events were seen in both groups but the high dose patients experienced a higher number of severe infections, weight gain and steroid induced diabetes. We demonstrate that markedly reduced dose IV MTP with a lower overall cumulative dose GC is safe and effective in the management of severe AAV disease, with no significant difference in primary outcomes.

Increased risk of cardiovascular disease preceding diagnosis of incident ANCA-associated vasculitis: a Danish nationwide study.

To examine whether patients with ANCA-associated vasculitis (AAV) have an increased risk of cardiovascular disease in the months prior to diagnosis of AAV. Using a nested case-control framework, patients with granulomatosis with polyangiitis and microscopic polyangiitis were identified through the Danish Nationwide Registries from 1996 to 2021 and matched 1:3 with age- and sex-matched controls without AAV. Each control was assigned the same index date (date of AAV diagnosis) as their corresponding case. Conditional logistic regression was used to compute adjusted hazard ratios (HRs) for major adverse cardiovascular events (MACE), ischaemic heart disease, coronary angiogram, heart failure, venous thromboembolism, atrial fibrillation, ischaemic stroke, pericarditis and ventricular arrhythmias/implantable cardioverter defibrillator implantation/cardiac arrest (VA/ICD/CA) within 12 months, 6 months, 3 months, 2 months and 1 month before index date. A total of 2371 patients with AAV (median age 63 years, 53.7% male) were matched with 7113 controls. The prevalence of any cardiovascular outcome and MACE within 12 months preceding index date were 10.3% and 2.4% for AAV, compared with 3.8% [HR 3.05 (95% CI 2.48-3.75)] and 1.3% [HR 1.98 (95% CI 1.39-2.82)] of controls. The risk of cardiovascular outcomes was similarly increased in temporal proximity to the diagnosis, with the highest HR at 1 month prior to index date: any cardiovascular outcome [HR 10.73 (95% CI 7.05-16.32)] and MACE [HR 5.78 (95% CI 2.67-12.52)]. In individual analysis, a significantly higher rate was observed for all outcomes (excluding VA/ICD/CA). AAV disease is associated with an increased risk of cardiovascular disease in the months preceding diagnosis, which underlines the importance of early clinical vigilance towards cardiovascular disease.

Using a Network-Based Analysis Approach to Investigate the Involvement of S. aureus in the Pathogenesis of Granulomatosis with Polyangiitis.

Chronic nasal carriage of Staphylococcus aureus (SA) has been shown to be significantly higher in GPA patients when compared to healthy subjects, as well as being associated with increased endonasal activity and disease relapse. The aim of this study was to investigate SA involvement in GPA by applying a network-based analysis (NBA) approach to publicly available nasal transcriptomic data. Using these data, our NBA pipeline generated a proteinase 3 (PR3) positive ANCA associated vasculitis (AAV) disease network integrating differentially expressed genes, dysregulated transcription factors (TFs), disease-specific genes derived from GWAS studies, drug-target and protein-protein interactions. The PR3+ AAV disease network captured genes previously reported to be dysregulated in AAV associated. A subnetwork focussing on interactions between SA virulence factors and enriched biological processes revealed potential mechanisms for SA's involvement in PR3+ AAV. Immunosuppressant treatment reduced differential expression and absolute TF activities in this subnetwork for patients with inactive nasal disease but not active nasal disease symptoms at the time of sampling. The disease network generated identified the key molecular signatures and highlighted the associated biological processes in PR3+ AAV and revealed potential mechanisms for SA to affect these processes.

Ocular manifestations of ANCA-associated vasculitis.

ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

PULMONARY LIMITED SERONEGATIVE GRANULOMATOSIS WITH POLYANGIITIS VASCULITIS

PULMONARY LIMITED SERONEGATIVE GRANULOMATOSIS WITH POLYANGIITIS VASCULITIS

Interstitial Lung Disease in ANCA-Associated Vasculitis: Pathogenic Considerations and Impact for Patients' Outcomes.

This review provides an update on recent advances in the diagnosis, pathogenesis, clinical presentation, histopathological findings, and treatment approaches for antineutrophil cytoplasmic antibody (ANCA) vasculitis-associated interstitial lung disease (AAV-ILD) with a focus on literature published in the last 3years. Although there is no validated definition of AAV-ILD, which contributes to some of the heterogeneity seen in study results, there has been an increasing number of publications in recent years on this topic. Most patients with AAV-ILD have MPO-ANCA vasculitis, and this association appears to reduce their 5-year-survival to 60-66% (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020). Median age of diagnosis ranges from mid-60s to mid-70s (Ando et al. Respir Med 107(4), 2013), Kagiyama et al. BMJ Open Respir Res 2(1):1-9, 2015, Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019). Computed tomography (CT) chest imaging for patients with AAV-ILD often shows a usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) pattern (12-58% and 13-61%, respectively) (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019, Baqir at al. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 36(3):195-201, 2019). Additionally, lung biopsies typically do not demonstrate active inflammation, or capillaritis, questioning whether these patients should be treated with either immunotherapy or anti-fibrotic therapy, or both (Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Kitching at al. Nat Rev Dis Prim 6(1):71, 2020, Tanaka et al. Respir Med 106(12):1765-70, 2012). Besides immunosuppressive treatments, recent advances in anti-fibrotic therapy may offer patients with progressive AAV-ILD an alternative and/or more effective and individualized treatment option.

Interstitial lung disease in ANCA-associated vasculitis: associated factors, radiographic features and mortality.

To evaluate the prevalence, clinical and radiographic features, and long-term outcomes of interstitial lung disease (ILD) in a United States-based ANCA-associated vasculitis (AAV) cohort. In this retrospective cohort study, we identified cases of ILD within the 2002-2019 Mass General Brigham AAV Cohort, a consecutive inception cohort of PR3- or MPO-ANCA+ AAV patients. ILD diagnosis and classification as fibrotic or non-fibrotic were confirmed by review of available chest imaging by two board-certified radiologists. Cox proportional hazard models, with age as the time scale, were used to estimate the association of AAV-ILD with all-cause mortality. Of 684 patients in the MGB AAV Cohort, 91 (13%) had ILD which preceded the diagnosis of AAV by a mean of 2.2 years. AAV-ILD patients were older (67 vs 60 years, P < 0.001) than patients without ILD but the distribution of sex and race was similar. AAV-ILD patients were more often MPO-ANCA+ (93% vs 65%, P < 0.001); among MPO-ANCA+ patients (n = 470), 85 (18%) had ILD. The majority of ILD was fibrotic (76%) and UIP was the most common ILD pattern (42%). The baseline forced vital capacity (FVC) % predicted among ILD patients was 81 ± 20%. Fibrotic AAV-ILD was associated with a 58% higher risk of death (aHR 1.58, 95% CI 1.06, 2.37) compared with AAV patients without ILD. ILD is a frequent complication of AAV, especially MPO-ANCA+ AAV, often preceding recognition of AAV. Fibrotic AAV-ILD is associated with a higher risk of death than AAV without ILD.

Distinguishing active from quiescent disease in ANCA-associated vasculitis using attenuated total reflection Fourier-transform infrared spectroscopy

The current lack of a reliable biomarker of disease activity in anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitis poses a significant clinical unmet need when determining relapsing or persisting disease. In this study, we demonstrate for the first time that attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy offers a novel and functional candidate biomarker, distinguishing active from quiescent disease with a high degree of accuracy. Paired blood and urine samples were collected within a single UK centre from patients with active disease, disease remission, disease controls and healthy controls. Three key biofluids were evaluated; plasma, serum and urine, with subsequent chemometric analysis and blind predictive model validation. Spectrochemical interrogation proved plasma to be the most conducive biofluid, with excellent separation between the two categories on PC2 direction (AUC 0.901) and 100% sensitivity (F-score 92.3%) for disease remission and 85.7% specificity (F-score 92.3%) for active disease on blind predictive modelling. This was independent of organ system involvement and current ANCA status, with similar findings observed on comparative analysis following successful remission-induction therapy (AUC > 0.9, 100% sensitivity for disease remission, F-score 75%). This promising technique is clinically translatable and warrants future larger study with longitudinal data, potentially aiding earlier intervention and individualisation of treatment.

FRAX scores are increased in patients with ANCA-associated vasculitis

Prognosis in ANCA-associated vasculitis (AAV) has greatly improved with immunosuppressive use whereas incidence of treatment-related comorbidities such as osteoporosis has increased. However, studies investigating bone disease in AAV are limited. Fracture Risk Assesment Tool (FRAX) was developed to estimate 10-year hip and major osteoporotic fracture risks. Aim of this study was to estimate FRAX scores in AAV patients and compare them to healthy controls. 30 AAV patients and 20 healthy controls were included. Demographic, disease, and medication history were recorded from patient files. Femoral neck, lumbar spine and forearm bone mineral densitometry, and thoracolumbar radiographs were performed. FRAX fracture risk scoring was assessed for all participants. There were 18 male and 12 female patients. Mean age was 58.5 ± 11.7years. Osteoporosis and osteopenia were present in 23.3% and 50% of patients, respectively. There were fractures in eight patients (26.7%). FRAX major fracture (9.4 ± 7.3% vs 5.9 ± 3.2%, p = 0.02) and hip fracture (2.2 ± 3.2% vs 0.9 ± 0.8%, p = 0.03) scores were higher in patients than controls. In seven (23.3%) patients, the 10-year probability of hip fracture was ≥ 3% and in five (16%) patients the 10-year risk of a major osteoporosis-related fracture was ≥ 20%. None of the controls exceeded these thresholds. AAV patients are at high risk for future fractures as calculated with FRAX. Life-long monitoring for bone disease and fractures are essential. Large studies with longer follow-up are needed to determine the accuracy of FRAX risk scoring in predicting fractures.

Blood CD3-(CD56 or 16)+ natural killer cell distributions are heterogeneous in healthy adults and suppressed by azathioprine in patients with ANCA-associated vasculitides

BackgroundCytotoxic Natural Killer (NK) cells are increasingly recognized as a powerful tool to induce targeted cell death in cancer and autoimmune diseases. Still, basic blood NK cell parameters are poorly defined. The aims of this study were 1) to establish reference values of NK cell counts and percentages in healthy adults; 2) to describe these parameters in the prototype autoimmune disease group ANCA-associated vasculitis (AAV); and 3) to investigate whether NK cell counts and percentages may be used as activity biomarkers in the care of AAV patients, as suggested by a preceding study.MethodsCD3-(CD56 or 16)+ NK cell counts and percentages were determined in 120 healthy adults. Lymphocyte subset and clinical data from two German vasculitis centers were analyzed retrospectively (in total 407 measurements, including 201/49/157 measurements from 64/16/39 patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), respectively).ResultsCD3-(CD56 or 16)+ NK cell counts and percentages in healthy adults were highly variable, not Gaussian distributed and independent of age and sex. NK cell percentages ranged from 1.9 to 37.9% of lymphocytes, and were significantly more dispersed in AAV (0.3 to 57.6%), while the median percentage was not different between AAV and healthy donors. In contrast, median NK cell counts were significantly lower in AAV compared to healthy donors. Sub-group analyses revealed that NK cell counts were low independent of AAV entity and disease activity. Azathioprine therapy was associated with significantly lower NK cell counts and percentages compared to non-azathioprine therapies. In 13.6% of azathioprine-treated patients, percentages were </= 1% which may be interpreted as temporary NK cell deficiency. NK cell counts and percentages could not separate active from inactive AAV.ConclusionsNK cell counts and percentages in blood are heterogeneous and can presently not be recommended as biomarker in clinical care of AAV patients. Azathioprine treatment was associated with significantly low NK cells. These findings may be relevant for the development of drugs that aim at exploiting NK cell cytotoxicity and may help to identify patients at risk to develop malignant or infectious co-morbidities.

The biology, pathogenetic role, clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.

Double positivity for antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody could predict end-stage renal disease in ANCA-associated vasculitis: a monocentric pilot study.

To investigate the detection rate of double positivity for antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody at diagnosis and its clinical implication during follow-up in Korean patients with ANCA-associated vasculitis (AAV). We retrospectively reviewed the medical records of 96 Korean AAV patients. We obtained data at diagnosis and assessed the poor outcomes of AAV such as all-cause mortality, relapse and end-stage renal disease (ESRD). Comparison of cumulative survivals were analysed by the Kaplan-Meier survival analysis, and hazard ratios (HRs) were obtained by the multivariable Cox hazard model. Seven of 96 AAV patients (7.3%) had double positivity for ANCA and anti-GBM. Among variables at diagnosis, there were no significant differences between patients with double positivity for ANCA and anti-GBM and those without. In the cumulative survival analysis, AAV patient with double positivity for ANCA and anti-GBM at diagnosis exhibited the lower cumulative ESRD-free survival rate than those without (P = 0.044) and furthermore, than those with positive for only ANCA and those with double negativity (P = 0.022). Myeloperoxidase (MPO)-ANCA, renal manifestation and five-factor score at diagnosis were also associated with ESRD occurrence in AAV patients. In the multivariable Cox hazards model using these 4 variables, only double positivity for ANCA and anti-GBM exhibited the significant association with ESRD occurrence during follow-up (HR 3.831). Double positivity for ANCA and anti-GBM at diagnosis were observed in 7.3% of AAV patients, and it could predict ESRD occurrence during follow-up in Korean patients with AAV.Key Points• 7.3% of AAV patients had double positivity for ANCA and anti-GBM at diagnosis (total n = 96)• Double positivity for ANCA and anti-GBM could predict ESRD occurrence during follow-up (HR 9.021, P = 0.004)• AAV patients with double positivity for ANCA and anti-GBM exhibited the lower cumulative ESRD-free survival rate compared with those without (P = 0.044).

Anti-High-Density Lipoprotein Antibodies and Antioxidant Dysfunction in Immune-Driven Diseases.

Impaired high-density lipoprotein (HDL) levels and antioxidant functionality of HDL, mainly attributed to a decreased paraoxonase-1 (PON1) functionality, have been described in autoimmune conditions. In this setting, a role for humoral response in cardiovascular disease is emerging. This study evaluates the role of immunoglobulin G (IgG) antibodies against HDL and disease-related autoantibodies on HDL dysfunction in immune-driven diseases. Serum IgG anti-HDL antibodies, PON1 activity, and total antioxidant capacity (TAC) were quantified in 381 patients with different immune-driven diseases [18 mixed connective tissue disease (MCTD), 35 primary Sjögren syndrome (pSS), 38 systemic sclerosis (SSc), 33 ANCA-associated vasculitis (AAV), 60 diabetes mellitus 1, 29 autoimmune B12 deficiency/pernicious anemia, 29 primary biliary cirrhosis, 46 IBD/Crohn, 54 IBD/UC, and 39 celiac disease (CD)] and 138 healthy controls. IgG anti-HDL antibodies were increased in MCTD, pSS, AAV, and inflammatory bowel disease (IBD) [Crohn and ulcerative colitis (UC)], even after correcting for total IgG levels, but not in organ-specific autoimmune diseases. Anti-HDL antibodies were negatively associated with PON1 activity in MCTD (r = -0.767, p < 0.001) and AAV (r = -0.478, p = 0.005), whereas both anti-HDL and anti-neutrophil cytoplasm antibod levels were related to an impaired PON1 activity and TAC in IBD/UC. In SSc, anti-centromere antibodies correlated PON1 activity. anti-Saccharomyces cerevisiae antibodies levels were negatively associated with PON1 activity (r = -0.257, p = 0.012) and PON1/TAC ratio (r = -0.261, p = 0.009) in IBD/Crohn. HDL dysfunction in CD was only related to anti-transglutaminase levels. IgG anti-HDL antibodies and HDL dysfunction are common hallmarks of systemic autoimmunity. Anti-HDL and disease-related autoantibodies account for the HDL antioxidant dysfunction in immune-driven conditions, mainly in systemic autoimmune disorders.

Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis.

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

End-stage renal disease in ANCA-associated vasculitis.

The outcomes in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have improved significantly over the past decades, although a significant proportion of them still reach end-stage renal disease (ESRD). Renal replacement therapy (RRT) is associated with a relatively low risk of relapsing vasculitis as a result of anti-rejection treatment after kidney transplantation or quiescence of the autoimmune process in haemodialysis patients, but a flare of vasculitis in the latter setting presents a challenge because the treatment is poorly tolerated. There are benefits of rituximab in haemodialysed patients, as it is more steroid sparing in the treatment of extrarenal disease. More favourable outcomes of kidney transplantation compared with haemodialysis support its use as a preferable method of RRT in patients with vasculitis remission or low disease activity.