The available evidence suggests that AAV treatment might be optimized using a personalized approach guided by a patient’s ANCA type. Table 3 Future direction of research regarding ANCA type in AAV. thead th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Topic /th th valign=”top” align=”left” rowspan=”1″ colspan=”1″ Research Question /th /thead Genetics and Pathogenesis? Can unique genetic risk factors be used to identify patients at risk of MPO- or PR3-ANCA+ AAV before the onset of clinical symptoms or findings?Risk Factors? Are there modifiable risk factors for AAV that differ according to ANCA type? br / ? How do certain drugs induce an MPO-ANCA+ AAV?Organ Involvement? Why might fibrotic lung disease and bronchiectasis be more common in MPO-ANCA+ AAV? br / ? Why is renal disease more severe at presentation in MPO-ANCA+ AAV? br / ? Why does PR3-ANCA+ AAV tend to affect the upper airway more often?Remission Induction? Should remission induction treatment decisions be influenced by ANCA type? br / ? Should clinical trials be powered to detect significant differences in treatment arms stratified by ANCA type?Remission Maintenance? Should maintenance strategies (continuous vs. of ANCA specificity to study and personalize the care of AAV patients (Table 1). We focus particularly on patients with GPA or MPA. Table 1 Distinguishing features between PR3-ANCA+ and MPO-ANCA+ AAV. and and and haplotype explained much of the genetic risk in patients with AAV. In contrast, MPO-ANCA+ disease is usually associated with and variants (4, 5). Non-MHC variants such as those in the and genes have been associated with PR3-ANCA+ but not MPO-ANCA+ disease, but variants in are observed in both MPO- and PR3-ANCA+ disease (4, 5). Functional studies have expanded upon previous GWAS studies and confirmed the potential pathogenic link between genetic variants and AAV (6). Given the associations between genetic variants and ANCA specificity, genetic testing may play a future role in identifying patients at risk for AAV. In fact, the presence of several of these variants (e.g., MHC and non-MHC) in the same individual increases the odds that the individual will develop AAV (4). However, additional studies are necessary to understand how genetic testing might be used in the clinical setting. Moreover, our knowledge of genetic associations in AAV stems from studies of patients of European descent and may be difficult to extrapolate to patients with other ancestry. One previous case-control study found that genetic variants at Rabbit polyclonal to GR.The protein encoded by this gene is a receptor for glucocorticoids and can act as both a transcription factor and a regulator of other transcription factors. might predispose African American patients to PR3-ANCA+ AAV (7), but additional studies in patients of non-European descent are needed. Pathogenesis of PR3- and MPO-ANCA+ AAV The pathogenesis Pyridoxine HCl of AAV is usually complex and the precise cause or causes remain unknown, but MPO- and PR3-ANCA are generally considered to have substantial functions in the pathophysiology of most patients’ disease (8). Direct proof of a relationship between the presence of these antibodies and the initiation of disease in humans, however, remains lacking, despite the fact that compelling animal models for AAV exist. This is particularly true for MPO-ANCA, as discussed below (9). MPO- and PR3-ANCA+ AAV appear to share many features of pathogenesis, yet certain differences have also been observed. Myeloperoxidase and proteinase 3, the targets of MPO- and PR3-ANCA, respectively, are both found in neutrophil granules and monocyte lysosomes. PR3 is normally expressed around the neutrophil cell surface, more so in PR3-ANCA+ patients than healthy controls. In contrast, MPO is not spontaneously expressed on neutrophil cell surfaces but surface MPO expression is usually detectable after neutrophil activation (10). In AAV, Pyridoxine HCl the binding Pyridoxine HCl Pyridoxine HCl of MPO- or PR3-ANCA to neutrophils induces activation and degranulation as well as adhesion and transmigration of neutrophils across the vascular endothelium, culminating in endothelial cell damage. The role of monocytes in AAV is usually less well comprehended. The pathogenic importance of MPO-ANCA is supported by the ability of these antibodies to induce a vasculitis syndrome resembling AAV when MPO-ANCA are transferred into experimental mouse models (9). The development of a similar animal model for PR3-ANCA+ AAV has been elusive to date, in part due to differences in PR3 expression in mice and humans. Several additional observations support the importance of PR3- and MPO-ANCA in the pathogenesis of AAV. These include: (1) the great majority of patients with AAV are MPO- or PR3-ANCA+ (2, 11) there are consistent differences in clinical features of AAV according to ANCA type (see below); (3) B-cell targeted therapies and/or plasma exchange are efficacious in both PR3- and MPO-ANCA+ AAV (4, 12, 13) there is some correlation between ANCA titer and disease activity (see below); (5) transplacental transfer of MPO-ANCA is usually reported to have caused AAV in a newborn (6, 14); PR3-ANCA+ antibodies are known to appear in patients’ blood years before clinical presentation (15); and (7) genetic.
