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ANCA-associated vasculitis (AAV) poses a significant risk of kidney failure, kidney biopsy remains a key prognostic tool. The histopathologic classification of AAV glomerulonephritis (GN) developed by Berden et al. showed correlation between GN classes and kidney outcomes, ANCA Renal Risk Score (ARRS) included tubular atrophy and interstitial fibrosis (TA/IF) as an additional parameter for risk assessment. We aimed to evaluate kidney survival across AAV GN classes and ARRS groups. A single-center retrospective study included 85 adult patients with biopsy-proven AAV kidney disease followed in the period of 2000–2020. Primary outcome was kidney survival at the end of 18 (5, 66) months follow-up, and kidney death was considered as stage 5 CKD. We found significant differences in kidney survival for sclerotic, mixed, crescentic and focal AAV GN classes: 19%, 76.2%, 91.7% and 100%, respectively (p = 0.009). Kidney survival was 0%, 75.6% and 100% for the high-, medium- and low-risk ARRS groups, respectively (p &lt, 0.001), TA/IF analysis showed kidney survival at 49.6% vs. 87.7% for widespread and mild TA/IF, respectively (p = 0.003). Kidney survival was significantly lower in anti-MPO-ANCA versus anti-PR3-ANCA carriers (50.3% and 78.1%, respectively, p = 0.045). We conclude that unfavorable AAV kidney outcomes are associated with sclerotic GN class by Berden’s classification, ARRS high risk group, and anti-MPO-ANCA subtype.

Summary We compared the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternative pathway components factor B and properdin in patients with ANCA-associated vasculitis (AAV) and healthy controls, and conducted a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV. Complement components were evaluated in 59 patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis and 36 healthy volunteers. In 28 patients, testing was repeated in remission. Next, we performed a meta-analysis by searching databases to identify studies comparing complement levels in AAV patients and controls. A random-effects model was used for statistical analyses. The median concentrations of MAC, C5a, C3a and factor B were higher in active AAV patients (P < 0·001). Achievement of remission was associated with reductions in C3a (P = 0·005), C5a (P = 0·035) and factor B levels (P = 0·045), whereas MAC and properdin levels did not change. In active AAV, there were no effects of ANCA specificity, disease phenotype, previous immunosuppression or disease severity on complement levels. A total of 1122 articles were screened, and five studies, including this report, were entered into the meta-analysis. Plasma MAC, C5a and factor B in patients with active AAV were increased compared to patients in remission (excluding factor B) and controls. Changes in C3a were of borderline significance. Our findings and the results of the meta-analysis support activation of the complement system predominantly via the alternative pathway in AAV patients.

Systemic vasculitis is a heterogeneous group of inflammatory diseases, which are classified according to the diameter of the affected vessels. The treatment of systemic vasculitis is no longer empirical, because of increasing number of randomized clinical trials in this field. In recent years, there was a trend to limit the cumulative dose of glucocorticosteroids and immunosuppressive drugs, partially through biological drugs usage. However, biologic therapy is not always superior to combination of glucocorticosteroids and cytotoxic drugs. The efficacy of different biologic drugs varies in patients with different forms of systemic vasculitis, which creates the ground for personalized therapy of these diseases. Another serious problem is the absence of strict criteria to immunosuppressive therapy intensification, especially in vasculitis, affecting large vessels, due to the lack of reliable laboratory markers of disease activity. The article reviews modern approaches to the treatment of some types of systemic vasculitis, including ANCA-associated vasculitides, giant cell arteritis, Takayasu`s arteritis and cryoglobulinemic vasculitis.

Background:There is increasing evidence that the complement system, in particular the alternative pathway, plays a crucial role in the pathogenesis of ANCA-associated vasculitis (AAV) [1]. Efficacy of C5a receptor antagonists indicates that chemoattraction mediated by C5a plays a key role in the inflammatory process observed in AAV [2]. Another promising research object are regulatory proteins such as factor B [3].Objectives:To study complement activation via the alternative pathway in patients with active ANCA-associated vasculitis.Methods:59 patients with newly diagnosed (n=35) or relapsing GPA or MPA (n=24) were enrolled in this prospective study. Median BVAS v.3 at the time of AAV onset was 16.5 (9.5; 20). In 28 patients activation of complement was reassessed during sustained remission (BVAS v.3 = 0) after a median of 16 months. Thirty six age-and gender-matched healthy volunteers comprised the control group. Levels of complement components (C3, C5, C3a, C5a, vitronectin, factor B and factor P) were measured by ELISA (Cloud Inc.). Data were not normally distributed, therefore, values are given as medians and IQRs and nonparametric statistical tests were used.Results:The concentrations of C5, C3, vitronectin and CFB were significantly higher in patients with active AAV than control group. There were no significant differences in the levels of factor P in patients with active AAV and control group (388000 (371960; 417150)) vs 416000 (400200; 437000), ng/ml, p >0.05) (Fig. 1).Fig 1.Concentration of complement components in patients with active AAV and healthy controls (*pSerum level of C5a and C3a were higher in patients with active AAV than in healthy controls (22.9 (14.4; 33.0) vs 3.0 (0.35; 6.73), ng/ml, pThe levels of complement components were similar in PR3-ANCA and MPO-ANCA disease, and severe and non-severe AAV. C5a/C5 and C3a/C3 ratios were not influenced by disease activity, severity or ANCA type.After immunosuppressive treatment concentrations of C5, C3, and their activated products, C5a, C3a significantly decreased (Fig. 2). However, concentrations of regulatory proteins such as factor B, factor P and vitronectin were unaffected. Interestingly, that there was no significant difference in MAC levels before and after immunosuppressive treatment (24646 (15342; 46681) vs 20057.4 (19709.3; 41477.6), mAU/ml, p=0.925).Fig 2.Concentration of complement components in patients with active disease and remission (*pConclusion:The complement system plays an important role in AAV. While treatment affects some component, some remain unchanged and are not dependent on AAV severity or ANCA serotype.References:[1]Jennette JC, Xiao H, Hu P. Complement in ANCA-Associated Vasculitis. Seminars in Nephrology 2013; 33 (6): 557 – 564[2]Schreiber A, Xiao H, Jennette JC et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20(2): 289-298.[3]Gou SJ, Yuan J, Chen M et al. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 2013; 83(1): 129-137.Disclosure of Interests:Anastasiia Zykova Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Nikolai Bulanov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Andreas Kronbichler Grant/research support from: This work was supported by unrestricted grant from the Austrian Society of Rheumatology., Evgeny Gitel: None declared, Oxana Novikova: None declared, Mayra Bulanova: None declared, Elizaveta Safonova: None declared, Sergey Moiseev Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow

To the Editor: Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) form a group of necrotizing small-vessel vasculitides characterized by the presence of ANCA against either proteinase 3 (PR3) or myeloperoxidase (MPO). ANCA have a key role in the pathogenesis of AAV, inducing excessive activation of neutrophils, which results in injury to small vessels1. ANCA can target other neutrophil-derived molecules, among them lysosome-associated membrane glycoprotein 2 (LAMP-2). LAMP-2 is a glycosylated membrane protein expressed in lysosomes and on the surface of neutrophils and glomerular cells2. Antibodies against LAMP-2 were originally detected in cases with active AAV and pauci-immune crescentic glomerulonephritis3. Subsequent experimental studies showed that passive immunization with rabbit IgG to recombinant LAMP-2 or active immunization with recombinant FimH (a bacterial adhesion protein present in gram-negative bacteria and sharing 1 epitope of LAMP-2) can induce pauciimmune crescentic glomerulonephritis in rats, thus supporting the pathogenicity of anti–LAMP-2 antibodies4. Patients with active AAV defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥ 3 were included in our study. Serum concentration of anti–LAMP-2 antibodies was determined using … Address correspondence to Dr. S. Moiseev, Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Rossolimo, 11/5, Moscow, 119435, Russia. E-mail: avt420034{at}yahoo.com

Background: Interstitial lung diseases (ILD) are a group of diffuse inflammatory and/or fibrotic lung disorders with similar clinical, radiologic and histopathologic features. The coexistence of ILD and aNCA-associated vasculitis has been reported in case reports and small case series. Objectives: The aim of this study was to assess the prevalence, clinical and radiological characteristics of ILD in MPA patients admitted to the Rheumatology Department of our hospital. Methods: This retrospective single center cohort study included 102 patients diagnosed with MPA according to CHCC 2012 and EMA algorithm. We assessed Birmingham Vasculitis activity Score (BVAS) at disease onset and VDI (Vasculitis Damage index) at the end of the follow up in each patient. ANCA type and titer were assessed by enzyme-linked immunosorbent assay (ELISA). The results of repeated high resolution computed tomography (HRCT) of the chest were analyzed and interstitial changes (focal ground-glass opacity, reticular changes, honeycombing, traction bronchiectasis) were classified in four patterns: non-specific interstitial pneumonia (NSIP), typical interstitial pneumonia, possible interstitial pneumonia, and “inconsistent” usual interstitial pneumonia (UIP). Results: ILD-features on HRCT was found in 11 (11.8%) of 102 patients with MPA. Their median age was 55 [53; 63] years. All of them were aNCA-positive (Table 1). In 5 cases interstitial pneumonia was the first and the sole manifestation that preceded for the occurrence of overt systemic vasculitis for a median of 3 years. The radiologic patterns included non-specific interstitial pneumonia in 5 cases, usual interstitial pneumonia in 3 cases and unclassifiable interstitial pneumonia in 3 cases. The most common clinical manifestations were non-productive cough (82%), progressive dyspnea (82%) and crepitation (27%). The most common extrathoracic manifestations of MPA in patients with ILD were glomerulonephritis with decreased renal function (91%), fever (100%) and arthritis (91%). All patients received induction therapy with glucocorticosteroids combined with cyclophosphamide, rituximab, azathioprine or methotrexate. Conclusion: ILD is a rare manifestation of MPA, which can precede systemic manifestations. ANCA-associated vasculitis should be included in the spectrum of differential diagnosis in patients with ILD. Disclosure of interests: None declared

Background:The role of ANCA type is well established for the risk of relapses of ANCA-associated vasculitis (AAV). However their association with renal involvement and its outcomes is less well understood.Objectives:To assess clinical and morphological features of ANCA-associated glomerulonephritis (ANCA-GN) and renal survival in ANCA-negative patients, proteinase-3-ANCA (pr3-ANCA) positive and myeloperoxidase-ANCA (MPO-ANCA) positive patients.Methods:We enrolled 53 patients with AAV, diagnosed according to Chapel Hill Consensus Conference (2012) definition and/or ACR (1990) criteria, with histologically proven renal involvement. There were 13 (24.5%) males, median age at onset was 48 (33; 57) years. Seven patients were ANCA-negative (13.3%), 17 (32.0%) patients were pr-3-ANCA positive and 29 (54.7%) patients were MPO-ANCA-positive. ANCA-associates glomerulonephritis (ANCA-GN) class was established according to Berden et al classification.1We retrospectively assessed ANCA renal risk score (ARRS) at disease onset.2Twelve patients (22.6%) developed end-stage renal disease (ESRD) after a median of 12 (6.5; 28) months. Renal survival rates were assessed by Kaplan-Meier method and compared by log-rank test.Results:The only significant difference was median BVAS score which was significantly higher in pr3-ANCA-positive (18 (17;20)) than in MPO-ANCA positive patients (15 (12; 18), p=0.012). Creatinine levels, eGFR, percentage of glomeruli with crescents, global sclerosis, and interstitial fibrosis and tubular atrophy didn’t depend on the presence of ANCA or type of the antibodies. The proportion of patients with focal, crescentic, mixed of sclerotic class of ANCA-GN was similar in all groups. There was no significant difference in the numbers of patients with low, medium or high risk of ESRD according to ARRS. One- and three-year renal survival rates were similar in ANCA-negative (81.7% and 60.0% respectively) and ANCA-positive patients (84.2% and 74.6% respectively, Figure 1A). One-year and three-year survival rates were higher in MPO-ANCA-positive (84.4% and 84.4% respectively) than in pr3-ANCA-positive patients (73.1% and 50.1% respectively), however the difference was not statistically significant (Figure 1B).Figure 1.Kaplan-Meier curves showing renal survival in ANCA-positive and ANCA-negative patients (A), and pr3-ANCA-positive and MPO-ANCA-positive patients (B)Conclusion:Our small study indicates that clinical and morphological features of renal involvement, as well as renal survival are similar in ANCA-negative and ANCA-positive patients and don’t depend on the type of ANCA.References:[1]Berden AE, Ferrario F, Hagen EC, et al. Histopathologic Classification of ANCA-Associated Glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628–1636.[2]Brix RB, Noriega M, Tennstedt P, et al. Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int. 2018;94(6):1177-1188.Disclosure of Interests: :Nikolai Bulanov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Ekaterina Stolyarevich: None declared, Anastasiia Zykova: None declared, Elizaveta Safonova: None declared, Elena Shchegoleva: None declared, Ekaterina Kuznezova: None declared, Mayra Bulanova: None declared, Pavel Novikov Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow, Sergey Moiseev Grant/research support from: This work was supported by the 5-100 Project, Sechenov University, Moscow

In a recent observational study, Kronbichler et al recorded 95 severe/life-threatening infections in 49 of 192 patients (25.5%) with associated vasculitides (AAV) within approximately 2 years following rituximab initiation.1 Respiratory tract infections were the most common infectious complications. In patients with a positive culture, opportunistic pathogens were frequently seen, though Pneumocystis jirovecii was identified in only one case. Trimethoprim/sulfamethoxazole prophylaxis was administered in 73 of 192 patients (38.0%) and resulted in an impressive reduction in the risk of severe infectious complications by 70%. Approximately half of patients were treated with 480 mg or 960 mg on alternate days. The optimum prophylactic dose of trimethoprim/sulfamethoxazole in patients with non-HIV remains unknown. The current recommendations for the management of AAV encourage prophylaxis against P. jirovecii infection with trimethoprim/sulfamethoxazole 960 mg on alternate days or 480 mg daily in all patients being treated with cyclophosphamide, where not contraindicated.2 There is some evidence suggesting that a lower dose of trimethoprim/sulfamethoxazole may be equally effective and more safe than 480 mg daily. In a randomised controlled …

Objectives To study efficacy and safety of biosimilar (intended copy) rituximab (Acellbia, BIOCAD) in patients with systemic vasculitides. Methods We enrolled in our case series all consecutive patients with systemic vasculitides diagnosed according to CHCC2012 and ACR criteria (if applicable) who were treated with biosimilar rituximab since 2015. Activity of vasculitis was evaluated using BVAS3. CD19+ B-cells count was measured by standard method. Patients received intravenous rituximab at a 500 mg dose (four weekly infusions for remission induction or two weekly every 6 months infusions for maintenance treatment). Results In total, 45 patients were treated with biosimilar rituximab (29 GPA, 12 MPA, 1 EGPA, 2 cryoglobulemic vasculitis, 1 rheumatoid vasculitis). In 12 patients (7 GPA, 3 MPA, 1 CryoVas, 1 RheumVas), rituximab was administered for induction of remission due to high activity and relapsing course of vasculitis and low efficacy of previous treatment. 33 patients (22 GPA, 9 MPA, 1 EGPA, 1 CryoVas) received rituximab for maintenance of remission. Median duration of follow-up was 12 months.6–26 At 1 and 3 months, all patients achieved B-cell depletion. At 6 months, B-cell repopulation was shown in 9 patients (20%). Remission induction therapy with rituximab resulted in decrease of median BVAS from 16 10–24 to 1 (0–4) at 3 months and to 0 (0–2) at 6 months. At 3 and 6 months, median prednisone dose was tapered from 50 mg 35–80 to 25 mg 15–40 and 10 mg, 5–20 respectively. In patients who received rituximab for maintenance treatment, median BVAS showed no disease activity (0–1) both at baseline and at 3 or 6 months. At baseline and at 3 months median doses of prednisolone were 5 mg (0–7.5) and 5 mg (0–5). At 6 months, it was reduced to 2.5 mg (0–5). Biosimilar rituximab had acceptable safety profile. Adverse events included mild infusion reaction,2 urinary3 and bronchopulmonary5 infections which required intravenous antibiotics (median 4 months after infusions), hypogammaglobulinemia2 that persisted for at least 12 months and 1 case of late-onset neutropenia in 8 months. Conclusions Biosimilar rituximab showed high efficacy and acceptable safety in patients with systemic vasculitides. Disclosure of Interest None declared

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening disease characterised by a recurrent course and progressive accumulation of irreversible damage of vital organs, that is, kidney and lungs. Before the advent of immunosuppression, AAV was usually fatal, that is, up to 80%–90% of patients were expected to die within 1 to 2 years after diagnosis. Aggressive immunosuppressive treatment with cyclophosphamide and high-dose corticosteroids has improved the outcomes in patients with AAV at the cost of significant toxicity.1 Not surprisingly, the researchers are focused on exploring the new regimens of immunosuppression that can provide a similar efficacy with an improved safety. These attempts were at least partly successful particularly due to the introduction of rituximab both for remission induction and maintenance treatment. Moreover, current evidence suggests that a proportion of patients with AAV are overtreated with rituximab and may benefit from an optimised maintenance therapy. In the recently published multicentre, randomised controlled, phase III trial (MAINRITSAN2), the investigators from the French Vasculitis Study Group compared the efficacy and safety of a tailored rituximab regimen, based on monitoring of ANCA titre and CD19+ B-cell counts, with fixed-schedule rituximab infusions in 162 patients with granulomatosis with polyangiitis or microscopic polyangiitis, who were in complete remission at the time of enrolment.2 Patients from the first group were scheduled to receive 500 mg of rituximab at randomisation, while rituximab infusions were repeated only when serial monitoring showed an increase in ANCA titre …

To the editor, In the excellent study recently published in the Annals of the Rheumatic Disease ,1 Damoiseaux et al showed a high diagnostic performance of antigen-specific immunoassay for the detection of myeloperoxidase (MPO) and proteinase 3 (PR3) antineutrophil cytoplasmic antibodies (ANCAs). These data challenge the role of indirect immunofluorescence in the ANCA testing algorithm. In our centre, we have discarded ANCA indirect immunofluorescence more than a decade ago. Therefore, new data showing the feasibility of screening by antigen-specific immunoassay have a particular value for us. In the recent series of 284 patients with ANCA-associated vasculitides, we have detected ANCAs by this approach in 96.9% of patients with microscopic polyangiitis (MPA) but only in 72.7% of patients with granulomatosis with polyangiitis (GPA) (table 1). The latter result can be explained by a relatively high occurrence of localised GPA in our series,2 since a rate of ANCA positivity reached 92.2% in patients with renal GPA. View this table: Table 1 Results of ANCA testing in 284 patients with ANCA-associated vasculitis, n (%) ANCA testing should be performed only in the clinical context since PR3-ANCA and MPO-ANCA can be found in the other conditions …