Selective small molecule inhibitors for hidradenitis suppurativa: Today and tomorrow

Hidradenitis suppurativa (HS) is an autoinflammatory condition characterized by abscesses, inflammatory nodules, and tunnels in intertriginous sites of the body. The pathogenesis of HS involves follicular occlusion in combination with environmental, genetic, hormonal, and metabolic factors. HS lesions are characterized by an influx of neutrophils, histiocytes, B and T cells, and upregulation of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1, interleukin-17, and interferons. Selective small molecule inhibitors (SMIs) are organic compounds that bind to active sites on target proteins involved in inflammatory signaling pathways, most commonly blocking enzymes, ion channels and receptors. SMIs are divided into conventional and selective SMIs. Selective SMIs are further subdivided into kinase and nonkinase SMIs. Currently there are five selective SMIs available in the United States with demonstrated efficacy for HS in clinical studies including apremilast, topical ruxolitinib, upadacitinib, fostamatinib, and sirolimus. These selective SMIs target four pathways hypothesized to be important to HS pathogenesis including phosphodiestase 4, Janus kinases, spleen tyrosine kinase, and mammalian target of rapamycin. Several new SMIs are currently in the clinical trial pipeline targeting Bruton's tyrosine kinase, aryl hydrocarbon receptors, heat shock protein 90 as well as interleukin-1 and -17 signaling pathways.