Hidradenitis suppurativa (HS) is a painful, non-contagious chronic inflammatory skin disease [1] affecting primarily apocrine gland-rich areas of the body, presenting painful nodules and abscesses that lead to the formation of sinus and fistula tracts, and scarring upon rupture [2, 3]. Affected body parts are the terminal hair follicle units of the axilla, inframammary folds, groin and buttocks [4]. Due to its chronicity and the deep painful lesions, HS has a substantial negative effect on patients’ quality of life [5]. The prevalence of HS is ~ 1% and the disease typically begins during or after puberty [6].
A plethora of factors are believed to cause HS: genetics, the cutaneous microbiome, immunologic factors and hormonal predisposition, as well as environmental factors such as obesity, smoking and skin occlusion [3, 7–10], translating into phenotypic disease heterogeneity and a variable response to therapy [11].
HS belongs to the heterogenous group of neutrophilic dermatoses (inflammatory skin disorders), which are characterised by sterile neutrophilic infiltrates in the skin [12, 13]. In patients with HS, neutrophil extracellular trap (NET) formation is enhanced in circulating neutrophils, which undergo spontaneous NETosis [14]. Moreover, NETotic neutrophils have been found in HS lesions, particularly in the lesional tunnel [15], as well as a high number of polymorphonuclear cells [16]; importantly, a positive correlation between the amount of NETs within skin lesions and HS disease severity has been reported [17].
HS is characterised by aberrant activation of innate immunity [18] and a large inflow of pro-inflammatory mediators (i.e. interferon [IFN]-γ, tumour necrosis factor [TNF]-α, interleukin [IL]−6, −8, −17 and −12/23) [19–21]. Three main events occur in HS pathogenesis, namely (i) follicular occlusion, (ii) rupture of the dilated follicle and (iii) chronic inflammation with sinus tract formation, each of which is characterised by a cascade of events [19]. Follicular occlusion is defined by hyperkeratosis and hyperplasia of the follicular epithelium, causing the formation of a keratin plug due to the accumulation of cellular debris. Rupture of the dilated follicle follows, with dispersion of keratin fibres, bacteria and pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) into the dermis, triggering an acute and severe immune response that induces a large inflow of immune cells and the release of cytokines including IL-1β and TNF-α [12]. This can lead to the formation of nodules, abscesses or fistulas. Subsequently, chemokines, such as CXCL8, CXCL11, CCL2 and CCL20 in keratinocytes, and CXCL1 and CXCL6 in fibroblasts are produced [12], recruiting in turn more inflammatory cells. Importantly, at this stage, activated dendritic cells produce IL-12, inducing T helper (Th) 1 polarisation, and IL-23, which maintains the Th17 phenotype. Lastly, chronic inflammation is characterised by the formation of epithelialised tunnels, sinus tracts and keloid scars, further triggering inflammation and the production of IFN-γ (which recruits more inflammatory cells) and TNF-α (which supports Th17 polarisation), among others. Th17 cells are characterised by the production of IL-17 [22] that, in turn, stimulates neutrophil- and macrophage-induced production of IL-1β, IL-6, TNF-α and matrix metalloproteinases, and, consequently, the formation of fibrosis and sinus tracts [19].
Several staging systems have been developed for the assessment of HS: the Hurley staging system [23]; Hidradenitis Suppurativa Clinical Response (HiSCR) [24]; Hidradenitis Suppurativa Physician Global Assessment [25, 26]; Hidradenitis Suppurativa Severity Index [26, 27]; Modified Sartorius Score [28, 29]; and International Hidradenitis Suppurativa Severity Score System (IHS4) [30] and its dichotomous version IHS4-55 [31, 32]. Each of these systems serves a different purpose, such as assessment of disease severity (e.g. mild, moderate and severe) or efficacy of intervention [19, 33].
Despite recent advances, and the fact that HS was first described in the mid-1800s, the pathogenesis is not fully understood, and the main challenges remain disease management and treatment [2]. In fact, patients experience significant physical and emotional burdens, with HS negatively impacting their lives and well-being [3].
There are a number of limitations to the treatment of HS, namely diagnostic delay (ranging from 3 to 10 years); misdiagnosis, associated with diagnostic delay due to flawed understanding and lack of disease awareness among non-dermatologic providers; the progressive nature of HS [34]; and, importantly, management guidelines, which generally present agreement only on first-line treatments due to disease heterogeneity [35, 36]. The recently published German S2k guidelines on HS therapy address some of these issues [37], and European guidelines are being developed.
Currently, HS treatment therapy includes topical, systemic, surgical and combined treatment, which can help manage the disease [19, 37]. Conventional therapies (oral antibiotics and topical treatments) are used to treat mild and moderate HS, and as adjuvant treatment in moderate-to-severe HS, although some patients show resistance to such treatment [33, 38]. More recently, biological therapy has become a promising option in the treatment of HS, with adalimumab (a TNF-α inhibitor), secukinumab (an IL-17A inhibitor) and bimekizumab (an IL-17A and −17F inhibitor) now approved for the treatment of HS. Several other targeted therapies (such as IL-1, IL-6 and IL-23 inhibitors, and Janus kinase [JAK] inhibitors) may be used off-label and have shown variable clinical response [33, 39]. Despite a significant improvement in clinical outcomes upon treatment with adalimumab [40], the first biological agent approved for the treatment of moderate-to-severe HS, not all patients achieve a primary response and some develop a secondary loss of response; thus, its long-term effectiveness is highly variable [19]. Nonetheless, biological agents are used in patients with severe HS who show a suboptimal response to these agents in order reduce the area required for surgical resection [33, 41]. Indeed, a better outcome has been observed in patients with moderate-to-severe HS undergoing a combination of adalimumab treatment and surgery compared with adalimumab alone [42, 43].
In 2023, both the European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA) approved secukinumab for the treatment of moderate-to-severe HS in adults [44], based on two major phase III, randomised, controlled clinical trials that showed promising results with a favourable safety profile and sustained response for up to 52 weeks [45]. The IL-17A and −17F inhibitor bimekizumab is approved for HS in Europe and is undergoing regulatory review for this indication in the US.
The aim of this paper is to describe the expert authors’ opinions of the current management of HS, as well as the pathogenic role of IL-17 in HS and emerging targeted therapies, with a focus on secukinumab. We also aim to define the components of a comprehensive multidisciplinary team (MDT), which is indispensable for the optimal management of HS, both in terms of early diagnosis and early implementation of personalised therapy.