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Immunological Pathways in Hidradenitis Suppurativa www.symbiosisonline.org Symbiosis www.symbiosisonlinepublishing.com Review Article Clinical Research in Dermatology: Open Access Open Access Immunological Pathways in Hidradenitis Suppurativa: Current Concepts and Innovative Therapies José Antonio Guzmán Cubilla1*, Beatrice Martinez Zugaib Abdalla2, Paulo Ricardo Criado1 and Luiza Keiko Oyafuso1 1Dermatology, ABC School of Medicine, Santo André, SP, Brazil 2General Medicine, ABC School of Medicine, Santo André, SP, Brazil Received: April 04, 2018; Accepted: April 17, 2018 ; Published: April 23, 2018 *Corresponding author: José Antonio Guzmán Cubilla, Rua da Fonte 77, APTO 163, Santo André, SP, Brazil, Zip code: 09040270; Tel: +55 11 982060707; E-mail: [email protected] Abstract Introduction Hidradenitis Suppurativa is a chronic and disabling disease Hidradenitis Suppurativa (HS), also known as “acne inversa” characterized by pustules, nodules, abscesses, and scaring. It affects natural body folds (inguinal, axillary, inframammary), perianal about 0.035% to 4% of the world population suffer from this region and genitalia. Several comorbidities are related to this disease, condition,or “maladie mostly de Verneuil,”, affecting is aadults rare inflammatoryand adolescents skin withdisorder, few such as: obesity, smoking, acne, folliculitis, and hyperandrogenism. reported cases in prepubertal children [1,2]. Disease course Disorders in keratinization, systemic upregulation of complement is recurrent or intermittent and chronic, with multiple clinical (C5a) activation and changes in cutaneous microbiome stimulate the variants, a 3:1 female-male ratio, and apparently without ethnic CD4+ T- helper lymphocytes (Th-17 and Th-1). These changes stimulate preference [2]. However, Afro-descendants seem to develop more thedevelopment expression of ofautoinflammatory toll-like receptors state, type promoting 2, enabling the theincrease NLRP3 of exuberant lesions than Caucasians patients. Usually the onset is puberty-related, suggesting an endocrine component and cascade. Intralesional increase of dendritic cells, macrophage and associated with increased levels of androgenic hormones [2]. inflammasome and triggering of the caspase-dependent inflammatory Due to a delay in diagnosis and lack of awareness by neutrophil influx stimulate the production of pus, promoting necrosis addition,and apoptosis patients of inflammatory affected with cellsthis conditionundergoing presents a special an type imbalance of cell years [2]. Also, HS patients score high values in the Dermatology death program, releasing proinflammatory cytokines (pyroptosis). In Qualityphysicians, of Life final Index diagnostic (DLQI), iswith achieved higher valuesafter an than average the average of 12 antagonist receptor IL-36Ra. Treatment is frustrating and includes found in psoriasis [3]. High values in this score are related to a theof IL-36use of proinflammatorybroad-spectrum antibiotics,cytokines surgicaland decreased procedures, levels and of oral its greater impact in patient’s life [3]. inhibitor (Adalimumab); other alternatives are under development, Heterogeneous mutation in the intramembranous protease inhibitingretinoids. TheIL-17 first (Secukinumab, and only one biologic Bimekizumab therapy andapproved CJM112) is a TNF-αIL-12 and IL-23 (Ustekinumab); and IL-1 (Anakinra, Canakinumab). Recent articles showed that liraglutide, a glucagon-like-1 pep-tide (GLP-1) complex ɣ-secretase and its subunits genes NCSTN, PSENEN, agonist, could be used to treat one of the comorbidities associated HS. These mutations have been associated with impaired inhibitionand PSEN1 of hasthe innatebeen associatedimmunity by with the Notch-MKP-1familial inheritance signaling, of be an option to treat this recalcitrant and exhausting disease. with HS (insulin resistance). Finally, inhibition of IL-36 and C5a could Highlights: Pathogenesis of HS involves genetic and environmental inducing follicular keratinization and epidermal hyperplasia. promoting cutaneous proinflammatory microenvironment, factors that trigger the innate immune response. implicated in Alzheimer’s Disease (AD); however, no link between Furthermore, mutations of ɣ -secretase complex have also been skin. HS and AD has been documented. About 42% of patients report Several cytokines participate in the inflammatory response of the family history, early onset at puberty and more severe disease HS is chronic and relapsing causing a negative impact on patient´s quality of life, expensive medical approaches, and huge number of to be present in patients with Dowling-Degos Disease (DDD). comorbidities. Aroundmanifestations half of patients[4]. In addition, with DDD mutations develop inHS PSENEN and share are similar found New biological drugs, former medical treatments and cutaneous trigger factors [5]. surgical interventions can be combined to better assist of patients suffering of HS. Discussion Keywords: Hidradenitis suppurativa; Biologics; IL-17; IL-1; IL- Clinical Features HS is characterized by papules, nodules, abscesses, and painful 23; C5a; Autoinflammatory diseases; Symbiosis Group *Corresponding author email: [email protected] Immunological Pathways in Hidradenitis Suppurativa: Current Concepts and Innovative Copyright: © Therapies 2018 Cubilla JAG, et al. infundibulum associated to defects in keratin proteins production plaques, keloids, or atrophic scars, decreasing and disabling (decreased number of cytokeratin CK17, with upregulated CK5 thesuppurating patient movementsinus, these [6]. lesions Inguinal, can progress axillary, intointer fibrosclerotic gluteal and and CK6) [10,11]. This suggests fragility of the draining sinus inframammary folds are predominantly affected, however, ectopic epithelium, which may allow rupture to occur more easily, thus locations such as the head, torso, genitals, dorsum, and limbs are resulting in a subcutaneous abscess formation. Blocked follicles uncommonly found in some patients [6]. Chronic and advanced modify the skin microbiome and increases bacterial proliferation cases may develop lower limb and genitalia lymphedema, as well as, hinder social and sexual relationships [7]. The disease has a recurrent course with an average of 2 to 3 crises every 6 months stimulating(S. epidermidis skin andoverexpressed P. acnes), generatingToll-like receptors a film-like type substance 2 (TLR2) [2]. [12-15].that remain fixed to the follicular unit (bacterial biofilm), and Diagnosis of HS is often clinical. Cutaneous biopsies are not TLR2 is a vital component of the innate immunity, present required in most cases [2]. There are several scoring systems in polymorphonuclear cells, keratinocytes, and dendritic cells. for assessing disease severity: Hurley Staging System (HSS), HS- patterns associated with pathogens) activate this receptor and and Hidradenitis Suppurativa Severity Index). Unfortunately, all Fragments of bacterial antigens called PAMPS (Molecular ofPhysician´s them have Global some limitationsAssessment, in Modifieddaily practice, Sartorius with noScore consensus (MSS), Activation of TLR2, increase intralesional expression of among the outcome measures used for HS [2]. initiate skin inflammation. endogenous antibiotics called antimicrobial Peptides (AMPs), HSS and MSS are the most widely applied disease activity such as is human beta defensin-2 (HBD2) and cathelicidin LL37 Stage I: single or multiple abscess, without scars and sinus tracts process and induce hyperkeratinization of the hair follicle, formation.scores [2]. HurleyStage scoringII: recurrent is usually single stratified or multiple into three abscess stages with [2]. (LL37) [15]. These peptides interfere further in the inflammatory sinus tracts and scars formation, lesions are widely separated. Stage III: diffuse involvement or multiple interconnected tracts triggering the formation of the NLRP3 inflammasome and of and abscesses formation across entire area. the pro inflammatory cytokines (IL-1β, IL-12, IL-23, IL-17, and TNF-α). Smoking, obesity, hyperandrogenism and women with cascade, increasing caspase-1 expression, this enzyme plays Polycystic Ovarian Syndrome (PCOS) seem be related to HS, an importantNLRP3 inflammasome role in phagocytes activates tissue the caspasemigration, inflammatory promoting worsening the disease evolution [8]. polymorphonuclear cells death in presences of newly formed Remarkably, the presence of other associated diseases such as acne, pyoderma gangrenosum, neutrophilic diseases, Crohn’s interleukin-1beta (IL-1β) by a process called pyroptosis (cell disease, pilonidal cyst, spondyloarthropathies and psoriatic deathThis with process release leads of inflammatory to cellular DNA cytokines) damage [16]. and rapid pore arthritis are commonly seen in some patients. These conditions formation in dendritic and macrophages cells membrane, could be overlapping and develop syndromes such as the SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis), PASH (Pyoderma gangrenosum, Acne and Hidradenitis suppurativa), resulting in cellular lysis and release of intracellular inflammatory PAPA (Pyogenic Arthritis, Acne, and Hidradenitis suppurativa) stressed-cellscontents, including leads toInterleukin-1beta the recruitment ofand hematopoietic alpha (IL-1β, cells IL-1α) that and PAPASH (Arthritis, Pyoderma, Acne, and Hidradenitis [17]. Excess release of IL-1α from the cytosol of necrotic and suppurativa) [8]. activation and disruption of vascular walls [17]. can further sustain perilesional inflammation through endothelial Due to its
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