A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

| Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.NATURE REVIEWS | RHEUMATOLOGY VOLUME 13 | NOVEMBER 2017 | 683 CONSENSUS STATEMENT © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .Given the improvements in antigen-specific immuno assays, the international consensus on the testing of ANCAs in small-vessel vasculitis seems in need of updating [7][8][9][10] . In this manuscript, a revised 2017 international consensus is proposed by a group of international experts (from North and Central America, Australia, Europe and Asia) in the ANCA field. This Consensus Statement highlights the value of ANCA testing as a tool for diagnosis (but not follow-up) of GPA and MPA and gives a historical perspective of ANCAs in small-vessel vasculitis. This Consensus Statement does not, however, present evidence-based guidelines or a meta-analysis. MethodsThis Consensus Statement was prepared by a group of experts from four European laboratories (X.B., J.D., N.R., J.W.C.T. and E.C.) in person and by correspondence. The draft was circulated to each contributor and modified, and the resulting document was distributed by e-mail to 16 experts from four continents, selected based on their expertise and knowledge in clinical and/or laboratory aspects of AAV. This revised document resulted in a second round of discussions and revisions. The final document was returned to all contributors for ratification.The Consensus Statement is based on the results of a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of IIF versus antigen-specific immunoassays for ANCA detection 6,11,12 . This study, which showed a large variability between different IIF methods and a good diagnostic performance of PR3-ANCA and MPO-ANCA immunoassays 6 , indicated that the 1999 international consensus on ANCA testing for AAV needed revision. When the consensus was put toget...

The value of measuring ANCA during follow-up to predict a relapse is controversial. On the basis of recently obtained pathophysiologic insights, we postulated that measuring ANCA is useful in patients with renal involvement but is less valuable in patients with nonrenal disease. One hundred sixty-six consecutive patients with ANCA-associated vasculitis, positive for either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA, were included in our study, followed at regular intervals, and tested for PR3-ANCA and MPO-ANCA. In this cohort, 104 patients had renal involvement (72 with PR3-ANCA, 32 with MPO-ANCA) and 62 patients had nonrenal disease (36 with PR3-ANCA, 26 with MPO-ANCA). During an average (6SD) follow-up of 49633 months and 18614 ANCA measurements, 89 ANCA rises and 74 relapses were recorded. ANCA rises correlated with relapses in patients who presented with renal involvement (hazard ratio [HR], 11.09; 95% confidence interval [95% CI], 5.01 to 24.55), but in comparison, associated only weakly with relapses in patients who presented with nonrenal disease (HR, 2.79; 95% CI, 1.30 to 5.98). In conclusion, longitudinal ANCA measurements may be useful in patients with renal involvement but is less valuable in patients with nonrenal disease.

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Background Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. Methods We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO 2 /FiO 2 ) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO 2 /FiO 2 in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov ( NCT04333420 ). Findings Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO 2 /FiO 2 assessments (irrespective of position). At day 5 after randomisation, the mean PaO 2 /FiO 2 (irrespective of position) was 158 mm Hg (SD 63; range 84–265) in the IFX-1 group and 189 mm Hg (89; 71–329) in the control group. Analyses of the least squares mean relative change in PaO 2 /FiO 2 at day 5 showed no differences between treatment groups (17% change in the IFX-1 group vs 41% in the control group; difference −24% [95% CI −58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the IFX-1 group and 27% (4–49) for the control group (adjusted hazard ratio for death 0·65 [95%...

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ISRCTN28528813.

In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.