In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. ...The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.
The complement system is critical for the pathogenesis of ANCA‐associated vasculitis (AAV). Complement activation via the alternative pathway is triggered by ANCA‐induced neutrophil degranulation and ...leads to the generation of C5a, a potent anaphylatoxin that enhances recruitment and priming of further neutrophils. Avacopan, an oral inhibitor of the C5a receptor, disrupts this pathogenic loop and may allow glucocorticoid‐free disease control, marking a new era in the treatment of AAV.
Summary
The complement system plays a central role in autoimmune diseases, including anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV). Although complement deposition is scarce in AAV pathological samples, complement activation is required for the development of necrotizing crescentic glomerulonephritis (NCGN) in mouse models of AAV and occurs via the alternative pathway. The anaphylatoxin C5a, produced by the final complement pathway, is determinant to drive the disease in animal models. C5a primes human neutrophils and enhances their activation induced by ANCA; activated neutrophils, in turn, release factors that lead to C5a generation, establishing a self‐amplifying loop. C5a is also significantly increased in the serum of AAV patients with active disease compared to those in remission or healthy controls. Inhibition of the C5a receptor with avacopan is an emerging therapy that will probably allow AAV treatment with glucocorticoid‐free regimens.
Eosinophilic granulomatosis with polyangiitis (Churg–Strauss, EGPA) is a systemic small‐vessel vasculitis associated with asthma and eosinophilia. Histology of EGPA shows tissue eosinophilia, ...necrotizing vasculitis, and eosinophil‐rich granulomatous inflammation. EGPA commonly presents with upper airway tract and lung involvement, peripheral neuropathy, cardiac and skin lesions. Antineutrophil cytoplasmic antibodies (ANCA) are positive in ∼40% of the cases and more often in patients with clinical manifestations due to small‐vessel vasculitis. The pathogenesis of EGPA is multifactorial: the disease can be triggered by exposure to allergens or drugs, but a genetic background has also been recognized, particularly an association with HLA‐DRB4. Th2 responses are prominent, with up‐regulation of IL‐4, IL‐13, and IL‐5; however, Th1 and Th17 responses are not negligible. Eosinophils are activated, have a prolonged lifespan and probably cause tissue damage by releasing their granule proteins; their tissue recruitment can be regulated by chemokines such as eotaxin‐3 and CCL17. Humoral immunity is also dysregulated, as demonstrated by prominent IgG4 and IgE responses. EGPA promptly responds to glucocorticoid therapy, although combinations of glucocorticoids and immunosuppressants (e.g., cyclophosphamide, azathioprine) are eventually required in most cases. Newer therapeutic options include the anti‐IL5 antibody mepolizumab, whose efficacy has been described in small clinical trials, and the B‐cell‐depleting agent rituximab, reported in several case series.
The genetics of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex area of investigation because of the low frequency of AAVs, the rarity of familial cases and the ...complexity of disease phenotypes. However, recent studies have been able to gather significant numbers of patients, and multicentre collaborative efforts have allowed the performance of two genome-wide association studies (GWASs). Genetic association studies based on candidate gene approaches and the two GWASs have greatly contributed to our current understanding of the genetic basis of AAV. The central role of autoimmunity has been confirmed by the significant association with HLA polymorphisms; interestingly, the three main AAV subtypes are associated with distinct HLA variants, i.e. granulomatosis with polyangiitis (Wegener's GPA) with HLA-DP1, microscopic polyangiitis with HLA-DQ and eosinophilic GPA (Churg-Strauss) with HLA-DRB4. GWASs also revealed that polymorphic variants of genes encoding proteinase 3 (PR3), the predominant antigenic target of ANCA in GPA, and its main inhibitor, alpha-1 antitrypsin, are highly associated with GPA and, even more significantly, with PR3-ANCA positivity (regardless of the clinical diagnosis); this emphasizes the central pathogenic role of PR3 and humoral autoimmunity in PR3-ANCA positive vasculitis. Finally, candidate gene approach studies have shown associations with other variants involved in autoimmunity, such as those belonging to the CTLA-4 and PTPN22 genes, although these findings warrant replication in larger studies. Additional studies are underway to better characterize disease associations within the AAV spectrum, which could provide new pathogenetic clues and possibly new treatment targets.
Retroperitoneal fibrosis (RPF) is an uncommon disease characterized by a fibrous reaction that takes place in the peri-aortic retroperitoneum and often entraps the ureters causing obstructive ...uropathy. RPF is idiopathic in the majority of cases, but can also be secondary to malignancies, infections, drugs, radiotherapy, and rare histiocytic disorders such as Erdheim–Chester disease. Idiopathic RPF is an immune-mediated disease, which can either be isolated, associated with other autoimmune diseases, or arise in the context of a multifocal fibro-inflammatory disorder recently renamed as IgG4-related disease. The differential diagnosis between idiopathic, IgG4-related and secondary RPF is crucial, essentially because the therapeutic approaches – especially of idiopathic vs. secondary RPF – can be dramatically different. This review focuses on the clinical, laboratory and imaging features of the different RPF forms, and also provides an overview of the available treatment options.
Pretransplant donor biopsy (PTDB)‐based marginal donor allocation systems to single or dual renal transplantation could increase the use of organs with Kidney Donor Profile Index (KDPI) in the ...highest range (e.g. >80 or >90), whose discard rate approximates 50% in the United States. To test this hypothesis, we retrospectively calculated the KDPI and analyzed the outcomes of 442 marginal kidney transplants (340 single transplants: 278 with a PTDB Remuzzi score <4 median KDPI: 87; interquartile range (IQR): 78–94 and 62 with a score = 4 median KDPI: 87; IQR: 76–93; 102 dual transplants median KDPI: 93; IQR: 86–96) and 248 single standard transplant controls (median KDPI: 36; IQR: 18–51). PTDB‐based allocation of marginal grafts led to a limited discard rate of 15% for kidneys with KDPI of 80–90 and of 37% for kidneys with a KDPI of 91–100. Although 1‐year estimated GFRs were significantly lower in recipients of marginal kidneys (−9.3, −17.9 and −18.8 mL/min, for dual transplants, single kidneys with PTDB score <4 and =4, respectively; p < 0.001), graft survival (median follow‐up 3.3 years) was similar between marginal and standard kidney transplants (hazard ratio: 1.20 95% confidence interval: 0.80–1.79; p = 0.38). In conclusion, PTDB‐based allocation allows the safe transplantation of kidneys with KDPI in the highest range that may otherwise be discarded.
This study shows that the standardized assessment of formalin‐fixed pretransplant biopsies helps recover donors with KDPI in the highest range that would be otherwise discarded, and by providing the expected graft outcomes based on KDPI and pretransplant biopsy, it guides the clinician facing the difficult decision whether to accept or reject these organs. See editorial by Gupta et al on page 2444.
Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often causing obstructive uropathy. We evaluated the clinicopathologic features of 24 patients with IRF to characterize the histopathology ...of the disease and to provide a framework for the differential diagnosis with other retroperitoneal fibrosing conditions. Retroperitoneal specimens were analyzed by light and electron microscopy and by immunohistochemistry. Most patients presented with abdominal/lumbar pain, constitutional symptoms, and high acute-phase reactants. Overall, 20 had ureteral involvement and 13 developed acute renal failure. The retroperitoneal tissue consisted of a fibrous component and a chronic inflammatory infiltrate with the former characterized by myofibroblasts within a type-I collagen matrix. The infiltrate displayed perivascular and diffuse patterns containing lymphocytes, macrophages, plasma cells, and eosinophils. The perivascular aggregates had a central core of CD20+ cells and a mantle of CD3+ cells in equal proportions. In the areas of diffuse infiltrate, CD3+ cells outnumbered the CD20+ cells. Most plasma cells were positive for the IgG4 isotype. Small vessel vasculitis was found in the specimens of 11 patients. Our study indicates that a sclerotic background with myofibroblasts associated with a diffuse and perivascular infiltrate mainly consisting of T and B lymphocytes may be a pathological hallmark of IRF.
Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate ...the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis.
A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearman's correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physician's global assessment (PGA), the physician's treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity.
WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI ρ = 0.82 (95% CI 0.77, 0.85), PGA ρ = 0.85 (95% CI 0.81, 0.88) and the physician's treatment decision ρ = 0.54 (95% CI 0.44, 0.62). There was little or no correlation between BVAS v. 3 and the CRP level ρ = 0.18 (95% CI 0.05, 0.30) or with the VDI ρ = -0.10 (95% CI 0.22, 0.03). The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score.
The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis.
Antibody mediated rejection (AMR) is associated with a variety of graft‐reactive antibodies following kidney transplant. To characterize these antibodies, we immortalized 107 B cell clones from a ...patient with AMR. In a previous study, we showed that six clones were reacting to multiple self‐antigens as well as to HLA and MICA for two of them, thus displaying a pattern of polyreactivity. We show here that all six polyreactive clones also reacted to apoptotic but not viable cells. More generally we observed a nearly perfect overlap between polyreactivity and reactivity to apoptotic cells. Functionally, polyreactive antibodies can activate complement, resulting in the deposition of C3d and C4d at the surface of target cells. Testing the serum of 88 kidney transplant recipients revealed a significantly higher IgG reactivity to apoptotic cells in AMR patients than in patients with stable graft function. Moreover, total IgG purified from AMR patients had increased complement activating properties compared to IgG from non‐AMR patients. Overall, our studies show the development of polyreactive antibodies cross‐reactive to apoptotic cells during AMR. Further studies are now warranted to determine their contribution to the detection of C4d in graft biopsies as well as their role in the pathophysiology of AMR.
The authors show that antibody‐mediated rejection is accompanied by the development of serum polyreactive antibodies that bind apoptotic cells and activate complement, potentially triggering C4d deposition in damaged graft tissues.
The immune cell function assay (ICFA) and de novo anti‐donor‐specific HLA antibodies (DSA) have been proposed as assays for immune monitoring in renal transplantation, but longitudinal studies ...examining the modification of both parameters over time and their relation with clinical events are lacking. We prospectively measured longitudinal changes in ICFA and DSA levels in 55 kidney transplant recipients over 3‐year follow‐up (534 visits) and analyzed their relation with the risk of developing acute rejections or infections. Seven patients (12.7%) developed biopsy‐proven acute rejection, and 20 (36.4%) developed viral infections. At 3 years posttransplant, 28% of the patients had developed de novo DSA. ICFA levels peaked at 1–2 months posttransplant (p = 0.005) and leveled off thereafter. They were not associated with the risk of acute rejections, viral infections or development of de novo DSA. Instead, the incidence of de novo DSA was higher in patients who previously had viral infections (adjusted‐odds ratio of de novo DSA associated with prior infections: 6.03 95% CI, 1.64–22.06; p = 0.007). Our prospective, longitudinal study does not support using ICFA to quantify the immune risk in kidney transplantation. Further studies are needed to confirm the relationship between viral infections and the subsequent development of de novo DSA.
In this prospective longitudinal study examining an immune function assay and de novo donor‐specific alloantibodies in kidney transplant recipients, the authors find that the immune function assay was not related to the future development of rejection, infection, or donor‐specific antibodies, but that the risk of developing donorspecific antibodies was increased in patients who suffered from previous viral infection.
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