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The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

BACKGROUND AND AIMS ANCA-associated vasculitis (AAV) is rare among children but leads to kidney failure (KF) in almost 30% of cases with renal involvement [1]. Kidney transplantation (KT) is the treatment of choice in adults with AAV and KF, while data among children are limited to small case series [2, 3]. We report the outcomes of KT in a multicentre cohort of patients with childhood-onset AAV. METHOD Patients with AAV diagnosed before the age of 18 years who had undergone KT were identified at one Canadian and 20 European centres. We analysed patient and graft survival and the rates of rejection, AAV relapse and infections. Eighteen patients from this cohort had already been reported in previous articles [1, 2]; their follow-up was extended and further relevant data were retrieved. RESULTS We included 55 patients, of whom 38 (69%) had microscopic polyangiitis (MPA) and 17 (31%) granulomatosis with polyangiitis (GPA). Their median age at diagnosis and transplantation was, respectively, 12 (interquartile range, IQR 9–14) and 14 (IQR 12–16) years (Table 1). Living donor transplantation was performed in 20 cases (36%) and deceased donor transplantation in 35 (64%). At the time of transplantation, all patients were in clinical remission and ANCA was positive in 14/54 (26%). As immunosuppressive therapy, 46 patients (84%) received glucocorticoids, tacrolimus and either mycophenolate mofetil or azathioprine. The median follow-up after transplantation was 54 months (IQR 21–91). Acute rejection was reported in 22 patients (40%), 12 of whom experienced it during the first post-transplant year, while chronic rejection was established in two (4%). AAV relapsed in five cases (9%) and involved the graft in 4/5. Positive ANCA at transplantation was significantly associated with relapse (29% versus 2%; P = 0.02). Infections occurred in 34 patients (62%), and were mainly bacterial infections of the urinary tract or viral infections due to CMV (8/34), EBV (5/34) and BK virus (4/34). No patient developed malignancy. At last visit, all patients were alive and 48 (87%) had a functioning graft. Graft function impairment (eGFR CONCLUSION KT in childhood-onset AAV has a relatively good graft and patient survival, while the rate of complications and the risk of vasculitis relapse appear low. Positive ANCA at the time of transplantation may be a risk factor for both AAV relapse and graft function impairment.

Background and Aims Renal involvement in ANCA-associated vasculitis (AAV) impacts significantly on patients’ prognosis. The role of different induction regimens on remission rates and long-term renal outcomes according to renal histological characteristics has not been explored yet. Method AAV patients with biopsy-proven renal involvement were collected retrospectively from eleven centers and stratified according to the induction regimen employed: Rituximab (RTX), Cyclophosphamide (CYC) or both (RTX-CYC). Kidney biopsies were classified according to the Berden and Brix classifications. Renal remission rate was assessed 6 months after the induction regimen and defined as a renal Birmingham Vasculitis Activity Score (BVAS) of 0. Among patients who achieved remission at 6 months, renal relapse was defined as a renal-BVAS>0 associated with an increase in immunosuppressive treatment. ESRD was defined as an eGFR Results 323 patients were identified and followed-up for a median time of 36 months (IQR 18-72). The cohort included 38% patients with GPA and 62% with MPA, 53% patients were MPO-ANCA and 41% PR3-ANCA positive. The median baseline eGFR in the overall cohort was 19 ml/min/1,73m2 (IQR 12- 34). 58% of patients were treated with CYC, 24% with RTX-CYC and 18% with RTX. According to the Berden classification, 24% biopsies were classified as Focal, 31% as Crescentic, 33% as Mixed and 12% as Sclerotic. The Brix score was assessable in 270/323 (84%) patients: 17%, 52% and 31% were respectively in the Low, Medium and High-risk class. The overall renal remission at 6 months was 90%; according to the Berden classification, 94% patients achieved remission in the Focal, 88% in the Crescentic, 91% in the Mixed and 86% in the Sclerotic class. According to the Brix risk score, 88% patients achieved remission in the High risk, 91% in the Medium and 96% in the Low-risk class. According to induction regimen employed, 91%, 90% and 90% patients achieved remission in the RTX, CYC and RTX plus CYC group respectively. In a logistic regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen employed was not predictive of renal remission at 6 months, neither in Berden Focal plus Crescentic and Mixed plus Sclerotic classes, nor in Brix High and Low plus Medium risk classes. Of the 185 patients with at least 6 months of follow-up available after remission, 25% experienced a renal relapse. In a Cox regression model adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria at onset, the induction regimen or histological score were not predictive of renal relapse. In the unadjusted survival analysis with the Kaplan-Maier curve, patients in the Crescentic group treated with RTX had a shorter ESRD-free survival compared to the CYC group (p=0.033) and the RTX-CYC group (p=0.044); figure 1: This was confirmed also with a Cox regression analysis adjusted for sex, age, ANCA type, AAV diagnosis, creatinine and proteinuria when comparing the RTX group with the CYC one (HR 8.30 [95% CI 1.64 to 42.01], p=0.011); figure 2: While the eGFR changes over time in the Focal plus Crescentic and Mixed plus Sclerotic classes showed a similar trend between treatment groups, in the Crescentic class the median eGFR values in the RTX group tended to be lower compared to the CYC and the RTX-CYC ones; figure 3: The rate of severe infections in the RTX, CYC and RTX-CYC group was respectively 6.3, 8.5 and 8.8 per 100 patient-years during the first 12 months. Conclusion in a retrospective multicenter survey, response rates and relapse risk after different induction regimens in AAV patients with renal involvement were comparable in the overall cohort and in the different histopathological subgroups. Although in a small subset of patients, the ESRD-free survival in the Crescentic class was shorter in the RTX group compared to the CYC one.

Background and Aims Glucocorticoids (GC) and/or immunosuppressive agents are the mainstay of therapy for adult-onset IgA Vasculitis (IgAV), but their efficacy is often partial while their toxicity is relevant. Recently, rituximab (RTX) has been reported as a safe and effective option but only few data on renal outcome are available.1 RTX has also been used in a few cases of crescentic IgA Nephropathy (cIgAN), an IgAN subset with vasculitic lesions and poor response to conventional immunosuppressive regimens.2 We present the results of a multicentre cohort of patients with IgAV and cIgAN treated with RTX. Method The databases of 16 consorted European centres were investigated to screen for patients with adult-onset, biopsy-proven IgAV and cIgAN (crescents in ≥25% glomeruli and rapid eGFR worsening at presentation), who received RTX as induction therapy. We selected patients with active renal manifestations at the time of RTX. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS)=0 or Results We identified 38 patients with IgAV and 12 patients with cIgAN who received RTX and had active renal involvement at the time of treatment. The median age at onset was 40 years (interquartile range, IQR, 25-53) and more than two-thirds of patients were male (Table 1). The median follow-up after RTX was 41 months (IQR 18-60). Renal outcomes are reported in Table 2. At the time of treatment, 24 patients (48%) had eGFR ≥60 mL/min/1.73 m2. All had IgAV and their median BVAS was 17 (IQR 10-22). Furthermore, all had microhaematuria and proteinuria. Renal histology showed mesangial or focal endocapillary proliferation in 12/17 (71%) patients who underwent biopsy (class II-IIIA according to Pillebout3). Twenty patients (83%) achieved remission; after a median of 12 months (range 9-14), four experienced a minor relapse and one had a major relapse with significant renal disease progression. Renal function remained stable in all but two patients who developed end-stage renal disease (ESRD). Micro-haematuria subsided in 14/24 (58%) and median 24h proteinuria decreased from 1750 mg (IQR 865-3275) to 175 mg (IQR 100-800) at last follow-up (p=0.029). Of the 26 patients with eGFR Remission rate and ESRD-free survival were respectively 86% and 92% in patients with IgAV, while they were respectively 42% and 42% in cIgAN patients. Furthermore, 21/24 (87%) patients who received RTX alone or combined to glucocorticoids but not to immunosuppressive agents achieved remission and 22/24 (92%) were ESRD-free at last follow-up. Of the 26 patients receiving immunosuppressive agents, 17 (65%) obtained remission and 18 (69%) were ESRD-free at last assessment. Over the whole follow-up, only one patient reported a severe adverse effect related to RTX (pneumonia). Conclusion Renal involvement in adult-onset IgAV and cIgAN is frequently severe. RTX, combined or not with other immunosuppressive agents, may improve renal manifestations and is well tolerated. IgAV patients show higher remission rates and a longer ESRD-free survival as compared to cIgAN patients.

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.

Background and Aims Proteinuria selectivity index (PSI) predicts steroid responsiveness in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). Rituximab, a monoclonal antibody targeting CD20, has increasingly recognized as a potential therapy of idiopathic podocytopathies, such as MCD and FSGS, although the mechanism of action is still unrecognized and randomized controlled studies are still lacking. Currently, no tools are available to predict responsiveness to RTX. We explored the role of PSI as a potential predictor of RTX responsiveness in MCD and FSGS. Method We analysed cases of biopsy-proven MCD and FSGS followed at one single centre, who received RTX therapy. Baseline data, including proteinuria and PSI, were collected. Proteinuria was considered selective with PSI (clearance of urinary IgG/transferrin ratio) 50%) and substantial improvement of clinical symptoms. Results RTX was administered to 14 patients with MCD and 16 patients with FSGS and, of them, PSI was available before treatment for 10 and 14 patients, respectively. Baseline characteristics of the patients are shown in Table 1. Among the 24 cases with available PSI, CR was reported in 12 and PR in 5, while 9 did not respond to RTX. All patients who achieved CR and PR had selective proteinuria at baseline, while all patients with PSI >0.20 did not respond to RTX (Figure 2). Median relapse-free survival was 25.4 months. Among responders, in 10 out of 19 patients (53%) the relapse occurred between 4 and 60 months from initial treatment. No potentially life-threatening adverse events have been observed. Conclusion Selective proteinuria before treatment can predict the response to RTX in adult patients with steroid-dependent and refractory forms of MCD and FSGS.

Background Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. Methods We screened patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction Results Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64–78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15–35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670–2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden’s classification, 6/28 biopsies (21%) were ‘focal’, 1/28 (4%) ‘crescentic’, 9/28 (32%) ‘mixed’ and 12/28 (43%) ‘sclerotic’. At last follow-up (median 32 months, IQR 12–52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT. Conclusions AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.

ANCA-associated vasculitides (AAVs) are small-vessel vasculitides with a broad spectrum of manifestations, since almost all organs can be affected. Miscellaneous organ manifestations including the involvement of cardiovascular and musculoskeletal system, gastrointestinal and urogenital tract, occur in only a minority of patients but may have a profound impact on morbidity and mortality. As an example, cardiac involvement, including subclinical forms, is emerging as a diffuse and insidious disease component. In eosinophilic granulomatosis with polyangiitis (EGPA), cardiac abnormalities have been related to eosinophil infiltration and occur in up to 50% of patients, accounting for the first disease-related cause of death. Overall, AAV patients experience an increased frequency of ischemic heart disease, due to “accelerated atherosclerosis.” Gastrointestinal manifestations are not specific and may range from mild to life-threatening complications, even requiring surgery. A small number of granulomatosis with polyangiitis (GPA) male patients develop prostatitis as the most common urogenital manifestation, while therapy based on cyclophosphamide may cause hemorrhagic cystitis and urothelial cancer. In isolated cases, muscle vessels may be affected by vasculitis resulting in chronic ischemia and fiber degeneration. Although the list of manifestations is potentially infinite, it must be kept in mind that AAV may associate with a number of autoimmune and fibro-inflammatory diseases. Thus, patients with AAV should be carefully and periodically evaluated for new or modified manifestations and should receive a serological screening to exclude the development of overlap syndromes.

Eosinophilic granulomatosis with polyangiitis is characterized by asthma, blood and tissue eosinophilia and small-vessel vasculitis. The clinical presentation is variable, but two main clinic-pathologic subsets can be distinguished: one hallmarked by positive ANCA and predominant ‘vasculitic’ manifestations (e.g. glomerulonephritis, purpura and mononeuritis multiplex) and the other by negative ANCA and prominent ‘eosinophilic’ manifestations (e.g. lung infiltrates and cardiomyopathy). The pathogenesis is not fully understood but probably results from the interplay between T and B cells and eosinophils. Eosinophilic granulomatosis with polyangiitis must be differentiated from several conditions, including hypereosinophilic syndromes and other small-vessel vasculitides. The overall survival is good; however, patients frequently relapse and have persistent symptoms. The recently developed monoclonal antibodies targeting B cells and eosinophilopoietic cytokines such as IL-5 are emerging as valid alternatives to conventional immunosuppressive therapies. In this review, we discuss the essential features of eosinophilic granulomatosis with polyangiitis, with particular respect to the most relevant issues concerning clinical presentation and management.

Chronic periaortitis (CP) is a rare condition characterised by a peri-aortoiliac fibro-inflammatory tissue. A total of 20%–50% of the cases are immunoglobulin G4 (IgG4)-related, based on histological evidence of IgG4+ plasma cell infiltration (on a background of dense lymphoplasmacytic infiltrates, storiform fibrosis and tissue eosinophilia) and/or increased serum IgG4.1 Glucocorticoids are the first-line therapy for CP.2 However, some patients are refractory, frequently relapsing or have contraindications to glucocorticoids. The anti-CD20 monoclonal antibody rituximab proved efficacious in systemic forms of IgG4-related disease (IgG4-RD) including IgG4-related CP,3 but data on IgG4-unrelated CP are scarce.4–6 In this study, we tested rituximab in CP patients without evidence of IgG4-RD who had relapsing/refractory disease or contraindications to standard-dose glucocorticoids. We included patients with active, IgG4-unrelated CP who received rituximab (October 2009 to April 2017). Online supplementary methods describe the diagnostic and follow-up procedures, the definitions of remission and refractory, and the statistical analysis.### Supplementary data [annrheumdis-2019-216258supp001.pdf] Twenty consecutive patients were included. Two of them were previously reported.5 Of the eight patients with available CP biopsies, none had significant IgG4+-plasma cell infiltration. None had other biopsy-proven …

OBJECTIVE: Adult-onset IgA vasculitis (Henoch-Schönlein) (IgAV) is a rare systemic vasculitis characterized by IgA1-dominant deposits. The treatment of adult-onset IgAV is controversial and is based on the combination of glucocorticoids and immunosuppressive agents, but many patients have refractory or relapsing disease despite treatment. Rituximab (RTX) is a B cell-depleting antibody of proven efficacy in antineutrophil cytoplasmic antibody-associated vasculitis. We undertook this study to test the efficacy and safety of RTX in a multicenter cohort of patients with adult-onset IgAV. METHODS: In this multicenter observational study, we included patients with adult-onset IgAV who had received RTX either for refractory/relapsing disease or because they had contraindications to conventional glucocorticoid/immunosuppressive therapy. We analyzed the rates of remission (defined on the basis of the Birmingham Vasculitis Activity Score [BVAS]) and relapse as well as the variations over time in estimated glomerular filtration rate (GFR), proteinuria, C-reactive protein (CRP) level, BVAS, and prednisone dose. RESULTS: Twenty-two patients were included; their median duration of follow-up was 24 months (interquartile range 18-48 months). Sixteen patients received RTX as add-on therapy and 6 as monotherapy. Twenty patients (90.9%) achieved remission, and 7 of those 20 patients (35%) had subsequent relapse of disease. There were significant reductions in 24-hour proteinuria (P < 0.0001), CRP level (P = 0.0005), BVAS (P < 0.0001), and prednisone dose (P < 0.0001) from RTX initiation through the last follow-up visit; estimated GFR remained stable. RTX was generally well tolerated. One patient died after 60 months of follow-up. CONCLUSION: Our data suggest that RTX is an effective and safe therapeutic option for adult-onset IgAV.