British Journal of Dermatology

Petukhova, Lynn; Colvin, Annelise; Koerts, Nicole D K; Horváth, Barbara

doi: 10.1093/bjd/ljae399pmid: 39895593

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition with many unmet needs. It is characterized by significant clinical heterogeneity, which suggests that a diagnosis of HS captures multiple distinct disease entities and that research aimed at identifying medically relevant HS subtypes will improve its management. Precision medicine is an approach to disease management that uses information encoded in a patient’s genome, and operationalized in clinical presentations and drug responses, to identify disease subtypes. Prior research aimed at identifying HS subtypes has largely focused on phenotypic classifications derived from clinical features of cutaneous lesions. Limitations of existing HS taxonomies emphasize a need for a more nuanced understanding of disease subtypes. Evidence that has emerged from initial genetic studies of HS suggests the presence of at least three HS subtypes, each of which has different clinical implications in terms of disease risks and drug responses. These preliminary findings are instructive in terms of expanding our definitions of HS phenotypes to not only include characteristics of skin lesions, but also disease comorbidities and molecular and cellular phenotypes. Here we provide a comprehensive review of HS phenotype and genotype knowledge, and propose a strategic framework for implementing precision medicine in HS management. Future research should focus on expanding phenotype assessments to include data on multiple scales. Iterative research designs performed with phenotype and genotype data from large diverse cohorts are needed to rigorously define clinically relevant HS subtypes.

Ingram, John R

doi: 10.1093/bjd/ljae455pmid: 39895592

Sayed, Christopher J; Shams, Rayad B; Midgette, Bria; Garg, Amit

doi: 10.1093/bjd/ljae318pmid: 39895591

The therapeutic pipeline for moderate-to-severe hidradenitis suppurativa (HS) is robust. Successes and lessons learned have led to improvements in trial designs aimed at avoiding prior pitfalls, as well as high placebo response in HS, which remains a fundamental threat to drug development.Herein, we review the evolutions in HS trials over the last 20 years with respect to overall design, sample size, diversity in enrolment, inclusion criteria, concomitant medications, rescue therapy, endpoints and statistical design analysis plans. Areas of focus that merit future consideration are also highlighted.

Frew, John W

doi: 10.1093/bjd/ljae238pmid: 39895594

Hidradenitis suppurativa (HS) is a complex inflammatory disease, with rapid advances being made in our understanding of the complex immunological pathogenesis of the condition. New insights into the genomic landscape of HS have identified a number of genes that contribute to the development of HS in a polygenic manner, contributing to inflammatory dysregulation and alterations in epidermal stem cell fate in the follicular unit. These genomic variations can explain unique aspects of the disease such as the development and presence of epithelialized tunnels and abnormalities in wound healing. From genetic and translational studies, it is likely that these genetic alterations predispose to an innate immune dysregulation that can be triggered through sex hormone-responsive transcription factors with hormonal changes such as puberty, pregnancy and the menstrual cycle. The role of sex hormones in HS also has direct effects upon the development and maturation of inflammatory cells such as monocytes, which has the potential to explain differential patient response to treatments such as interleukin-23 antagonism. The role of adipose tissue as an active immunological organ also plays a role in the immune dysregulation seen in the disease. Fibrotic tissue and immunologically active fibroblasts play a significant role in the perpetuation of inflammation and development of adaptive immune dysfunction in the disease. The cutaneous and gut microbiomes play significant roles in the activation of innate immunity, although conflicting data exist as to their central or peripheral role in disease pathogenesis. Overall, our understanding of disease pathogenesis in HS is moving toward a more nuanced, complex paradigm in which patient heterogeneity in presentation and immunological characteristics are moving closer to the identification of therapeutic biomarkers to guide therapeutic modalities in the management of this burdensome condition.