Antineutrophil cytoplasmic antibodies (ANCA) that target the third neutral serine proteinase (PR3) and myeloperoxidase (MPO) of human neutrophils are associated with primary systemic vasculitis that predominantly affects small and medium blood vessels.1,2 There is an international consensus that testing for ANCA should specifically be focused on identifying antibodies against those 2 antigenic targets.3 In this edition of the journal, Wójcik et al4 discuss the data from the Polish Vasculitis Register (POLVAS) including information from 536 individuals who presented with vasculitis over 27 years, in the demographic context

Mukhtyar, Chetan B.

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EDITORIAL Testing for antineutrophil cytoplasmic antibodies 1inflammation to a pure vasculitis end that is ex-plosive on its onset, and that the 2 ends behave very differently.9 Using the Chapel Hill nomencla-ture, we call the pure vasculitis end MPA. The as-sociation of MPA with renal involvement and the risk of death is therefore not interesting, as it is circuitous, while the association of MPO-ANCA with the risk of renal involvement is certainly interesting. If we did the same thing to the no-menclature of GPA and only used that term for the pure granulomatous end of the AAV spectrum, we might find the same sort of association of it being a homogenous disorder with PR3-ANCA, associated with indolent but relapsing inflamma-tory disease. Then, what should we do about all the other cases between the 2 ends of the spec-trum, and how do the double ANCA-positive pa-tients fit in?Diseases should be identified and named after their pathogenetic mechanisms, not phenotypes. A chest infection can be caused by many different organisms and not all of them would respond to the same antibiotics. We therefore strive to iden-tify the microbe involved and treat each person accordingly. If we think PR3- and MPO-ANCA are pathogenic, can we call the AAV simply by its se-rotypes and discard the GPA, MPA and EGPA de-scriptors? We probably cannot! EGPA has a strong argument for being classified into the domain of eosinophilic disorders rather than AAV. We also know that the phenotype of a MPO-ANCA–posi-tive GPA is very different to what we might expect from MPO-positive MPA. If the disease pheno-type is a function of the ANCA sub type, then we might expect MPO-ANCA GPA to present more like MPO-ANCA MPA. However, MPO-ANCA GPA appears to have a presentation which is less se-vere and may have a better survival outcome than PR3-ANCA GPA.7 This suggests that the classifi-cation may reflect the disease mechanism as well as the serotype.Wójcik et al4 showed that ANCA antibody pro-duction may be a function of age. We know that Antineutrophil cytoplasmic antibodies (ANCA) that target the third neutral serine proteinase (PR3) and myeloperoxidase (MPO) of human neu-trophils are associated with primary systemic vas-culitis that predominantly affects small and medi-um blood vessels.1,2 There is an international con-sensus that testing for ANCA should specifically be focused on identifying antibodies against those 2 antigenic targets.3 In this edition of the journal, Wójcik et al4 discuss the data from the Polish Vas-culitis Register (POLVAS) including information from 536 individuals who presented with vascu-litis over 27 years, in the demographic context.The  basic premise of their analysis is fo-cused around the need for ANCA testing. We know that there is evidence that distinct geno-types predict the generation of either PR3-AN-CA or MPO-ANCA serotypes in individuals with ANCA-associated vasculitis (AAV).5 There are also genotypes that produce associations for PR3-AN-CA and MPO-ANCA in different directions, where an association for increased risk for one sero-type is associated with a reduction for another serotype.6 Observational data tell us that these serotypes have a weak association with distinct phenotypes.7 Indeed, the POLVAS data demon-strated that most individuals with MPO-ANCA had MPA (n = 86 / 127), most individuals with PR3-ANCA had GPA (n = 316 / 338), and most individuals with ANCA-negative vasculitis had EGPA (n = 47 / 75). This is in line with previous observations. It is slightly surprising that in such a large cohort of individuals with AAV, there were no patients with dual positivity. In a similar size pan -European cohort of 535 cases, 16 patients (3%) were dual positive.8Vasculitis academics have long grappled with the classification of AAV. As in the POLVAS data, GPA is a heterogenous disease and MPA is a ho-mogenous disease. This may purely be a function of the way we classify the disease. We know that AAV is a spectral disorder, ranging from a pure granulomatous end that is typified by indolent EDITORIALDiagnostic utility of testing for antineutrophil cytoplasmic antibodiesChetan B. MukhtyarRheumatology Department, Norfolk and Norwich University Hospital, Norwich, United KingdomCorrespondence to:Chetan B. Mukhtyar, MBBS, MSc, MD, FRCP, FRCP Edin, Vasculitis Service, Rheumatology Department, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, United Kingdom, phone: +44 1603 286286, email: chetan.mukhtyar@nnuh.nhs.ukReceived: February 6, 2022.Accepted: February 7, 2022.Published online: March 30, 2022.Pol Arch Intern Med. 2022;  132 (3): 16224doi:10.20452/pamw.16224Copyright by the Author(s), 2022RELATED ARTICLEby Wójcik et alPOLISH ARCHIVES OF INTERNAL MEDICINE 2022; 132 (3)28 Flossmann O, Berden A, de Groot K, et al. Long ‑term patient survival in ANCA ‑associated vasculitis. Ann Rheum Dis. 2011; 70: 488‑494. 9 Luqmani RA, Bacon PA, Beaman M, et al. Classical versus non ‑renal Wegener’s granulomatosis. Q J Med. 1994; 87: 161‑167.10 Pfister H, Ollert M, Frohlich LF, et al. Antineutrophil cytoplasmic autoan‑tibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood. 2004; 104: 1411‑1418. 11 Heeringa P, Foucher P, Klok PA, et al. Systemic injection of products of activated neutrophils and H2O2 in myeloperoxidase ‑immunized rats leads to necrotizing vasculitis in the lungs and gut. Am J Pathol. 1997; 151: 131‑140.12 Hagen EC, Andrassy K, Csernok E, et al. Development and standard‑ization of solid phase assays for the detection of anti ‑neutrophil cytoplasmic antibodies (ANCA). A report on the second phase of an international coop‑erative study on the standardization of ANCA assays. J Immunol Methods. 1996; 196: 1‑15. 13 Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009; 68: 310‑317. the production of antinuclear antibodies rises with age. Could this just mean that as the body gets older, there is a degree of immune senescence that just results in greater antibody production? After all, we do not know precisely what the back-ground ANCA positivity rate in the population is. There are several flaws in that argument, not least because ANCA are known to be pathogen-ic in vivo and in vitro.10,11 It is therefore unlike-ly that these antibodies are innocent bystanders if present in a large fraction of the population. However, if they are pathogenic, we do not un-derstand why 75 out of 536 patients (14%) are ANCA negative. Do they just have a different dis-ease that looks a lot like AAV?ANCA testing has been around since the 1980s and has been standardized since 1996.12 The test-ing to support the diagnosis of a small and medi-um vessel vasculitis has been recommended since 2009.13 We know that we cannot rely on serial titers for monitoring the disease and therefore their only utility is in establishing a diagnosis in individuals that have manifestation of a small and medium vessel vasculitis. The POLVAS data helped by filling in a small part of the knowledge gap in understanding the need for ANCA testing. There are very few national registries in the world and the establishment of such a concerted effort is likely to help us understand these rare diseases more than we currently do, and for that it must be commended.ARTICLE InfORmATIOnDIsCLAImER The opinions expressed by the author(s) are not necessarily those of the journal editors, Polish Society of Internal Medicine, or publisher.COnfLICT Of InTEREsT None declared.OpEn ACCEss This is an Open Access article distributed under the terms of the Creative Commons AttributionNonCommercialShareAlike 4.0 Interna‑tional License (CC BY ‑NC ‑SA 4.0), allowing third parties to copy and redis‑tribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited, distrib‑uted under the same license, and used for noncommercial purposes only. For commercial use, please contact the journal office at pamw@mp.pl.HOw TO CITE Mukhtyar CB. Diagnostic utility of testing for antineutro‑phil cytoplasmic antibodies. Pol Arch Intern Med. 2022; 132: 16224. doi: 10.20452/pamw.16224REfEREnCEs1 Ludemann J, Utecht B, Gross WL. Anti ‑neutrophil cytoplasm antibodies in Wegener’s granulomatosis recognize an elastinolytic enzyme. J Exp Med. 1990; 171: 357‑362. 2 Falk RJ, Jennette JC. Anti ‑neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and id‑iopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988; 318: 1651‑1657. 3 Bossuyt X, Cohen Tervaert JW, Arimura Y, et al. Position paper: revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nat Rev Rheumatol. 2017; 13: 683‑692. 4 Wójcik K, Masiak A, Jeleniewicz R, et al. Association of antineutro‑phil cytoplasmic antibody (ANCA) specificity with demographic and clinical characteristics of patients with ANCA ‑associated vasculitides. Pol Arch In‑tern Med. 2022; 132: 16187. 5 Lyons PA, Rayner TF, Trivedi S, et al. Genetically distinct subsets within ANCA ‑associated vasculitis. N Engl J Med. 2012; 367: 214‑223. 6 Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA ‑associated vasculitis: a meta ‑analysis. Ann Rheum Dis. 2016; 75: 1687‑1692. 7 Fordham S, Mukhtyar C. Are PR3 positive and MPO positive GPA the same disease? Int J Rheum Dis. 2019; 22 Suppl 1: 86‑89. 

Diagnostic utility of testing for antineutrophil cytoplasmic antibodies

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Diagnostic utility of testing for antineutrophil cytoplasmic antibodies

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