ANCA-associated vasculitis not a single clinical entity

By Ingrid Grasmo

Study findings show distinct subtypes of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, distinguished by the target of autoantigen reactivity.

ANCA-associated vasculitis is a severe condition encompassing granulomatosis with polyangiitis and microscopic polyangiitis. Its cause is unknown and there has been debate about whether or not it is a single disease entity and the role that the serologic marker ANCA plays in its pathogenesis.

"The genetic difference between proteinase 3-ANCA and myeloperoxidase-ANCA polyangiitis could have immunopathogenic and therapeutic implications," say Kenneth Smith (Addenbrooke's Hospital, Cambridge, UK) and colleagues.

The researchers performed a genomewide association study among 1233 UK patients with ANCA-associated vasculitis and 5884 controls, to screen for single-nucleotide polymorphisms (SNPs) potentially associated with the condition. Findings were replicated in a cohort of 1454 Northern European patients and 1666 controls.

The findings link five SNPs to ANCA-associated vasculitis, three of which were in the region of the major histocompatibility complex (MHC). All these SNPs were associated to some degree with granulomatosis with polyangiitis, but none were linked to microscopic polyangiitis.

The MHC SNP with the strongest association with ANCA-associated vasculitis was found in HLA-DP and the non-MHC association was in the serpin A1 gene (SERPINA1), which encodes for α1-antitrypsin - a protease inhibitor involved in the inactivation of the autoantigen proteinase 3.

Further analysis showed that both the HLA and SERPINA1 associations with granulomatosis with polyangiitis were seen in patients with proteinase 3 autoreactivity, but not in those with myeloperoxidase autoreactivity.

The researchers say this finding suggests that genetic background may contribute to the clinical classifications of granulomatosis with polyangiitis and microscopic polyangiitis.

"This firm association between key components of the autoimmune response - MHC, the proteinase 3 autoantigen itself, and perhaps α1-antitrypsin - puts anti-proteinase 3 autoreactivity at the center of the cause of disease, potentially resolving a long-standing controversy," says the team in TheNew England Journal of Medicine.

They add that since proteinase 3-ANCA and myeloperoxidase-ANCA polyangiitis have distinct genetic causes, clinical trials that have considered ANCA-associated vasculitis as a single entity must be interpreted carefully, since subsets defined by ANCA specificity may respond differently to therapeutic intervention.

In an associated editorial, Maria Cid (University of Barcelona, Spain) says that the large study size and the lack of additional SNP associations studied highlights the relevance of those identified. However, she notes that the results should be interpreted with caution as carriers of certain SNPs in the study were shown to only have a moderate or slight increased risk for this very rare condition. Future studies are therefore needed to draw definitive conclusions.

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