B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies ...have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (B
) cells attenuate inflammation and contribute to the maintenance of immune tolerance. B
cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and B
cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression.
Abstract
Glucocorticoids have been a cornerstone of treatment for inflammatory and autoimmune kidney diseases for almost 70 years, yet it is fair to say, we still do not know how ‘best’ to use them. ...Significant adverse events are associated with their continued use, which contribute to premature patient mortality. Steroid avoidance or minimization is possible and has been tested in various glomerular diseases, as a result of novel agents or innovative regimens using established therapeutics. It is now time to seriously address our use of steroids and educate physicians on better ways of managing inflammatory kidney diseases.
Clinical relapses are common in ANCA associated vasculitis, necessitating repeated treatment with immunosuppressive therapy, and increasing the risks of severe adverse events. Better understanding ...the basis of relapse would help stratify patients, testing the notion that more treatment may prevent development of relapse, while in those at low risk of disease flares, treatment minimisation may be appropriate, reducing risks of adverse events, most notably infectious complications and drug toxicity. However, relapse can only occur following remission, and although defining clinical remission may seem straightforward, there is evidence in many remission patients of persistent inflammatory and immunological activity, at levels above those found in healthy individuals. This suggests that we may not truly be achieving disease remission in many patients and these persistent responses may set the patient up for subsequent disease flares. Understanding the underlying pathophysiological basis of disease activity and remission is paramount to help define better biomarkers of relapse, which should positively impact on adverse events and patient outcomes.
Abstract
Two immune complex vasculitides, IgA vasculitis (IgAV) and anti-GBM disease, represent polar extremes with regard to our understanding of disease pathogenesis, standardized management ...protocols and outcomes. This report compares our current approach to these uncommon entities in adults. Both diseases demonstrate degrees of small vessel necrosis and glomerular crescent formation. IgAV has an antibody response directed against unknown antigens, is often treated conservatively and has poorly studied long term renal outcomes. By contrast, anti-GBM disease presents with rapidly progressive glomerulonephritis and often results in end stage renal failure, despite intensive immunosuppression. Rarely, some cases of anti-GBM disease may be IgA predominant and bind other α-chains present in the GBM, but their clinical course is as for other anti-GBM disease patients but not IgAV, suggesting that the antigenic target rather than the antibody subclass is the critical factor in determining disease outcome. However, both conditions are associated with increased mortality in adults and result in significant chronic kidney disease and hypertension.
ABSTRACT
Background
Current guidelines advise that rituximab or cyclophosphamide should be used for the treatment of organ-threatening disease in anti-neutrophil cytoplasm antibody (ANCA)-associated ...vasculitis (AAV), although few studies have examined the efficacy and safety of these agents in combination.
Methods
We conducted a single-centre cohort study of 66 patients treated with a combination of oral corticosteroids, rituximab and low-dose pulsed intravenous cyclophosphamide followed by a maintenance regimen of azathioprine and tapered steroid for the treatment of biopsy-proven renal involvement in AAV. Patients were followed for a median of 56 months. Case–control analysis with 198 propensity-matched cases from European Vasculitis Study Group (EUVAS) trials compared long-term differences in relapse-free, renal and patient survival.
Results
At entry, the median Birmingham Vasculitis Activity Score (BVAS) was 19 and estimated glomerular filtration rate was 25 mL/min. Cumulative doses of rituximab, cyclophosphamide and corticosteroids were 2, 3 and 4.2 g, respectively, at 6 months. A total of 94% of patients achieved disease remission by 6 months (BVAS < 0) and patient and renal survival were 84 and 95%, respectively, at 5 years. A total of 84% achieved ANCA-negative status and 57% remained B cell deplete at 2 years, which was associated with low rates of major relapse (15% at 5 years). The serious infection rate during long-term follow-up was 1.24 per 10 patient-years. Treatment with this regimen was associated with a reduced risk of death {hazard ratio HR 0.29 95% confidence interval (CI) 0.125–0.675, P = 0.004}, progression to end-stage renal disease (ESRD) HR 0.20 (95% CI 0.06–0.65), P = 0.007 and relapse HR 0.49 (95% CI 0.25–0.97), P = 0.04 compared with propensity-matched patients enrolled in EUVAS trials.
Conclusions
This regimen is potentially superior to current standards of care, and controlled studies are warranted to establish the utility of combination drug approaches in the treatment of AAV.
Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case ...reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.
Small-vessel vasculitides are uncommon autoimmune diseases characterised by inflammation and necrosis of arterioles, capillaries and venules, frequently described as various (previously eponymous) ...clinical syndromes. Some are associated with vessel wall immune complex deposition, whereas others are pauci-immune but paradoxically often associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA). Most is known about the pathogenesis of the pauci-immune ANCA-associated syndromes, which are gradually becoming better understood with regard to their genetic predisposition and the critical pathways mediating disease initiation, as well as their particular phenotypic features. Through better understanding of key cellular and molecular players, we have been able to develop novel biomarkers and treatment strategies, which should translate to improved diagnostics, treatment protocols and, ultimately, better patient outcomes. These conditions are treatable but not yet curable, although it is clear that patients may follow different disease courses, which for some include restoration of their pre-morbid immune status.
Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ...ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN.
We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage
, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis.
All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation.
, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage.
, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses.
Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.
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