Eosinophilic granulomatosis with polyangiitis: an overview.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic disorder, belonging to the small vessel anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, defined as an eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium-sized vessels, associated with asthma and eosinophilia. EGPA pathogenesis is not well known: HLA-DRB1*04 and *07, HLA-DRB4 and IL10.2 haplotype of the IL-10 promoter gene are the most studied genetic determinants. Among the acquired pathogenetic factors, the exposure to different allergens, infections, vaccinations, drugs, and silica exposure have been involved. Eosinophils are the most characteristic cells in EGPA and different studies have demonstrated their role as effector and immunoregulatory cells. EGPA is considered as a disease with a prevalent activation of the Th-2 cellular-mediated inflammatory response and also humoral immunity plays an important role. A link between B and T inflammatory responses may explain different disease features. EGPA typically develops into three sequential phases: the allergic phase, distinguished by the occurrence of asthma, allergic rhinitis, and sinusitis, the eosinophilic phase, in which the main pathological finding is the eosinophilic organ infiltrations (e.g., lungs, heart, and gastrointestinal system), and the vasculitic phase, characterized by purpura, peripheral neuropathy, and constitutional symptoms. ANCA (especially pANCA anti-myeloperoxidase) are present in 40-60% of the patients. An elevation of IgG4 is frequently found. Corticosteroids and cyclophosphamide are classically used for remission induction, while azathioprine and methotrexate are the therapeutic options for remission maintenance. B-cell depletion with rituximab has shown promising results for remission induction.

Genetics of ANCA-associated vasculitides: HLA and beyond.

The pathogenesis of ANCA-associated vasculitis (AAV) is multifactorial and most likely involves the interaction of environmental and genetic factors. During the past few years, a number of studies have investigated genetic associations with AAV; earlier studies explored associations with single nucleotide polymorphisms (SNPs) at genes of potential pathogenetic interest ('candidate gene' studies), whereas more recent larger studies analysed associations with SNPs covering ~90% of the human genome (genome-wide association studies - GWAS). The latter studies have significantly advanced our understanding of the genetic aspects of AAV, confirming some previously reported findings and uncovering new genetic associations. In addition, these studies have also shown that different AAV subtypes such as granulomatosis with polyangiitis (Wegener's, GPA) and microscopic polyangiitis (MPA) are underpinned by distinct genetic risk factors, with GPA being associated with HLA-DP, SERPINA1 (encoding α1-antitrypsin), PRTN3 (encoding proteinase-3, PR3, the main GPA-related autoantigen) and SEMA6A (semaphorin 6A), whereas MPA has been mainly associated with HLA-DQ. Interestingly, in the European GWAS, which included both GPA and MPA patients, the HLA-DP, SERPINA1, PRTN3 and HLA-DQ SNPs were more significantly associated with ANCA-specificities (PR3 vs. myeloperoxidase, MPO) than with the clinical syndromes. In addition, the finding of GPA and PR3-positive subsets being associated with SNPs of genes encoding PR3 and α1-antitrypsin, a protease able to inactivate PR3, highlighted the central role of PR3 as an auto-antigen in AAV. This paper reviews the main genetic association studies in AAV, with particular emphasis on the two GWAS performed so far.