Inborn Errors of Immunity in Hidradenitis Suppurativa Pathogenesis and Disease Burden.

Hidradenitis suppurativa (HS), also known as Verneuil's disease and acne inversa, is a prevalent, debilitating, and understudied inflammatory skin disease. It is marked by repeated bouts of pathological inflammation causing pain, hyperplasia, aberrant healing, and fibrosis. HS is difficult to manage and has many unmet medical needs. There is clinical and pharmacological evidence for extensive etiological heterogeneity with HS, suggesting that this clinical diagnosis is capturing a spectrum of disease entities. Human genetic studies provide robust insight into disease pathogenesis. They also can be used to resolve etiological heterogeneity and to identify drug targets. However, HS has not been extensively investigated with well-powered genetic studies. Here, we review what is known about its genetic architecture. We identify overlap in molecular, cellular, and clinical features between HS and inborn errors of immunity (IEI). This evidence indicates that HS may be an underrecognized component of IEI and suggests that undiagnosed IEI are present in HS cohorts. Inborn errors of immunity represent a salient opportunity for rapidly resolving the immunological landscape of HS pathogenesis, for prioritizing drug repurposing studies, and for improving the clinical management of HS.

Inborn Errors of Immunity Contribute to the Burden of Skin Disease and Create Opportunities for Improving the Practice of Dermatology.

Opportunities to improve the clinical management of skin disease are being created by advances in genomic medicine. Large-scale sequencing increasingly challenges notions about single-gene disorders. It is now apparent that monogenic etiologies make appreciable contributions to the population burden of disease and that they are underrecognized in clinical practice. A genetic diagnosis informs on molecular pathology and may direct targeted treatments and tailored prevention strategies for patients and family members. It also generates knowledge about disease pathogenesis and management that is relevant to patients without rare pathogenic variants. Inborn errors of immunity are a large class of monogenic etiologies that have been well-studied and contribute to the population burden of inflammatory diseases. To further delineate the contributions of inborn errors of immunity to the pathogenesis of skin disease, we performed a set of analyses that identified 316 inborn errors of immunity associated with skin pathologies, including common skin diseases. These data suggest that clinical sequencing is underutilized in dermatology. We next use these data to derive a network that illuminates the molecular relationships of these disorders and suggests an underlying etiological organization to immune-mediated skin disease. Our results motivate the further development of a molecularly derived and data-driven reorganization of clinical diagnoses of skin disease.