Health-related quality of life in patients with ANCA vasculitides compared to rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: There are limited data regarding health-related quality of life (HRQoL) in patients with ANCA-associated vasculitides (AAVs). We aimed to evaluate the HRQoL in patients with AAVs and compare it to another chronic inflammatory disease like RA and to healthy controls (HC). METHODS: This was a multicentre, cross-sectional study of patients with AAVs and RA recruited from three tertiary rheumatology clinics. HRQoL was assessed with the Short Form 36 Health Survey, which included the physical and mental component summary scores (PCS and MCS). Data from 1007 HC served as historical controls. RESULTS: Sixty-six patients with AAVs and 71 with RA were included. Both AAV and RA patients had significantly lower PCS and MCS scores compared with HC (P < 0.05). HRQoL in AAV patients was worse in patients with microscopic polyangiitis compared with granulomatosis with polyangiitis (physical components) and those with high (VDI ≥ 3) vs low (VDI < 3) damage scores while it did not differ between those with active (BVASv3 ≥ 1) vs. inactive (BVASv3 < 1) disease. In contrast, in RA patients, HRQoL correlated both with disease activity (assessed by the DAS28-ESR) and functional impairment/damage (assessed by the HAQ). Although overall patients with RA had similar HRQoL compared with those with AAVs, those with active RA had worse HRQoL compared with those with active AAV. CONCLUSIONS: In patients with AAVs, HRQoL correlated more with organ damage and less with disease activity whereas in RA patients, it correlated with both. These data emphasize the need for AAV therapies aiming at preventing organ damage and thus improving HRQoL.

Avacopan for ANCA-associated vasculitis with hypoxic pulmonary haemorrhage.

BACKGROUND AND HYPOTHESIS: Pulmonary haemorrhage with hypoxia caused by ANCA-associated vasculitis (AAV) has a high early mortality. Avacopan, an oral C5a receptor antagonist, is an approved treatment for AAV, but patients with pulmonary haemorrhage requiring invasive pulmonary ventilation support were excluded from the ADVOCATE trial. METHODS: A retrospective, observational, multicentre case series of AAV patients with hypoxic pulmonary haemorrhage, requiring oxygen support or mechanical ventilation, who received avacopan. RESULTS: Eight patients (62.5% female), median age 64 years (range 17-80), seven with kidney involvement, median glomerular filtration rate (GFR) 11 (range 5-99) ml/min per 1.73m2, were followed for a median of 6 months from presentation. Seven were newly diagnosed (87.5%), five were MPO-ANCA and three PR3-ANCA positive. All had hypoxia, four requiring mechanical ventilation (three invasive and one non-invasive). Intensive care unit (ICU) stay for the four patients lasted a median of 9 days (range 6-60). Four received rituximab and cyclophosphamide combination, three rituximab and one cyclophosphamide. Four underwent plasma exchange and one received two months of daily extracorporeal membrane oxygenation (ECMO) therapy. Following the initiation of avacopan after a median of 10 days (range 2-40), pulmonary haemorrhage resolved in all patients, even two who had one month of refractory pulmonary haemorrhage prior to avacopan. Additionally, after one month, the median prednisolone dose was 5 mg/day (range 0-50), with three patients successfully discontinuing steroid use. Two patients suffered serious infections, two discontinued avacopan, one permanently due to a rash and one temporarily after three months due to neutropenia. All patients survived and no re-hospitalization occurred. CONCLUSION: We report the use of avacopan as a component of the treatment for pulmonary haemorrhage with hypoxia in AAV. Despite the life-threatening presentations all patients recovered, but attribution of the positive outcomes to avacopan is limited by the concomitant therapies and retrospective observational design.

Plasma exchange in patients with ANCA-associated vasculitis.

ANCA-associated Vasculitides (AAV) are characterized by small vessel necrotizing inflammation and can present with multisystem organ involvement, including organ/life threatening manifestations of rapidly progressive glomerulonephritis and diffuse alveolar haemorrhage, where immediate and aggressive intervention is needed to prevent further organ damage. Although, the rationale of plasma exchange (PLEX) in AAV is strong, through removing the pathogenic ANCAs; target either myeloperoxidase (MPO) or proteinase 3 (PR3), and other inflammatory molecules, especially in the initiation when the immunosuppressive treatment is no sufficient to prevent the organ damage, overall impact on patient outcomes is not well-established, while the risk of infections seems to be higher in the PLEX-treated patients. A comprehensive overview of the challenges and uncertainties surrounding the use of PLEX in the management of AAV will be reviewed, providing the current practice recommendations guiding treatment decisions.

ANCA-associated vasculitis - Treatment Standard.

ANCA-associated Vasculitides (AAV) are characterized by small vessel necrotizing inflammation and prior to the advent of immunosuppressive therapy frequently had a fatal outcome. Treatment has transformed AAV into a relapsing/remitting disease with increased drug-related toxicities and organ damage. The use of glucocorticoids, cyclophosphamide and immunosuppressives (including azathioprine, mycophenolate, methotrexate) was optimised through a sequence of clinical trials establishing a standard of care against which subsequent targeted therapies could be developed. Improved understanding of pathophysiology has supported the development of B cell depletion and complement inhibition, in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and interleukin 5 inhibition for eosinophilic granulomatosis with polyangiitis (EGPA), leading to the approval of newer agents for these conditions. There has been an increased attention on minimising the adverse effects of treatment and of understanding the epidemiology of co-morbidities in AAV. This review will focus on recent evidence from clinical trials, especially with respect to glucocorticoids, avacopan, plasma exchange, rituximab and mepolizumab, and their interpretation in the 2022 management recommendations by the European League of Associations of Rheumatology (EULAR).

Transforming Growth Factor-ß1/Smad Signaling in Glomerulonephritis and Its Association with Progression to Chronic Kidney Disease.

INTRODUCTION: Transforming growth factor-ß1 (TGF-ß1) is a multifunctional cytokine, with diverse roles in fibrosis and inflammation, which acts through Smad signaling in renal pathology. We intended to investigate the expression of TGF-ß/Smad signaling in glomerulonephritis (GN) and to assess its role as risk factor for progression to chronic kidney disease (CKD). METHODS: We evaluated the immunohistochemical expression of TGF-ß1, phosphorylated Smad3 (pSmad3), and Smad7 semiquantitatively and quantitatively using computerized image analysis program in different compartments of 50 renal biopsies with GN, and the results were statistically analyzed with clinicopathological parameters. We also examined the associations among their expressions, the impact of their co-expression, and their role in progression to CKD. RESULTS: TGF-ß1 expression correlated positively with segmental glomerulosclerosis (p= 0.025) and creatinine level at diagnosis (p = 0.002), while pSmad3 expression with interstitial inflammation (p = 0.024). In glomerulus, concomitant expressions of high Smad7 and medium pSmad3 were observed to be correlated with renal inflammation, such as cellular crescent (p = 0.011), intense interstitial inflammation (p = 0.029), and lower serum complement (C) 3 (p = 0.028) and C4 (p = 0.029). We also reported a significant association between pSmad3 expression in glomerular endothelial cells of proliferative GN (p = 0.045) and in podocytes of nonproliferative GN (p = 0.005). Finally, on multivariate Cox-regression analysis, TGF-ß1 expression (hazard ratio = 6.078; 95% confidence interval: 1.168-31.627; p = 0.032) was emerged as independent predictor for CKD. DISCUSSION/CONCLUSION: TGF-ß1/Smad signaling is upregulated with specific characteristics in different forms of GN. TGF-ß1 expression is indicated as independent risk factor for progression to CKD, while specific co-expression pattern of pSmad3 and Smad7 in glomerulus is correlated with renal inflammation.

Hypocomplementemia is associated with more severe renal disease and worse renal outcomes in patients with ANCA-associated vasculitis: a retrospective cohort study.

BACKGROUND: The complement system has been recently proposed to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). This study evaluated the value of serum and kidney deposited C3 in predicting renal outcomes in AAV. METHODS: This was a retrospective study of 47 patients with AAV, who were categorized according to their serum C3 levels as hypo- or normo-complementemic and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3. Baseline characteristics as well as progression to end-stage renal disease (ESRD) between the 2 groups were compared. RESULTS: In total, 23% (11/47) were hypo-complementemic; these patients were older (74 vs. 65 years, p = 0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL, p = 0.006), were more often hemodialysis dependent (64% vs. 19%, p = 0.009) and progressed more often to ESRD (55% vs. 11%, p = 0.01) compared to normo-complementemic patients (n = 36). On multivariate analysis, serum creatinine at diagnosis (HR = 16.8, 95%CI: 1.354-208.62, p = 0.028) and low serum C3 (HR = 2.492; 95% CI: 1.537-11.567; p = 0.044) were independent predictors for ESRD. Among 25 patients with an available kidney biopsy, 56% had C3 deposition by IF and displayed more often a mixed histological pattern (72% vs. 27%, p = 0.033), low serum C3 levels (42% vs. 18%, p < 0.001) and serious infections during follow-up (57% vs. 18%, p = 0.047) compared to those with negative (n = 11) IF staining. CONCLUSION: Almost one of four patients with AAV has low C3 levels at diagnosis which is associated with more severe renal disease and worse renal outcomes (ESRD). This should be taken into account in therapeutic and monitoring strategies.

Urine Nephrin and Podocalyxin Reflecting Podocyte Damage and Severity of Kidney Disease in Various Glomerular Diseases-A Cross-Sectional Study.

Background/Objectives: Glomerulopathy is a term used to describe a broad spectrum of renal diseases, characterized by dysfunction of glomerular filtration barrier, especially of podocytes. Several podocyte-associated proteins have been found and proved their usefulness as urine markers of podocyte dysfunction. Two of them are nephrin (NEP) and prodocalyxin (PDC). This study aims to evaluate the association of podocyte damage, as it is demonstrated via the concentrations of urinary proteins, with clinical and histological data from patients with several types of glomerulonephritis. Methods: We measured urine levels of two podocyte-specific markers, NEP and PDC (corrected for urine creatinine levels), in patients with a wide range of glomerulopathies. Serum and urine parameters as well as histological parameters from renal biopsy were recorded. Results: In total, data from 37 patients with glomerulonephritis and 5 healthy controls were analyzed. PDC and NEP concentrations correlated between them and with serum creatinine levels (p = 0.001 and p = 0.013 respectively), and with histological lesions associated with chronicity index of renal cortex, such as severe interstitial fibrosis, severe tubular atrophy and hyalinosis (for PDC/NEP, all p < 0.05). In addition, the PDC and NEP demonstrated statistically significant correlations with interstitial inflammation (p = 0.018/p = 0.028). Regarding electron microscopy evaluation, PDC levels were correlated with distinct characteristics, such as fibrils and global podocyte foot process fusion, whereas the NEP/CR ratio was uniquely significantly associated with podocyte fusion only in non-immune-complex-mediated glomerulonephritis (p = 0.02). Among the other clinical and histological parameters included in our study, a strong correlation between proteinuria >3 g/24 h and diffuse fusion of podocyte foot processes (p = 0.016) was identified. Conclusions: Podocalyxin and nephrin concentrations in urine are markers of podocyte dysfunction, and in our study, they were associated both with serum creatinine and histological chronicity indices.

Pulmonary-Renal Syndrome During COVID-19 Pandemic Revealed a Rare Case of Anti-GBM Disease.

Anti-GBM disease is a rare, life-threatening small vessel vasculitis caused by circulating anti-GBM antibodies resulting to rapidly progressive glomerulonephritis and/or pulmonary haemorrhage. The gold standard for the diagnosis is the renal biopsy with the pathognomonic finding of linear deposition of IgG along the glomerular capillaries. Early diagnosis and intervention are key determinants of the response to therapy and long-term prognosis of these patients. However, during COVID-19 pandemic recognizing a pulmonary-renal syndrome caused by autoimmune diseases has become challenging. Herein, we aimed to describe a rare case of anti-GBM disease with pulmonary haemorrhage and rapidly progressive glomerulonephritis in a young man in a tertiary referral hospital in Greece, while COVID-19 pandemic was at its peak. Although the patient presented high level of creatinine and crescents, the early diagnosis and start of treatment resulted to favourable renal prognosis.

The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus.

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE). Methods: We performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients. Results: We report here that "Pan-vasculitis" signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy. Discussion: We conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.

TGF-ß1/Smad Signalling in Proliferative Glomerulonephritis Associated with Autoimmune Diseases.

Glomerulonephritis is a common cause of chronic kidney disease, which has emerged as a major cause of end-stage renal disease. Autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) and ANCA-associated vasculitis (AAV) are often associated with proliferative glomerulonephritis. Transforming growth factor-ß1 (TGF-ß1) is a cytokine with pleiotropic effects in chronic renal diseases, based on in vivo and in vitro studies. The Smad-dependent signalling pathway plays an important role in the regulation of renal fibrosis (excessive production of extracellular matrix [ECM]) and inflammation. However, clinical trials targeting TGF-ß1 have presented disappointing results, suggesting that the downstream signalling is quite complex. The diversity of the effects may associate with the interactions between TGF-ß1 signalling and other downstream signalling, as well as the different cellular responses, which TGF-ß1 promotes. Recently, macrophage chemoattract and epigenetic effects have also been identified as new mechanisms, wherefore TGF-ß1/Smad signalling mediates renal injury. This review provides an overview of the role of TGF-ß1/Smad signalling pathway from in vivo and in vitro studies in the pathogenesis of glomerulonephritis and particularly in proliferative glomerulonephritis, which is associated with autoimmune diseases.

Distal renal tubular acidosis and nephrocalcinosis as initial manifestation of primary sjögren's syndrome.

There is a well-established association between primary Sjögren's syndrome and distal renal tubular acidosis (dRTA). dRTA is a relatively infrequent manifestation of primary Sjögren's syndrome which can present with life-threatening electrolyte abnormalities while, in some patients, it could be the first manifestation of the syndrome. We report the case of a 35-year-old woman who presented with unexplained episodes of generalized weakness, severe hypokalemia, nephrocalcinosis, and normal anion gap metabolic acidosis. Subsequent evaluation revealed primary Sjögren's syndrome as her underlying condition. The patient responded well to potassium supplementation, sodium bicarbonate, and oral prednisolone. After four years of follow-up, there were no other extraglandular manifestations, the renal function remained stable and the acidosis was partially improved without the need for oral bicarbonate. This case demonstrates that dRTA could be the initial manifestation of primary Sjögren's syndrome and highlights the necessity for increased vigilance for patients presenting with persistent hypokalemia or nephrocalcinosis so that an early diagnosis can be made allowing for better control and prevention of disease progression.

Fibrillary Glomerulonephritis with Atypical Immunoglobulin M Deposits and Hypocomplementemia Revealed Human Immunodeficiency Virus Infection.

Fibrillary glomerulonephritis (FGN) is a rare form of glomerulonephritis, and the incidence in native renal biopsies is less than 1%. The diagnosis of FGN is defined by the ultrastructural finding of organized, randomly oriented, nonbranching fibrils with a diameter of 10-30 nm. FGN is immune-mediated glomerulonephritis with predominant immunoglobulin (Ig) G deposits. Hypocomplementemia is very rare. We report the case of a 68-year-old Caucasian man with renal impairment, hematuria, subnephrotic proteinuria, hypocomplementemia (low C4, normal C3), and hypergammaglobulinemia. The kidney biopsy revealed a mesangial proliferative pattern with IgM deposits, and the electron microscopy demonstrated FGN. Upon further investigation, secondary causes, such as malignancy, monoclonal gammopathy, or autoimmune disease were excluded, and human immunodeficiency virus (HIV) infection was revealed. Only three cases with FGN associated with HIV infection without concurrent hepatitis C virus have been reported and all of them in already known medical records. Our patient received treatment with corticosteroids and highly active antiretroviral therapy, and the renal function improved.

Serious infections in ANCA-associated vasculitides in the biologic era: real-life data from a multicenter cohort of 162 patients.

BACKGROUND: Serious infections (SI) are common in patients with ANCA-associated vasculitides (AAV) like granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Real-life data regarding their incidence and predisposing factors-after the introduction of B cell depleting agents-are limited while data quantifying the risk per treatment modality and year of the disease are missing. Here, we aim to describe in details the incidence and the risk factors for SI in a contemporary AAV cohort. METHODS: Multicenter, observational, retrospective study of AAV patients followed in three tertiary referral centers. RESULTS: We included 162 patients with GPA (63%) and MPA (37%), males 51.9%, mean age 60.9 years, ΑΝCA+ 86%, and generalized disease 80%. During follow-up (891.2 patient-years, mean 5.4 years), 67 SI were recorded in 50 patients at an incidence rate of 7.5 per 100 patient-years. The SI incidence rate was higher during induction with cyclophosphamide (CYC) compared to rituximab (RTX, 19.3 vs. 11.3 per 100 patient-years, respectively) while it was lower and comparable between RTX and other regimens (5.52 vs. 4.54 per 100 patient-years, respectively) in the maintenance phase. By multivariate analysis, plasmapheresis (PLEX) and/or dialysis was a strong predictor for an SI during the 1st year after diagnosis (OR = 3.16, 95% CI 1.001-9.96) and throughout the follow-up period (OR = 5.21, 95% CI 1.93-14.07). In contrast, a higher baseline BVAS (OR = 1.11, 95% CI 1.01-1.21) was associated with SI only during the 1st year. CONCLUSIONS: In this real-life study of patients with AAV, the SI incidence was higher during CYC compared to RTX induction while there was no difference between RTX and other agents used for maintenance therapy. Higher disease activity at baseline and need for PLEX and/or dialysis were independent factors associated with an SI.