Granulomatosis With Polyangiitis

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

PRTN3, HLA-DPB1, HLA-DPA1, CTLA4, PTPN22, FCGR3B, WG, MPO, GYPA, SERPINA1, IL10, HLA-DRB1, KRT20, IL4, ACR, CD28, MS4A1, TNF, CCR5, ANP32B, CD226, TNFSF13, TNFSF11, IL2, IL1B, NT5E, TGFB1, IFNG, SEMA6A, FCGR3A, ETS1, CRP, RBM45, TST, DEFB104A, SERPINA13P, CDR3, VDI, MIR142, VCAM1, TNFRSF4, DEFB104B, IGHV3OR16-7, TP53, TNXB, DEFB4B, TNFRSF1A, TNFAIP3, LINC-ROR, TLR4, TIMP3, LOC102723407, USO1, BANF1, TNFRSF18, GREM1, IGHV3-69-1, FOXP3, GCA, TLR9, SMUG1, THBD, SEC14L2, CYCS, GBA3, KDM6B, NOD2, SLC27A5, PPARGC1A, TNFSF13B, PARP9, NXF1, MAMLD1, TIMP1, PLAT, TGFB2, DHX15, HLA-DQA1, HLA-A, GLA, FLNB, F2RL1, FBL, ELANE, DPP4, DEFB4A, DEFB1, ACE, IGH, CTSK, CTSC, CEL, CDK6, SERPINA6, CALCR, C5AR1, C5, BTK, BPI, HLA-DRB4, IL6, XCL1, NBN, S100A7, RXRB, RING1, PTX3, PNN, PML, AGT, PDCD1, SERPINA5, NME1, MMP9, IL17A, MMP8, MMP2, MIP, MIF, CIITA, MDM2, LEPR, KRT3, KLRB1, IRF5, LOC102724971

Drugs

Antagonist of the complement 5a receptor, Avacopan, Gusperimus trihydrochloride ( SPANIDIN )

Antagonist of the complement 5a receptor, Avacopan, Gusperimus trihydrochloride ( SPANIDIN ), Rituximab ( BLITZIMA, MABTHERA, TRUXIMA, RITEMVIA, RITUXAN, RITUZENA, RIXATHON, RIXIMYO, Ruxience )

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Description

Granulomatosis with polyangiitis, formerly termed Wegener granulomatosis, is a systemic disease with a complex genetic background. It is characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis, vasculitis, and the presence of antineutrophil cytoplasmatic autoantibodies (ANCAs) in patient sera. These ANCAs are antibodies to a defined target antigen, proteinase-3 (PR3, PRTN3; 177020), which is present within primary azurophil granules of neutrophils (PMNs) and lysozymes of monocytes. On cytokine priming of PMNs, PR3 translocates to the cell surface, where PR3-ANCAs can interact with their antigens and activate PMNs. PMNs from patients with active GPA express PR3 on their surface, produce respiratory burst, and release proteolytic enzymes after activation with PR3-ANCAs. The consequence is a self-sustaining inflammatory process (Jagiello et al., 2004).

Nomenclature

Noting evidence that Dr. Friedrich Wegener was a member of the Nazi party before and during World War II, Falk et al. (2011), writing for the American College of Rheumatology, the American Society of Nephrology, and the European League Against Rheumatism, proposed that the eponym 'Wegener granulomatosis' be discontinued and replaced by the name 'granulomatosis with polyangiitis,' symbolized GPA. Falk et al. (2011) stated that granulomatosis with polyangiitis was initially described by Klinger (1931) as a variant of polyarteritis nodosa, and then in greater detail as a separate syndrome by Wegener (1936, 1939).

Mapping

Jagiello et al. (2004) performed an extended association screen with 202 microsatellite markers, representing apoptosis-related genes, using pooled DNA of 150 northern German patients from GPA and 100 healthy northern German controls. Six microsatellite allele patterns were significantly associated with the disorder. One marker remained significantly associated after multiple corrections. This marker, representing the retinoid X receptor-beta gene (RXRB; 180246), is located in the major histocompatibility complex (MHC) on chromosome 6p21.3 between the HLA-DPB1 (142858) and DAXX (603186) genes. HLA-DPB1 typing and fine mapping of the region with additional microsatellites and SNPs revealed a strong association of WG with the DPB1*0401 allele (odds ratio of 3.91) compared with controls. In addition, an extended haplotype, DPB1*0401/RXRB03, showed an even stronger association with GPA (odds ratio of 6.41).

Lyons et al. (2012) performed a genomewide association study in a discovery cohort of 1,233 U.K. patients with ANCA-associated vasculitis and 5,884 controls and replicated the study in 1,454 northern European patients and 1,666 controls. Lyons et al. (2012) found both MHC and non-MHC associations with ANCA-associated vasculitis, and also showed that granulomatosis with polyangiitis and microscopic polyangiitis are genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Granulomatosis with polyangiitis was associated with HLA-DP (142858) at rs3117242 (p = 3.1 x 10(-85) vs control; odds ratio = 5.39). Anti-proteinase-3 ANCA was associated with HLA-DP and the genes encoding alpha-1-antitrypsin (SERPINA1; 107400) and proteinase-3 (p = 6.2 x 10(-89); p = 5.6 x 10(-12), and p = 2.6 x 10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (p = 2.1 x 10(-8)). Lyons et al. (2012) concluded that their study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase-3 is a central pathogenic feature of proteinase-3 ANCA-associated vasculitis. Lyons et al. (2012) further suggested that their data provide preliminary support for the concept that proteinase-3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes.