Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:In this review, we aimed to highlight recent findings from "-omics" studies in Behçet's disease. RECENT FINDINGS/RESULTS:Recent genomic studies in Behçet's disease identified possible risk loci associated with Behçet's disease related uveitis, neurologic involvement and gastrointestinal involvement. Additionally, sex-specific genetic effects were determined in Behçet's disease. Transcriptomic analyses of immune cells in Behçet's disease revealed that key inflammatory pathways such as NF-κB and MAPK have roles in Behçet's disease pathogenesis. Proteomic studies have highlighted the role of immune cell derived extracellular vesicles and identified potential biomarkers for vascular involvement and examined HLA I-bound immunopeptidomes. Metabolomics studies are still limited, but recent research has pointed to alterations in fatty acid metabolism and lipid profiles in Behçet's disease patient. SUMMARY/CONCLUSIONS:Omics studies have gained importance in the field of Behçet's disease through the generation of large data sets and efforts to extend their application are intensifying. These studies can provide opportunities for understanding Behçet's disease pathogenesis when they lead to testable hypotheses. Current challenges include the choice of appropriately homogeneous patient and control groups, effective data management and sharing, high cost and a rapidly increasing gap between the wealth of observational data generated and the relative paucity of controlled experimental efforts that could lead to mechanistic understanding.

Human leukocyte antigen (HLA) class I association is a well-established feature of common and uncommon inflammatory diseases, but it is unknown whether it impacts the pathogenesis of these disorders. The "arthritogenic peptide" hypothesis proposed initially for HLA-B27-associated ankylosing spondylitis (AS) seems the most intuitive to serve as a model for other HLA class I-associated diseases, but evidence supporting it has been scarce. Recent technological advances and the discovery of epistatic relationships between disease-associated HLA class I and endoplasmic reticulum aminopeptidase (ERAP) coding variants have led to the generation of new data and conceptual approaches to the problem requiring its re-examination. Continued success in these endeavors holds promise to resolve a Gordian Knot in human immunobiology. It may ultimately benefit patients by enabling the development of new therapies and precision tools for assessing disease risk and predicting treatment responses.

Behçet's disease (BD) is a multi-system inflammatory disorder with vasculitic features. It does not suit any of the current pathogenesis-driven disease classifications well, a unifying concept of its pathogenesis is not unanimously conceivable at present, and its etiology is obscure. Still, evidence from immunogenetic and other studies supports the notion of a complex-polygenic disease with robust innate effector responses, reconstitution of regulatory T cells upon successful treatment, and first clues to the role of an, as of yet, underexplored adaptive immune system and its antigen recognition receptors. Without an attempt to be comprehensive, this review aims to collect and organize impactful parts of this evidence in a way that allows the reader to appreciate the work done and define the efforts needed now. The focus is on literature and notions that drove the field into new directions, whether recent or more remote.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

PURPOSE OF REVIEW:This review provides a framework for understanding inflammatory eye disease diagnosis, differential diagnosis, and management for rheumatologists. Uveitis, scleritis, episcleritis, peripheral ulcerative keratitis, and orbital inflammation are all discussed. The goal is to facilitate the development of approaches to inflammatory eye diseases that will help rheumatologists co-manage these patients with eye care providers specializing in ocular inflammation. RECENT FINDINGS:In recent years, studies have aimed to advance biologic treatments and define standard-of-care therapy. Inflammatory eye diseases are highly heterogeneous and often rare, which poses significant challenges to their research and the interpretation of existing data. To date, glucocorticoids, mycophenolate, methotrexate, and TNF inhibitors remain the mainstay of treatment options for many of these diseases. SUMMARY:Patients with inflammatory eye diseases require multidisciplinary care for best outcomes, frequently including rheumatologists. Understanding the differentials, diagnostics, and treatment are essential to preserving vision in these patients. The diverse nature of the disease processes within this field requires focusing on specific disease phenotypes and endotypes in research and clinical practice.

Normal lung development critically depends on Hedgehog (HH) and Platelet-derived growth factor (PDGF) signaling, which coordinate mesenchymal differentiation and proliferation. PDGF signaling is required for postnatal alveolar septum formation by myofibroblasts. Recently, we demonstrated a requirement for HH in postnatal lung development involving alveolar myofibroblast differentiation. Given shared features of HH and PDGF signaling and their impact/convergence on this key cell type, we sought to clarify their relationship during murine postnatal lung development. Timed experiments revealed that HH inhibition phenocopies the key lung myofibroblast phenotypes of Pdgfa and Pdgfra knockouts during secondary alveolar septation. Utilizing a dual signaling reporter, Gli1^IZ;Pdgfra^EGFP